Gonadotropin-releasing hormone antagonist regimens for the treatment of endometriosis - Patent Application 20070233633

Abstract

To provide a method of treating endometriosis in a patient according to a predicted dosing regimen based on anti-mullerian hormone (AMH) or β17-estradiol (E2) as well as a method for determining dosing regimen.SOLUTION: A method of treating endometriosis in a human patient involves determining the concentration of anti-mullerian hormone (AMH) in a sample isolated from the patient, then: a. comparing this concentration of AMH with an AMH reference range; b. administering a GnRH antagonist to the patient at a higher daily dose and / or a higher dosing frequency if the concentration of AMH in the sample isolated from the patient is above the AMH reference range; or c. administering a GnRH antagonist to the patient at a lower daily dose and / or less frequent dosing if the concentration of AMH in the sample isolated from the patient is below the AMH reference range.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for determining the dosage regimen of a gonadotropin-releasing hormone antagonist for the treatment of endometriosis. [Background technology]

[0002] Endometriosis is an estrogen-dependent gynecological condition characterized by the presence of endometrial-like tissue outside the uterus, and is one of the most common sex hormone-dependent diseases. The symptoms are mainly observed in women of reproductive age and disappear naturally after menopause. Endometriosis, a chronic inflammatory reaction induced by ectopic endometrial cells, can lead to infertility and various pain symptoms, including dysmenorrhea, dyspareunia, chronic pelvic pain, urinary disorders, and bowel disorders, among others.

[0003] The primary goal of treating endometriosis is to achieve symptomatic relief. Treatment options for women with endometriosis-related pain are diverse and include analgesic therapy, hormone therapy, conservative or minimally invasive surgery, or a combination of these treatment options. Hormonal therapy aims to inhibit ovulation, prevent cyclic endometrial growth, and eliminate menstruation through achieving a stable steroid hormone environment. These strategies are based on the concept that the response of eutopic and ectopic endometrium to steroid hormones is substantially similar.

[0004] Combined oral contraceptives (COCs) are not currently approved for the treatment of endometriosis-associated pain, but they are often used as initial treatment. Their use results in anovulation, reduced menstrual flow, decidualization of endometriotic lesions, attenuation of cell proliferation, and enhanced apoptosis in the endometrium. However, over time, many women taking COCs no longer experience adequate pain relief and often require secondary treatment.

[0005] Progestin monotherapy can be effective in reducing endometriosis-related pain because it induces anovulation and hypoestrogenism through the suppression of pituitary gonadotropin release.In addition, progestin exerts a direct effect on endometrium, causing decidualization of eutopic and ectopic endometrium, and leading to atrophy of endometriosis implants.However, progestin monotherapy is often associated with breakthrough bleeding, mood swings, weight gain, and breast tenderness.

[0006] Other therapies that have been proven effective for the treatment of endometriosis-related pain are often limited by undesirable side effects.For example, GnRH agonists induce constant stimulation of GnRH receptor at the pituitary level, thus desensitizing this receptor, ultimately causing the suppression of ovulation and the reduction of serum estrogen levels.Therefore, the use of GnRH receptor agonists is associated with significant hypoestrogenic side effects.Short-term effects include menopausal symptoms such as hot flashes, vaginal dryness, loss of libido and mood swings, while long-term use is limited by the substantial reduction of bone mineral density (BMD).

[0007] GnRH antagonists represent a therapeutic approach for the treatment of endometriosis that allows dose-dependent control of β17-estradiol (E2) levels. There is a need for improved GnRH antagonist dosing regimens that can reduce endometriosis implants and endometriosis-associated pain without inducing hypoestrogenic side effects such as hot flashes and BMD loss, as well as methods for determining such dosing schedules based on the concentration of one or more endogenous hormones in patients. Summary of the Invention

[0008] The present invention provides compositions and methods for administering a gonadotropin-releasing hormone (GnRH) receptor antagonist to a patient for the treatment of endometriosis based on the level of one or more endogenous substances in the patient. In some embodiments of the present invention, the GnRH antagonist dosing regimen is determined by analyzing the concentration of anti-Müllerian hormone (AMH) in a sample isolated from the patient. In some embodiments, the GnRH antagonist dosing regimen is determined by analyzing the concentration of β17-estradiol (E2) in a sample isolated from the patient. The GnRH antagonist can be a thieno[3,4d]pyrimidine derivative or variant, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid, or a choline salt thereof. In some embodiments, the GnRH antagonist is, inter alia, elagolix, relugolix, ASP-1707, SKI2670, BAY-784, or a derivative or variant thereof.

[0009] In a first aspect, the invention features a method of treating endometriosis in a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In another aspect, the invention features a method of reducing E2, follicle-stimulating hormone (FSH), and / or luteinizing hormone (LH) levels in the blood of a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In another aspect, the invention features a method of reducing pain (e.g., endometriosis-associated pain) in a patient (e.g., a female human patient, e.g., a premenopausal female human patient).

[0010] In any of the above aspects of the present invention, the method may include determining the concentration of AMH in a sample (e.g., a blood sample) isolated from a patient. In some embodiments, the concentration of AMH in the sample (e.g., a blood sample) isolated from a patient has been previously determined. The method includes: a. Comparing AMH concentrations to the AMH reference range; and b. administering a higher amount (e.g., a higher daily dose or more frequent administration) of a GnRH antagonist to the patient if the concentration of AMH in the sample isolated from the patient is above the AMH reference range; c. administering a lower amount (e.g., a lower daily dose or less frequent administration) of a GnRH antagonist to the patient if the concentration of AMH in the sample isolated from the patient is below the AMH reference range; or d. If the concentration of AMH in the sample isolated from the patient is within the AMH reference range, an intermediate amount (e.g., an intermediate daily dose or intermediate dosing frequency) of GnRH antagonist may be administered to the patient.

[0011] In some embodiments, the method includes determining that the concentration of AMH in a sample isolated from the patient is greater than the AMH reference range, and may further include administering a higher amount (e.g., a higher daily dose or more frequent administration) of a GnRH antagonist to the patient accordingly.

[0012] In some embodiments, the method includes determining that the concentration of AMH in a sample isolated from the patient is lower than the AMH reference range, and may further include administering a lower amount (e.g., a lower daily dose or less frequent administration) of a GnRH antagonist to the patient accordingly.

[0013] In some embodiments, the method includes determining that the concentration of AMH in the sample isolated from the patient is within the AMH reference range, and may further include administering an intermediate amount (e.g., an intermediate daily dose or intermediate dosing frequency) of a GnRH antagonist to the patient accordingly.

[0014] In some embodiments, the method comprises administering 5 to 700 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0015] For example, in some embodiments, the method may include administering a dose of AMH of 10 to 600 mg / day, 20 to 590 mg / day, 30 to 580 mg / day, 40 to 570 mg / day, 50 to 560 mg / day, 60 to 550 mg / day, 70 to 540 mg / day, 80 to 530 mg / day, 90 to 520 mg / day, 100 to 510 mg / day, or 110 to 500 mg / day (e.g., 5 mg / day, 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50mg / day, 55mg / day, 60mg / day, 65mg / day, 70mg / day, 75mg / day, 80mg / day, 85mg / day, 90mg / day, 95mg / day, 100mg / day, 105mg / day, 110mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg g / day, 215mg / day, 220mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 2 90mg / day, 295mg / day, 300mg / day, 305mg / day, 310mg / day, 315mg / day, 320mg / day, 325mg / day, 330mg / day, 335mg / day, 340mg / day, 345mg / day, 350mg / day, 355mg / day, 360mg / day, 365mg / day Days, 370mg / day, 375mg / day, 380mg / day, 385mg / day, 390mg / day, 395mg / day, 400mg / day, 405mg / day, 410mg / day, 415mg / day, 420mg / day, 425mg / day, 430mg / day, 435mg / day, 440mg / day, 445mg / day, 450mg / day, 455mg / day, 460mg / day, 465mg / day, 470mg / day, 475mg / day, 480mg / day, 485mg / day, 490mg / day, 495mg / day, 500mg / day, 505mg / day, 510mg / day, 515mg / day, 520mg / day,525mg / day, 530mg / day, 535mg / day, 540mg / day, 545mg / day, 550mg / day, 555mg / day, 560mg / day, 565mg / day, 570mg / day , 575mg / day, 580mg / day, 585mg / day, 590mg / day, 595mg / day, 600mg / day, 605mg / day, 610mg / day, 615mg / day, 620mg / day The present invention also includes administering to a patient at least 600 mg / day, 625 mg / day, 630 mg / day, 635 mg / day, 640 mg / day, 645 mg / day, 650 mg / day, 655 mg / day, 660 mg / day, 665 mg / day, 670 mg / day, 675 mg / day, 680 mg / day, 685 mg / day, 690 mg / day, 695 mg / day, or 700 mg / day of a GnRH antagonist.

[0016] In some embodiments, the method comprises administering to the patient more than 10 mg / day of GnRH antagonist when the concentration of AMH in the sample isolated from the patient is above the AMH reference range.For example, the method can comprise administering to the patient more than 10 mg / day of ASP-1707 when the concentration of AMH in the sample isolated from the patient is above the AMH reference range.

[0017] In some embodiments, the method comprises administering to the patient more than 40 mg / day of a GnRH antagonist if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. For example, the method can comprise administering to the patient more than 40 mg / day of relugolix if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0018] In some embodiments, the method comprises administering 75 mg / day to 200 mg / day of a GnRH antagonist to the patient when the concentration of AMH in the sample isolated from the patient is above the AMH reference range.For example, the method can comprise administering 75 mg / day, 100 mg / day, or 200 mg / day of a thieno[3,4d]pyrimidine derivative or variant, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or its choline salt to the patient when the concentration of AMH in the sample isolated from the patient is above the AMH reference range.

[0019] In some embodiments, the method comprises administering to the patient more than 150 mg / day of a GnRH antagonist if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. For example, the method may comprise administering to the patient more than 150 mg / day of elagolix if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method comprises administering to the patient more than 400 mg / day of a GnRH antagonist if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. For example, the method may comprise administering to the patient more than 400 mg / day of elagolix if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0020] In some embodiments, the method comprises administering 5 to 400 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0021] For example, in some embodiments, the method may include administering a dose of 5 to 190 mg / day, 15 to 180 mg / day, 35 to 170 mg / day, 50 to 160 mg / day, 60 to 150 mg / day, 70 to 140 mg / day, 80 to 130 mg / day, 90 to 120 mg / day, 100 to 110 mg / day, 200 to 400 mg / day, 225 to 375 mg / day, 250 to 350 mg / day, or 275 to 325 mg / day (e.g., 5 mg / day) if the concentration of AMH in the sample isolated from the patient is below the AMH reference range. Days, 10mg / day, 15mg / day, 20mg / day, 25mg / day, 30mg / day, 35mg / day, 40mg / day, 45mg / day, 50mg / day, 55mg / day, 60mg / day, 65mg / day, 70mg / day, 75mg / day, 80mg / day, 85mg / day, 90mg / day, 95mg / day, 100mg / day, 105mg / day, 110mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day , 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg / day, 215mg / day, 22 0mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day day, 290 mg / day, 295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395 mg / day, or 400 mg / day) of a GnRH antagonist to the patient.

[0022] In some embodiments, the method comprises administering to the patient less than 10 mg / day of a GnRH antagonist if the concentration of AMH in the sample isolated from the patient is below the AMH reference range.For example, the method can comprise administering to the patient less than 10 mg / day of ASP-1707 if the concentration of AMH in the sample isolated from the patient is below the AMH reference range.

[0023] In some embodiments, the method includes administering less than 40 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. For example, the method can include administering less than 40 mg / day of relugolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0024] In some embodiments, the method comprises administering 50 mg / day to 200 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. For example, the method can comprise administering 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a thieno[3,4d]pyrimidine derivative or variant, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or its choline salt, to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0025] In some embodiments, the method comprises administering to the patient less than 150 mg / day of a GnRH antagonist if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. For example, the method may comprise administering to the patient less than 150 mg / day of elagolix if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method comprises administering to the patient less than 400 mg / day of a GnRH antagonist if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. For example, the method may comprise administering to the patient less than 400 mg / day of elagolix if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0026] In some embodiments, the method comprises administering 10 to 500 mg / day of a GnRH antagonist to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.

[0027] For example, in some embodiments, the method provides for administering a dose of AMH of 10 to 490 mg / day, 25 to 480 mg / day, 50 to 470 mg / day, or 100 to 450 mg / day (e.g., 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95mg / day, 100mg / day, 105mg / day, 110mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg / day, 215mg / day, 220mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 290mg / day, 295mg / day, 300mg / day, 305mg / day , 310mg / day, 315mg / day, 320mg / day, 325mg / day, 330mg / day, 335mg / day, 340mg / day, 345mg / day, 350mg / day, 355mg / day, 360mg / day, 365mg / day, 370mg / day, 375mg / day, 3 The present invention relates to a method for treating GnRH antagonist in a patient, the method comprising administering to the patient at least 80 mg / day, 385 mg / day, 390 mg / day, 395 mg / day, 400 mg / day, 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / day, 465 mg / day, 470 mg / day, 475 mg / day, 480 mg / day, 485 mg / day, 490 mg / day, 495 mg / day, or 500 mg / day) of a GnRH antagonist.

[0028] In some embodiments, the method comprises administering 10 mg / day of a GnRH antagonist to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.For example, the method can comprise administering 10 mg / day of ASP-1707 to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.

[0029] In some embodiments, the method includes administering 40 mg / day of a GnRH antagonist to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. For example, the method can include administering 40 mg / day of relugolix to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.

[0030] In some embodiments, the method comprises administering 50 mg / day to 200 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is within the AMH reference range. For example, the method may comprise administering 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a thieno[3,4d]pyrimidine derivative or variant, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or a choline salt thereof to the patient if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0031] In some embodiments, the method comprises administering 150 mg / day of a GnRH antagonist to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. For example, the method may comprise administering 150 mg / day of elagolix to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. In some embodiments, the method comprises administering 400 mg / day of a GnRH antagonist to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. For example, the method may comprise administering 400 mg / day of elagolix to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.

[0032] In another aspect, the invention features a method for determining a dosing regimen for treating endometriosis in a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In another aspect, the invention features a method for determining a dosing regimen that reduces pain (e.g., endometriosis-associated pain) in a patient (e.g., a female human patient, e.g., a premenopausal female human patient).

[0033] In any of the above aspects of the present invention, the method may include determining the concentration of AMH in a sample (e.g., a blood sample) isolated from a patient. In some embodiments, the concentration of AMH in the sample (e.g., a blood sample) isolated from a patient has been previously determined. The method includes: a.Comparing AMH concentrations with the AMH reference range; b. determining that a higher amount (e.g., a higher daily dose or more frequent administration) of a GnRH antagonist be administered to the patient if the concentration of AMH in the sample isolated from the patient is above the AMH reference range; c. determining that a lower amount (e.g., a lower daily dose or less frequent administration) of a GnRH antagonist be administered to the patient if the concentration of AMH in the sample isolated from the patient is below the AMH reference range; or d. If the concentration of AMH in the sample isolated from the patient is within the AMH reference range, determining to administer an intermediate amount (e.g., an intermediate daily dose or intermediate dosing frequency) of GnRH antagonist to the patient.

[0034] In some embodiments, the method comprises administering a GnRH antagonist to the patient in the determined dose.

[0035] For example, in some embodiments, the method may include administering a dose of AMH of 10 to 600 mg / day, 20 to 590 mg / day, 30 to 580 mg / day, 40 to 570 mg / day, 50 to 560 mg / day, 60 to 550 mg / day, 70 to 540 mg / day, 80 to 530 mg / day, 90 to 520 mg / day, 100 to 510 mg / day, or 110 to 500 mg / day (e.g., 5 mg / day, 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50mg / day, 55mg / day, 60mg / day, 65mg / day, 70mg / day, 75mg / day, 80mg / day, 85mg / day, 90mg / day, 95mg / day, 100mg / day, 105mg / day, 110mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg g / day, 215mg / day, 220mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 2 90mg / day, 295mg / day, 300mg / day, 305mg / day, 310mg / day, 315mg / day, 320mg / day, 325mg / day, 330mg / day, 335mg / day, 340mg / day, 345mg / day, 350mg / day, 355mg / day, 360mg / day, 365mg / day Days, 370mg / day, 375mg / day, 380mg / day, 385mg / day, 390mg / day, 395mg / day, 400mg / day, 405mg / day, 410mg / day, 415mg / day, 420mg / day, 425mg / day, 430mg / day, 435mg / day, 440mg / day, 445mg / day, 450mg / day, 455mg / day, 460mg / day, 465mg / day, 470mg / day, 475mg / day, 480mg / day, 485mg / day, 490mg / day, 495mg / day, 500mg / day, 505mg / day, 510mg / day, 515mg / day, 520mg / day,525mg / day, 530mg / day, 535mg / day, 540mg / day, 545mg / day, 550mg / day, 555mg / day, 560mg / day, 565mg / day, 570mg / day, 5 75mg / day, 580mg / day, 585mg / day, 590mg / day, 595mg / day, 600mg / day, 605mg / day, 610mg / day, 615mg / day, 620mg / day, 62 The method includes determining whether to administer to the patient a GnRH antagonist at a dose of 5 mg / day, 630 mg / day, 635 mg / day, 640 mg / day, 645 mg / day, 650 mg / day, 655 mg / day, 660 mg / day, 665 mg / day, 670 mg / day, 675 mg / day, 680 mg / day, 685 mg / day, 690 mg / day, 695 mg / day, or 700 mg / day.

[0036] In some embodiments, the method comprises determining that if the concentration of AMH in the sample separated from the patient is above the AMH reference range, then administer more than 10mg / day of GnRH antagonist to the patient.For example, the method can comprise determining that if the concentration of AMH in the sample separated from the patient is above the AMH reference range, then administer more than 10mg / day of ASP-1707 to the patient.

[0037] In some embodiments, the method includes determining that if the concentration of AMH in a sample isolated from the patient is above the AMH reference range, then administering more than 40 mg / day of a GnRH antagonist to the patient. For example, the method can include determining that if the concentration of AMH in a sample isolated from the patient is above the AMH reference range, then administering more than 40 mg / day of relugolix to the patient.

[0038] In some embodiments, the method comprises determining that if the concentration of AMH in the sample isolated from the patient is above the AMH reference range, administer about 50 mg / day to about 200 mg / day of a GnRH antagonist to the patient.For example, the method can comprise determining that if the concentration of AMH in the sample isolated from the patient is above the AMH reference range, administer about 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a thieno[3,4d]pyrimidine derivative or variant, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or its choline salt to the patient.

[0039] In some embodiments, the method comprises determining to administer more than 150 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. For example, the method may comprise determining to administer more than 150 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method comprises determining to administer more than 400 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. For example, the method may comprise determining to administer more than 400 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0040] In some embodiments, the method includes determining to administer 5 to 400 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. For example, in some embodiments, the method determines to administer 5 to 190 mg / day, 15 to 180 mg / day, 35 to 170 mg / day, 50 to 160 mg / day, 60 to 150 mg / day, 70 to 140 mg / day, 80 to 130 mg / day, 90 to 120 mg / day, 100 to 110 mg / day, 200 to 400 mg / day, 225 to 375 mg / day, 250 to 350 mg / day, or 275 to 325 mg / day (e.g., 5 mg / day) of a GnRH antagonist if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. , 10mg / day, 15mg / day, 20mg / day, 25mg / day, 30mg / day, 35mg / day, 40mg / day, 45mg / day, 50mg / day, 55mg / day, 60mg / day, 65mg / day, 70mg / day, 75mg / day, 80mg / day, 85mg / day, 90mg / day, 95mg / day, 100mg / day, 105mg / day, 110mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 15 5mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg / day, 215mg / day, 220mg / day day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 290 The method includes determining to administer to the patient at least 400 mg / day of a GnRH antagonist (295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395 mg / day, or 400 mg / day).

[0041] In some embodiments, the method comprises determining that if the concentration of AMH in the sample isolated from the patient is below the AMH reference range, administer less than 10mg / day of GnRH antagonist to the patient.For example, the method can comprise determining that if the concentration of AMH in the sample isolated from the patient is below the AMH reference range, administer less than 10mg / day of ASP-1707 to the patient.

[0042] In some embodiments, the method includes determining that if the concentration of AMH in a sample isolated from the patient is below the AMH reference range, then administering less than 40 mg / day of a GnRH antagonist to the patient. For example, the method can include determining that if the concentration of AMH in a sample isolated from the patient is below the AMH reference range, then administering less than 40 mg / day of relugolix to the patient.

[0043] In some embodiments, the method comprises determining that if the concentration of AMH in a sample isolated from a patient is below the AMH reference range, administer to the patient about 50 mg / day to about 200 mg / day of a GnRH antagonist. For example, the method can comprise determining that if the concentration of AMH in a sample isolated from a patient is below the AMH reference range, administer to the patient about 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a thieno[3,4d]pyrimidine derivative or variant, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or its choline salt.

[0044] In some embodiments, the method includes determining to administer less than 150 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. For example, the method may include determining to administer less than 150 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes determining to administer less than 400 mg / day of a GnRH antagonist to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. For example, the method may include determining to administer less than 400 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes administering the GnRH antagonist to the patient at the determined dose.

[0045] In some embodiments, the method includes determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administering 10 to 500 mg / day of a GnRH antagonist to the patient.For example, in some embodiments, the method provides for administering a dose of AMH of 10 to 490 mg / day, 25 to 480 mg / day, 50 to 470 mg / day, or 100 to 460 mg / day (e.g., 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 9 ... 5mg / day, 100mg / day, 105mg / day, 110mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg / day, 215mg / day, 220mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 290mg / day, 295mg / day, 300mg / day, 305mg / day, 310 mg / day, 315mg / day, 320mg / day, 325mg / day, 330mg / day, 335mg / day, 340mg / day, 345mg / day, 350mg / day, 355mg / day, 360mg / day, 365mg / day, 370mg / day, 375mg / day, 380mg / day day, 385 mg / day, 390 mg / day, 395 mg / day, 400 mg / day, 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / day, 465 mg / day, 470 mg / day, 475 mg / day, 480 mg / day, 485 mg / day, 490 mg / day, 495 mg / day, or 500 mg / day) of a GnRH antagonist to the patient.

[0046] In some embodiments, the method comprises determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 10 mg / day of GnRH antagonist to the patient.For example, the method can comprise determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 10 mg / day of ASP-1707 to the patient.

[0047] In some embodiments, the method includes determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 40 mg / day of a GnRH antagonist to the patient. For example, the method can include determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 40 mg / day of relugolix to the patient.

[0048] In some embodiments, the method includes determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer about 50 mg / day to about 200 mg / day of a GnRH antagonist to the patient. For example, the method can include determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer about 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a thieno[3,4d]pyrimidine derivative or variant, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or its choline salt, to the patient.

[0049] In some embodiments, the method includes determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 150 mg / day of a GnRH antagonist to the patient. For example, the method may include determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 150 mg / day of elagolix to the patient. In some embodiments, the method includes determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 400 mg / day of a GnRH antagonist to the patient. For example, the method may include determining that if the concentration of AMH in the sample isolated from the patient is within the AMH reference range, then administer 400 mg / day of elagolix to the patient. In some embodiments, the method includes administering the GnRH antagonist to the patient at the determined dose.

[0050] In some embodiments, the AMH reference range is 15-35 pM.Therefore, it will be understood that AMH concentrations less than 15 pM (e.g., 1 pM, 2 pM, 3 pM, 4 pM, 5 pM, 6 pM, 7 pM, 8 pM, 9 pM, 10 pM, 11 pM, 12 pM, 13 pM, or 14 pM) are considered to be below the AMH reference range of 15-35 pM.Similarly, it will be understood that AMH concentrations greater than 35 pM (e.g., 36 pM, 37 pM, 38 pM, 39 pM, 40 pM, 50 pM, 55 pM, or more) are considered to be above the AMH reference range of 15-35 pM.

[0051] In some embodiments, the methods comprise administering to the patient a GnRH antagonist in an amount sufficient to relieve or alleviate the symptoms of endometriosis.

[0052] In some embodiments, the method includes administering a GnRH antagonist to the patient in an amount sufficient to reduce the serum concentration of β17-estradiol (E2) in the patient to about 20 to about 50 pg / ml (e.g., about 20 pg / ml, 25 pg / ml, 30 pg / ml, 35 pg / ml, 40 pg / ml, 45 pg / ml, or 50 pg / ml). In some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 4 weeks after initiating administration of the GnRH antagonist to the patient. In some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 12 weeks after starting to administer the GnRH antagonist to the patient, hi some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 24 weeks after starting to administer the GnRH antagonist to the patient.

[0053] In some embodiments, the method includes administering a GnRH antagonist to the patient in an amount sufficient to reduce the serum concentration of follicle-stimulating hormone (FSH) in the patient to about 0.1 to about 10 mIU / ml (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mIU / ml). In some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 4 weeks after initiating administration of the GnRH antagonist to the patient. In some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 12 weeks after starting to administer the GnRH antagonist to the patient, hi some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 24 weeks after starting to administer the GnRH antagonist to the patient.

[0054] In some embodiments, the method includes administering a GnRH antagonist to the patient in an amount sufficient to reduce the serum concentration of luteinizing hormone (LH) in the patient to about 0.1 to about 10 mIU / ml (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mIU / ml). In some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 4 weeks after initiating administration of the GnRH antagonist to the patient. In some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 12 weeks after starting to administer the GnRH antagonist to the patient, hi some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 24 weeks after starting to administer the GnRH antagonist to the patient.

[0055] In some embodiments, the method includes administering a GnRH antagonist to a patient in an amount sufficient to reduce endometriosis-associated pain in the patient. In some embodiments, the endometriosis-associated pain is reduced within about 4 to about 36 weeks of initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks of initiating administration of the GnRH antagonist to the patient). In some embodiments, endometriosis-associated pain is reduced within about 4 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, endometriosis-associated pain is reduced within about 12 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, endometriosis-associated pain is reduced within about 24 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the endometriosis-associated pain is selected from the group consisting of pelvic pain, dyspareunia, and bowel disorders.

[0056] In some embodiments, endometriosis-associated pain is assessed by determining the patient's Numerical Rating Score (NRS). In some embodiments, the NRS is reduced by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some embodiments, the NRS is reduced by about 30%.

[0057] In some embodiments, endometriosis-associated pain is assessed by determining the patient's Verbal Rating Score (VRS). In some embodiments, the VRS is reduced by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some embodiments, the VRS is reduced by about 30%.

[0058] In some embodiments, the methods include administering a GnRH antagonist to a patient in an amount sufficient to relieve a symptom selected from the group consisting of dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. In some embodiments, the symptoms are relieved within about 4 to about 36 weeks of initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks of initiating administration of the GnRH antagonist to the patient). In some embodiments, the symptoms are alleviated within about 4 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the symptoms are alleviated within about 12 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the symptoms are alleviated within about 24 weeks of starting to administer the GnRH antagonist to the patient.

[0059] In some embodiments, symptoms are assessed by determining the patient's Biberoglu and Behrman (B&B) scale score. In some embodiments, the B&B score is reduced by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%).

[0060] In some embodiments, the methods include administering a GnRH antagonist to a patient in an amount sufficient to reduce an Endometriosis Health Profile-5 (EHP-5) score assessed for the patient. In some embodiments, the EHP-5 score is reduced within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the EHP-5 score decreases within about 4 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the EHP-5 score decreases within about 12 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the EHP-5 score decreases within about 24 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the EHP-5 score decreases by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%).

[0061] In some embodiments, the method comprises administering a GnRH antagonist to a patient in an amount that does not cause a decrease in bone mineral density (BMD) in the patient by more than 5%. In some embodiments, the method comprises administering a GnRH antagonist to a patient in an amount that does not cause a decrease in BMD in the patient by more than 1%.

[0062] In some embodiments, the method includes administering an add-back therapy to the patient. The add-back therapy can be administered to the patient simultaneously with, before, or after the administration of a GnRH antagonist. In some embodiments, the add-back therapy is administered as a fixed-dose combination drug containing a GnRH antagonist, an estrogen, and one or more additional agents, such as a progestin, in a single pharmaceutical composition. For example, the add-back therapy may be administered as a fixed-dose combination of a GnRH antagonist, an estrogen (e.g., in the form of β17-estradiol, ethinyl estradiol, or a conjugated estrogen, e.g., conjugated equine estrogens), and / or a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (also referred to herein as "NETA"), e.g., progesterone, norgestimate, medroxyprogesterone, and drospirenone, among other drugs) in a single pharmaceutical composition, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy is administered orally, transdermally, or intravaginally.

[0063] In some embodiments, the add-back therapy is administered to the patient in one or more doses daily, weekly, monthly, or yearly, e.g., daily, e.g., 1 to 10 times daily, or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times daily). In some embodiments, the add-back therapy is administered to the patient once daily, e.g., simultaneously with a GnRH antagonist. For example, the GnRH antagonist may be administered orally to the patient, and the add-back therapy may be administered orally, transdermally, or intravaginally to the patient simultaneously with oral administration of the GnRH antagonist. In some embodiments, the add-back therapy is administered to the patient in the form of a pharmaceutical composition further comprising a GnRH antagonist, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension, e.g., as described above and herein.

[0064] In some embodiments, add-back therapy is administered to patient once a day after compound administration.For example, GnRH antagonist can be orally administered to patient, and after oral administration of GnRH antagonist, add-back therapy can be orally, transdermally or intravaginally administered to patient.

[0065] In some embodiments, add-back therapy is administered to patient once a day before administering compound.For example, GnRH antagonist can be orally administered to patient, and before oral administration of GnRH antagonist, add-back therapy can be orally, transdermally or intravaginally administered to patient.

[0066] In some embodiments, the add-back therapy comprises an estrogen, hi some embodiments, the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens, e.g., conjugated equine estrogens.

[0067] In some embodiments, the estrogen is β17-estradiol. β17-estradiol is administered to a patient, for example, orally, at a dose of about 0.1 mg to about 2.5 mg, for example, about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, or 2.5 mg. In some embodiments, β17-estradiol is administered to a patient, for example, orally, at a dose of 1.0 mg. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg, for example, by oral administration.

[0068] β17-estradiol may be administered to the patient one or more times daily, weekly, or monthly. β17-estradiol can be administered to a patient, e.g., by oral administration, at a dose of about 0.1 mg / day to about 2.5 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, or 2.5 mg / day. In some embodiments, β17-estradiol is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg / day, e.g., orally.

[0069] In some embodiments, the estrogen is ethinyl estradiol. Ethinyl estradiol is administered at a dose of, for example, about 1.0 μg to about 6.0 μg, for example, about 1.0 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2.0 μg, 2.1 μg, 2.2 μg, 2.3 μg, 2.4 μg, 2.5 μg, 2.6 μg, 2.7 μg, 2.8 μg, 2.9 μg, 3.0 μg, 3.1 μg, 3.2 μg, 3.3 μg, 3.4 μg, The dose of ethinyl estradiol can be administered to the patient by oral administration, for example, at 3.5 μg, 3.6 μg, 3.7 μg, 3.8 μg, 3.9 μg, 4.0 μg, 4.1 μg, 4.2 μg, 4.2 μg, 4.3 μg, 4.4 μg, 4.5 μg, 4.6 μg, 4.7 μg, 4.8 μg, 4.9 μg, 5.0 μg, 5.1 μg, 5.2 μg, 5.3 μg, 5.4 μg, 5.5 μg, 5.6 μg, 5.7 μg, 5.8 μg, 5.9 μg or 6.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 5.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 2.5 μg.

[0070] Ethinyl estradiol may be administered to the patient one or more times daily, weekly, or monthly. Ethinylestradiol is administered at a dose of, for example, about 1.0 μg / day to about 6.0 μg / day, e.g., about 1.0 μg / day, 1.1 μg / day, 1.2 μg / day, 1.3 μg / day, 1.4 μg / day, 1.5 μg / day, 1.6 μg / day, 1.7 μg / day, 1.8 μg / day, 1.9 μg / day, 2.0 μg / day, 2.1 μg / day, 2.2 μg / day, 2.3 μg / day, 2.4 μg / day, 2.5 μg / day, 2.6 μg / day, 2.7 μg / day, 2.8 μg / day, 2.9 μg / day, 3.0 μg / day, 3.1 μg / day, 3.2 μg / day, 3.3 μg / day, 3.4 μg / day, It may be administered to a patient, for example by oral administration, at a dose of 3.5 μg / day, 3.6 μg / day, 3.7 μg / day, 3.8 μg / day, 3.9 μg / day, 4.0 μg / day, 4.1 μg / day, 4.2 μg / day, 4.2 μg / day, 4.3 μg / day, 4.4 μg / day, 4.5 μg / day, 4.6 μg / day, 4.7 μg / day, 4.8 μg / day, 4.9 μg / day, 5.0 μg / day, 5.1 μg / day, 5.2 μg / day, 5.3 μg / day, 5.4 μg / day, 5.5 μg / day, 5.6 μg / day, 5.7 μg / day, 5.8 μg / day, 5.9 μg / day, or 6.0 μg / day. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 5.0 μg / day, e.g., orally. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 2.5 μg / day, e.g., orally.

[0071] In some embodiments, the estrogen is a conjugated estrogen, e.g., conjugated equine estrogen. The conjugated estrogen may be administered to a patient, e.g., orally, at a dose of about 0.1 mg to about 2.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.625 mg, e.g., orally. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.45 mg, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg, for example, by oral administration.

[0072] The conjugated estrogen can be administered to the patient once or more daily, weekly, or monthly. The conjugated estrogen can be administered to the patient at a dose of, for example, about 0.1 mg / day to about 2.0 mg / day, for example, about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day, for example, orally. In some embodiments, the conjugated estrogen is administered to the patient at a dose of 0.625 mg / day, for example, orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.45 mg / day, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg / day, e.g., orally.

[0073] In some embodiments, the add-back therapy includes a progestin, hi some embodiments, the progestin is selected from the group consisting of norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent, e.g., progesterone, norgestimate, medroxyprogesterone, or drospirenone.

[0074] In some embodiments, the progestin is norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0075] In some embodiments, the progestin is norethindrone. Norethindrone may be administered in a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 ... In some embodiments, norethindrone is administered to a patient at a dose of 0.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 1.0 mg / day, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg / day, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg / day, e.g., by oral administration.

[0076] Norethindrone may be administered to a patient one or more times daily, weekly, or monthly. Norethindrone may be administered, for example, at a dose of about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 ... In some embodiments, norethindrone may be administered to a patient at a dose of 1.0 mg, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg, e.g., orally.

[0077] In some embodiments, the progestin is norethindrone acetate. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, In some embodiments, norethindrone acetate is administered to a patient at a dose of 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg, e.g., orally.

[0078] Norethindrone acetate may be administered to the patient one or more times daily, weekly, or monthly. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2. It may be administered to a patient, for example, by oral administration, at a dose of 2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 3.0 mg / day, 3.1 mg / day, 3.2 mg / day, 3.3 mg / day, 3.4 mg / day, 3.5 mg / day, 3.6 mg / day, 3.7 mg / day, 3.8 mg / day, 3.9 mg / day, 4.0 mg / day, 4.1 mg / day, 4.2 mg / day, 4.3 mg / day, 4.4 mg / day, 4.5 mg / day, 4.6 mg / day, 4.7 mg / day, 4.8 mg / day, 4.9 mg / day, or 5.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient, for example, by oral administration, at a dose of 1.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0079] In some embodiments, the progestin is progesterone. Progesterone may be administered to a patient, e.g., by oral administration, at a dose of about 50 mg to about 250 mg, e.g., about 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg. In some embodiments, progesterone is administered to a patient at a dose of 200 mg, e.g., orally. In some embodiments, progesterone is administered to a patient at a dose of 100 mg, e.g., orally.

[0080] Progesterone may be administered to a patient one or more times daily, weekly, or monthly. Progesterone may be administered, for example, at a dose of about 50 mg / day to about 250 mg / day, for example, about 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, The progesterone may be administered to a patient at a dose of, for example, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, or 250 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 200 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 100 mg / day, for example, by oral administration.

[0081] In some embodiments, the progestin is norgestimate. Norgestimate can be administered to a patient, for example, orally, at a dose of about 0.01 mg to about 2.0 mg, for example, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, norgestimate is administered to a patient, for example, orally, at a dose of 0.09 mg.

[0082] Norgestimate may be administered to a patient one or more times daily, weekly, or monthly. Norgestimate may be administered, for example, at a dose of about 0.01 mg / day to about 2.0 mg / day, for example, about 0.01 mg / day, 0.02 mg / day, 0.03 mg / day, 0.04 mg / day, 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 ...9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg In some embodiments, norgestimate may be administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration, in an amount of 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day. In some embodiments, norgestimate is administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration.

[0083] In some embodiments, the progestin is medroxyprogesterone. Medroxyprogesterone is available in doses of, for example, about 0.5 mg to about 10.0 mg, such as about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8 mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5 mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, The medroxyprogesterone may be administered to a patient at a dose of 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 5.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 2.5 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 1.5 mg, for example, orally.

[0084] Medroxyprogesterone may be administered to a patient one or more times daily, weekly, or monthly. Medroxyprogesterone may be administered at a dose of, for example, about 0.5 mg / day to about 10.0 mg / day, such as about 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, or 2.6 mg / day. / day, 2.6mg / day, 2.7mg / day, 2.8mg / day, 2.9mg / day, 3.0mg / day, 3.1mg / day, 3.2mg / day, 3.3mg / day, 3.4mg / day, 3.5mg / day, 3.6mg / day, 3.7mg / day, 3.8mg / day, 3.9mg / day, 4.0mg / day, 4.1mg / day, 4.2mg / day, 4.3mg / day, 4.4mg / day, 4.5mg / day, 4.6mg / day, 4.7mg / day, 4.8mg / day, 4.9mg / day, 5.0mg / day, 5.1mg / day, 5.2mg / day, 5.3mg / day, 5.4mg / day, 5.5mg / day, 5.6mg / day, 5.7mg / day, 5.8mg / day, 5.9mg / day, 6.0mg / day, 6.1mg / day, 6.2mg / day, 6.3mg / day, 6.4mg / day, 6.5mg / day, 6.6mg / day, 6.7mg / day, 6.8mg / day, 6.9mg / day, 7.0mg / day, 7.1mg / day, 7.2mg / day, 7.3mg / day, 7.4mg / day, 7.5mg / day, 7.6mg / day, 7.7mg / day, 7.8mg / day In some embodiments, medroxyprogesterone may be administered to a patient at a dose of 7.9 mg / day, 8.0 mg / day, 8.1 mg / day, 8.2 mg / day, 8.3 mg / day, 8.4 mg / day, 8.5 mg / day, 8.6 mg / day, 8.7 mg / day, 8.8 mg / day, 8.9 mg / day, 9.0 mg / day, 9.1 mg / day, 9.2 mg / day, 9.3 mg / day, 9.4 mg / day, 9.5 mg / day, 9.6 mg / day, 9.7 mg / day, 9.8 mg / day, 9.9 mg / day, or 10.0 mg / day, e.g., by oral administration. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 5.0 mg / day, e.g., by oral administration.In some embodiments, medroxyprogesterone is administered to a patient at a dose of 2.5 mg / day, e.g., orally. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 1.5 mg / day, e.g., orally.

[0085] In some embodiments, the progestin is drospirenone. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg to about 1.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1.0 mg. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg, e.g., orally.

[0086] Drospirenone may be administered to a patient one or more times daily, weekly, or monthly. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg / day to about 1.0 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, or 1.0 mg / day. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg / day, e.g., orally.

[0087] In some embodiments, the add-back therapy includes an estrogen and a progestin, hi some embodiments, the add-back therapy includes β17-estradiol and norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0088] In some embodiments, the add-back therapy includes about 0.75 mg to about 1.25 mg of β17-estradiol (e.g., administered orally) and about 0.25 mg to about 0.75 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy includes 1.0 mg of β17-estradiol (e.g., administered orally) and 0.5 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 1.0 mg of β17-estradiol (e.g., administered orally) and, in the same pharmaceutical composition, 0.5 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 1.0 mg of β17-estradiol (e.g., administered orally) and, in the same pharmaceutical composition, 0.5 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally).

[0089] In some embodiments, the GnRH antagonist is a compound represented by Formula (I), (II), or (III) herein and is administered to the patient in a fixed dose composition comprising about 50 mg, 75 mg, 100 mg, or 200 mg of the compound, about 0.75 mg to about 1.25 mg of β17-estradiol, and about 0.25 mg to about 0.75 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate. In some embodiments, the compound is administered to a patient in a fixed dose composition comprising about 50 mg, 75 mg, 100 mg, or 200 mg of the compound, about 1.0 mg of β17-estradiol (e.g., 1.0 mg of β17-estradiol), and about 0.5 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., 0.5 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate).

[0090] In some embodiments, the fixed dose compositions are administered in one or more doses every 12 hours, 24 hours, 48 ​​hours, 72 hours, week, month, or year, for example, 1 to 10 doses every 12 hours (e.g., 1 dose every 12 hours, 2 doses every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5 doses every 12 hours, 6 doses every 12 hours, 7 doses every 12 hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses every 12 hours), among others. 1 to 10 doses every 24 hours (e.g., 1 dose every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4 doses every 24 hours, 5 doses every 24 hours, 6 doses every 24 hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses every 24 hours, or 10 doses every 24 hours), 1 to 10 doses every 48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3 doses every 48 hours, 4 doses every 48 hours, 5 doses every 48 hours, 6 doses every 48 hours, 7 doses every 48 hours), doses, 8 doses every 48 hours, 9 doses every 48 hours, or 10 doses every 48 hours), 1 to 10 doses every 72 hours (e.g., 1 dose every 72 hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9 doses every 72 hours, or 10 doses every 72 hours), 1 to 10 doses weekly (e.g., 1 dose weekly, 2 doses weekly, 3 doses weekly, 4 doses every 72 hours, or 10 doses every 72 hours). In some embodiments, the fixed dose composition is administered to a patient once daily. In some embodiments, the fixed dose composition is administered to a patient once daily.

[0091] In some embodiments, the add-back therapy comprises about 0.25 mg to about 0.75 mg of β17-estradiol (e.g., administered orally) and about 0.05 mg to about 0.2 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 0.5 mg of β17-estradiol (e.g., administered orally) and 0.1 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 0.5 mg of β17-estradiol (e.g., administered orally) and, in the same pharmaceutical composition, 0.1 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 0.5 mg of β17-estradiol (e.g., administered orally) and, in a separate pharmaceutical composition, 0.1 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally).

[0092] In some embodiments, the GnRH antagonist is a compound represented by Formula (I), (II), or (III) herein and is administered to the patient in a fixed dose composition comprising about 50 mg, 75 mg, 100 mg, or 200 mg of the compound, about 0.25 mg to about 0.75 mg of β17-estradiol, and about 0.05 mg to about 0.2 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate. In some embodiments, the compound is administered to a patient in a fixed dose composition comprising about 50 mg, 75 mg, 100 mg, or 200 mg of the compound, about 0.5 mg of β17-estradiol (e.g., 0.5 mg of β17-estradiol), and about 0.1 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., 0.1 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate).

[0093] In some embodiments, the fixed dose compositions are administered in one or more doses every 12 hours, 24 hours, 48 ​​hours, 72 hours, week, month, or year, for example, 1 to 10 doses every 12 hours (e.g., 1 dose every 12 hours, 2 doses every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5 doses every 12 hours, 6 doses every 12 hours, 7 doses every 12 hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses every 12 hours), 24 hours, 48 ​​hours, 72 hours, week, month, or year, among others. 1 to 10 doses every 24 hours (e.g., 1 dose every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4 doses every 24 hours, 5 doses every 24 hours, 6 doses every 24 hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses every 24 hours, or 10 doses every 24 hours), 1 to 10 doses every 48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3 doses every 48 hours, 4 doses every 48 hours, 5 doses every 48 hours, 6 doses every 48 hours, 7 doses every 48 hours, 8 doses every 48 hours, 9 doses every 24 hours, or 10 doses every 24 hours), 7 doses, 8 doses every 48 hours, 9 doses every 48 hours, or 10 doses every 48 hours), 1 to 10 doses every 72 hours (e.g., 1 dose every 72 hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9 doses every 72 hours, or 10 doses every 72 hours), 1 to 10 doses weekly (e.g., 1 dose weekly, 2 doses weekly, 3 doses weekly, 4 doses every 72 hours, or 10 doses every 72 hours). In some embodiments, the fixed dose composition is administered to the patient once daily. In some embodiments, the fixed dose composition is administered to the patient once daily.

[0094] In some embodiments, the patient does not experience a decline in BMD of more than 5% after administration of the GnRH antagonist and the add-back therapy. In some embodiments, the patient does not experience a decline in BMD of more than 1% after administration of the GnRH antagonist and the add-back therapy. The add-back therapy may be formulated for oral administration. For example, the add-back therapy may be formulated as a tablet, capsule, gelcap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, such as β17-estradiol, and a progestin, such as norethindrone acetate or norethindrone. The estrogen and progestin may be administered separately or may be combined into a single composition, such as a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension.

[0095] In some embodiments, BMD is assessed by dual energy x-ray absorptiometry. In some embodiments, BMD is assessed at the patient's spine or femur.

[0096] In some embodiments, the GnRH antagonist has formula (I): [ka] (I) a compound represented by wherein ring A is a thiophene ring; each R A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3, or SO2NW2W3, where W1 to W3 are independently a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; Ring B is an aryl group or a monocyclic heteroaryl group; each R is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW, COW, COOW, or CONWW, where W-W are independently a hydrogen atom or an optionally substituted lower alkyl group, or W and W may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by -SLY, -OLY, -CO-LY, or -SO2-LY, where L is an optionally substituted lower alkylene group; Y is Z or a group represented by -NW7W8, where W7 and W8 are independently a hydrogen atom, an optionally substituted lower alkyl group, or Z, provided that W7 and W8 are not simultaneously hydrogen atoms or W 7 and W 8 may be joined together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group; Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, ring A is a group represented by formula (A): [ka] (A) is a thiophene ring represented by

[0098] In some embodiments, m is 1 or 2. In some embodiments, m is 1. For example, ring A is a group represented by formula (B): [ka] (B) The thiophene ring may be an optionally substituted thiophene ring represented by:

[0099] Each R may independently be, for example, a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally substituted lower alkyl group, COO W, or CONWW, where W-W are independently hydrogen atoms or optionally substituted lower alkyl groups, or W and W may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group. In some embodiments, each R is COOH or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, Ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring. For example, Ring B is [ka] ; [ka] ; [ka] ; [ka] ; [ka] ; [ka] and [ka] The compound may be represented by a formula selected from the group consisting of:

[0101] In some embodiments, n is 1 or 2. For example, in some embodiments, n is 1. Ring B can be, for example, [ka] ; [ka] and [ka] The compound may be represented by a formula selected from the group consisting of:

[0102] In some embodiments, each R is independently a halogen atom, an optionally substituted lower alkyl group, or O W , where each W is independently a hydrogen atom or an optionally substituted lower alkyl group. For example, each R may independently be a fluorine atom, a chlorine atom, a bromine atom, a methyl group, or a methoxy group.

[0103] In some embodiments, U is a single bond. X may be, for example, a group represented by -OLY. L may be, for example, a methylene group. In some embodiments, Y is a group represented by formula (C): [ka] (C) and an optionally substituted benzene ring represented by wherein each R C is independently a halogen atom, an optionally substituted lower alkyl group, or W O , wherein each W is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer of 0 to 3.

[0104] In some embodiments, Y is a group represented by formula (D): [ka] (D) is a substituted benzene ring represented by

[0105] In some embodiments, the compound has formula (II): [ka] (II) or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound is a choline salt of the compound represented by Formula (II), i.e., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline.

[0107] In some embodiments, the GnRH antagonist comprises a compound represented by formula (II) in a crystalline state. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks at about 7.1°2θ, 11.5°2θ, 19.4°2θ, 20.3°2θ, 21.5°2θ, 22.0°2θ, 22.6°2θ, 23.5°2θ, and 26.2°2θ. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks centered at about 155.8 ppm, 149.8 ppm, 145.3 ppm, 118.0 ppm, 113.7 ppm, 111.6 ppm, 110.3 ppm, 98.1 ppm, 69.8 ppm, 58.7 ppm, 57.1 ppm, and 55.5 ppm. 13 In some embodiments, the compound exhibits C solid-state nuclear magnetic resonance (NMR) peaks centered at about -131.6 ppm, -145.2 ppm, and -151.8 ppm. 19 F solid-state NMR peaks.

[0108] In some embodiments, the method comprises administering a dose of AMH of about 50 mg / day to about 200 mg / day (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, The present invention also includes administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day.

[0109] In some embodiments, the method includes administering to the patient about 50 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0110] In some embodiments, the method includes administering to the patient about 75 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0111] In some embodiments, the method includes administering to the patient about 100 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0112] In some embodiments, the method includes administering to the patient about 200 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0113] In some embodiments, the method comprises administering a dose of AMH between 50 mg / day and about 200 mg / day (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, 510 mg / day, 520 mg / day, 530 mg / day, 540 mg / day, 550 mg / day, 560 mg / day, 570 mg / day, 580 mg / day, 590 mg The present invention includes administering to a patient a compound of formula (II) at a dose of 20 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day.

[0114] In some embodiments, the method includes administering to the patient about 50 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0115] In some embodiments, the method includes administering to the patient about 75 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0116] In some embodiments, the method includes administering to the patient about 100 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0117] In some embodiments, the method includes administering to the patient about 200 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0118] In some embodiments, the method comprises administering a dose of AMH of about 50 mg / day to about 200 mg / day (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, The present invention also includes administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day.

[0119] In some embodiments, the method includes administering to the patient about 50 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0120] In some embodiments, the method includes administering to the patient about 75 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0121] In some embodiments, the method includes administering to the patient about 100 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0122] In some embodiments, the method includes administering to the patient about 200 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0123] In some embodiments, the method comprises administering a dose of AMH between 50 mg / day and about 200 mg / day (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, 510 mg / day, 520 mg / day, 530 mg / day, 540 mg / day, 550 mg / day, 560 mg / day, 570 mg / day, 580 mg / day, 590 mg The present invention includes administering to a patient a compound of formula (II) at a dose of 20 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day.

[0124] In some embodiments, the method includes administering to the patient about 50 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0125] In some embodiments, the method includes administering to the patient about 75 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0126] In some embodiments, the method includes administering to the patient about 100 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0127] In some embodiments, the method includes administering to the patient about 200 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0128] In some embodiments, the method provides for administering a dose of AMH of about 50 mg / day to about 200 mg / day (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, The present invention also includes administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day.

[0129] In some embodiments, the method includes administering to the patient about 50 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0130] In some embodiments, the method includes administering to the patient about 75 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0131] In some embodiments, the method includes administering to the patient about 100 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0132] In some embodiments, the method includes administering to the patient about 200 mg / day of the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0133] In some embodiments, the method comprises administering a dose of AMH from 50 mg / day to about 200 mg / day (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg The present invention includes administering to a patient a compound of formula (II) at a dose of 20 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day.

[0134] In some embodiments, the method includes administering to the patient about 50 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0135] In some embodiments, the method includes administering to the patient about 75 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0136] In some embodiments, the method includes administering to the patient about 100 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0137] In some embodiments, the method includes administering to the patient about 200 mg / day of a compound represented by Formula (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof, if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0138] In some embodiments, the method includes administering to the patient 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of a compound represented by Formula (I) if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method includes administering to the patient 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a compound represented by Formula (I) if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method includes administering to the patient 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of a compound represented by Formula (II) if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method includes administering to the patient 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a compound represented by Formula (II) if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method includes administering 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.In some embodiments, the method includes administering 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0139] In some embodiments, the method includes administering to the patient 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of a compound represented by Formula (I) if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes administering to the patient 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a compound represented by Formula (I) if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes administering to the patient 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of a compound represented by Formula (II) if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes administering to the patient 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a compound represented by Formula (II) if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes administering 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.In some embodiments, the method includes administering 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0140] In some embodiments, the method includes administering to the patient 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of a compound represented by Formula (I) if the concentration of AMH in a sample isolated from the patient is within the AMH reference range. In some embodiments, the method includes administering to the patient 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a compound represented by Formula (I) if the concentration of AMH in a sample isolated from the patient is within the AMH reference range. In some embodiments, the method includes administering to the patient 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of a compound represented by Formula (II) if the concentration of AMH in a sample isolated from the patient is within the AMH reference range. In some embodiments, the method includes administering to the patient 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of a compound represented by Formula (II) if the concentration of AMH in a sample isolated from the patient is within the AMH reference range. In some embodiments, the method includes administering 40 to 225 mg / day (e.g., 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day) of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline to the patient if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.In some embodiments, the method includes administering 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline to the patient if the concentration of AMH in a sample isolated from the patient is within the AMH reference range.

[0141] In some embodiments, the GnRH antagonist is selected from the group consisting of elagolix, relugolix, ASP-1707, SKI2670, and BAY-784, or a derivative or variant thereof.

[0142] In some embodiments, the GnRH antagonist is elagolix or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 7,056,927; 7,176,211; 7,419,983; 8,765,948; or 9,382,214; or U.S. Patent Application Publication Nos. 2014 / 0288031 or 2017 / 0056403, the disclosures of which are incorporated by reference in their entireties. In some embodiments, the method comprises administering 150 mg / day or more (e.g., 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, 250 mg / day, 255 mg / day, 260 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 400 mg / day, 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / day, 465 mg / day 1 mg / day, 265 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395, 400 mg / day, or more) of elagolix to the patient. In some embodiments, the method includes administering 145 mg / day to 405 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0143] In some embodiments, the method further comprises administering a dose of more than 400 mg / day (e.g., 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / day, 465 mg / day, 470 mg / day, 475 mg / day, 480 mg / day, 485 mg / day, 490 mg / day, 495 mg / day, 500 mg / day, 505 mg / day, 510 mg / day, 515 mg / day, 520 mg / day, 525 mg / day, 530 mg / day, 535 mg / day, 540 mg / day, 545 mg / day, 550 mg / day, 555 mg / day, 560 mg / day, 565 mg / day, 570 mg / day, 575 mg / day, 580 mg / day, 585 mg / day, 590 mg / day, 595 mg / day, 600 mg / day, 605 ... These include administering to the patient elagolix at doses of 545mg / day, 550mg / day, 555mg / day, 560mg / day, 565mg / day, 570mg / day, 575mg / day, 580mg / day, 585mg / day, 590mg / day, 595mg / day, 600mg / day, 605mg / day, 610mg / day, 615mg / day, 620mg / day, 625mg / day, 630mg / day, 635mg / day, 640mg / day, 645mg / day, 650mg / day, 655mg / day, 660mg / day, 665mg / day, 670mg / day, 675mg / day, 680mg / day, 685mg / day, 690mg / day, 695mg / day, 700mg / day, or more. In some embodiments, the method includes administering 400 mg / day to 600 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0144] When administered at high doses (e.g., 150 mg / day, 400 mg / day, or higher doses), elagolix may be administered in combination with add-back therapy, which may be administered to the patient simultaneously with elagolix, before administration of elagolix, or after administration of elagolix.

[0145] In some embodiments, the add-back therapy comprises an estrogen, hi some embodiments, the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens, e.g., conjugated equine estrogens.

[0146] In some embodiments, the estrogen is β17-estradiol. β17-estradiol is administered to a patient, for example, orally, at a dose of about 0.1 mg to about 2.5 mg, for example, about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, or 2.5 mg. In some embodiments, β17-estradiol is administered to a patient, for example, orally, at a dose of 1.0 mg. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg, for example, by oral administration.

[0147] β17-estradiol may be administered to the patient one or more times daily, weekly, or monthly. β17-estradiol can be administered to a patient, e.g., by oral administration, at a dose of about 0.1 mg / day to about 2.5 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, or 2.5 mg / day. In some embodiments, β17-estradiol is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg / day, e.g., orally.

[0148] In some embodiments, the estrogen is ethinyl estradiol. Ethinyl estradiol is administered at a dose of, for example, about 1.0 μg to about 6.0 μg, for example, about 1.0 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2.0 μg, 2.1 μg, 2.2 μg, 2.3 μg, 2.4 μg, 2.5 μg, 2.6 μg, 2.7 μg, 2.8 μg, 2.9 μg, 3.0 μg, 3.1 μg, 3.2 μg, 3.3 μg, 3.4 μg, The dose of ethinyl estradiol can be administered to the patient by oral administration, for example, at 3.5 μg, 3.6 μg, 3.7 μg, 3.8 μg, 3.9 μg, 4.0 μg, 4.1 μg, 4.2 μg, 4.2 μg, 4.3 μg, 4.4 μg, 4.5 μg, 4.6 μg, 4.7 μg, 4.8 μg, 4.9 μg, 5.0 μg, 5.1 μg, 5.2 μg, 5.3 μg, 5.4 μg, 5.5 μg, 5.6 μg, 5.7 μg, 5.8 μg, 5.9 μg or 6.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 5.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 2.5 μg.

[0149] Ethinyl estradiol may be administered to the patient one or more times daily, weekly, or monthly. Ethinylestradiol is administered at a dose of, for example, about 1.0 μg / day to about 6.0 μg / day, e.g., about 1.0 μg / day, 1.1 μg / day, 1.2 μg / day, 1.3 μg / day, 1.4 μg / day, 1.5 μg / day, 1.6 μg / day, 1.7 μg / day, 1.8 μg / day, 1.9 μg / day, 2.0 μg / day, 2.1 μg / day, 2.2 μg / day, 2.3 μg / day, 2.4 μg / day, 2.5 μg / day, 2.6 μg / day, 2.7 μg / day, 2.8 μg / day, 2.9 μg / day, 3.0 μg / day, 3.1 μg / day, 3.2 μg / day, 3.3 μg / day, 3.4 μg / day, It may be administered to a patient, for example by oral administration, at a dose of 3.5 μg / day, 3.6 μg / day, 3.7 μg / day, 3.8 μg / day, 3.9 μg / day, 4.0 μg / day, 4.1 μg / day, 4.2 μg / day, 4.2 μg / day, 4.3 μg / day, 4.4 μg / day, 4.5 μg / day, 4.6 μg / day, 4.7 μg / day, 4.8 μg / day, 4.9 μg / day, 5.0 μg / day, 5.1 μg / day, 5.2 μg / day, 5.3 μg / day, 5.4 μg / day, 5.5 μg / day, 5.6 μg / day, 5.7 μg / day, 5.8 μg / day, 5.9 μg / day, or 6.0 μg / day. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 5.0 μg / day, e.g., orally. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 2.5 μg / day, e.g., orally.

[0150] In some embodiments, the estrogen is a conjugated estrogen, e.g., conjugated equine estrogen. The conjugated estrogen may be administered to a patient, e.g., orally, at a dose of about 0.1 mg to about 2.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.625 mg, e.g., orally. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.45 mg, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg, for example, by oral administration.

[0151] The conjugated estrogen can be administered to the patient once or more daily, weekly, or monthly. The conjugated estrogen can be administered to the patient at a dose of, for example, about 0.1 mg / day to about 2.0 mg / day, for example, about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day, for example, orally. In some embodiments, the conjugated estrogen is administered to the patient at a dose of 0.625 mg / day, for example, orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.45 mg / day, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg / day, e.g., orally.

[0152] In some embodiments, the add-back therapy includes a progestin, hi some embodiments, the progestin is selected from the group consisting of norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent, e.g., progesterone, norgestimate, medroxyprogesterone, or drospirenone.

[0153] In some embodiments, the progestin is norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0154] In some embodiments, the progestin is norethindrone. Norethindrone may be administered in a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 ... In some embodiments, norethindrone is administered to a patient at a dose of 0.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 1.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg, e.g., by oral administration.

[0155] Norethindrone may be administered to a patient one or more times daily, weekly, or monthly. Norethindrone may be administered, for example, at a dose of about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 ... In some embodiments, norethindrone may be administered to a patient at a dose of 1.0 mg, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0156] In some embodiments, the progestin is norethindrone acetate. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, In some embodiments, norethindrone acetate is administered to a patient at a dose of 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg, e.g., orally.

[0157] Norethindrone acetate may be administered to the patient one or more times daily, weekly, or monthly. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2. In some embodiments, norethindrone acetate is administered to a patient at a dose of 1 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0158] In some embodiments, the progestin is progesterone. Progesterone may be administered to a patient, e.g., by oral administration, at a dose of about 50 mg to about 250 mg, e.g., about 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg. In some embodiments, progesterone is administered to a patient at a dose of 200 mg, e.g., orally. In some embodiments, progesterone is administered to a patient at a dose of 100 mg, e.g., orally.

[0159] Progesterone may be administered to a patient one or more times daily, weekly, or monthly. Progesterone may be administered, for example, at a dose of about 50 mg / day to about 250 mg / day, for example, about 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, The progesterone may be administered to a patient at a dose of, for example, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, or 250 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 200 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 100 mg / day, for example, by oral administration.

[0160] In some embodiments, the progestin is norgestimate. Norgestimate can be administered to a patient, for example, orally, at a dose of about 0.01 mg to about 2.0 mg, for example, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, norgestimate is administered to a patient, for example, orally, at a dose of 0.09 mg.

[0161] Norgestimate may be administered to a patient one or more times daily, weekly, or monthly. Norgestimate may be administered, for example, at a dose of about 0.01 mg / day to about 2.0 mg / day, for example, about 0.01 mg / day, 0.02 mg / day, 0.03 mg / day, 0.04 mg / day, 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 ...9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg In some embodiments, norgestimate may be administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration, in an amount of 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day. In some embodiments, norgestimate is administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration.

[0162] In some embodiments, the progestin is medroxyprogesterone. Medroxyprogesterone is available in doses of, for example, about 0.5 mg to about 10.0 mg, such as about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8 mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5 mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, The medroxyprogesterone may be administered to a patient at a dose of 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 5.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 2.5 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 1.5 mg, for example, orally.

[0163] Medroxyprogesterone may be administered to a patient one or more times daily, weekly, or monthly. Medroxyprogesterone may be administered at a dose of, for example, about 0.5 mg / day to about 10.0 mg / day, such as about 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, or 2.6 mg / day. / day, 2.6mg / day, 2.7mg / day, 2.8mg / day, 2.9mg / day, 3.0mg / day, 3.1mg / day, 3.2mg / day, 3.3mg / day, 3.4mg / day, 3.5mg / day, 3.6mg / day, 3.7mg / day, 3.8mg / day, 3.9mg / day, 4.0mg / day, 4.1mg / day, 4.2mg / day, 4.3mg / day, 4.4mg / day, 4.5mg / day, 4.6mg / day, 4.7mg / day, 4.8mg / day, 4.9mg / day, 5.0mg / day, 5.1mg / day, 5.2mg / day, 5.3mg / day, 5.4mg / day, 5.5mg / day, 5.6mg / day, 5.7mg / day, 5.8mg / day, 5.9mg / day, 6.0mg / day, 6.1mg / day, 6.2mg / day, 6.3mg / day, 6.4mg / day, 6.5mg / day, 6.6mg / day, 6.7mg / day, 6.8mg / day, 6.9mg / day, 7.0mg / day, 7.1mg / day, 7.2mg / day, 7.3mg / day, 7.4mg / day, 7.5mg / day, 7.6mg / day, 7.7mg / day, 7.8mg / day In some embodiments, medroxyprogesterone may be administered to a patient at a dose of 7.9 mg / day, 8.0 mg / day, 8.1 mg / day, 8.2 mg / day, 8.3 mg / day, 8.4 mg / day, 8.5 mg / day, 8.6 mg / day, 8.7 mg / day, 8.8 mg / day, 8.9 mg / day, 9.0 mg / day, 9.1 mg / day, 9.2 mg / day, 9.3 mg / day, 9.4 mg / day, 9.5 mg / day, 9.6 mg / day, 9.7 mg / day, 9.8 mg / day, 9.9 mg / day, or 10.0 mg / day, e.g., by oral administration. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 5.0 mg / day, e.g., by oral administration.In some embodiments, medroxyprogesterone is administered to a patient at a dose of 2.5 mg / day, e.g., orally. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 1.5 mg / day, e.g., orally.

[0164] In some embodiments, the progestin is drospirenone. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg to about 1.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1.0 mg. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg, e.g., orally.

[0165] Drospirenone may be administered to a patient one or more times daily, weekly, or monthly. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg / day to about 1.0 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, or 1.0 mg / day. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg / day, e.g., orally.

[0166] In some embodiments, the add-back therapy includes an estrogen and a progestin, hi some embodiments, the add-back therapy includes β17-estradiol and norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0167] In some embodiments, the patient does not experience a decline in BMD of more than 5% after administration of elagolix and the add-back therapy. In some embodiments, the patient does not experience a decline in BMD of more than 1% after administration of elagolix and the add-back therapy. The add-back therapy may be formulated for oral administration. For example, the add-back therapy may be formulated as a tablet, capsule, gelcap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, e.g., β17-estradiol, and a progestin, e.g., norethindrone acetate or norethindrone. The estrogen and progestin may be administered separately or may be combined in a single composition, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension.

[0168] In some embodiments, the method comprises administering 400 mg / day, 150 mg / day, or less (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, or 145 mg / day) of elagolix to the patient if the concentration of AMH in the sample isolated from the patient is below the AMH reference range. In some embodiments, the method comprises administering 50 mg / day to 125 mg / day of elagolix to the patient if the concentration of AMH in the sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes administering 100 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0169] In some embodiments, the method comprises administering a dose of AMH of 400 mg / day or less (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 28 mg / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160m g / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg / day, 215mg / day, 220mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 290mg / day, 295mg / day, 300mg / day, 305mg / day, 310mg / day , 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, or 395 mg / day) of elagolix to the patient. In some embodiments, the method comprises administering 150 mg / day to 375 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method comprises administering 150 mg / day of elagolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0170] In some embodiments, the method comprises administering a dose of AMH between 150 mg / day and 400 mg / day (e.g., 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, 250 mg / day, 255 mg / day, 260 mg / day, 265 ... These include administering to the patient elagolix at a dose of 0 mg / day, 265 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395, or 400 mg / day). In some embodiments, the method includes administering 150 mg / day of elagolix to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. In some embodiments, the method includes administering 400 mg / day of elagolix to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. For example, the method can include administering 200 mg / day of elagolix to the patient twice daily if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.

[0171] In some embodiments, the GnRH antagonist is relugolix or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 7,300,935; 8,058,280; 8,735,401; or 9,346,822; or U.S. Patent Application Publication No. 2015 / 0266891, the disclosures of which are incorporated by reference in their entireties. In some embodiments, the method includes administering 40 mg / day or more (e.g., 40 mg / day to 150 mg / day or more, e.g., 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, or more) of relugolix to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method includes administering 50 mg / day to 75 mg / day of relugolix to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0172] In some embodiments, the method includes administering 40 mg / day or less (e.g., 10 mg / day to 35 mg / day, e.g., 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, or 35 mg / day) of relugolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method includes administering 10 mg / day to 30 mg / day of relugolix to the patient if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0173] In some embodiments, the method includes administering 35 mg / day to 45 mg / day (e.g., 35 mg / day, 40 mg / day, or 45 mg / day) of relugolix to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. In some embodiments, the method includes administering 40 mg / day of relugolix to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.

[0174] When administered at high doses (e.g., 40 mg / day or higher), relugolix may be administered in combination with add-back therapy, which may be administered to the patient simultaneously with relugolix, before administration of relugolix, or after administration of relugolix.

[0175] In some embodiments, the add-back therapy comprises an estrogen, hi some embodiments, the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens, e.g., conjugated equine estrogens.

[0176] In some embodiments, the estrogen is β17-estradiol. β17-estradiol is administered to a patient, for example, orally, at a dose of about 0.1 mg to about 2.5 mg, for example, about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, or 2.5 mg. In some embodiments, β17-estradiol is administered to a patient, for example, orally, at a dose of 1.0 mg. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg, for example, by oral administration.

[0177] β17-estradiol may be administered to the patient one or more times daily, weekly, or monthly. β17-estradiol can be administered to a patient, e.g., by oral administration, at a dose of about 0.1 mg / day to about 2.5 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, or 2.5 mg / day. In some embodiments, β17-estradiol is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg / day, e.g., orally.

[0178] In some embodiments, the estrogen is ethinylestradiol. Ethinylestradiol is administered at a dose of, for example, about 1.0 μg to about 6.0 μg, for example, about 1.0 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2.0 μg, 2.1 μg, 2.2 μg, 2.3 μg, 2.4 μg, 2.5 μg, 2.6 μg, 2.7 μg, 2.8 μg, 2.9 μg, 3.0 μg, 3.1 μg, 3.2 μg, 3.3 μg, 3.4 μg, The dose of ethinyl estradiol can be administered to the patient by oral administration, for example, at 3.5 μg, 3.6 μg, 3.7 μg, 3.8 μg, 3.9 μg, 4.0 μg, 4.1 μg, 4.2 μg, 4.2 μg, 4.3 μg, 4.4 μg, 4.5 μg, 4.6 μg, 4.7 μg, 4.8 μg, 4.9 μg, 5.0 μg, 5.1 μg, 5.2 μg, 5.3 μg, 5.4 μg, 5.5 μg, 5.6 μg, 5.7 μg, 5.8 μg, 5.9 μg or 6.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 5.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 2.5 μg.

[0179] Ethinyl estradiol may be administered to the patient one or more times daily, weekly, or monthly. Ethinylestradiol is administered at a dose of, for example, about 1.0 μg / day to about 6.0 μg / day, e.g., about 1.0 μg / day, 1.1 μg / day, 1.2 μg / day, 1.3 μg / day, 1.4 μg / day, 1.5 μg / day, 1.6 μg / day, 1.7 μg / day, 1.8 μg / day, 1.9 μg / day, 2.0 μg / day, 2.1 μg / day, 2.2 μg / day, 2.3 μg / day, 2.4 μg / day, 2.5 μg / day, 2.6 μg / day, 2.7 μg / day, 2.8 μg / day, 2.9 μg / day, 3.0 μg / day, 3.1 μg / day, 3.2 μg / day, 3.3 μg / day, 3.4 μg / day, It may be administered to a patient, for example by oral administration, at a dose of 3.5 μg / day, 3.6 μg / day, 3.7 μg / day, 3.8 μg / day, 3.9 μg / day, 4.0 μg / day, 4.1 μg / day, 4.2 μg / day, 4.2 μg / day, 4.3 μg / day, 4.4 μg / day, 4.5 μg / day, 4.6 μg / day, 4.7 μg / day, 4.8 μg / day, 4.9 μg / day, 5.0 μg / day, 5.1 μg / day, 5.2 μg / day, 5.3 μg / day, 5.4 μg / day, 5.5 μg / day, 5.6 μg / day, 5.7 μg / day, 5.8 μg / day, 5.9 μg / day, or 6.0 μg / day. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 5.0 μg / day, e.g., orally. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 2.5 μg / day, e.g., orally.

[0180] In some embodiments, the estrogen is a conjugated estrogen, e.g., conjugated equine estrogen. The conjugated estrogen may be administered to a patient, e.g., orally, at a dose of about 0.1 mg to about 2.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.625 mg, e.g., orally. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.45 mg, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg, for example, by oral administration.

[0181] The conjugated estrogen can be administered to the patient once or more daily, weekly, or monthly. The conjugated estrogen can be administered to the patient at a dose of, for example, about 0.1 mg / day to about 2.0 mg / day, for example, about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day, for example, orally. In some embodiments, the conjugated estrogen is administered to the patient at a dose of 0.625 mg / day, for example, orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.45 mg / day, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg / day, e.g., orally.

[0182] In some embodiments, the add-back therapy includes a progestin, hi some embodiments, the progestin is selected from the group consisting of norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent, e.g., progesterone, norgestimate, medroxyprogesterone, or drospirenone.

[0183] In some embodiments, the progestin is norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0184] In some embodiments, the progestin is norethindrone. Norethindrone may be administered in a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 ... In some embodiments, norethindrone is administered to a patient at a dose of 0.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 1.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg, e.g., by oral administration.

[0185] Norethindrone may be administered to a patient one or more times daily, weekly, or monthly. Norethindrone may be administered, for example, at a dose of about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 ... In some embodiments, norethindrone may be administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0186] In some embodiments, the progestin is norethindrone acetate. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, In some embodiments, norethindrone acetate is administered to a patient at a dose of 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg, e.g., orally.

[0187] Norethindrone acetate may be administered to the patient one or more times daily, weekly, or monthly. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2. It may be administered to a patient, for example, by oral administration, at a dose of 2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 3.0 mg / day, 3.1 mg / day, 3.2 mg / day, 3.3 mg / day, 3.4 mg / day, 3.5 mg / day, 3.6 mg / day, 3.7 mg / day, 3.8 mg / day, 3.9 mg / day, 4.0 mg / day, 4.1 mg / day, 4.2 mg / day, 4.3 mg / day, 4.4 mg / day, 4.5 mg / day, 4.6 mg / day, 4.7 mg / day, 4.8 mg / day, 4.9 mg / day, or 5.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient, for example, by oral administration, at a dose of 1.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0188] In some embodiments, the progestin is progesterone. Progesterone may be administered to a patient, e.g., by oral administration, at a dose of about 50 mg to about 250 mg, e.g., about 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg. In some embodiments, progesterone is administered to a patient at a dose of 200 mg, e.g., orally. In some embodiments, progesterone is administered to a patient at a dose of 100 mg, e.g., orally.

[0189] Progesterone may be administered to a patient one or more times daily, weekly, or monthly. Progesterone may be administered, for example, at a dose of about 50 mg / day to about 250 mg / day, for example, about 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, The progesterone may be administered to a patient at a dose of, for example, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, or 250 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 200 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 100 mg / day, for example, by oral administration.

[0190] In some embodiments, the progestin is norgestimate. Norgestimate can be administered to a patient, for example, orally, at a dose of about 0.01 mg to about 2.0 mg, for example, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, norgestimate is administered to a patient, for example, orally, at a dose of 0.09 mg.

[0191] Norgestimate may be administered to a patient one or more times daily, weekly, or monthly. Norgestimate may be administered, for example, at a dose of about 0.01 mg / day to about 2.0 mg / day, for example, about 0.01 mg / day, 0.02 mg / day, 0.03 mg / day, 0.04 mg / day, 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 ...9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg In some embodiments, norgestimate may be administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration, in an amount of 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day. In some embodiments, norgestimate is administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration.

[0192] In some embodiments, the progestin is medroxyprogesterone. Medroxyprogesterone is available in doses of, for example, about 0.5 mg to about 10.0 mg, such as about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8 mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5 mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, The medroxyprogesterone may be administered to a patient at a dose of 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 5.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 2.5 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 1.5 mg, for example, orally.

[0193] Medroxyprogesterone may be administered to a patient one or more times daily, weekly, or monthly. Medroxyprogesterone may be administered at a dose of, for example, about 0.5 mg / day to about 10.0 mg / day, such as about 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, or 2.6 mg / day. / day, 2.6mg / day, 2.7mg / day, 2.8mg / day, 2.9mg / day, 3.0mg / day, 3.1mg / day, 3.2mg / day, 3.3mg / day, 3.4mg / day, 3.5mg / day, 3.6mg / day, 3.7mg / day, 3.8mg / day, 3.9mg / day, 4.0mg / day, 4.1mg / day, 4.2mg / day, 4.3mg / day, 4.4mg / day, 4.5mg / day, 4.6mg / day, 4.7mg / day, 4.8mg / day, 4.9mg / day, 5.0mg / day, 5.1mg / day, 5.2mg / day, 5.3mg / day, 5.4mg / day, 5.5mg / day, 5.6mg / day, 5.7mg / day, 5.8mg / day, 5.9mg / day, 6.0mg / day, 6.1mg / day, 6.2mg / day, 6.3mg / day, 6.4mg / day, 6.5mg / day, 6.6mg / day, 6.7mg / day, 6.8mg / day, 6.9mg / day, 7.0mg / day, 7.1mg / day, 7.2mg / day, 7.3mg / day, 7.4mg / day, 7.5mg / day, 7.6mg / day, 7.7mg / day, 7.8mg / day In some embodiments, medroxyprogesterone may be administered to a patient at a dose of 7.9 mg / day, 8.0 mg / day, 8.1 mg / day, 8.2 mg / day, 8.3 mg / day, 8.4 mg / day, 8.5 mg / day, 8.6 mg / day, 8.7 mg / day, 8.8 mg / day, 8.9 mg / day, 9.0 mg / day, 9.1 mg / day, 9.2 mg / day, 9.3 mg / day, 9.4 mg / day, 9.5 mg / day, 9.6 mg / day, 9.7 mg / day, 9.8 mg / day, 9.9 mg / day, or 10.0 mg / day, e.g., by oral administration. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 5.0 mg / day, e.g., by oral administration.In some embodiments, medroxyprogesterone is administered to a patient at a dose of 2.5 mg / day, e.g., orally. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 1.5 mg / day, e.g., orally.

[0194] In some embodiments, the progestin is drospirenone. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg to about 1.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1.0 mg. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg, e.g., orally.

[0195] Drospirenone may be administered to a patient one or more times daily, weekly, or monthly. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg / day to about 1.0 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, or 1.0 mg / day. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg / day, e.g., orally.

[0196] In some embodiments, the add-back therapy includes an estrogen and a progestin, hi some embodiments, the add-back therapy includes β17-estradiol and norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0197] In some embodiments, the patient does not experience a decline in BMD of more than 5% after administration of relugolix and the add-back therapy. In some embodiments, the patient does not experience a decline in BMD of more than 1% after administration of relugolix and the add-back therapy. The add-back therapy may be formulated for oral administration. For example, the add-back therapy may be formulated as a tablet, capsule, gelcap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, e.g., β17-estradiol, and a progestin, e.g., norethindrone acetate or norethindrone. The estrogen and progestin may be administered separately or may be combined in a single composition, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension.

[0198] In some embodiments, the GnRH antagonist is ASP-1707 or a derivative or variant thereof, such as a compound described in U.S. Patent Nos. 6,960,591; 7,569,688; 7,960,562; or 9,527,818, the disclosures of which are incorporated herein by reference in their entireties. In some embodiments, the method comprises administering 10 mg / day or more (e.g., 15 mg / day to 100 mg / day or more, e.g., 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, or more) of ASP-1707 to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range. In some embodiments, the method comprises administering 15 mg / day to 50 mg / day of ASP-1707 to the patient if the concentration of AMH in a sample isolated from the patient is above the AMH reference range.

[0199] In some embodiments, the method comprises administering to the patient less than 10 mg / day (e.g., from 5 mg / day to 9 mg / day, e.g., 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, or 9 mg / day) of ASP-1707 if the concentration of AMH in a sample isolated from the patient is below the AMH reference range. In some embodiments, the method comprises administering to the patient 5 mg / day to 7.5 mg / day of ASP-1707 if the concentration of AMH in a sample isolated from the patient is below the AMH reference range.

[0200] In some embodiments, the method comprises administering 7.5 mg / day to 15 mg / day (e.g., 7.5 mg / day, 10 mg / day, 12.5 mg / day, or 15 mg / day) of ASP-1707 to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range. In some embodiments, the method comprises administering 10 mg / day of ASP-1707 to the patient if the concentration of AMH in the sample isolated from the patient is within the AMH reference range.

[0201] In some embodiments, the GnRH antagonist is BAY-784 or its derivative or variant.The GnRH antagonist can be the compound described in US Patent Application Publication No. 2014 / 0357655 or US Patent Application Publication No. 2016 / 0052936, the disclosures of which are incorporated herein by reference in their entirety.

[0202] When administered at high doses (e.g., doses of 40 mg / day or greater), ASP-1707 and / or BAY-784 may be administered in combination with add-back therapy, which may be administered to the patient simultaneously with, before, or after the administration of a GnRH antagonist.

[0203] In some embodiments, the add-back therapy comprises an estrogen, hi some embodiments, the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens, e.g., conjugated equine estrogens.

[0204] In some embodiments, the estrogen is β17-estradiol. β17-estradiol is administered to a patient, for example, orally, at a dose of about 0.1 mg to about 2.5 mg, for example, about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, or 2.5 mg. In some embodiments, β17-estradiol is administered to a patient, for example, orally, at a dose of 1.0 mg. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg, for example, by oral administration.

[0205] β17-estradiol may be administered to the patient one or more times daily, weekly, or monthly. β17-estradiol can be administered to a patient, e.g., by oral administration, at a dose of about 0.1 mg / day to about 2.5 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, or 2.5 mg / day. In some embodiments, β17-estradiol is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg / day, e.g., orally.

[0206] In some embodiments, the estrogen is ethinyl estradiol. Ethinyl estradiol is administered at a dose of, for example, about 1.0 μg to about 6.0 μg, for example, about 1.0 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2.0 μg, 2.1 μg, 2.2 μg, 2.3 μg, 2.4 μg, 2.5 μg, 2.6 μg, 2.7 μg, 2.8 μg, 2.9 μg, 3.0 μg, 3.1 μg, 3.2 μg, 3.3 μg, 3.4 μg, The dose of ethinyl estradiol can be administered to the patient by oral administration, for example, at 3.5 μg, 3.6 μg, 3.7 μg, 3.8 μg, 3.9 μg, 4.0 μg, 4.1 μg, 4.2 μg, 4.2 μg, 4.3 μg, 4.4 μg, 4.5 μg, 4.6 μg, 4.7 μg, 4.8 μg, 4.9 μg, 5.0 μg, 5.1 μg, 5.2 μg, 5.3 μg, 5.4 μg, 5.5 μg, 5.6 μg, 5.7 μg, 5.8 μg, 5.9 μg or 6.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 5.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 2.5 μg.

[0207] Ethinyl estradiol may be administered to the patient one or more times daily, weekly, or monthly. Ethinylestradiol is administered at a dose of, for example, about 1.0 μg / day to about 6.0 μg / day, e.g., about 1.0 μg / day, 1.1 μg / day, 1.2 μg / day, 1.3 μg / day, 1.4 μg / day, 1.5 μg / day, 1.6 μg / day, 1.7 μg / day, 1.8 μg / day, 1.9 μg / day, 2.0 μg / day, 2.1 μg / day, 2.2 μg / day, 2.3 μg / day, 2.4 μg / day, 2.5 μg / day, 2.6 μg / day, 2.7 μg / day, 2.8 μg / day, 2.9 μg / day, 3.0 μg / day, 3.1 μg / day, 3.2 μg / day, 3.3 μg / day, 3.4 μg / day, It may be administered to a patient, for example by oral administration, at a dose of 3.5 μg / day, 3.6 μg / day, 3.7 μg / day, 3.8 μg / day, 3.9 μg / day, 4.0 μg / day, 4.1 μg / day, 4.2 μg / day, 4.2 μg / day, 4.3 μg / day, 4.4 μg / day, 4.5 μg / day, 4.6 μg / day, 4.7 μg / day, 4.8 μg / day, 4.9 μg / day, 5.0 μg / day, 5.1 μg / day, 5.2 μg / day, 5.3 μg / day, 5.4 μg / day, 5.5 μg / day, 5.6 μg / day, 5.7 μg / day, 5.8 μg / day, 5.9 μg / day, or 6.0 μg / day. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 5.0 μg / day, e.g., orally. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 2.5 μg / day, e.g., orally.

[0208] In some embodiments, the estrogen is a conjugated estrogen, e.g., conjugated equine estrogen. The conjugated estrogen may be administered to a patient, e.g., orally, at a dose of about 0.1 mg to about 2.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.625 mg, e.g., orally. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.45 mg, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg, for example, by oral administration.

[0209] The conjugated estrogen can be administered to the patient once or more daily, weekly, or monthly. The conjugated estrogen can be administered to the patient at a dose of, for example, about 0.1 mg / day to about 2.0 mg / day, for example, about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day, for example, orally. In some embodiments, the conjugated estrogen is administered to the patient at a dose of 0.625 mg / day, for example, orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.45 mg / day, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg / day, e.g., orally.

[0210] In some embodiments, the add-back therapy includes a progestin, hi some embodiments, the progestin is selected from the group consisting of norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent, e.g., progesterone, norgestimate, medroxyprogesterone, or drospirenone.

[0211] In some embodiments, the progestin is norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0212] In some embodiments, the progestin is norethindrone. Norethindrone may be administered in a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 ... In some embodiments, norethindrone is administered to a patient at a dose of 0.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 1.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg, e.g., by oral administration.

[0213] Norethindrone may be administered to a patient one or more times daily, weekly, or monthly. Norethindrone may be administered, for example, at a dose of about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 ... In some embodiments, norethindrone may be administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0214] In some embodiments, the progestin is norethindrone acetate. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, In some embodiments, norethindrone acetate is administered to a patient at a dose of 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg, e.g., orally.

[0215] Norethindrone acetate may be administered to the patient one or more times daily, weekly, or monthly. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2. It may be administered to a patient, for example, by oral administration, at a dose of 2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 3.0 mg / day, 3.1 mg / day, 3.2 mg / day, 3.3 mg / day, 3.4 mg / day, 3.5 mg / day, 3.6 mg / day, 3.7 mg / day, 3.8 mg / day, 3.9 mg / day, 4.0 mg / day, 4.1 mg / day, 4.2 mg / day, 4.3 mg / day, 4.4 mg / day, 4.5 mg / day, 4.6 mg / day, 4.7 mg / day, 4.8 mg / day, 4.9 mg / day, or 5.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient, for example, by oral administration, at a dose of 1.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0216] In some embodiments, the progestin is progesterone. Progesterone may be administered to a patient, e.g., by oral administration, at a dose of about 50 mg to about 250 mg, e.g., about 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg. In some embodiments, progesterone is administered to a patient at a dose of 200 mg, e.g., orally. In some embodiments, progesterone is administered to a patient at a dose of 100 mg, e.g., orally.

[0217] Progesterone may be administered to a patient one or more times daily, weekly, or monthly. Progesterone may be administered, for example, at a dose of about 50 mg / day to about 250 mg / day, for example, about 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, The progesterone may be administered to a patient at a dose of, for example, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, or 250 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 200 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 100 mg / day, for example, by oral administration.

[0218] In some embodiments, the progestin is norgestimate. Norgestimate can be administered to a patient, for example, orally, at a dose of about 0.01 mg to about 2.0 mg, for example, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, norgestimate is administered to a patient, for example, orally, at a dose of 0.09 mg.

[0219] Norgestimate may be administered to a patient one or more times daily, weekly, or monthly. Norgestimate may be administered, for example, at a dose of about 0.01 mg / day to about 2.0 mg / day, for example, about 0.01 mg / day, 0.02 mg / day, 0.03 mg / day, 0.04 mg / day, 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 ...9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg In some embodiments, norgestimate may be administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration, in an amount of 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day. In some embodiments, norgestimate is administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration.

[0220] In some embodiments, the progestin is medroxyprogesterone. Medroxyprogesterone is available in doses of, for example, about 0.5 mg to about 10.0 mg, such as about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8 mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5 mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, The medroxyprogesterone may be administered to a patient at a dose of 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 5.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 2.5 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 1.5 mg, for example, orally.

[0221] Medroxyprogesterone may be administered to a patient one or more times daily, weekly, or monthly. Medroxyprogesterone may be administered at a dose of, for example, about 0.5 mg / day to about 10.0 mg / day, such as about 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, or 2.6 mg / day. / day, 2.6mg / day, 2.7mg / day, 2.8mg / day, 2.9mg / day, 3.0mg / day, 3.1mg / day, 3.2mg / day, 3.3mg / day, 3.4mg / day, 3.5mg / day, 3.6mg / day, 3.7mg / day, 3.8mg / day, 3.9mg / day, 4.0mg / day, 4.1mg / day, 4.2mg / day, 4.3mg / day, 4.4mg / day, 4.5mg / day, 4.6mg / day, 4.7mg / day, 4.8mg / day, 4.9mg / day, 5.0mg / day, 5.1mg / day, 5.2mg / day, 5.3mg / day, 5.4mg / day, 5.5mg / day, 5.6mg / day, 5.7mg / day, 5.8mg / day, 5.9mg / day, 6.0mg / day, 6.1mg / day, 6.2mg / day, 6.3mg / day, 6.4mg / day, 6.5mg / day, 6.6mg / day, 6.7mg / day, 6.8mg / day, 6.9mg / day, 7.0mg / day, 7.1mg / day, 7.2mg / day, 7.3mg / day, 7.4mg / day, 7.5mg / day, 7.6mg / day, 7.7mg / day, 7.8mg / day In some embodiments, medroxyprogesterone may be administered to a patient at a dose of 7.9 mg / day, 8.0 mg / day, 8.1 mg / day, 8.2 mg / day, 8.3 mg / day, 8.4 mg / day, 8.5 mg / day, 8.6 mg / day, 8.7 mg / day, 8.8 mg / day, 8.9 mg / day, 9.0 mg / day, 9.1 mg / day, 9.2 mg / day, 9.3 mg / day, 9.4 mg / day, 9.5 mg / day, 9.6 mg / day, 9.7 mg / day, 9.8 mg / day, 9.9 mg / day, or 10.0 mg / day, e.g., by oral administration. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 5.0 mg / day, e.g., by oral administration.In some embodiments, medroxyprogesterone is administered to a patient at a dose of 2.5 mg / day, e.g., orally. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 1.5 mg / day, e.g., orally.

[0222] In some embodiments, the progestin is drospirenone. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg to about 1.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1.0 mg. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg, e.g., orally.

[0223] Drospirenone may be administered to a patient one or more times daily, weekly, or monthly. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg / day to about 1.0 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, or 1.0 mg / day. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg / day, e.g., orally.

[0224] In some embodiments, the add-back therapy includes an estrogen and a progestin, hi some embodiments, the add-back therapy includes β17-estradiol and norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0225] In some embodiments, the patient does not experience a decline in BMD of more than 5% after administration of ASP-1707 or BAY-784 and the add-back therapy. In some embodiments, the patient does not experience a decline in BMD of more than 1% after administration of ASP-1707 or BAY-784 and the add-back therapy. The add-back therapy may be formulated for oral administration. For example, the add-back therapy may be formulated as a tablet, capsule, gelcap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, e.g., β17-estradiol, and a progestin, e.g., norethindrone acetate or norethindrone. The estrogen and progestin may be administered separately or may be combined in a single composition, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension.

[0226] In some embodiments, the method comprises orally administering a GnRH antagonist to the patient. In some embodiments, the method comprises intravenously administering a GnRH antagonist to the patient.

[0227] In another aspect, the invention features a kit including a GnRH antagonist of any of the above aspects or embodiments of the invention. The kit may further include one or more agents capable of detecting AMH and / or a package insert. The package insert may instruct a user of the kit to perform the method of any of the above aspects or embodiments of the invention.

[0228] In some embodiments, the kit includes one or more agents capable of detecting a compound selected from the group consisting of E2, LH, and FSH. In some embodiments, the kit includes a thienopyrimidine GnRH antagonist, such as a compound represented by Formula (II), or a choline salt thereof. In some embodiments, the kit includes a GnRH antagonist selected from the group consisting of elagolix, relugolix, ASP-1707, SKI2670, and BAY-784, or a derivative or variant thereof.

[0229] In another aspect, the invention features a method of treating endometriosis in a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In another aspect, the invention features a method of reducing E2, follicle-stimulating hormone (FSH), and / or luteinizing hormone (LH) levels in the blood of a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In another aspect, the invention features a method of reducing pain (e.g., endometriosis-associated pain) in a patient (e.g., a female human patient, e.g., a premenopausal female human patient).

[0230] In any of the aforementioned aspects of the invention, the method may include determining the concentration of E2 in a sample (e.g., a blood sample) isolated from the patient. In some embodiments, the concentration of E2 in the sample (e.g., a blood sample) isolated from the patient has been previously determined. The method may include: a. Comparing E2 concentrations to E2 reference ranges; and b. If the concentration of E2 in the sample isolated from the patient is above the E2 reference range, administering an increased dose of GnRH antagonist to the patient, or if the concentration of E2 in the sample isolated from the patient is below the E2 reference range, administering a reduced dose of GnRH antagonist to the patient.

[0231] In some embodiments, the method includes administering to the patient the initially administered dose of GnRH antagonist if the concentration of E2 in the sample isolated from the patient is within the E2 reference range.

[0232] In some embodiments, the initially administered dose of GnRH antagonist is 10 to 500 mg / day (e.g., 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day) , 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day , 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg / day, 215mg / day, 220mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day , 250mg / day, 255mg / day, 260mg / day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 290mg / day, 295mg / day, 300mg / day, 305mg / day, 310mg / day , 315mg / day, 320mg / day, 325mg / day, 330mg / day, 335mg / day, 340mg / day, 345mg / day, 350mg / day, 355mg / day, 360mg / day, 365mg / day, 370mg / day, 375mg / day , 380mg / day, 385mg / day, 390mg / day, 395mg / day, 400mg / day, 405mg / day, 410mg / day, 415mg / day, 420mg / day, 425mg / day, 430mg / day, 435mg / day, 440mg / day, 445mg / day, 450mg / day, 455mg / day, 460mg / day, 465mg / day, 470mg / day, 475mg / day, 480mg / day, 485mg / day, 490mg / day, 495mg / day, or 500mg / day).

[0233] For example, in some embodiments, the initially administered dose of the GnRH antagonist is 50 mg / day, 75 mg / day, 100 mg / day, or 200 mg / day, and the GnRH antagonist is a compound represented by formula (I), e.g., a compound represented by formula (II), or a choline salt thereof.

[0234] In some embodiments, the initial administered dose of the GnRH antagonist is 150 mg / day, and the GnRH antagonist is elagolix or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 7,056,927; 7,176,211; 7,419,983; 8,765,948; or 9,382,214; or U.S. Patent Application Publication Nos. 2014 / 0288031 or 2017 / 0056403, the disclosures of which are incorporated herein by reference in their entireties. In some embodiments, the initial administered dose of the GnRH antagonist is 400 mg / day, and the GnRH antagonist is elagolix or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 7,056,927; 7,176,211; 7,419,983; 8,765,948; or 9,382,214; or U.S. Patent Application Publication Nos. 2014 / 0288031 or 2017 / 0056403, the disclosures of which are incorporated herein by reference in their entireties.

[0235] In some embodiments, the initial administered dose of the GnRH antagonist is 40 mg / day, and the GnRH antagonist is relugolix or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 7,300,935; 8,058,280; 8,735,401; or 9,346,822; or U.S. Patent Application Publication No. 2015 / 0266891, the disclosures of which are incorporated herein by reference in their entireties.

[0236] In some embodiments, the initial administered dose of the GnRH antagonist is 10 mg / day, and the GnRH antagonist is ASP-1707 or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 6,960,591; 7,569,688; 7,960,562; or 9,527,818, the disclosures of which are incorporated herein by reference in their entireties.

[0237] In another aspect, the present invention provides a method for optimizing a dosing regimen for treating endometriosis in a patient (e.g., a female human patient, e.g., a premenopausal female human patient) receiving treatment with a GnRH antagonist. In another aspect, the present invention provides a method for optimizing a dosing regimen for reducing blood E2, follicle-stimulating hormone (FSH), and / or luteinizing hormone (LH) concentrations in a patient (e.g., a female human patient, e.g., a premenopausal female human patient) receiving treatment with a GnRH antagonist. In another aspect, the present invention provides a method for optimizing a dosing regimen for reducing pain (e.g., endometriosis-associated pain) in a patient (e.g., a female human patient, e.g., a premenopausal female human patient) receiving treatment with a GnRH antagonist.

[0238] In any of the above aspects of the invention, the method may include determining the concentration of E2 in a sample (e.g., a blood sample) isolated from the patient. In some embodiments, the concentration of E2 in the sample (e.g., a blood sample) isolated from the patient has been previously determined. The method may include: a.Comparing E2 concentrations with E2 reference ranges; b. determining to administer an increased dose of GnRH antagonist to the patient if the concentration of E2 in the sample isolated from the patient is above the E2 reference range, determining to administer a reduced dose of GnRH antagonist to the patient if the concentration of E2 in the sample isolated from the patient is below the E2 reference range, or determining to administer the initially administered dose of GnRH antagonist to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range; and optionally, c. Administering a GnRH antagonist to the patient at the dose determined in (b).

[0239] In some embodiments, the sample is isolated from the patient about 4 to about 36 weeks (e.g., about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, or 36 weeks) after initiation of GnRH antagonist therapy. In some embodiments, the sample is isolated from the patient about 4 weeks after initiation of GnRH antagonist therapy. In some embodiments, the sample is isolated from the patient about 8 weeks after initiation of GnRH antagonist therapy. In some embodiments, the sample is isolated from the patient about 12 weeks after initiation of GnRH antagonist therapy. In some embodiments, the sample is isolated from the patient about 24 weeks after initiation of GnRH antagonist therapy.

[0240] In some embodiments, the patient is administered a newly determined dose of GnRH antagonist about 4 to about 36 weeks (e.g., about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, or 36 weeks) after initiation of GnRH antagonist therapy. For example, a sample can be isolated from a patient about 4 weeks after the initiation of GnRH antagonist therapy, after which the concentration of E2 in the sample can be compared to an E2 reference range to determine an appropriate GnRH dosage as described herein, and the patient can then be administered the newly determined GnRH dosage either about 4 weeks after the initiation of GnRH antagonist therapy or at a later date, for example, about 12 weeks after the initiation of GnRH antagonist therapy. In some embodiments, the patient is administered the newly determined GnRH antagonist dosage about 24 weeks after the initiation of GnRH antagonist therapy. In some embodiments, a sample can be isolated from a patient about 8 weeks after the initiation of GnRH antagonist therapy, after which the concentration of E2 in the sample can be compared to an E2 reference range to determine an appropriate GnRH dosage as described herein. The patient can then be administered the newly determined GnRH dosage either about 8 weeks after the initiation of GnRH antagonist therapy or later, for example, about 12 weeks after the initiation of GnRH antagonist therapy. In some embodiments, the patient is administered the newly determined GnRH antagonist dosage about 24 weeks after the initiation of GnRH antagonist therapy.

[0241] In some embodiments, the E2 reference range is 20-50 pg / ml. Thus, it will be understood that an E2 concentration of less than 20 pg / ml (e.g., 1 pg / ml, 2 pg / ml, 3 pg / ml, 4 pg / ml, 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, or 19 pg / ml) is considered to be below the E2 reference range of 20-50 pg / ml. Similarly, an E2 concentration greater than 50 pg / ml (e.g., 51 pg / ml, 52 pg / ml, 53 pg / ml, 54 pg / ml, 55 pg / ml, 60 pg / ml, 75 pg / ml, or more) is considered above the E2 reference range of 20 to 50 pg / ml.

[0242] In some embodiments, the methods involve administering to the patient a GnRH antagonist in an amount sufficient to relieve or alleviate symptoms of endometriosis, eg, endometriosis-associated pain.

[0243] In some embodiments, the method includes administering a GnRH antagonist to the patient in an amount sufficient to reduce the serum concentration of E2 in the patient to about 20 to about 50 pg / ml (e.g., about 20 pg / ml, 25 pg / ml, 30 pg / ml, 35 pg / ml, 40 pg / ml, 45 pg / ml, or 50 pg / ml). In some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 4 weeks after initiating administration of the GnRH antagonist to the patient. In some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 12 weeks after starting to administer the GnRH antagonist to the patient, hi some embodiments, the serum concentration of E2 decreases to about 20 to about 50 pg / ml within about 24 weeks after starting to administer the GnRH antagonist to the patient.

[0244] In some embodiments, the method includes administering a GnRH antagonist to the patient in an amount sufficient to reduce the serum concentration of follicle-stimulating hormone (FSH) in the patient to about 0.1 to about 10 mIU / ml (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mIU / ml). In some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 4 weeks after initiating administration of the GnRH antagonist to the patient. In some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 12 weeks after starting to administer the GnRH antagonist to the patient, hi some embodiments, the serum concentration of FSH decreases to about 0.1 to about 10 mIU / mL within about 24 weeks after starting to administer the GnRH antagonist to the patient.

[0245] In some embodiments, the method includes administering a GnRH antagonist to the patient in an amount sufficient to reduce the serum concentration of luteinizing hormone (LH) in the patient to about 0.1 to about 10 mIU / ml (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mIU / ml). In some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 4 weeks after initiating administration of the GnRH antagonist to the patient. In some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 12 weeks after starting to administer the GnRH antagonist to the patient, hi some embodiments, the serum concentration of LH decreases to about 0.1 to about 10 mIU / mL within about 24 weeks after starting to administer the GnRH antagonist to the patient.

[0246] In some embodiments, the method includes administering a GnRH antagonist to a patient in an amount sufficient to reduce endometriosis-associated pain experienced by the patient. In some embodiments, the endometriosis-associated pain is reduced within about 4 to about 36 weeks of initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks of initiating administration of the GnRH antagonist to the patient). In some embodiments, endometriosis-associated pain is reduced within about 4 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, endometriosis-associated pain is reduced within about 12 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, endometriosis-associated pain is reduced within about 24 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the endometriosis-associated pain is selected from the group consisting of pelvic pain, dyspareunia, and bowel disorders.

[0247] In some embodiments, endometriosis-associated pain is assessed by determining the patient's Numerical Rating Score (NRS). In some embodiments, the NRS is reduced by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some embodiments, the NRS is reduced by about 30%.

[0248] In some embodiments, endometriosis-associated pain is assessed by determining the patient's Verbal Rating Score (VRS). In some embodiments, the VRS is reduced by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some embodiments, the VRS is reduced by about 30%.

[0249] In some embodiments, the methods include administering a GnRH antagonist to a patient in an amount sufficient to relieve a symptom selected from the group consisting of dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. In some embodiments, the symptoms are relieved within about 4 to about 36 weeks of initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks of initiating administration of the GnRH antagonist to the patient). In some embodiments, the symptoms are alleviated within about 4 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the symptoms are alleviated within about 12 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the symptoms are alleviated within about 24 weeks of starting to administer the GnRH antagonist to the patient.

[0250] In some embodiments, symptoms are assessed by determining the patient's Biberoglu and Behrman (B&B) scale score. In some embodiments, the B&B score is reduced by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%).

[0251] In some embodiments, the methods include administering a GnRH antagonist to a patient in an amount sufficient to reduce an Endometriosis Health Profile-5 (EHP-5) score assessed for the patient. In some embodiments, the EHP-5 score is reduced within about 4 to about 36 weeks after initiating administration of the GnRH antagonist to the patient (e.g., within about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 weeks after initiating administration of the GnRH antagonist to the patient). In some embodiments, the EHP-5 score is reduced within about 4 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the EHP-5 score is reduced within about 12 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the EHP-5 score is reduced within about 24 weeks of starting to administer the GnRH antagonist to the patient. In some embodiments, the EHP-5 score is reduced by about 1% to about 50% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%).

[0252] In some embodiments, the method comprises administering a GnRH antagonist to a patient in an amount that does not cause a decrease in bone mineral density (BMD) in more than 5% of patients. In some embodiments, the method comprises administering a GnRH antagonist to a patient in an amount that does not cause a decrease in BMD in more than 1% of patients.

[0253] In some embodiments, the method includes administering add-back therapy to the patient. In some embodiments, the add-back therapy is administered to the patient only if the dosage of the GnRH antagonist is increased in response to the finding that the concentration of E2 in the sample isolated from the patient is greater than the E2 reference range. In some embodiments, the add-back therapy is administered to the patient regardless of whether the dose of the GnRH antagonist increases, decreases, or remains the same when evaluating the concentration of E2 in the sample obtained from the patient.

[0254] When administered, the add-back therapy can be administered to a patient simultaneously with, before, or after the administration of a GnRH antagonist. In some embodiments, the add-back therapy is administered as a fixed-dose combination drug containing a GnRH antagonist, an estrogen, and one or more additional drugs, such as a progestin, in a single pharmaceutical composition. For example, the add-back therapy can be administered as a fixed-dose combination drug containing a GnRH antagonist, an estrogen (e.g., in the form of E2), and a progestin (e.g., norethindrone, or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate) in a single pharmaceutical composition, such as a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension.

[0255] In some embodiments, the add-back therapy comprises an estrogen, hi some embodiments, the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens, e.g., conjugated equine estrogens.

[0256] In some embodiments, the estrogen is β17-estradiol. β17-estradiol is administered to a patient, for example, orally, at a dose of about 0.1 mg to about 2.5 mg, for example, about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, or 2.5 mg. In some embodiments, β17-estradiol is administered to a patient, for example, orally, at a dose of 1.0 mg. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg, for example, by oral administration.

[0257] β17-estradiol may be administered to the patient one or more times daily, weekly, or monthly. β17-estradiol can be administered to a patient, e.g., by oral administration, at a dose of about 0.1 mg / day to about 2.5 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, or 2.5 mg / day. In some embodiments, β17-estradiol is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg / day, e.g., orally.

[0258] In some embodiments, the estrogen is ethinyl estradiol. Ethinyl estradiol is administered at a dose of, for example, about 1.0 μg to about 6.0 μg, for example, about 1.0 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2.0 μg, 2.1 μg, 2.2 μg, 2.3 μg, 2.4 μg, 2.5 μg, 2.6 μg, 2.7 μg, 2.8 μg, 2.9 μg, 3.0 μg, 3.1 μg, 3.2 μg, 3.3 μg, 3.4 μg, The dose of ethinyl estradiol can be administered to the patient by oral administration, for example, at 3.5 μg, 3.6 μg, 3.7 μg, 3.8 μg, 3.9 μg, 4.0 μg, 4.1 μg, 4.2 μg, 4.2 μg, 4.3 μg, 4.4 μg, 4.5 μg, 4.6 μg, 4.7 μg, 4.8 μg, 4.9 μg, 5.0 μg, 5.1 μg, 5.2 μg, 5.3 μg, 5.4 μg, 5.5 μg, 5.6 μg, 5.7 μg, 5.8 μg, 5.9 μg or 6.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 5.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 2.5 μg.

[0259] Ethinyl estradiol may be administered to the patient one or more times daily, weekly, or monthly. Ethinylestradiol is administered at a dose of, for example, about 1.0 μg / day to about 6.0 μg / day, e.g., about 1.0 μg / day, 1.1 μg / day, 1.2 μg / day, 1.3 μg / day, 1.4 μg / day, 1.5 μg / day, 1.6 μg / day, 1.7 μg / day, 1.8 μg / day, 1.9 μg / day, 2.0 μg / day, 2.1 μg / day, 2.2 μg / day, 2.3 μg / day, 2.4 μg / day, 2.5 μg / day, 2.6 μg / day, 2.7 μg / day, 2.8 μg / day, 2.9 μg / day, 3.0 μg / day, 3.1 μg / day, 3.2 μg / day, 3.3 μg / day, 3.4 μg / day, It may be administered to a patient, for example by oral administration, at a dose of 3.5 μg / day, 3.6 μg / day, 3.7 μg / day, 3.8 μg / day, 3.9 μg / day, 4.0 μg / day, 4.1 μg / day, 4.2 μg / day, 4.2 μg / day, 4.3 μg / day, 4.4 μg / day, 4.5 μg / day, 4.6 μg / day, 4.7 μg / day, 4.8 μg / day, 4.9 μg / day, 5.0 μg / day, 5.1 μg / day, 5.2 μg / day, 5.3 μg / day, 5.4 μg / day, 5.5 μg / day, 5.6 μg / day, 5.7 μg / day, 5.8 μg / day, 5.9 μg / day, or 6.0 μg / day. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 5.0 μg / day, e.g., orally. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 2.5 μg / day, e.g., orally.

[0260] In some embodiments, the estrogen is a conjugated estrogen, e.g., conjugated equine estrogen. The conjugated estrogen may be administered to a patient, e.g., orally, at a dose of about 0.1 mg to about 2.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.625 mg, e.g., orally. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.45 mg, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg, for example, by oral administration.

[0261] The conjugated estrogen can be administered to the patient once or more daily, weekly, or monthly. The conjugated estrogen can be administered to the patient at a dose of, for example, about 0.1 mg / day to about 2.0 mg / day, for example, about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day, for example, orally. In some embodiments, the conjugated estrogen is administered to the patient at a dose of 0.625 mg / day, for example, orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.45 mg / day, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg / day, e.g., orally.

[0262] In some embodiments, the add-back therapy includes a progestin, hi some embodiments, the progestin is selected from the group consisting of norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent, e.g., progesterone, norgestimate, medroxyprogesterone, or drospirenone.

[0263] In some embodiments, the progestin is norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0264] In some embodiments, the progestin is norethindrone. Norethindrone may be administered in a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 ... In some embodiments, norethindrone is administered to a patient at a dose of 0.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 1.0 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg, e.g., by oral administration. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg, e.g., by oral administration.

[0265] Norethindrone may be administered to a patient one or more times daily, weekly, or monthly. Norethindrone may be administered, for example, at a dose of about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 ... In some embodiments, norethindrone may be administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0266] In some embodiments, the progestin is norethindrone acetate. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, In some embodiments, norethindrone acetate is administered to a patient at a dose of 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg, e.g., orally.

[0267] Norethindrone acetate may be administered to the patient one or more times daily, weekly, or monthly. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2. It may be administered to a patient, for example, by oral administration, at a dose of 2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 3.0 mg / day, 3.1 mg / day, 3.2 mg / day, 3.3 mg / day, 3.4 mg / day, 3.5 mg / day, 3.6 mg / day, 3.7 mg / day, 3.8 mg / day, 3.9 mg / day, 4.0 mg / day, 4.1 mg / day, 4.2 mg / day, 4.3 mg / day, 4.4 mg / day, 4.5 mg / day, 4.6 mg / day, 4.7 mg / day, 4.8 mg / day, 4.9 mg / day, or 5.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient, for example, by oral administration, at a dose of 1.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0268] In some embodiments, the progestin is progesterone. Progesterone may be administered to a patient, e.g., by oral administration, at a dose of about 50 mg to about 250 mg, e.g., about 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg. In some embodiments, progesterone is administered to a patient at a dose of 200 mg, e.g., orally. In some embodiments, progesterone is administered to a patient at a dose of 100 mg, e.g., orally.

[0269] Progesterone may be administered to a patient one or more times daily, weekly, or monthly. Progesterone may be administered, for example, at a dose of about 50 mg / day to about 250 mg / day, for example, about 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, The progesterone may be administered to a patient at a dose of, for example, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, or 250 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 200 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 100 mg / day, for example, by oral administration.

[0270] In some embodiments, the progestin is norgestimate. Norgestimate can be administered to a patient, for example, orally, at a dose of about 0.01 mg to about 2.0 mg, for example, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, norgestimate is administered to a patient, for example, orally, at a dose of 0.09 mg.

[0271] Norgestimate may be administered to a patient one or more times daily, weekly, or monthly. Norgestimate may be administered, for example, at a dose of about 0.01 mg / day to about 2.0 mg / day, for example, about 0.01 mg / day, 0.02 mg / day, 0.03 mg / day, 0.04 mg / day, 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 ...9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg In some embodiments, norgestimate may be administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration, in an amount of 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day. In some embodiments, norgestimate is administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration.

[0272] In some embodiments, the progestin is medroxyprogesterone. Medroxyprogesterone is available in doses of, for example, about 0.5 mg to about 10.0 mg, such as about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8 mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5 mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, The medroxyprogesterone may be administered to a patient at a dose of 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 5.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 2.5 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 1.5 mg, for example, orally.

[0273] Medroxyprogesterone may be administered to a patient one or more times daily, weekly, or monthly. Medroxyprogesterone may be administered at a dose of, for example, about 0.5 mg / day to about 10.0 mg / day, such as about 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, or 2.6 mg / day. / day, 2.6mg / day, 2.7mg / day, 2.8mg / day, 2.9mg / day, 3.0mg / day, 3.1mg / day, 3.2mg / day, 3.3mg / day, 3.4mg / day, 3.5mg / day, 3.6mg / day, 3.7mg / day, 3.8mg / day, 3.9mg / day, 4.0mg / day, 4.1mg / day, 4.2mg / day, 4.3mg / day, 4.4mg / day, 4.5mg / day, 4.6mg / day, 4.7mg / day, 4.8mg / day, 4.9mg / day, 5.0mg / day, 5.1mg / day, 5.2mg / day, 5.3mg / day, 5.4mg / day, 5.5mg / day, 5.6mg / day, 5.7mg / day, 5.8mg / day, 5.9mg / day, 6.0mg / day, 6.1mg / day, 6.2mg / day, 6.3mg / day, 6.4mg / day, 6.5mg / day, 6.6mg / day, 6.7mg / day, 6.8mg / day, 6.9mg / day, 7.0mg / day, 7.1mg / day, 7.2mg / day, 7.3mg / day, 7.4mg / day, 7.5mg / day, 7.6mg / day, 7.7mg / day, 7.8mg / day In some embodiments, medroxyprogesterone may be administered to a patient at a dose of 7.9 mg / day, 8.0 mg / day, 8.1 mg / day, 8.2 mg / day, 8.3 mg / day, 8.4 mg / day, 8.5 mg / day, 8.6 mg / day, 8.7 mg / day, 8.8 mg / day, 8.9 mg / day, 9.0 mg / day, 9.1 mg / day, 9.2 mg / day, 9.3 mg / day, 9.4 mg / day, 9.5 mg / day, 9.6 mg / day, 9.7 mg / day, 9.8 mg / day, 9.9 mg / day, or 10.0 mg / day, e.g., by oral administration. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 5.0 mg / day, e.g., by oral administration.In some embodiments, medroxyprogesterone is administered to a patient at a dose of 2.5 mg / day, e.g., orally. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 1.5 mg / day, e.g., orally.

[0274] In some embodiments, the progestin is drospirenone. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg to about 1.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1.0 mg. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg, e.g., orally.

[0275] Drospirenone may be administered to a patient one or more times daily, weekly, or monthly. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg / day to about 1.0 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, or 1.0 mg / day. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg / day, e.g., orally.

[0276] In some embodiments, the add-back therapy includes an estrogen and a progestin, hi some embodiments, the add-back therapy includes β17-estradiol and norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0277] In some embodiments, the patient does not experience a decline in BMD of more than 5% after administration of elagolix and the add-back therapy. In some embodiments, the patient does not experience a decline in BMD of more than 1% after administration of elagolix and the add-back therapy. The add-back therapy may be formulated for oral administration. For example, the add-back therapy may be formulated as a tablet, capsule, gelcap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, e.g., β17-estradiol, and a progestin, e.g., norethindrone acetate or norethindrone. The estrogen and progestin may be administered separately or may be combined in a single composition, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension.

[0278] In some embodiments, BMD is assessed by dual energy x-ray absorptiometry. In some embodiments, BMD is assessed at the patient's spine or femur.

[0279] In some embodiments, the GnRH antagonist has formula (I): [ka] (I) a compound represented by wherein ring A is a thiophene ring; each R A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3, or SO2NW2W3, where W1 to W3 are independently a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; Ring B is an aryl group or a monocyclic heteroaryl group; each R B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW, COW, COOW, or CONWW, where W through W are independently a hydrogen atom or an optionally substituted lower alkyl group, or W and W may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by -SLY, -OLY, -CO-LY, or -SO2-LY, where L is an optionally substituted lower alkylene group; Y is Z or a group represented by -NW7W8, where W7 and W8 are independently a hydrogen atom, an optionally substituted lower alkyl group, or Z, provided that W7 and W8 are not both hydrogen atoms, or W7 and W8 may be joined together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group; Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, ring A is a group represented by formula (A): [ka] (A) is a thiophene ring represented by

[0281] In some embodiments, m is 1 or 2. In some embodiments, m is 1. For example, ring A is a group represented by formula (B): [ka] (B) The thiophene ring may be an optionally substituted thiophene ring represented by:

[0282] Each R may independently be, for example, a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally substituted lower alkyl group, COO W, or CONWW, where W-W are independently hydrogen atoms or optionally substituted lower alkyl groups, or W and W may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group. In some embodiments, each R is COOH or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, Ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring. For example, Ring B is [ka] ; [ka] ; [ka] ; [ka] ; [ka] ; [ka] and [ka] The compound may be represented by a formula selected from the group consisting of:

[0284] In some embodiments, n is 1 or 2. For example, in some embodiments, n is 1. Ring B can be, for example, [ka] ; [ka] and [ka] The compound may be represented by a formula selected from the group consisting of:

[0285] In some embodiments, each R is independently a halogen atom, an optionally substituted lower alkyl group, or O W , where each W is independently a hydrogen atom or an optionally substituted lower alkyl group. For example, each R may independently be a fluorine atom, a chlorine atom, a bromine atom, a methyl group, or a methoxy group.

[0286] In some embodiments, U is a single bond. X may be, for example, a group represented by -OLY. L may be, for example, a methylene group. In some embodiments, Y is a group represented by formula (C): [ka] (C) and an optionally substituted benzene ring represented by wherein each R C is independently a halogen atom, an optionally substituted lower alkyl group, or W O , wherein each W is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer of 0 to 3.

[0287] In some embodiments, Y is a group represented by formula (D): [ka] (D) is a substituted benzene ring represented by

[0288] In some embodiments, the compound has formula (II): [ka] (II) or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the compound is a choline salt of a compound represented by Formula (II), or choline 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid.

[0290] In some embodiments, the GnRH antagonist comprises a compound represented by formula (II) in a crystalline state. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks at about 7.1°2θ, 11.5°2θ, 19.4°2θ, 20.3°2θ, 21.5°2θ, 22.0°2θ, 22.6°2θ, 23.5°2θ, and 26.2°2θ. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks centered at about 155.8 ppm, 149.8 ppm, 145.3 ppm, 118.0 ppm, 113.7 ppm, 111.6 ppm, 110.3 ppm, 98.1 ppm, 69.8 ppm, 58.7 ppm, 57.1 ppm, and 55.5 ppm. 13 In some embodiments, the compound exhibits C solid-state NMR peaks centered at about −131.6 ppm, −145.2 ppm, and −151.8 ppm. 19 F solid-state NMR peaks.

[0291] In some embodiments, the method provides for administering a dose of E2 in a sample isolated from a patient that is within an E2 reference range, between 85 mg / day and 115 mg / day (e.g., 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, or 115 mg / day) or more, e.g., between about 185 mg / day and about 215 mg / day (e.g., 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, or 215 mg / day). The method includes administering to a patient a compound represented by formula (I), formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) at a dose of 205 mg / day, 210 mg / day, or 215 mg / day. In some embodiments, the method includes administering to the patient 60 to 90 mg / day (e.g., 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, or 90 mg / day) of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is within an E2 reference range. In some embodiments, the method includes administering to the patient 35 to 65 mg / day (e.g., 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, or 65 mg / day) of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is within an E2 reference range.

[0292] In some embodiments, the method includes administering to the patient about 100 mg / day or about 200 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is within the E2 reference range. In some embodiments, the method includes administering to the patient about 75 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is within the E2 reference range. In some embodiments, the method includes administering to the patient about 50 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is within the E2 reference range.

[0293] In some embodiments, the method further comprises administering a dose of 85 mg / day to 115 mg / day (e.g., 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, or 115 mg / day) or more, e.g., about 185 mg / day to about 215 mg / day (e.g., 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, or 215 mg / day), if the concentration of E2 in the sample isolated from the patient is above an E2 reference range. The method includes administering to a patient a compound represented by formula (I), formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) at a dose of 205 mg / day, 210 mg / day, or 215 mg / day. In some embodiments, the method includes administering to the patient 60 to 90 mg / day (e.g., 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, or 90 mg / day) of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is above the E2 reference range. In some embodiments, the method includes administering to the patient 35 to 65 mg / day (e.g., 35 mg / day, 40 mg / day, 45 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, or 65 mg / day) of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is above the E2 reference range.

[0294] In some embodiments, the method includes administering to the patient about 100 mg / day or about 200 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is above the E2 reference range. In some embodiments, the method includes administering to the patient about 75 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is above the E2 reference range. In some embodiments, the method includes administering to the patient about 50 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is above the E2 reference range.

[0295] In some embodiments, the method further comprises administering a dose of 85 mg / day to 115 mg / day (e.g., 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, or 115 mg / day) or more, e.g., about 185 mg / day to about 215 mg / day (e.g., 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, or 215 mg / day), if the concentration of E2 in the sample isolated from the patient is below the E2 reference range. The method includes administering to a patient a compound represented by formula (I), formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) at a dose of 205 mg / day, 210 mg / day, or 215 mg / day. In some embodiments, the method includes administering to the patient 60 to 90 mg / day (e.g., 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, or 90 mg / day) of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is below the E2 reference range. In some embodiments, the method includes administering to the patient 35 to 65 mg / day (e.g., 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, or 65 mg / day) of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is below the E2 reference range.

[0296] In some embodiments, the method includes administering to the patient about 100 mg / day or about 200 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is below the E2 reference range. In some embodiments, the method includes administering to the patient about 75 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is below the E2 reference range. In some embodiments, the method includes administering to the patient about 50 mg / day of a compound represented by Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline) if the concentration of E2 in a sample isolated from the patient is below the E2 reference range.

[0297] In some embodiments, the GnRH antagonist is selected from the group consisting of elagolix, relugolix, ASP-1707, SKI2670, and BAY-784.

[0298] In some embodiments, the GnRH antagonist is elagolix or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 7,056,927; 7,176,211; 7,419,983; 8,765,948; or 9,382,214; or U.S. Patent Application Publication Nos. 2014 / 0288031 or 2017 / 0056403, the disclosures of which are incorporated by reference in their entireties. In some embodiments, the method comprises administering 150 mg / day or more (e.g., 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, 250 mg / day, 255 mg / day, 260 mg / day, 26 ...0 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day, 260 mg / day These include administering to the patient elagolix at a dose of 5 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395, 400 mg / day, or more. In some embodiments, the method includes administering 155 mg / day to 395 mg / day of elagolix to the patient if the concentration of E2 in a sample isolated from the patient is above the E2 reference range.

[0299] In some embodiments, the method further comprises administering a dose of 400 mg / day or more (e.g., 400 mg / day, 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / day, 465 mg / day, 470 mg / day, 475 mg / day, 480 mg / day, 485 mg / day, 490 mg / day, 495 mg / day, 500 mg / day, 505 mg / day, 510 mg / day, 515 mg / day, 520 mg / day, 525 mg / day, 530 mg / day, 535 mg / day, 540mg / day, 545mg / day, 550mg / day, 555mg / day, 560mg / day, 565mg / day, 570mg / day, 575mg / day, 580mg / day, 5 85mg / day, 590mg / day, 595mg / day, 600mg / day, 605mg / day, 610mg / day, 615mg / day, 620mg / day, 625mg / day, 630 In some embodiments, the method comprises administering elagolix to the patient at a dose of 400 mg / day to 600 mg / day of elagolix if the concentration of E2 in the sample isolated from the patient is above the E2 reference range.

[0300] In some embodiments, the method comprises administering 150 mg / day or less (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, or 150 mg / day) elagolix to the patient if the concentration of E2 in the sample isolated from the patient is below the E2 reference range. In some embodiments, the method comprises administering 50 mg / day to 125 mg / day of elagolix to the patient if the concentration of E2 in the sample isolated from the patient is below the E2 reference range. In some embodiments, the method comprises administering 100 mg / day of elagolix to the patient if the concentration of E2 in a sample isolated from the patient is below the E2 reference range.

[0301] In some embodiments, the method comprises administering a dose of 400 mg / day or less (e.g., 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, 510 mg / day, 520 mg / day, 530 mg / day, 540 mg / day, 550 mg / day, 560 mg / day, 570 mg / day, 580 mg / day, 590 mg / day, 600 mg / / day, 115mg / day, 120mg / day, 125mg / day, 130mg / day, 135mg / day, 140mg / day, 145mg / day, 150mg / day, 155mg / day, 160mg / day, 165mg / day, 170mg / day, 175mg / day, 180mg / day, 185mg / day, 190mg / day, 195mg / day, 200mg / day, 205mg / day, 210mg / day, 215mg / day, 220mg / day, 225mg / day, 230mg / day, 235mg / day, 240mg / day, 245mg / day, 250mg / day, 255mg / day, 260mg / day day, 265mg / day, 270mg / day, 275mg / day, 280mg / day, 285mg / day, 290mg / day, 295mg / day, 300mg / day, 305mg / day, 310mg / day , 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, or 395 mg / day) of elagolix to the patient. In some embodiments, the method comprises administering 150 mg / day to 375 mg / day of elagolix to the patient if the concentration of E2 in a sample isolated from the patient is below the E2 reference range. In some embodiments, the method comprises administering 150 mg / day of elagolix to the patient if the concentration of E2 in a sample isolated from the patient is below the E2 reference range.

[0302] In some embodiments, the method comprises administering a dose of 150 mg / day to 400 mg / day (e.g., 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, 250 mg / day, 255 mg / day, 260 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 400 mg / day, 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / These include administering to the patient elagolix at doses of 265 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395, or 400 mg / day). In some embodiments, the method includes administering 150 mg / day of elagolix to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range. In some embodiments, the method includes administering 400 mg / day of elagolix to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range. For example, the method may include administering 200 mg of elagolix twice daily to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range.

[0303] In some embodiments, the GnRH antagonist is relugolix or a derivative or variant thereof, such as a compound described in U.S. Pat. Nos. 7,300,935; 8,058,280; 8,735,401; or 9,346,822; or U.S. Patent Application Publication No. 2015 / 0266891, the disclosures of which are incorporated by reference in their entireties. In some embodiments, the method includes administering 40 mg / day or more (e.g., 40 mg / day to 150 mg / day or more, e.g., 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, or more) of relugolix to the patient if the concentration of E2 in the sample isolated from the patient is above the E2 reference range. In some embodiments, the method includes administering 50 mg / day to 75 mg / day of relugolix to the patient if the concentration of E2 in a sample isolated from the patient is above the E2 reference range.

[0304] In some embodiments, the method includes administering 40 mg / day or less (e.g., 10 mg / day to 40 mg / day, e.g., 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, or 35 mg / day) of relugolix to the patient if the concentration of E2 in the sample isolated from the patient is below the E2 reference range. In some embodiments, the method includes administering 10 mg / day to 35 mg / day of relugolix to the patient if the concentration of E2 in the sample isolated from the patient is below the E2 reference range.

[0305] In some embodiments, the method includes administering 35 mg / day to 45 mg / day (e.g., 35 mg / day, 40 mg / day, or 45 mg / day) of relugolix to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range. In some embodiments, the method includes administering 40 mg / day of relugolix to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range.

[0306] In some embodiments, the GnRH antagonist is ASP-1707 or a derivative or variant thereof, such as a compound described in U.S. Patent Nos. 6,960,591; 7,569,688; 7,960,562; or 9,527,818, the disclosures of which are incorporated herein by reference in their entireties. In some embodiments, the method comprises administering 10 mg / day or more (e.g., 15 mg / day to 100 mg / day or more, e.g., 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, or more) of ASP-1707 to the patient if the concentration of E2 in the sample isolated from the patient is above the E2 reference range. In some embodiments, the method comprises administering 15 mg / day to 50 mg / day of ASP-1707 to the patient if the concentration of E2 in the sample isolated from the patient is above the E2 reference range.

[0307] In some embodiments, the method comprises administering 10 mg / day or less (e.g., 5 mg / day to 9 mg / day, e.g., 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, or 9 mg / day) of ASP-1707 to the patient if the concentration of E2 in the sample isolated from the patient is below the E2 reference range. In some embodiments, the method comprises administering 5 mg / day to 7.5 mg / day of ASP-1707 to the patient if the concentration of E2 in the sample isolated from the patient is below the E2 reference range.

[0308] In some embodiments, the method comprises administering 7.5 mg / day to 15 mg / day (e.g., 7.5 mg / day, 10 mg / day, 12.5 mg / day, or 15 mg / day) of ASP-1707 to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range. In some embodiments, the method comprises administering 10 mg / day of ASP-1707 to the patient if the concentration of E2 in the sample isolated from the patient is within the E2 reference range.

[0309] In some embodiments, the GnRH antagonist is BAY-784 or its derivative or variant.The GnRH antagonist can be the compound described in US Patent Application Publication No. 2014 / 0357655 or US Patent Application Publication No. 2016 / 0052936, the disclosures of which are incorporated herein by reference in their entirety.

[0310] In some embodiments, the method comprises orally administering a GnRH antagonist to the patient. In some embodiments, the method comprises intravenously administering a GnRH antagonist to the patient.

[0311] In another aspect, the present invention provides a kit comprising a GnRH antagonist according to any of the above aspects or embodiments of the present invention. The kit may further comprise one or more agents capable of detecting E2 and / or a package insert. The package insert may instruct a user of the kit to carry out the method according to any of the above aspects or embodiments of the present invention.

[0312] In some embodiments, the kit includes one or more agents capable of detecting a compound selected from the group consisting of LH and FSH. In some embodiments, the kit includes a thienopyrimidine GnRH antagonist, such as a compound represented by Formula (II), or a choline salt thereof. In some embodiments, the kit includes a GnRH antagonist selected from the group consisting of elagolix, relugolix, ASP-1707, SKI2670, and BAY-784, or a derivative or variant thereof.

[0313] In yet another aspect, the invention features a method of treating endometriosis in a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In another aspect, the invention features a method of reducing E2, follicle-stimulating hormone (FSH), and / or luteinizing hormone (LH) levels in the blood of a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In another aspect, the invention features a method of reducing pain (e.g., endometriosis-associated pain) in a patient (e.g., a female human patient, e.g., a premenopausal female human patient). In these aspects, the method comprises: [ka] (I) a compound represented by wherein ring A is a thiophene ring; each R A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3, or SO2NW2W3, where W1 to W3 are independently a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; Ring B is an aryl group or a monocyclic heteroaryl group; each R is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW, COW, COOW, or CONWW, where W-W are independently a hydrogen atom or an optionally substituted lower alkyl group, or W and W may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by -SLY, -OLY, -CO-LY, or -SO2-LY, where L is an optionally substituted lower alkylene group; Y is Z or a group represented by -NW7W8, where W7 and W8 are independently a hydrogen atom, an optionally substituted lower alkyl group, or Z, provided that W7 and W8 are not both hydrogen atoms, or W7 and W8 may be joined together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group; Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof in an amount of about 25 mg / dose to about 300 mg / dose (e.g., about 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 211 mg, 212 mg, 213 mg, 214 mg, 215 mg, 216 mg, 217 mg, 218 In some embodiments, the compound is administered to a patient in an amount of 0 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg / dose. In some embodiments, the compound is administered in an amount of 50 mg / dose. In some embodiments, the compound is administered in an amount of 75 mg / dose. In some embodiments, the compound is administered in an amount of 100 mg / dose. In some embodiments, the compound is administered in an amount of 200 mg / dose.

[0314] In some embodiments, the compound is administered orally in the form of a tablet, capsule, gelcap, powder, liquid solution, or liquid suspension.

[0315] The compound can be administered in one or more doses every 12 hours, 24 hours, 48 ​​hours, 72 hours, week, month, or year, for example, 1 to 10 doses every 12 hours (e.g., 1 dose every 12 hours, 2 doses every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5 doses every 12 hours, 6 doses every 12 hours, 7 doses every 12 hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses every 12 hours), 1 to 10 doses every 24 hours (e.g., 1 dose every 24 hours, 24 doses ...), among others. 1 dose every hour, 2 doses every 24 hours, 3 doses every 24 hours, 4 doses every 24 hours, 5 doses every 24 hours, 6 doses every 24 hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses every 24 hours, or 10 doses every 24 hours), 1 to 10 doses every 48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3 doses every 48 hours, 4 doses every 48 hours, 5 doses every 48 hours, 6 doses every 48 hours, 7 doses every 48 hours, 8 doses every 48 hours, 9 doses every 48 hours, or 10 doses every 24 hours). doses, 9 doses every 48 hours, or 10 doses every 48 hours), 1 to 10 doses every 72 hours (e.g., 1 dose every 72 hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9 doses every 72 hours, or 10 doses every 72 hours), 1 to 10 doses weekly (e.g., 1 dose weekly, 2 doses weekly, 3 doses weekly, 4 doses weekly, 5 doses every 72 hours, 6 doses every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9 doses every 72 hours, or 10 doses every 72 hours), The patient may be administered 1 to 60 doses per month (e.g., 5 doses per week, 6 doses per week, 7 doses per week, 8 doses per week, 9 doses per week, or 10 doses per week), or 1 to 60 doses per month (e.g., 30 to 60 doses per month, e.g., once per day, twice per day, three times per day, four times per day, five times per day, six times per day, seven times per day, eight times per day, nine times per day, ten times per day, seven times per week, eight times per week, nine times per week, ten times per week, eleven times per week, twelve times per week, thirteen times per week, fourteen times per week, or more).

[0316] In some embodiments, the compound is administered to the patient in an amount of about 200 mg per day (e.g., 200 mg per day). In some embodiments, the compound is administered to the patient in an amount of about 400 mg every 48 hours (e.g., 400 mg every 48 hours). In some embodiments, the compound is administered to the patient in an amount of about 600 mg every 72 hours (e.g., 600 mg every 72 hours). In some embodiments, the compound is administered to the patient in an amount of about 1,400 mg per week (e.g., 1,400 mg per week).

[0317] In some embodiments, the compound is administered to a patient in an amount of about 100 mg every 12 hours (e.g., 100 mg every 12 hours), in an amount of about 50 mg every 6 hours (e.g., 50 mg every 6 hours), in an amount of about 33.33 mg every 4 hours (e.g., 33.33 mg every 4 hours), in an amount of about 25 mg every 3 hours (e.g., 25 mg every 3 hours), etc., to achieve, for example, an amount of 200 mg / day.

[0318] In some embodiments, the compound is administered to the patient in an amount of about 100 mg per day (e.g., 100 mg per day). In some embodiments, the compound is administered to the patient in an amount of about 200 mg every 48 hours (e.g., 200 mg every 48 hours). In some embodiments, the compound is administered to the patient in an amount of about 300 mg every 72 hours (e.g., 300 mg every 72 hours). In some embodiments, the compound is administered to the patient in an amount of about 700 mg per week (e.g., 700 mg per week).

[0319] In some embodiments, the compound is administered to a patient in an amount of about 50 mg every 12 hours (e.g., 50 mg every 12 hours), in an amount of about 25 mg every 6 hours (e.g., 25 mg every 6 hours), in an amount of about 16.67 mg every 4 hours (e.g., 16.67 mg every 4 hours), in an amount of about 12.5 mg every 3 hours (e.g., 12.5 mg every 3 hours), etc., to achieve, for example, a dose of 100 mg / day.

[0320] In some embodiments, the compound is administered to the patient in an amount of about 50 mg / day (e.g., 50 mg / day). In some embodiments, the compound is administered to the patient in an amount of about 100 mg every 48 hours (e.g., 100 mg every 48 hours). In some embodiments, the compound is administered to the patient in an amount of about 150 mg every 72 hours (e.g., 150 mg every 72 hours). In some embodiments, the compound is administered to the patient in an amount of about 350 mg / week (e.g., 350 mg / week).

[0321] In some embodiments, the compound is administered to a patient in an amount of about 25 mg every 12 hours (e.g., 25 mg every 12 hours), in an amount of about 12.5 mg every 6 hours (e.g., 12.5 mg every 6 hours), in an amount of about 8.33 mg every 4 hours (e.g., 8.33 mg every 4 hours), in an amount of about 6.25 mg every 3 hours (e.g., 6.25 mg every 3 hours), etc., to achieve a dose of, for example, 50 mg / day.

[0322] In some embodiments, the compound is administered to the patient in an amount of about 75 mg / day (e.g., 75 mg / day). In some embodiments, the compound is administered to the patient in an amount of about 150 mg every 48 hours (e.g., 150 mg every 48 hours). In some embodiments, the compound is administered to the patient in an amount of about 225 mg every 72 hours (e.g., 225 mg every 72 hours). In some embodiments, the compound is administered to the patient in an amount of about 525 mg / week (e.g., 525 mg / week).

[0323] In some embodiments, the compound is administered to a patient in an amount of about 37.5 mg every 12 hours (e.g., 37.5 mg every 12 hours), in an amount of about 18.75 mg every 6 hours (e.g., 18.75 mg every 6 hours), in an amount of about 12.5 mg every 4 hours (e.g., 12.5 mg every 4 hours), in an amount of about 9.375 mg every 3 hours (e.g., 9.375 mg every 3 hours), etc., to achieve a dose of, for example, 75 mg / day.

[0324] In some embodiments, ring A is a group represented by formula (A): [ka] (A) is a thiophene ring represented by

[0325] In some embodiments, m is 1 or 2. In some embodiments, m is 1. For example, ring A is a group represented by formula (B): [ka] (B) The thiophene ring may be an optionally substituted thiophene ring represented by:

[0326] Each R may independently be, for example, a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally substituted lower alkyl group, COO W, or CONWW, where W-W are independently hydrogen atoms or optionally substituted lower alkyl groups, or W and W may be joined together with adjacent nitrogen atoms to form an optionally substituted cyclic amino group. In some embodiments, each R is COOH or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, Ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring. For example, Ring B is [ka] ; [ka] ; [ka] ; [ka] ; [ka] ; [ka] and [ka] The compound may be represented by a formula selected from the group consisting of:

[0328] In some embodiments, n is 1 or 2. For example, in some embodiments, n is 1. Ring B can be, for example, [ka] ; [ka] and [ka] The compound may be represented by a formula selected from the group consisting of:

[0329] In some embodiments, each R is independently a halogen atom, an optionally substituted lower alkyl group, or O W , where each W is independently a hydrogen atom or an optionally substituted lower alkyl group. For example, each R may independently be a fluorine atom, a chlorine atom, a bromine atom, a methyl group, or a methoxy group.

[0330] In some embodiments, U is a single bond. X may be, for example, a group represented by -OLY. L may be, for example, a methylene group. In some embodiments, Y is a group represented by formula (C): [ka] (C) and an optionally substituted benzene ring represented by wherein each R C is independently a halogen atom, an optionally substituted lower alkyl group, or W O , wherein each W is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer of 0 to 3.

[0331] In some embodiments, Y is a group represented by formula (D): [ka] (D) is a substituted benzene ring represented by

[0332] In some embodiments, the compound has formula (II): [ka] (II) or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the compound is a choline salt of the compound represented by Formula (II), i.e., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid choline.

[0334] In some embodiments, the GnRH antagonist comprises a compound represented by formula (II) in a crystalline state. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks at about 7.1°2θ, 11.5°2θ, 19.4°2θ, 20.3°2θ, 21.5°2θ, 22.0°2θ, 22.6°2θ, 23.5°2θ, and 26.2°2θ. In some embodiments, the compound exhibits characteristic X-ray powder diffraction peaks centered at about 155.8 ppm, 149.8 ppm, 145.3 ppm, 118.0 ppm, 113.7 ppm, 111.6 ppm, 110.3 ppm, 98.1 ppm, 69.8 ppm, 58.7 ppm, 57.1 ppm, and 55.5 ppm. 13 In some embodiments, the compound exhibits C solid-state NMR peaks centered at about −131.6 ppm, −145.2 ppm, and −151.8 ppm. 19 F solid-state NMR peaks.

[0335] In some embodiments, the method includes administering an add-back therapy to the patient. The add-back therapy can be administered to the patient simultaneously with, before, or after the administration of a GnRH antagonist. In some embodiments, the add-back therapy is administered as a fixed-dose combination drug containing a GnRH antagonist, an estrogen, and one or more additional agents, such as a progestin, in a single pharmaceutical composition. For example, the add-back therapy may be administered as a fixed-dose combination of a GnRH antagonist, an estrogen (e.g., in the form of β17-estradiol, ethinyl estradiol, or a conjugated estrogen, e.g., conjugated equine estrogens), and / or a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (also referred to herein as "NETA"), e.g., progesterone, norgestimate, medroxyprogesterone, and drospirenone, among other drugs) in a single pharmaceutical composition, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy is administered orally, transdermally, or intravaginally.

[0336] In some embodiments, the add-back therapy is administered to the patient in one or more doses daily, weekly, monthly, or yearly, e.g., daily, e.g., 1 to 10 times daily, or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times daily). In some embodiments, the add-back therapy is administered to the patient once daily, e.g., simultaneously with a GnRH antagonist. For example, the GnRH antagonist may be administered orally to the patient, and the add-back therapy may be administered orally, transdermally, or intravaginally to the patient simultaneously with oral administration of the GnRH antagonist. In some embodiments, the add-back therapy is administered to the patient in the form of a pharmaceutical composition further comprising a GnRH antagonist, e.g., a single tablet, capsule, gelcap, powder, liquid solution, or liquid suspension, e.g., as described above and herein.

[0337] In some embodiments, add-back therapy is administered to patient once a day after compound administration.For example, GnRH antagonist can be orally administered to patient, and after oral administration of GnRH antagonist, add-back therapy can be orally, transdermally or intravaginally administered to patient.

[0338] In some embodiments, add-back therapy is administered to patient once a day before administering compound.For example, GnRH antagonist can be orally administered to patient, and before oral administration of GnRH antagonist, add-back therapy can be orally, transdermally or intravaginally administered to patient.

[0339] In some embodiments, the add-back therapy comprises an estrogen, hi some embodiments, the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens, e.g., conjugated equine estrogens.

[0340] In some embodiments, the estrogen is β17-estradiol. β17-estradiol is administered to a patient, for example, orally, at a dose of about 0.1 mg to about 2.5 mg, for example, about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, or 2.5 mg. In some embodiments, β17-estradiol is administered to a patient, for example, orally, at a dose of 1.0 mg. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg, for example, by oral administration.

[0341] β17-estradiol may be administered to the patient one or more times daily, weekly, or monthly. β17-estradiol can be administered to a patient, e.g., by oral administration, at a dose of about 0.1 mg / day to about 2.5 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, or 2.5 mg / day. In some embodiments, β17-estradiol is administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, β17-estradiol is administered to a patient at a dose of 0.5 mg / day, e.g., orally.

[0342] In some embodiments, the estrogen is ethinyl estradiol. Ethinyl estradiol is administered at a dose of, for example, about 1.0 μg to about 6.0 μg, for example, about 1.0 μg, 1.1 μg, 1.2 μg, 1.3 μg, 1.4 μg, 1.5 μg, 1.6 μg, 1.7 μg, 1.8 μg, 1.9 μg, 2.0 μg, 2.1 μg, 2.2 μg, 2.3 μg, 2.4 μg, 2.5 μg, 2.6 μg, 2.7 μg, 2.8 μg, 2.9 μg, 3.0 μg, 3.1 μg, 3.2 μg, 3.3 μg, 3.4 μg, The dose of ethinyl estradiol can be administered to the patient by oral administration, for example, at 3.5 μg, 3.6 μg, 3.7 μg, 3.8 μg, 3.9 μg, 4.0 μg, 4.1 μg, 4.2 μg, 4.2 μg, 4.3 μg, 4.4 μg, 4.5 μg, 4.6 μg, 4.7 μg, 4.8 μg, 4.9 μg, 5.0 μg, 5.1 μg, 5.2 μg, 5.3 μg, 5.4 μg, 5.5 μg, 5.6 μg, 5.7 μg, 5.8 μg, 5.9 μg or 6.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 5.0 μg. In some embodiments, ethinyl estradiol is administered to the patient by oral administration, for example, at a dose of 2.5 μg.

[0343] Ethinyl estradiol may be administered to the patient one or more times daily, weekly, or monthly. Ethinylestradiol is administered at a dose of, for example, about 1.0 μg / day to about 6.0 μg / day, e.g., about 1.0 μg / day, 1.1 μg / day, 1.2 μg / day, 1.3 μg / day, 1.4 μg / day, 1.5 μg / day, 1.6 μg / day, 1.7 μg / day, 1.8 μg / day, 1.9 μg / day, 2.0 μg / day, 2.1 μg / day, 2.2 μg / day, 2.3 μg / day, 2.4 μg / day, 2.5 μg / day, 2.6 μg / day, 2.7 μg / day, 2.8 μg / day, 2.9 μg / day, 3.0 μg / day, 3.1 μg / day, 3.2 μg / day, 3.3 μg / day, 3.4 μg / day, It may be administered to a patient, for example by oral administration, at a dose of 3.5 μg / day, 3.6 μg / day, 3.7 μg / day, 3.8 μg / day, 3.9 μg / day, 4.0 μg / day, 4.1 μg / day, 4.2 μg / day, 4.2 μg / day, 4.3 μg / day, 4.4 μg / day, 4.5 μg / day, 4.6 μg / day, 4.7 μg / day, 4.8 μg / day, 4.9 μg / day, 5.0 μg / day, 5.1 μg / day, 5.2 μg / day, 5.3 μg / day, 5.4 μg / day, 5.5 μg / day, 5.6 μg / day, 5.7 μg / day, 5.8 μg / day, 5.9 μg / day, or 6.0 μg / day. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 5.0 μg / day, e.g., orally. In some embodiments, ethinyl estradiol is administered to a patient at a dose of 2.5 μg / day, e.g., orally.

[0344] In some embodiments, the estrogen is a conjugated estrogen, e.g., conjugated equine estrogen. The conjugated estrogen may be administered to a patient, e.g., orally, at a dose of about 0.1 mg to about 2.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.625 mg, e.g., orally. In some embodiments, the conjugated estrogen is administered to a patient at a dose of 0.45 mg, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg, for example, by oral administration.

[0345] The conjugated estrogen can be administered to the patient once or more daily, weekly, or monthly. The conjugated estrogen can be administered to the patient at a dose of, for example, about 0.1 mg / day to about 2.0 mg / day, for example, about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day, for example, orally. In some embodiments, the conjugated estrogen is administered to the patient at a dose of 0.625 mg / day, for example, orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.45 mg / day, e.g., orally. In some embodiments, the conjugated estrogens are administered to the patient at a dose of 0.3 mg / day, e.g., orally.

[0346] In some embodiments, the add-back therapy includes a progestin, hi some embodiments, the progestin is selected from the group consisting of norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent, e.g., progesterone, norgestimate, medroxyprogesterone, or drospirenone.

[0347] In some embodiments, the progestin is norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0348] In some embodiments, the progestin is norethindrone. Norethindrone may be administered at a dose of, for example, about 0.05 mg to about 5.0 mg, e.g., about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 ... Norethindrone may be administered to a patient at a dose of 2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 1.0 mg, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg, e.g., orally.

[0349] Norethindrone may be administered to a patient one or more times daily, weekly, or monthly. Norethindrone may be administered, for example, at a dose of about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 2.9 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 ... In some embodiments, norethindrone may be administered to a patient at a dose of 1.0 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0350] In some embodiments, the progestin is norethindrone acetate. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg to about 5.0 mg, for example, about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 2.9 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 ... Norethindrone acetate may be administered to a patient at a dose of 0.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, e.g., by oral administration. In some embodiments, norethindrone acetate is administered to a patient at a dose of 1.0 mg / day, e.g., by oral administration. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg, e.g., by oral administration. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg, e.g., by oral administration.

[0351] Norethindrone acetate may be administered to the patient one or more times daily, weekly, or monthly. Norethindrone acetate is administered at a dose of, for example, about 0.05 mg / day to about 5.0 mg / day, for example, about 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2. It may be administered to a patient, for example, by oral administration, at a dose of 2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, 2.6 mg / day, 2.7 mg / day, 2.8 mg / day, 2.9 mg / day, 3.0 mg / day, 3.1 mg / day, 3.2 mg / day, 3.3 mg / day, 3.4 mg / day, 3.5 mg / day, 3.6 mg / day, 3.7 mg / day, 3.8 mg / day, 3.9 mg / day, 4.0 mg / day, 4.1 mg / day, 4.2 mg / day, 4.3 mg / day, 4.4 mg / day, 4.5 mg / day, 4.6 mg / day, 4.7 mg / day, 4.8 mg / day, 4.9 mg / day, or 5.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient, for example, by oral administration, at a dose of 1.0 mg / day. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, norethindrone acetate is administered to a patient at a dose of 0.1 mg / day, e.g., orally.

[0352] In some embodiments, the progestin is progesterone. Progesterone may be administered to a patient, e.g., by oral administration, at a dose of about 50 mg to about 250 mg, e.g., about 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg. In some embodiments, progesterone is administered to a patient at a dose of 200 mg, e.g., orally. In some embodiments, progesterone is administered to a patient at a dose of 100 mg, e.g., orally.

[0353] Progesterone may be administered to a patient one or more times daily, weekly, or monthly. Progesterone may be administered, for example, at a dose of about 50 mg / day to about 250 mg / day, for example, about 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day, 250 mg / day, 260 mg / day, 270 mg / day, 280 mg / day, 290 mg / day, 300 mg / day, 310 mg / day, 320 mg / day, 330 mg / day, 340 mg / day, 350 mg / day, 360 mg / day, 370 mg / day, 380 mg / day, 390 mg / day, 400 mg / day, 410 mg / day, 420 mg / day, 430 mg / day, 440 mg / day, 450 mg / day, 460 mg / day, 470 mg / day, 480 mg / day, 490 mg / day, 500 mg / day, The progesterone may be administered to a patient at a dose of, for example, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, or 250 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 200 mg / day, for example, by oral administration. In some embodiments, the progesterone is administered to a patient at a dose of 100 mg / day, for example, by oral administration.

[0354] In some embodiments, the progestin is norgestimate. Norgestimate can be administered to a patient, for example, orally, at a dose of about 0.01 mg to about 2.0 mg, for example, about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg. In some embodiments, norgestimate is administered to a patient, for example, orally, at a dose of 0.09 mg.

[0355] Norgestimate may be administered to a patient one or more times daily, weekly, or monthly. Norgestimate may be administered, for example, at a dose of about 0.01 mg / day to about 2.0 mg / day, for example, about 0.01 mg / day, 0.02 mg / day, 0.03 mg / day, 0.04 mg / day, 0.05 mg / day, 0.06 mg / day, 0.07 mg / day, 0.08 mg / day, 0.09 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 ...9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg / day, 0.9 mg In some embodiments, norgestimate may be administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration, in an amount of 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, or 2.0 mg / day. In some embodiments, norgestimate is administered to a patient at a dose of 0.09 mg / day, e.g., by oral administration.

[0356] In some embodiments, the progestin is medroxyprogesterone. Medroxyprogesterone is available in doses of, for example, about 0.5 mg to about 10.0 mg, such as about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8 mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5 mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, The medroxyprogesterone may be administered to a patient at a dose of 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 5.0 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 2.5 mg, for example, orally. In some embodiments, the medroxyprogesterone is administered to a patient at a dose of 1.5 mg, for example, orally.

[0357] Medroxyprogesterone may be administered to a patient one or more times daily, weekly, or monthly. Medroxyprogesterone may be administered at a dose of, for example, about 0.5 mg / day to about 10.0 mg / day, such as about 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 1.1 mg / day, 1.2 mg / day, 1.3 mg / day, 1.4 mg / day, 1.5 mg / day, 1.6 mg / day, 1.7 mg / day, 1.8 mg / day, 1.9 mg / day, 2.0 mg / day, 2.1 mg / day, 2.2 mg / day, 2.3 mg / day, 2.4 mg / day, 2.5 mg / day, or 2.6 mg / day. / day, 2.6mg / day, 2.7mg / day, 2.8mg / day, 2.9mg / day, 3.0mg / day, 3.1mg / day, 3.2mg / day, 3.3mg / day, 3.4mg / day, 3.5mg / day, 3.6mg / day, 3.7mg / day, 3.8mg / day, 3.9mg / day, 4.0mg / day, 4.1mg / day, 4.2mg / day, 4.3mg / day, 4.4mg / day, 4.5mg / day, 4.6mg / day, 4.7mg / day, 4.8mg / day, 4.9mg / day, 5.0mg / day, 5.1mg / day, 5.2mg / day, 5.3mg / day, 5.4mg / day, 5.5mg / day, 5.6mg / day, 5.7mg / day, 5.8mg / day, 5.9mg / day, 6.0mg / day, 6.1mg / day, 6.2mg / day, 6.3mg / day, 6.4mg / day, 6.5mg / day, 6.6mg / day, 6.7mg / day, 6.8mg / day, 6.9mg / day, 7.0mg / day, 7.1mg / day, 7.2mg / day, 7.3mg / day, 7.4mg / day, 7.5mg / day, 7.6mg / day, 7.7mg / day, 7.8mg / day In some embodiments, medroxyprogesterone may be administered to a patient at a dose of 7.9 mg / day, 8.0 mg / day, 8.1 mg / day, 8.2 mg / day, 8.3 mg / day, 8.4 mg / day, 8.5 mg / day, 8.6 mg / day, 8.7 mg / day, 8.8 mg / day, 8.9 mg / day, 9.0 mg / day, 9.1 mg / day, 9.2 mg / day, 9.3 mg / day, 9.4 mg / day, 9.5 mg / day, 9.6 mg / day, 9.7 mg / day, 9.8 mg / day, 9.9 mg / day, or 10.0 mg / day, e.g., by oral administration. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 5.0 mg / day, e.g., by oral administration.In some embodiments, medroxyprogesterone is administered to a patient at a dose of 2.5 mg / day, e.g., orally. In some embodiments, medroxyprogesterone is administered to a patient at a dose of 1.5 mg / day, e.g., orally.

[0358] In some embodiments, the progestin is drospirenone. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg to about 1.0 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1.0 mg. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg, e.g., orally.

[0359] Drospirenone may be administered to a patient one or more times daily, weekly, or monthly. Drospirenone may be administered to a patient, for example, orally, at a dose of about 0.1 mg / day to about 1.0 mg / day, e.g., about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, or 1.0 mg / day. In some embodiments, drospirenone is administered to a patient at a dose of 0.5 mg / day, e.g., orally. In some embodiments, drospirenone is administered to a patient at a dose of 0.25 mg / day, e.g., orally.

[0360] In some embodiments, the add-back therapy includes an estrogen and a progestin, hi some embodiments, the add-back therapy includes β17-estradiol and norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate.

[0361] In some embodiments, the add-back therapy includes about 0.75 mg to about 1.25 mg of β17-estradiol (e.g., administered orally) and about 0.25 mg to about 0.75 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy includes 1.0 mg of β17-estradiol (e.g., administered orally) and 0.5 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 1.0 mg of β17-estradiol (e.g., administered orally) and, in the same pharmaceutical composition, 0.5 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 1.0 mg of β17-estradiol (e.g., administered orally) and, in a separate pharmaceutical composition, 0.5 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally).

[0362] In some embodiments, the compound is administered to the patient in a fixed dose composition comprising about 200 mg of the compound (e.g., 200 mg of the compound), about 0.75 mg to about 1.25 mg of β17-estradiol, and about 0.25 mg to about 0.75 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate. In some embodiments, the compound is administered to a patient in a fixed dose composition comprising about 200 mg of the compound (e.g., 200 mg of the compound), about 1.0 mg of β17-estradiol (e.g., 1.0 mg of β17-estradiol), and about 0.5 mg of norethindrone, i.e., a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., 0.5 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate). In some embodiments, the compound is administered to the patient in a fixed dose composition comprising 200 mg of the compound, 1.0 mg of β17-estradiol, and 0.5 mg of norethindrone acetate.

[0363] In some embodiments, the fixed dose compositions are administered in one or more doses every 12 hours, 24 hours, 48 ​​hours, 72 hours, week, month, or year, for example, 1 to 10 doses every 12 hours (e.g., 1 dose every 12 hours, 2 doses every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5 doses every 12 hours, 6 doses every 12 hours, 7 doses every 12 hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses every 12 hours), among others. 1 to 10 doses every 24 hours (e.g., 1 dose every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4 doses every 24 hours, 5 doses every 24 hours, 6 doses every 24 hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses every 24 hours, or 10 doses every 24 hours), 1 to 10 doses every 48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3 doses every 48 hours, 4 doses every 48 hours, 5 doses every 48 hours, 6 doses every 48 hours, 7 doses every 48 hours), doses, 8 doses every 48 hours, 9 doses every 48 hours, or 10 doses every 48 hours), 1 to 10 doses every 72 hours (e.g., 1 dose every 72 hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9 doses every 72 hours, or 10 doses every 72 hours), 1 to 10 doses weekly (e.g., 1 dose weekly, 2 doses weekly, 3 doses weekly, 4 doses every 72 hours, or 10 doses every 72 hours). In some embodiments, the fixed dose composition is administered to a patient once daily. In some embodiments, the fixed dose composition is administered to a patient once daily.

[0364] In some embodiments, the add-back therapy comprises about 0.25 mg to about 0.75 mg of β17-estradiol (e.g., administered orally) and about 0.05 mg to about 0.2 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 0.5 mg of β17-estradiol (e.g., administered orally) and 0.1 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 0.5 mg of β17-estradiol (e.g., administered orally) and, in the same pharmaceutical composition, 0.1 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally). In some embodiments, the add-back therapy comprises 0.5 mg of β17-estradiol (e.g., administered orally) and, in a separate pharmaceutical composition, 0.1 mg of norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., administered orally).

[0365] In some embodiments, the compound is administered to the patient in a fixed dose composition comprising about 200 mg of the compound (e.g., 200 mg of the compound), about 0.25 mg to about 0.75 mg of β17-estradiol, and about 0.05 mg to about 0.2 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is de-esterified in vivo to produce norethindrone, e.g., norethindrone acetate. In some embodiments, the compound is administered to a patient in a fixed dose composition comprising about 200 mg of the compound (e.g., 200 mg of the compound), about 0.5 mg of β17-estradiol (e.g., 0.5 mg of β17-estradiol), and about 0.1 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate (e.g., 0.1 mg of norethindrone, or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate). In some embodiments, the compound is administered to the patient in a fixed dose composition comprising 200 mg of the compound, 0.5 mg of β17-estradiol, and 0.1 mg of norethindrone acetate.

[0366] In some embodiments, the fixed dose compositions are administered in one or more doses every 12 hours, 24 hours, 48 ​​hours, 72 hours, week, month, or year, for example, 1 to 10 doses every 12 hours (e.g., 1 dose every 12 hours, 2 doses every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5 doses every 12 hours, 6 doses every 12 hours, 7 doses every 12 hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses every 12 hours), among others. 1 to 10 doses every 24 hours (e.g., 1 dose every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4 doses every 24 hours, 5 doses every 24 hours, 6 doses every 24 hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses every 24 hours, or 10 doses every 24 hours), 1 to 10 doses every 48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3 doses every 48 hours, 4 doses every 48 hours, 5 doses every 48 hours, 6 doses every 48 hours, 7 doses every 48 hours, or 10 doses every 24 hours), dose, 8 doses every 48 hours, 9 doses every 48 hours, or 10 doses every 48 hours), 1 to 10 doses every 72 hours (e.g., 1 dose every 72 hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9 doses every 72 hours, or 10 doses every 72 hours), 1 to 10 doses weekly (e.g., 1 dose weekly, 2 doses weekly, 3 doses weekly, 4 doses every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9 doses every 72 hours, or 10 doses every 72 hours), In some embodiments, the fixed dose composition is administered to the patient once daily. In some embodiments, the fixed dose composition is administered to the patient once daily.

[0367] In some embodiments, the patient exhibits a serum concentration of β17-estradiol greater than 20 pg / ml, greater than 30 pg / ml, greater than 40 pg / ml, or greater than 50 pg / ml before administering the compound to the patient. The serum concentration of β17-estradiol can be reduced to less than 50 pg / ml after administering the compound to the patient. For example, in some embodiments, the patient exhibits a serum concentration of β17-estradiol that is reduced to less than 50 pg / ml, less than 45 pg / ml, less than 40 pg / ml, less than 35 pg / ml, less than 30 pg / ml, less than 25 pg / ml, less than 20 pg / ml, less than 15 pg / ml, or less than 10 pg / ml after administering the compound to the patient. In some embodiments, the patient exhibits a serum concentration of β17-estradiol that is reduced to less than 10 pg / ml to about 40 pg / ml, e.g., 5 pg / ml, 10 pg / ml, 15 pg / ml, 20 pg / ml, 25 pg / ml, 30 pg / ml, 35 pg / ml, or 40 pg / ml of β17-estradiol. In some embodiments, the patient has a serum concentration of β17-estradiol between 5 pg / ml and 50 pg / ml (e.g., 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, 19 pg / ml, 20 pg / ml, 21 pg / ml, 22 pg / ml, 23 pg / ml, 24 pg / ml, 25 pg / ml, 26 pg / ml, 27 pg / ml, 28 pg / ml, 29 pg / ml, 30 pg / ml, 31 pg / ml, 32 pg / ml, 33 pg / ml, 34 pg / ml, 35 pg / ml, 36 pg / ml, 37 pg / ml, 38 pg / ml, 39 pg / ml, 40 pg / ml, 41 pg / ml, 42 pg / ml, 43 pg / ml, 44 pg / ml, 45 pg / ml, 46 pg / ml, 47 pg / ml, 48 pg / ml, 49 pg / ml, 50 pg / ml, 51 pg / ml, 52 pg / ml, 53 pg / ml, 54 pg / ml, 55 pg / ml, 56 pg / ml, 57 pg / ml, 58 pg / ml, 59 pg / ml, 60 pg / ml, 61 pg / ml, 62 pg / ml, 63 pg / ml, 64 p l, 26pg / ml, 27pg / ml, 28pg / ml, 29pg / ml, 30pg / ml, 31pg / ml, 32pg / ml, 33pg / ml, 34pg / ml, 35pg / ml, 36pg / ml, 37pg / ml, 38pg / ml, 39pg / ml, 40pg / ml, 41pg / ml, 42pg / ml, 43pg / ml, 44pg / ml, 45pg / ml, 46pg / ml, 47pg / ml, 48pg / ml, 49pg / ml, or 50pg / ml of β17-estradiol serum concentration.In some embodiments, the patient exhibits a serum concentration of β17-estradiol of 5 pg / ml to 20 pg / ml (e.g., a serum concentration of β17-estradiol of 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, 19 pg / ml, or 20 pg / ml) after administering the compound to the patient. In some embodiments, the patient exhibits a serum concentration of β17-estradiol of 5 pg / ml to 10 pg / ml (e.g., a serum concentration of β17-estradiol of 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, or 10 pg / ml) after administering the compound to the patient.

[0368] In some embodiments, the patient exhibits a serum concentration of β17-estradiol of less than 50 pg / ml or within any of the ranges specified above within about 1 to about 22 days after the compound is first administered to the patient, e.g., within about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, or 22 days, e.g., within about 8 days to about 15 days after the compound is first administered to the patient.

[0369] In some embodiments, the patient exhibits a serum concentration of β17-estradiol of less than 20 pg / ml or within any of the ranges specified above within about 1 to about 22 days after the compound is first administered to the patient, e.g., within about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, or 22 days, e.g., within about 8 days to about 15 days after the compound is first administered to the patient.

[0370] In some embodiments, the patient exhibits a serum concentration of β17-estradiol of less than 10 pg / ml or within any of the ranges specified above within about 1 to about 22 days after the compound is first administered to the patient, e.g., within about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, or 22 days, e.g., within about 8 days to about 15 days after the compound is first administered to the patient.

[0371] In some embodiments of any of the above aspects or embodiments of the present invention, a GnRH antagonist, e.g., a compound represented by Formula (I) or (II), or a pharmaceutically acceptable salt thereof, e.g., a choline salt thereof (e.g., and add-back therapy) is administered to a patient daily (e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles. In some embodiments, a GnRH antagonist (e.g., and add-back therapy) is administered to a patient daily (e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each lasting from about 4 to 72 weeks or longer. For example, a GnRH antagonist (e.g., and add-back therapy) may be administered daily (e.g., once daily and / or at any of the doses / day specified above) to a patient for one or more treatment cycles, each lasting approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, Lasts for 1 week, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, or more.

[0372] In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient for one or more treatment cycles, each lasting for a period of about 4 to 64 weeks. For example, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient daily (e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each lasting for about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 weeks. , lasting 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64 weeks.

[0373] In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient in one or more treatment cycles, each lasting for a period of about 4 to 52 weeks. For example, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient daily (e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each lasting for about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks. lasts for 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks.

[0374] In some embodiments, the GnRH antagonist (eg, and add-back therapy) is administered to the patient for one or more treatment cycles, each lasting for a period of about 4 to 48 weeks. For example, the GnRH antagonist (e.g., and add-back therapy) is administered daily (e.g., once daily and / or at any of the doses / day specified above) to a patient for one or more treatment cycles, each lasting about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 weeks.

[0375] In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient in one or more treatment cycles, each lasting for a period of about 4 to 24 weeks. For example, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient daily (e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each lasting for about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks.

[0376] In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient for one or more treatment cycles, each lasting for a period of about 4 to 12 weeks. For example, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient daily (e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each lasting for about 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

[0377] In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 4 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 6 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 8 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 12 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 24 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 36 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 48 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 52 weeks.In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 64 weeks. In some embodiments, the GnRH antagonist (e.g., and add-back therapy) is administered to the patient (e.g., daily, e.g., once daily and / or at any of the doses / day specified above) for one or more treatment cycles, each treatment cycle lasting for a period of about 72 weeks.

[0378] In another aspect, the invention features a kit including a compound of any of the above aspects or embodiments of the invention. The kit may further include a package insert. The package insert may instruct a user of the kit to perform the method of any of the above aspects or embodiments of the invention.

[0379] definition As used herein, the term "about" refers to a value that is within 10% above or below the stated value.

[0380] As used herein, the term "add-back therapy" refers to the administration of estrogen during a treatment plan, for example, during treatment with a GnRH antagonist (e.g., based on the patient's AMH or E2 levels as described herein), to counteract the side effects of excessive estradiol suppression. Such side effects may include, for example, a decrease in bone mineral density (BMD). The patient's BMD can be assessed, for example, by dual-energy X-ray absorptiometry at the patient's spine or femur. Add-back therapy can be administered to a patient according to the methods described herein to mitigate the decrease in BMD caused by the administration of a GnRH antagonist. For example, add-back therapy can be administered to patients receiving GnRH antagonist therapy so that the patient does not experience a loss of BMD of more than 5% (e.g., not more than 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less). Add-back therapy can include estrogen in the form of E2 and can include one or more additional agents such as a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, e.g., an ester of norethindrone that is deesterified in vivo to produce norethindrone, e.g., norethindrone acetate). Add-back therapy can be formulated for oral adm...

Claims

1. A pharmaceutical composition comprising the compound 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid, or a pharma- ceutically acceptable salt thereof, for use in reducing endometriosis-associated pain in a female human patient having endometriosis, wherein said compound is administered to said patient at a dose of 100 mg / day.

2. A pharmaceutical composition comprising the compound 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid, or a pharma- ceutically acceptable salt thereof, for use in the treatment of endometriosis in a female human patient, said compound being administered to said patient in need thereof at a dosage of 100 mg / day.

3. A pharmaceutical composition comprising the compound 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid, or a pharma- ceutically acceptable salt thereof, for use in reducing beta 17-estradiol, follicle-stimulating hormone, and / or luteinizing hormone levels in a female human patient having endometriosis, wherein said compound is administered to said patient at a dosage of 100 mg / day.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the compound is administered to the patient in the form of a pharma- ceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, wherein the pharma- ceutically acceptable salt is a choline salt.

6. The pharmaceutical composition of claim 1, wherein the compound is administered orally to the patient.

7. The pharmaceutical composition of claim 1, wherein the compound is administered to the patient once daily.

8. The pharmaceutical composition of claim 1, wherein the patient is further administered add-back therapy.

9. The pharmaceutical composition of claim 8, wherein the add-back therapy is administered to the patient once daily.

10. The pharmaceutical composition of claim 8, wherein the add-back therapy comprises estrogen.

11. The pharmaceutical composition of claim 10, wherein the estrogen is β17-estradiol.

12. The pharmaceutical composition of claim 11, wherein the β17-estradiol is administered to the patient at a dose of 1.0 mg / day.

13. The pharmaceutical composition of claim 11, wherein the β17-estradiol is administered to the patient at a dose of 0.5 mg / day.

14. A pharmaceutical composition described in any one of claims 11 to 13, wherein the β17-estradiol is administered orally to the patient.

15. The pharmaceutical composition of claim 8, wherein the add-back therapy comprises a progestin.

16. The pharmaceutical composition of claim 15, wherein the progestin is norethindrone acetate.

17. The pharmaceutical composition of claim 16, wherein the norethindrone acetate is administered to the patient at a dose of 0.5 mg / day.

18. The pharmaceutical composition of claim 16, wherein the norethindrone acetate is administered to the patient at a dose of 0.1 mg / day.

19. The pharmaceutical composition of any one of claims 16 to 18, wherein the norethindrone acetate is administered orally to the patient.

20. The pharmaceutical composition of claim 8, wherein the add-back therapy comprises β17-estradiol and norethindrone acetate, the β17-estradiol being administered to the patient at a dose of 1.0 mg / day and the norethindrone acetate being administered at a dose of 0.5 mg / day.

21. The pharmaceutical composition of claim 8, wherein the add-back therapy comprises β17-estradiol and norethindrone acetate, the β17-estradiol being administered to the patient at a dose of 0.5 mg / day and the norethindrone acetate being administered at a dose of 0.1 mg / day.

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