Progesterone formulation to trigger ovulation and provide luteal phase support

Abstract

To provide a composition and method that are safe, efficacious, and inexpensive for ovulation induction.SOLUTION: An exemplary method of inducing ovulation includes steps of monitoring ovarian follicle development and size during the follicular phase of the menstrual cycle; and administering to the subject a pharmaceutical composition including progesterone or bioidentical progesterone in an amount effective to increase the plasma concentration of progesterone to between about 0.1 ng / ml to about 1 ng / ml when the follicle reaches a size of at least 15 mm.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 952,539, filed on December 23, 2019, which is incorporated herein by reference in its entirety.

[0002] The present invention generally relates to compositions and methods for inducing ovulation and treating infertility.

Background Art

[0003] A female menstrual cycle can be functionally divided into three phases: the follicular phase, the ovulatory phase, and the luteal phase. The follicular phase begins at the end of the luteal phase of the preceding anovulatory menstrual cycle, before or simultaneously with the onset of menstruation. The cycle begins with a transient increase in the blood level of FSH that stimulates the development of a cohort of ovarian follicles. Each follicle contains an immature egg. The size of the follicles recruited for growth is about 5 mm in diameter. In a natural menstrual cycle, usually one large or dominant follicle is established during the follicular phase and engages in growth towards maturity. In humans, the size of the follicle considered ready for ovulation is about 15 mm or more in diameter. Granulosa cells within ovarian follicles acquire LH receptors and become even more responsive to LH. The secretion of estradiol and estrone from the ovary initially increases slowly in parallel with the increase in follicle diameter and follicular sensitivity to LH.

[0004] Ovulation is the second stage of the ovarian cycle in which a mature egg is released from the ovarian follicle into the fallopian tube. The timing of ovulation in a woman's menstrual cycle is essential for fertilization. During the follicular phase, estradiol suppresses the release of luteinizing hormone (LH) from the anterior pituitary gland. When the egg is nearly mature, the level of estradiol reaches a threshold, beyond which this action reverses and estrogen stimulates the production of a large amount of LH. This process, known as the LH surge, begins around 12 days before the average cycle and can last for 48 hours. The release of LH matures the egg, weakens the wall of the ovarian follicle, and causes the secondary oocyte to be released from the fully developed follicle. The egg is sent into the fallopian tube and towards the uterus by a wave of small cilia. If fertilized by sperm, the secondary oocyte immediately matures into an egg cell and then into a mature egg. If not fertilized by sperm, the secondary oocyte degenerates. The mature egg is about 0.2 mm in diameter.

[0005] Inducing ovulation is a critically important step in the management of controlled ovarian stimulation in patients undergoing IVF, IUI, timing guidance, and other forms of infertility treatment. Ovulation-inducing agents are not only ultimately involved in the final maturation of the oocytes and the rupture of the follicles, but also prepare the endometrium for subsequent implantation. Currently, hCG is the only drug specifically approved by the FDA as an ovulation-inducing agent. However, its use has been rapidly decreasing due to the relatively high incidence of ovarian hyperstimulation syndrome (OHHS). Leuprolide acetate has seen an increase in its use as an off-label ovulation drug due to its low incidence of OHHS and generally good safety and efficacy record. However, leuprolide is expensive and has some unpleasant side effects. Therefore, there is a need for a safe, effective, and low-cost alternative to induce ovulation in women who require it.

[0006] It is an object of the present invention to provide compositions and methods for inducing ovulation in subjects in need thereof.

[0007] It is also an object of the present invention to provide a method for treating infertility in subjects in need thereof.

Summary of the Invention

Problems to be Solved by the Invention

[0008] Compositions and methods for inducing ovulation in women in need thereof are disclosed herein. Current methods of inducing ovulation have unpleasant side effects and are expensive. The disclosed compositions and methods are safe, effective, and inexpensive. An exemplary method of inducing ovulation includes monitoring the development and size of ovarian follicles during the follicular phase of the menstrual cycle; and administering to the subject a pharmaceutical composition comprising progesterone or a bioidentical progesterone in an amount effective to increase the plasma concentration of progesterone to about 0.1 ng / ml to about 1 ng / ml when the follicles reach a size of at least 15 mm. In one embodiment, administration of progesterone to the subject induces a luteinizing hormone (LH) surge and subsequent ovulation in the subject.

[0009] In another embodiment, the subject's baseline plasma progesterone concentration is determined prior to administering progesterone. This baseline plasma progesterone concentration is used to calculate the subject's target maximum progesterone concentration, which is calculated by multiplying the baseline level by a number from 3 to 20.

[0010] In some embodiments, the subject may also be administered additional infertility therapeutics such as GnRH antagonists, selective estrogen receptor modulators, anti-inflammatory agents, and non-steroidal aromatase inhibitors.

[0011] Another embodiment is a method for regulating the release of luteinizing hormone (LH) and ovulation during the menstrual cycle, comprising: a) administering an estrogen modulator to a subject for several days during the follicular phase; b) administering an anti-inflammatory agent to the subject for several days during the follicular phase; c) monitoring the development and size of ovarian follicles throughout the follicular phase of the menstrual cycle; and d) when the follicles reach a size of at least 15 mm, administering progesterone or a progestin to the subject in an amount effective to increase the plasma concentration of progesterone to about 0.1 ng / ml to about 1.0 ng / ml, wherein progesterone induces an LH surge and ovulation in the subject.

[0012] The estrogen modulator is a GnRH antagonist, a non-steroidal aromatase inhibitor, or a selective estrogen receptor modulator. The estrogen modulator is administered starting on the 3rd to 5th day of the subject's menstrual onset for about 3 to 5 days. The anti-inflammatory agent is a non-steroidal anti-inflammatory agent. The anti-inflammatory agent is administered at least 1 day prior to the administration of the pharmaceutical composition containing progesterone.

[0013] In some embodiments, additional infertility treatment drugs such as GnRH antagonists, selective estrogen receptor modulators, anti-inflammatory agents, and non-steroidal aromatase inhibitors may also be administered to the subject.

[0014] The pharmaceutical composition used in the disclosed method may be formulated for oral, intravenous, subcutaneous, intramuscular, vaginal, or rectal administration. The amount of progesterone in the pharmaceutical composition formulated for oral administration is about 5 mg to about 30 mg. The amount of progesterone in the pharmaceutical composition formulated for intramuscular administration is about 1 mg to about 3 mg. The administration of progesterone to the subject may be repeated several times over about 4 hours to about 12 hours. Progesterone may be administered daily to the subject for at least 1 day after the first administration of progesterone, and the daily progesterone is started at least 3 days after the first administration.

[0015] A controlled-release pharmaceutical implant comprising a controlled-release polymer implant having progesterone or bioidentical progesterone, wherein the implant releases a constant level of progesterone in an amount effective to increase the plasma concentration of progesterone to about 0.1 ng / ml to about 1.0 ng / ml for at least 5 days is also described. The implant is designed to be implanted subcutaneously in the arm of the subject. In another embodiment, the implant is designed to be implanted in the endometrium of the subject or placed in the uterine cavity.

[0016] The disclosed methods and compositions are useful for inducing ovulation in subjects desiring regulated ovarian stimulation and / or ovulation, as well as in subjects having ovulation problems, endometriosis, reduced egg quality, polycystic ovary syndrome (PCOS), fallopian tube problems, unexplained infertility, reduced sperm quality, infertility or low fertilization rates caused by advanced age or premature ovarian insufficiency.

Brief Description of the Drawings

[0017]

Figure 1A-1B

Figure 2

Figure 3

Figure 4A

Figure 4B-4C

Figure 5A

Figure 5B-5C

Figure 6A-6B

Figure 6C-6D

Figure 6E

Figure 6F-6G

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Figure 6I

Mode for Carrying Out the Invention

[0018] I. Definitions It should be recognized that the present disclosure is not limited to the compositions and methods described herein and the experimental conditions described, and can itself vary. Since the scope of the present disclosure is limited only by the appended claims, it should also be understood that the technical terms used herein are for the sole purpose of describing specific embodiments and are not intended to be limiting.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Any compositions, methods, and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention. All publications mentioned are hereby incorporated by reference in their entirety.

[0020] In the context of describing the presently claimed invention, and in particular in the context of the claims, the use of the terms "a", "an", "the" and similar referents should be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0021] The recitation of a range of values herein is merely intended to serve as a convenient method of referring individually to each separate value within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein.

[0022] The use of the term "about" is intended to describe any value that exceeds or is less than the specified value by up to plus or minus 10%, and in other embodiments, the value may extend to any value that exceeds or is less than the specified value by up to plus or minus 5%, and in other embodiments, the value may extend to any value that exceeds or is less than the specified value by up to plus or minus 2%, and in other embodiments, the value may extend to any value that exceeds or is less than the specified value by up to plus or minus 1%. The foregoing ranges are intended to be clarified by context and no further limitation is implied. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any example, or exemplary language (e.g., "such as") provided herein is merely intended to make the invention clearer and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0023] The terms "estradiol" and "E2" as used herein may be used interchangeably and may refer to the estrogen steroid hormone. This is the primary female sex hormone involved in the regulation of estrus and menstruation in the female reproductive cycle. Estradiol is produced within ovarian follicles but may also be produced in the testes, adrenals, fat, liver, breast, and brain.

[0024] The terms "progesterone" and "P4" as used herein may be used interchangeably and may refer to the endogenous steroid and progestogenic hormone involved in the menstrual cycle, pregnancy, and embryogenesis. This belongs to a group of steroid hormones called progestogens.

[0025] The terms "gonadotropin-releasing hormone" and "GnRH" as used herein may be used interchangeably and may refer to the releasing hormone involved in the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus.

[0026] The terms "luteinizing hormone", "LH", and "lutropin" as used herein may be used interchangeably and may refer to the hormone produced by gonadotrophic cells of the anterior pituitary gland. In females, a sudden increase in LH (referred to as the LH surge) induces ovulation and the development of the corpus luteum.

[0027] The terms "follicle-stimulating hormone" and "FSH" as used herein may be used interchangeably and may refer to a gonadotropin, more specifically a glycoprotein polypeptide hormone. FSH is synthesized and secreted by gonadotrophic cells of the anterior pituitary gland and regulates body development, growth, puberty maturation, and the reproductive process. FSH and LH work together in the reproductive system.

[0028] As used herein, the terms "in vitro fertilization" and "IVF" may be used interchangeably and may refer to a method of fertilization in which an egg is combined with sperm outside the body. The method involves monitoring and stimulating the ovulation process in a female, removing one or more eggs from the female's ovaries, and fertilizing these eggs with sperm in a laboratory fluid. After the fertilized eggs are cultured for 2 to 6 days, they are implanted into the uterus of the same or another female to establish a successful pregnancy. IVF can be performed by directly retrieving eggs from the fallopian tubes after natural ovulation, which is typically combined with other techniques that increase the likelihood of pregnancy success. These techniques include ovarian hyperstimulation to produce multiple eggs, direct retrieval of oocytes from the ovaries under transvaginal ultrasound guidance, co-incubation of eggs and sperm, and culture and selection of the resulting embryos prior to embryo transfer into the uterus, but are not limited thereto.

[0029] As used herein, the terms "intracytoplasmic sperm injection" and "ICSI" may be used interchangeably and refer to an IVF treatment in which a single sperm cell is directly injected into the cytoplasm of an egg. ICSI differs from IVF in that ICSI requires only one sperm cell per egg, while IVF requires 50,000 to 100,000 sperm cells.

[0030] As used herein, the terms "ovarian follicle" and "follicle" may be used interchangeably and may refer to a fluid-filled sac containing an immature egg. The ovarian follicle has a unique function but is closely related to the hair follicle. Similar to the hair follicle, it has a predictable life cycle and eventually ruptures to discharge its contents. The hair follicle discharges hair (Rosenfield and Lucky, 1993), while the ovarian follicle discharges an egg.

[0031] II. Methods of Inducing Ovulation Methods and compositions for inducing ovulation are disclosed herein. Inducing ovulation is a critically important step in the management of controlled ovarian stimulation in patients undergoing IVF, IUI, fertility awareness, and other forms of infertility therapy. Ovulation-inducing agents not only ultimately participate in the final maturation of the oocytes and the rupture of the follicles, but also prepare the endometrium for subsequent implantation. Currently, hCG is the only drug specifically approved by the FDA as an ovulation-inducing agent. However, its use is rapidly declining due to the relatively high incidence of ovarian hyperstimulation syndrome (OHHS). Leuprolide acetate has seen an increase in its use as an off-label ovulation drug due to its low incidence of OHHS and generally good safety and efficacy record. However, leuprolide is expensive and has some unpleasant side effects.

[0032] Several kisspeptin derivatives are under investigation (Phase II), and if they reach the market, they are expected to be expensive (Abbara et al., 2017). An important drawback of all currently available inducing agents containing kisspeptin is that they cannot fully reproduce the naturally occurring pulsatile pattern of GnRH release, which is considered a derivative feature of the method. To compensate for this drawback, kisspeptin, for example, has to be injected several times. Also, the successful use of pumps has been reported to mimic the pulsatility of GnRH release (Zheng J et al., 2017). Neither is clinically practical for the general infertility population.

[0033] These treatments are based on the currently approved ovulation paradigm, which assumes that an increase in E2 beyond 200 - 300 pg / ml for at least 50 hours induces GnRH release, which then binds to its receptors in the anterior pituitary, releasing LH and FSH into the circulation and leading to follicular rupture (Christensen et al., 2012). However, it has been discovered that there are two progesterone waves under physiological conditions. The first wave is a rapid, LH - independent increase in progesterone to approximately 0.5 ng / ml, 12 hours before the gonadotropin surge, which signals to the hypothalamus that the follicle is ready to rupture. This increase activates the GnRH signaling pathway, and the subsequent LH / FSH surge ruptures the follicle and luteinizes its granulosa membrane. The pre - ovulatory peak of progesterone at only approximately 0.5 ng / ml may seem low when compared to the approximately 10 - fold higher post - ovulatory peak. The relatively low pre - ovulatory peak makes it difficult to recognize its significance as an ovulation inducer. However, administration of progesterone to women after their ovarian follicles have reached a threshold size has been found to induce ovulation, even when the women are diagnosed with infertility problems.

[0034] A. Ovulation induction regimen Disclosed herein is a method of inducing ovulation in a subject in need thereof by administering progesterone during the follicular phase of the menstrual cycle. Exemplary methods include: a) monitoring the development and size of ovarian follicles during the follicular phase of the menstrual cycle; and b) administering to the subject a pharmaceutical composition comprising progesterone or a bio - identical progesterone in an amount effective to increase the plasma concentration of progesterone to about 0.1 ng / ml to about 100 ng / ml when the follicles reach a size of at least 15 mm. Without being bound by any one theory, increasing the plasma concentration of progesterone when the follicles reach maturity induces an LH surge, ruptures the follicles, and releases the oocytes.

[0035] In some embodiments, the subject's plasma progesterone level is monitored throughout the follicular phase to calculate the target level of progesterone that should be achieved to induce ovulation.

[0036] Another method includes: a) administering to the subject a non-steroidal or steroidal anti-inflammatory agent for several days during the follicular phase; b) administering to the subject a GnRH antagonist for at least one day during the secondary follicular phase; c) monitoring the development and size of ovarian follicles during the follicular phase of the menstrual cycle; and d) administering to the subject progesterone or a progestin in an amount effective to increase the plasma concentration of progesterone to about 0.1 ng / ml to about 1.0 ng / ml when the follicle reaches a size of at least 15 mm, wherein the progesterone induces an LH surge and ovulation in the subject.

[0037] A more detailed description of the methods and compositions is provided below.

[0038] 1. Follicular Phase and Ovulation In one embodiment, the disclosed method is performed during the follicular phase of the subject's menstrual cycle. The follicular phase begins at the end of the luteal phase of the preceding non-conceptive menstrual cycle, prior to or simultaneously with the onset of menstruation. The cycle begins with a transient increase in the blood level of FSH that stimulates the development of a cohort of ovarian follicles. Each follicle contains an immature egg. The size of the follicles replenished for growth is about 5 mm in diameter. In a natural menstrual cycle, usually one large or dominant follicle is established during the follicular phase and engages in growth towards maturity. In humans, the size of the follicle considered ready for ovulation is about 15 mm or more in diameter. The granulosa cells within the ovarian follicles acquire LH receptors and their responsiveness to LH further increases. The secretion of estradiol and estrone from the ovaries initially increases slowly in parallel with the increase in the diameter of the follicles and the follicles' sensitivity to LH.

[0039] In one embodiment, progesterone treatment is administered when the follicle reaches a size of at least 15 mm in diameter. In another embodiment, the follicle is from 15 mm to 30 mm in diameter. The follicle can be 15 mm, 15.5 mm, 16 mm, 16.5 mm, 17 mm, 17.5 mm, 18 mm, 18.5 mm, 19 mm, 19.5 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, or 30 mm.

[0040] In one embodiment, the administration of progesterone to a subject when the follicle reaches a threshold size induces ovulation by inducing an LH surge. Ovulation is the second stage of the ovarian cycle in which a mature egg is released from the ovarian follicle into the fallopian tube. During the follicular phase, estradiol suppresses the release of luteinizing hormone (LH) from the anterior pituitary gland. When the egg is nearly mature, the level of estradiol reaches a threshold, and beyond this, the effect is reversed and estrogen stimulates the production of a large amount of LH. This process, known as the LH surge, begins around 12 days before the average cycle and can last for 48 hours. The release of LH matures the egg, weakens the wall of the ovarian follicle, and causes the fully developed follicle to release its secondary oocyte. The egg is sent into the fallopian tube and towards the uterus by a wave of small cilia. If fertilized by sperm, the secondary oocyte immediately matures into an egg cell and then into a mature egg. If not fertilized by sperm, the secondary oocyte degenerates. The mature egg is approximately 0.2 mm in diameter.

[0041] In one embodiment, the administration of progesterone after the follicle reaches a size of at least 15 mm induces an LH surge and results in ovulation, independent of the estradiol level.

[0042] a. Monitoring of follicle formation and size The formation and size monitoring of follicles can be achieved using ultrasonic imaging techniques. In one embodiment, the continuous evaluation of the number and size of follicles can be measured using ultrasound, generally two-dimensional (2D) ultrasound. In such an embodiment, the ovaries of the subject are subjected to 2D ultrasound. An observer, such as a technician, nurse practitioner or physician, uses the 2D ultrasound image to identify the ovaries, then systematically scrolls through the ovaries and then measures each follicle.

[0043] In another embodiment, the continuous evaluation of the number and size of follicles can be measured using three-dimensional (3D) ultrasound. 3D ultrasound displays volume rendering of ultrasound data. When generating a 3D volume, the ultrasound data can be collected in four common ways. The first is freehand, where the probe is tilted, a series of ultrasound images are captured, and the orientation of the transducer for each slice is recorded. The second is a mechanical method where the tilt of an internal linear probe is manipulated by a motor inside the probe. The third is a method using an end probe that inserts the probe and then generates a volume by removing the transducer in a controlled manner. The fourth technique is a matrix array transducer that uses beam steering to sample points across a pyramidal volume. In some embodiments, 3D ultrasound can be combined with automated software that counts and measures follicles. Sono-AVC (Automated Volume Calculation: GE Medical Systems, Kretz, Austria) is a software program that identifies and quantifies hypoechoic regions within a 3D dataset and automatically estimates their absolute dimensions and volume (Raine Fenning et al., 2007a). Since each different volume is color-coded separately, Sono-AVC is an ideal tool for studying the development of follicles in response to ovulation stimulation. SonoAVC provides reliable and valid measurements of follicle diameter and volume.

[0044] In one embodiment, the development of the target follicle is measured by ultrasound that begins within 3 days, if early, from the start of menstruation. In other embodiments, the development of the target follicle is measured by ultrasound that begins 3 - 20 days after the start of menstruation. The follicles of the target ovary can be measured daily, every other day, or once every 3 days until the follicles reach a size appropriate for starting progesterone treatment. In some embodiments, the subject receives the first transvaginal ultrasound on the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, or 20th day from the start of menstruation.

[0045] 2. Progesterone and Bioidentical Progesterone In one embodiment, progesterone or bioidentical progesterone is administered to the subject to induce ovulation when the follicle reaches at least 15 mm in size. Progesterone can induce the LH surge and ovulation without the involvement of E2. Even in the early days of ovulation research, when a rapid increase in circulating progesterone was detected as early as 12 hours before any change in LH or E2, the role of E2 as an ovulation inducer was questioned (Hoff et al., 1983). Progesterone has all the "evidence - like" characteristics that are satisfactory for follicle preparation because its change is directly linked to the breakdown of the follicle's basement membrane, which signals that follicle rupture is imminent (Zalanyi 2001). Furthermore, unlike E2, pre - ovulatory progesterone remains relatively constant throughout the follicular phase.

[0046] In a natural cycle, progesterone rises to about 0.5 ng / ml approximately 12 hours before the LH and E2 surges, making progesterone the most upstream candidate in the series of events leading to ovulation. Historically, progesterone has been regarded as an ovulation blocker (Selye et al., 1936). This ability of progesterone is well-known and is supported by extensive experience with various progestins in oral contraceptives. At first glance, this does not coincide with the potential of progesterone to surge LH and induce ovulation. In particular, the circulating levels of progestins used in oral contraceptive formulations are considerably lower than the pre-ovulatory levels of 0.5 ng / ml of progesterone.

[0047] The first important step in resolving this contradiction is to recognize that for the gonadotropin surge, it is necessary to accumulate these within each granule during the aforementioned follicular phase. Without such accumulation, the surge does not occur. Second, as can be seen from Table 1, the activity of progestins is considerably higher than that of progesterone. Therefore, comparing progestins with progesterone in terms of the amount in circulation can be misleading. Instead, these should be compared in terms of their activity. The estimated activity of the total circulating progestin formulations is higher than that of 0.5 ng of pre-ovulatory progesterone (Table 1).

[0048]

Table 1

[0049] Consequently, at these levels, progestins are expected to desensitize progesterone, or perhaps instead the GnRH receptor as well, and / or continuously discharge LH and FSH from the pituitary, preventing these accumulations required for the surge. Therefore, when progesterone is very low during the follicular phase, it allows LH to accumulate and the receptor to be sensitized. As a result, when progesterone rises within the narrow window approximately 12 hours before the LH surge, this flares up LH and leads to subsequent ovulation.

[0050] On the other hand, if progesterone activity is continuously present at levels above its physiological pre-ovulatory levels, as in all contraceptives, during pregnancy or the luteal phase, this causes desensitization of itself or the GnRH receptor (McArdle et al., 1995), thus making it impossible to accumulate or surge LH, and ovulation is blocked.

[0051] In one embodiment, administration of progesterone or bioidentical progesterone induces an LH surge and subsequent ovulation in a subject.

[0052] Bioidentical progesterone is laboratory-produced progesterone that is similar to endogenously produced progesterone. Bioidentical hormones are made from plant estrogens. In one embodiment, bioidentical progesterone is used in the disclosed methods and compositions.

[0053] i. Determination of target progesterone level In one embodiment, the baseline circulating level of progesterone is calculated before progesterone is administered to a subject. The circulating level of progesterone can be determined from a blood sample using methods known in the art. Such methods for determining the level of progesterone in circulation include, but are not limited to, immunoassays such as microarrays or chips, coated beads, glass fibers or enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) using microcapillary disks, and radioreceptor assay (RRA).

[0054] In one embodiment, the baseline circulating level of progesterone is used to determine the target maximum progesterone concentration in a subject. The target concentration is calculated by multiplying the baseline level by a number from 3 to 20.

[0055] The circulating levels of progesterone can be monitored over the period of conditioning stimulation from the start of the menstrual period until ovulation occurs following administration of an inducing amount of progesterone.

[0056] 3. Additional Therapeutic Agents In one embodiment, the methods and compositions disclosed herein can be used in combination with other infertility therapeutic agents and treatment methods to ensure the greatest likelihood of success of ovulation, fertilization, and viable pregnancy. Additional therapeutic agents that can be incorporated into the disclosed methods are described below.

[0057] i. Anti-inflammatory Agents In some embodiments, for female subjects, an anti-inflammatory agent is administered prior to the administration of a priming amount of progesterone to prevent premature rupture of the follicle. By preventing premature rupture of the follicle, the follicle can safely reach a size large enough to rupture after progesterone injection. The anti-inflammatory agent may be non-steroidal, steroidal, or a combination thereof. One embodiment provides an oral composition containing from about 1% (w / w) to about 5% (w / w), typically about 2.5% (w / w) of the anti-inflammatory agent. Representative examples of non-steroidal anti-inflammatory agents include oxicams such as piroxicam, isoxicam, tenoxicam, sudoxicam; salicylates such as aspirin, disalcid, benorylate, trilisate, sulfaprin, solprin, diflunisal, and fendosal; acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, flufenac, thiopinic acid, zidometacin, acematacin, fentiazac, zomepirac, clidanac, oxepinac, felbinac, and ketorolac; fenamate salts such as mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid; propionic acid derivatives such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, thiaprofenic acid, suprofen, alminoprofen, and tiaprofenic acid; and pyrazoles such as phenylbutazone, oxyphenbutazone, febufazone, azapropazone, and trimethazone, but are not limited thereto. Mixtures of these non-steroidal anti-inflammatory agents can also be used.

[0058] Typical examples of steroid anti-inflammatory agents include, but are not limited to, hydrocortisone, hydroxyltriamcinolone, α-methyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, flucloronide acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butyl ester, fludrocortisone, fluprednylidene acetate (fluprednyliden), flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorozone diacetate, flurandrenolone, fludrocortisone, difluorozone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinaphide, betamethasone and the rest of its esters, chloroprednisone, chloroprednisone acetate, corticosterone, crescinolone, dichlorisone, difluprednate, flunisolide, fluorometholone, fluprednolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone and other corticosteroids, and mixtures thereof.

[0059] ii. Estrogen modulator In one embodiment, one or more estrogen modulators are administered to a subject prior to administering an inducing amount of progesterone to induce ovulation. The estrogen modulator is administered to the subject starting on the 3rd to 5th day of the subject's menstrual cycle for 3 to 5 days. In one embodiment, the estrogen modulator is administered to a female subject 3, 4, or 5 days after the start of the menstrual cycle. In another embodiment, the estrogen modulator is administered for 1, 2, 3, 4, or 5 days. Exemplary estrogen modulators include, but are not limited to, nonsteroidal aromatase inhibitors and selective estrogen receptor modulators.

[0060] Nonsteroidal aromatase inhibitors inhibit the conversion of androgens to estrogen by aromatase, thereby reducing the amount of circulating estrogen. Nonsteroidal aromatase inhibitors are useful for ovulation induction. Aromatase inhibitors increase ovarian sensitivity to FSH. Exemplary nonsteroidal aromatase inhibitors include, but are not limited to, anastrozole and letrozole.

[0061] Selective estrogen receptor modulators are a class of drugs that act on estrogen receptors. These are useful for the induction of ovulation. These have a dominant anti-estrogenic effect and deplete estrogen receptors over time. Exemplary selective estrogen receptor modulators include, but are not limited to, triphenylethylenes such as clomiphene citrate, tamoxifen, and toremifene, and benzothiophene, raloxifene.

[0062] iii. GnRH antagonist In one embodiment, one or more GnRH antagonists are administered before an inducing amount of progesterone is administered to a subject. The GnRH antagonist competitively and reversibly binds to GnRH receptors in the pituitary gland and blocks the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. Administration of the GnRH antagonist in the late follicular phase effectively prevents the early rise in serum luteinizing hormone (LH) levels in most women.

[0063] In one embodiment, the GnRH antagonist is administered for at least one day before an inducing amount of progesterone is administered to a female subject. The GnRH antagonist can be administered for 1, 2, 3, 4, or 5 days before the inducing amount of progesterone is administered. In some embodiments, the GnRH antagonist is administered to the female subject on the day before the inducing amount of progesterone is administered.

[0064] Exemplary GnRH antagonists include, but are not limited to, the peptide molecules abarelix, cetrorelix, degarelix, and ganirelix, and the small molecule compounds elagolix and relugolix.

[0065] C. Subjects to be Treated In one embodiment, the disclosed methods and compositions are used to induce ovulation in a subject in need thereof. Female subjects in need of ovulation stimulation or induction may be attempting natural conception, IVF, IUI, or frozen embryo transfer cycles. In some embodiments, the female subject is a healthy subject. In other embodiments, the female subject has a fertility problem or has not been diagnosed with a fertility problem but has historically had difficulty achieving a natural pregnancy. Causes of infertility or low fertilization rates include, but are not limited to, ovarian disorders, endometriosis, poor egg quality, polycystic ovary syndrome (PCOS), fallopian tube problems, unexplained infertility, poor sperm quality, age, and premature ovarian insufficiency. The disclosed methods and compositions can be used as part of an IVF, IUI, natural cycle, or frozen embryo transfer cycle.

[0066] 1. Ovulatory disorder Ovulatory disorder occurs when a woman ovulates little or not at all. This is the main cause of infertility in about 1 in 4 infertile couples. Problems with the regulation of reproductive hormones by the hypothalamus or pituitary gland, or problems with the ovaries, can cause ovulatory disorder. In one embodiment, the disclosed methods and compositions can induce ovulation in women suffering from ovulatory disorder. In such embodiments, progesterone induces ovulation in the woman, and the eggs may be retrieved by IVF, IUI, or frozen embryo transfer cycles, or the woman may attempt intercourse or natural conception. Specific ovulatory disorders are described below.

[0067] i. Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) causes hormonal imbalances and affects ovulation. PCOS is often associated with insulin resistance and obesity, abnormal hair growth on the face or body, and acne. This is the most common cause of female infertility. In one embodiment, the methods and compositions disclosed herein can be used to induce ovulation in female subjects with PCOS. In such embodiments, progesterone induces ovulation in the subject, and the eggs may be retrieved by IVF, IUI, or frozen embryo transfer cycles, or the woman may attempt intercourse or natural conception.

[0068] ii. Hypothalamic insufficiency In another embodiment, the disclosed compositions and methods can be used to induce ovulation in a female subject having hypothalamic insufficiency. Hypothalamic insufficiency occurs when the production of FSH and LH is halted, resulting in an imbalance in these levels and a failure to stimulate ovulation. Excessive physical or emotional stress, extreme weight, or recent significant weight gain or loss can halt the production of these hormones and affect ovulation. Irregular menstrual cycles or amenorrhea are the most common symptoms of hypothalamic insufficiency. In one embodiment, the methods and compositions disclosed herein can be used to induce ovulation in a female subject having hypothalamic insufficiency. In such an embodiment, progesterone induces ovulation in the subject, and the eggs may be retrieved by IVF, IUI, or frozen embryo transfer cycles, or the female may attempt natural fertilization.

[0069] In another embodiment, by inducing an LH surge and ovulation using the disclosed methods and compositions, the function of the hypothalamus can be reset by restoring the natural balance of LH and FSH, reducing or preventing future hypothalamic insufficiency in the subject.

[0070] iii. Early ovarian impairment In another embodiment, the disclosed methods and compositions can be used to induce ovulation in a subject having early ovarian impairment. Early ovarian impairment, also known as premature ovarian insufficiency, is usually caused by an autoimmune response or premature loss of eggs from the ovaries (which may be genetic or due to chemotherapy). The ovaries no longer produce many eggs and reduce estrogen production in women under 40 years of age. In one embodiment, the methods and compositions disclosed herein can be used to induce ovulation in a female subject having early-stage ovarian impairment. In such an embodiment, progesterone induces ovulation in the subject, and the eggs may be retrieved by IVF, IUI, or frozen embryo transfer cycles, or the female may attempt natural fertilization.

[0071] iv. Prolactin imbalance One embodiment provides a method for inducing ovulation in a subject having a problem of infertility due to excessive prolactin. When the pituitary gland causes excessive production of prolactin (hyperprolactinemia), as a result, the production of estrogen decreases, which can cause infertility. Usually, in relation to pituitary problems, this can also be caused by drugs prescribed for another disease. In one embodiment, the methods and compositions disclosed herein can be used to induce ovulation in a female subject having a prolactin imbalance. In such an embodiment, progesterone induces ovulation in the subject, and the oocytes may be retrieved by IVF, IUI, or a frozen embryo transfer cycle, or the female may attempt natural fertilization.

[0072] D. Pharmaceutical Compositions Pharmaceutical compositions are provided that contain progesterone or a bioidentical progesterone, with or without a delivery vehicle. The pharmaceutical compositions can be formulated for administration by parenteral (intramuscular, intraperitoneal, intravenous (IV), or subcutaneous injection), enteral, or transmucosal (transnasal, intravaginal, rectal, or sublingual) routes of administration, or for administration using a biodegradable implant, and can be formulated into dosage forms suitable for each route of administration.

[0073] In certain embodiments, the composition is administered locally, for example, by a suppository inserted into the vagina. In some embodiments, the composition is injected into the vascular tissue or otherwise directly administered to the vascular system at or adjacent to the intended site of treatment. Typically, local administration increases the local concentration of the composition, which is higher than the concentration that can be obtained by systemic administration.

[0074] a. Formulations for Parenteral Administration A pharmaceutical composition containing progesterone or bioidentical progesterone can be administered in an aqueous solution by parenteral injection. The formulation may be in the form of a suspension or an emulsion. Generally, a pharmaceutical composition containing an effective amount of the active agent(s) is provided, optionally containing a pharmaceutically acceptable diluent, preservative, solubilizer, emulsifier, adjuvant, and / or carrier. Such compositions include diluents, sterile water, buffered physiological saline with various buffer contents (e.g., Tris HCl, acetate, phosphate), pH, and ionic strength; and optionally additives such as detergents and solubilizers (e.g., TWEEN® 20 or 80, also known as polysorbate 20 or 80), antioxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., thimerosal, benzyl alcohol), and bulking substances (e.g., lactose, mannitol). Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. The formulation can be lyophilized and redissolved / resuspended immediately before use. The formulation can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating a sterilizing agent into the composition, by irradiating the composition, or by heating the composition.

[0075] b. Enteral formulations A pharmaceutical composition containing progesterone or bioidentical progesterone can be formulated for enteral administration. Suitable oral dosage forms of the progesterone pharmaceutical composition include tablets, capsules, solutions, suspensions, syrups, and lozenges. Tablets can be manufactured using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can be prepared as hard or soft capsule shells capable of encapsulating liquid, solid, and semi-solid filling materials using techniques well known in the art.

[0076] The formulation can be prepared using pharmaceutically acceptable carriers. As used herein generally, "carriers" include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrants, swelling agents, fillers, stabilizers, and combinations thereof.

[0077] The carrier also includes all components of the coating composition, which may include plasticizers, pigments, colorants, stabilizers, and lubricants. Sustained-release dosage forms can be prepared as described in standard references. These references provide information on carriers, materials, equipment, and methods for preparing tablets and capsules, as well as sustained-release dosage forms of tablets, capsules, and granules.

[0078] Examples of suitable coating materials include cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic polymers and copolymers, and methacrylic resins commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides, but are not limited thereto.

[0079] In addition, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, lubricants, stabilizers, pore formers, and surfactants.

[0080] Optional pharmaceutically acceptable excipients include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also referred to as "fillers", are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dried starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium dioxide, magnesium aluminum silicate, and powdered sugar.

[0081] Binders are used to impart cohesiveness to solid dosage forms and thus ensure that tablets or beads or granules retain their integrity after formation of the dosage form. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, saccharides (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, acacia, tragacanth, natural and synthetic rubbers such as sodium alginate, celluloses including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as copolymers of acrylic acid and methacrylic acid, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone.

[0082] Lubricants are used to facilitate the manufacture of tablets. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, polyethylene glycol, talc, and mineral oil.

[0083] Disintegrants are used to promote the disintegration or "collapse" of the dosage form after administration, and generally include, but are not limited to, starches, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, clays, celluloses, arginine, gums, or crosslinked polymers such as crosslinked PVP (Polyplasdone® XL from GAF Chemical Corp).

[0084] Stabilizers are used, for example, to inhibit or delay drug degradation reactions, including oxidation reactions. Suitable stabilizers include, but are not limited to, antioxidants, butylated hydroxytoluene (BHT); ascorbic acid, its salts and esters; vitamin E, tocopherol and its salts; sulfites such as sodium metabisulfite; cysteine and its derivatives; citric acid; propyl gallate, and butylated hydroxyanisole (BHA).

[0085] Oral dosage forms such as capsules, tablets, solutions, and suspensions can be formulated for controlled release. For example, one or more compounds and optionally one or more additional active agents can be formulated into nanoparticles, microparticles, and combinations thereof, encapsulated in soft or hard gelatin or non-gelatin capsules, or dispersed in a dispersion medium to form an oral suspension or syrup. The particles can be formed from the drug and a controlled release polymer or matrix. Alternatively, the drug particles can be coated with one or more controlled release coatings before being incorporated into the final dosage form.

[0086] In another embodiment, the one or more compounds and optional one or more additional active agents are dispersed in a matrix material that gels or emulsifies upon contact with an aqueous medium such as a physiological fluid. In the case of a gel, the matrix that captures the active agent released slowly over time by diffusion and / or degradation of the matrix material swells. Such a matrix can be formulated as a tablet or as a filling material for hard and soft capsules.

[0087] In yet another embodiment, the one or more compounds and optional one or more additional active agents are formulated into a solid oral dosage form such as a tablet or capsule, and the solid dosage form is coated with one or more controlled release coatings such as a delayed release coating or a sustained release coating. The coating(s) may also contain the compound and / or additional active agent.

[0088] c. Formulations for vaginal delivery In another embodiment, the progesterone pharmaceutical composition is formulated for vaginal delivery. The vaginal drug delivery system provides sustained delivery of progesterone or bioidentical progesterone to the vaginal epithelium and induces ovulation. The delivery system can be a solid delivery system such as, for example, a vaginal ring, pessary, tablet or suppository. In another embodiment, the composition for vaginal delivery is a paste or gel having a thickness sufficient to maintain long-term contact with the vaginal epithelium. In yet another embodiment, this can be a coating of a suppository wall or sponge or other absorbent material impregnated with a liquid drug containing a solution, lotion or suspension of bioadhesive particles. Any form of drug delivery system that effectively delivers the therapeutic agent to the vaginal epithelium is intended to be within the scope of the present invention. In a preferred embodiment, the vaginal delivery system for progesterone is a suppository drug delivery system. The vaginal delivery route of drugs to the uterus and / or systemic circulation through the vaginal mucosa is described, for example, in U.S. Pat. Nos. 6,086,909, 6,197,327 and 6,572,874.

[0089] d. Controlled release polymer matrix The progesterone-containing pharmaceutical compositions disclosed herein can also be administered in controlled release formulations. Controlled release polymer devices can be manufactured for long-term systemic release after implantation or injection (microparticles) of the polymer device (rod, cylinder, film, disk). The matrix can be in the form of microparticles such as microspheres, and the drug is dispersed in a solid polymer matrix or microcapsule, the core is a material different from the polymer shell, and the peptide is dispersed or suspended in a core that can be essentially liquid or solid. Unless otherwise defined herein, microparticles, microspheres and microcapsules are used interchangeably. Alternatively, the polymer can be cast as a thin slab or film in the range of nanometers to 4 centimeters, a powder produced by grinding or other standard techniques, or even a gel such as a hydrogel.

[0090] Either non-biodegradable or biodegradable matrices can be used for the delivery of progesterone or bioidentical progesterone. These can be natural or synthetic polymers. Synthetic polymers typically have good characterization of degradation and release profiles. The polymer is selected based on the period during which release is desired. In some cases, linear release may be most useful, while in others pulsed or "bulk release" may yield more effective results. The polymer may be in the form of a hydrogel (typically absorbing up to about 90% by weight of water) and may optionally be cross-linked with polyvalent ions or polymers.

[0091] The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art. Biodegradable microspheres can be prepared using any of the methods developed for manufacturing microspheres for drug delivery, for example, as described in Mathiowitz and Langer, J. Controlled Release, 5:13 - 22 (1987); Mathiowitz et al., Reactive Polymers, 6:275 - 283 (1987); and Mathiowitz et al., J. Appl. Polymer Sci., 35:755 - 774 (1988).

[0092] The device can be formulated for local release for treating an implant or injection area that delivers a dose far less than a typical dose for systemic therapy, or for systemic delivery. These can be implanted subcutaneously, intramuscularly, intrafatty, or injected, or swallowed.

[0093] In one embodiment, the controlled - release polymer device releases a constant level of progesterone in an amount effective to maintain a plasma concentration of progesterone from about 0.1 ng / ml to about 100 ng / ml for at least 5 days after administration or implantation of the device. In some embodiments, the device is an implantable polymer rod that is inserted subcutaneously into the subject's arm or leg, or implanted into the subject's endometrium. In another embodiment, the controlled - release polymer device can be a patch that is applied to the skin to release progesterone over time.

[0094] Examples Example 1. Case Study 1 Materials and Methods It was suggested that progesterone be used to induce ovulation in a 35-year-old nulligravid, nulliparous woman who did not conceive after two previous natural IUI cycles using hCG as an inducer. In the natural cycle, the woman was monitored by ultrasound at baseline on day 2, then on days 12 and 13. On day 13 of the cycle, the woman's dominant follicle reached a size of 17 mm (Figure 4B), P4 was 1.5 ng / ml, and LH was 5 IU / L. The woman received an intramuscular injection of 5 mg of progesterone. The protocol is outlined in Figure 4A.

[0095] Results LH was at ovulatory levels within 12 hours, but the follicle did not rupture and an active cyst developed (Figure 4C). The failure of the follicle to rupture was due to its size (17 mm) at the time of induction.

[0096] [Table 2]

[0097] Example 2. Case Study 2 Materials and Methods A 41-year-old nulligravid, nulliparous woman interested only in a modified natural IVF cycle. The treatment protocol is outlined in Figure 5A.

[0098] Results A single egg did not fertilize (Figures 5B - 5C).

[0099] Example 3. Case Study 3 Materials and Methods A 30-year-old G2 P1, SAB1, 152 cm tall, 164 lb woman who had not been able to conceive naturally for 6 months was referred for infertility treatment. The patient's medical history was notable for PCOS and asymptomatic hypothyroidism, for which the woman was taking 100 mcg of levothyroxine. The patient had menarche at age 12, an average menstrual cycle of 45 days, and an average menstrual period of 6 days. According to HSG, both of the patient's fallopian tubes were patent and the uterine cavity was normal (Figure 6E). The woman's AMH was 9.3 ng / ml.

[0100] In the first stimulation cycle, the patient received 100 mg of clomiphene citrate (CC) starting from the 5th day of menstruation for 5 days. The patient was induced on the 19th day after the first administration of CC, at which time the patient had a single follicle of 22 mm, and the patient's E2, LH, and P4 were 400 pg / ml, 38 mIU / ml, and 0.73 ng / ml, respectively. Additional luteal phase support was initiated on the 3rd day after the trigger shot with daily suppositories containing 10,000 IU of Novarel followed by 200 mg of progesterone. The patient's hCG was negative 2 weeks after induction, but this was not particularly surprising as the patient's LH on the day of induction was within the post-ovulatory range, indicating that a spontaneous LH surge had occurred before the trigger shot.

[0101] In the second stimulation cycle, the patient received 5 mg of letrozole in addition to 100 mg of clomiphene citrate (CC) starting from the 3rd day of menstruation for 5 days. Two days before the trigger shot, the patient received 50 mg of diclofenac as a suppository. The patient was induced on the 16th day after the first administration of CC, at which time the patient had two follicles (25 mm and 18 mm) in the left ovary and three follicles (23 mm, 12 mm, and 12 mm) in the right ovary. Additional luteal phase support was initiated on the 3rd day after the trigger shot with daily suppositories containing 200 mg of progesterone. The patient's hCG was 178 two weeks after induction and increased to 1459 four days later. Fetal heart sounds were not observed by ultrasound at 2 and 4 weeks, and cervical dilation and uterine curettage were performed.

[0102] At the start of the third trial, the drug regimen was the same as in the previous trial in which the patient became pregnant, with 5 mg of letrozole in addition to 100 mg of CC for 5 days starting from the 3rd day of menstruation. On the 13th day of stimulation, the patient received one suppository containing 50 mg of diclofenac and one injection of cetrorelix to prevent early luteinization. The next day, the patient was induced with a single injection of 5 mg of progesterone in oil. Before induction, the patient's P4 and LH were 0.62 ng / ml and 4.26 IU / L, respectively (Table 3), and three follicles of 22, 22, and 19 mm were identified by ultrasound (Figures 6C - 6D).

[0103] Seventeen hours later, P4 and LH increased to 8.01 ng / ml and 37.01 IU / L respectively, indicating that a gonadotropin surge had occurred. On the third day after the trigger shot, an ultrasound showed that all three follicles had ruptured (Figures 6F - 6G). The patient had fluid behind the uterus (Figure 6I), which is a classic feature of ovulation. Seven days after the trigger shot, the P4 level was 38.39 ng / ml, and at this point, the patient started daily progesterone vaginal suppositories of 200 mg. The patient had a menstrual period two weeks later, indicating that she did not become pregnant.

[0104]

Table 3

[0105] The minimum dose of progesterone reported to induce a gonadotropin surge is 10 mg by intramuscular injection (Leyendecker et al., 1972). In Case Report 3, in the first trial, this patient showed an apparently spontaneous LH surge at a progesterone level of 0.63 ng / ml, which was consistent with a previous report of a mean induced progesterone level in circulation of 0.5 ng / ml, so only 5 mg of progesterone injection was used (Hoff, Quigley, and Yen 1983).

[0106] As a result, the target cumulative progesterone level in circulation was 1 ng / ml. Based on the pharmacodynamics of progesterone (Leyendecker et al., 1972), it was estimated that in addition to the patient's own 0.63 ng / ml, an additional 0.35 ng / ml was required to bring the circulating progesterone level to 1 ng / ml at its peak (120 minutes after injection). This was achieved with approximately 5 mg of progesterone in sesame oil for intramuscular injection.

[0107] The results were that an injection of 5 mg of progesterone actually brought about an LH surge, rupture of all three follicles, and the appearance of fluid behind the uterus, all of which are classical features of ovulation. Furthermore, progesterone continued to rise to expected levels several days later. The P4 level of the patient on the 5th day after induction was extremely good, and subsequent additional supplementation of progesterone was carried out only with due care.

[0108] In the foregoing specification, the invention has been described in relation to its particular embodiments, and many details have been set forth by way of example. However, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that some of the details described herein may be substantially changed without departing from the basic principles of the invention.

[0109] All references cited herein are hereby incorporated by reference in their entirety. The invention can be embodied in other specific forms without departing from its spirit or essential attributes, and accordingly, reference should be made to the appended claims rather than the foregoing specification as indicating the scope of the invention.

Claims

Claim 1 A method for inducing ovulation in a subject in need thereof, comprising: monitoring the development and size of ovarian follicles during the follicular phase of the menstrual cycle of the subject; and administering to the subject a pharmaceutical composition comprising progesterone or a bioidentical progesterone in an amount effective to increase the plasma concentration of progesterone from about 0.1 ng / ml to about 0.5 ng / ml to reach a level of about 1 ng / ml when the follicle reaches a size of at least 15 mm. A method comprising the above steps. Claim 2 The method according to claim 1, wherein the pharmaceutical composition is formulated for oral, intravenous, subcutaneous, intramuscular, vaginal or rectal administration. Claim 3 The method according to claim 2, wherein the amount of progesterone in the pharmaceutical composition formulated for oral administration is about 5 mg to about 30 mg. Claim 4 The method according to claim 2, wherein the amount of progesterone in the pharmaceutical composition formulated for intramuscular administration is about 1 mg to about 3 mg. Claim 5 The method according to claim 1, wherein the administration of progesterone to the subject induces a luteinizing hormone (LH) surge and ovulation in the subject. Claim 6 The method according to claim 1, further comprising repeating the administration of progesterone to the subject several times over a period of about 4 hours to about 12 hours. Claim 7 The method according to claim 1, further comprising determining the baseline plasma progesterone concentration of the subject before administering progesterone. Claim 8 The method according to claim 7, wherein the baseline plasma progesterone concentration is used to calculate the target maximum progesterone concentration of the subject, and the target concentration is calculated by multiplying the baseline level by a number from 3 to 20. Claim 9 The method according to claim 1, further comprising subjecting the subject to a second infertility treatment. Claim 10 The method according to claim 1, further comprising administering a certain amount of progesterone to the subject daily for at least 1 day after the first administration of progesterone. Claim 11 The method according to claim 1, wherein the subject in need thereof has infertility or a low fertilization rate caused by ovulation problems, endometriosis, poor egg quality, polycystic ovary syndrome (PCOS), fallopian tube problems, unexplained infertility, poor sperm quality, age or premature ovarian insufficiency. Claim 12 A method for regulating the release of luteinizing hormone (LH) and ovulation in the menstrual cycle, comprising: a. administering an estrogen modulator to the subject for several days during the follicular phase; b. administering an anti-inflammatory agent to the subject for several days during the follicular phase; c. monitoring the development and size of ovarian follicles throughout the follicular phase of the menstrual cycle; d. administering progesterone or a progestin to the subject in an amount effective to increase the plasma concentration of progesterone to about 0.1 ng / ml to about 10 ng / ml when the follicle reaches a size of at least 15 mm, wherein the progesterone induces an LH surge and ovulation in the subject.

13. The method according to claim 12, wherein the estrogen modulator is a GnRH antagonist, a non-steroidal aromatase inhibitor or a selective estrogen receptor modulator.

14. The method according to claim 12, wherein the estrogen modulator is administered starting on the 3rd to 5th day of the subject's menstrual onset for about 3 to 5 days.

15. The method according to claim 12, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent.

16. The method according to claim 12, wherein the anti-inflammatory agent is administered at least 1 day before the administration of the pharmaceutical composition containing progesterone.

17. The method according to claim 12, wherein the pharmaceutical composition is formulated for oral, intravenous, subcutaneous, intramuscular, vaginal or rectal administration.

18. The method according to claim 12, wherein the amount of progesterone in the pharmaceutical composition formulated for oral administration is about 5 mg to about 30 mg.

19. The method according to claim 12, wherein the amount of progesterone in the pharmaceutical composition formulated for intramuscular administration is about 1 mg to about 3 mg.

20. The method according to claim 12, further comprising repeating the administration of progesterone to the subject several times over about 4 to 12 hours.

21. The method according to claim 12, further comprising determining the baseline plasma progesterone concentration of the subject before administering progesterone.

22. The method according to claim 12, wherein the baseline plasma progesterone concentration is used to calculate the target maximum progesterone concentration of the subject, and the target concentration is calculated by multiplying the baseline level by a number from 3 to 20.

23. The method according to claim 12, further comprising performing a second infertility treatment on the subject.

24. The method according to claim 12, further comprising administering a certain amount of progesterone to the subject daily for at least 1 day after the first administration of progesterone, wherein the daily progesterone starts at least 3 days after the first administration.

25. The method according to claim 12, wherein the subject in need thereof has infertility or low fertilization rate caused by ovulation problems, endometriosis, decreased egg quality, polycystic ovary syndrome (PCOS), fallopian tube problems, unexplained infertility, decreased sperm quality, age or premature ovarian insufficiency.

26. A controlled-release pharmaceutical implant comprising a controlled-release polymer implant containing progesterone or a bioidentical progesterone, wherein the implant releases a constant level of progesterone in an amount effective to increase the plasma concentration of progesterone to about 0.1 ng / ml to about 10 ng / ml for at least 5 days.

27. The controlled-release pharmaceutical implant according to claim 26, wherein the implant is designed to be subcutaneously implanted in the arm of the subject.

28. The controlled-release pharmaceutical implant according to claim 26, wherein the implant is designed to be implanted in the endometrium of the subject.

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