HP-hmg for use in treatment of infertility in patient with polycystic ovary syndrome

Abstract

To satisfy a need for improved assisted reproductive technology methods, particularly for women who experience oligoovulation and / or who have Polycystic Ovary Syndrome (PCOS) and who are predicted to have a high ovarian response to controlled ovarian stimulation.SOLUTION: The present invention provides assisted reproductive technology compositions and methods that stimulate follicle development using highly purified menotropin (HP-hMG), particularly in women diagnosed with oligoovulation and / or PCOS and predicted to have a high ovarian response to controlled ovarian stimulation.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention described herein relates to assisted reproductive technology. Specifically, described herein is a composition and method for treating infertility, including a controlled ovarian stimulation method that may be particularly useful for women who have experienced infrequent ovulation and / or have polycystic ovary syndrome (PCOS) and are expected to have a high ovarian response to controlled ovarian stimulation.

Background Art

[0002] Assisted reproductive technology (ART) procedures generally involve stimulating the growth and maturation of eggs, retrieving eggs from a woman's ovaries, combining the eggs and sperm in vitro, and transferring it to the uterus of a woman (donor or another woman). The success of ART is hampered by maternal and perinatal risks associated with the stimulation of egg growth and maturation (e.g., ovarian hyperstimulation syndrome (OHSS) and ectopic pregnancy). Other concerns in ART are the production of high-quality embryos and euploid blastocysts to support ongoing pregnancy rates and birth rates.

[0003] Gonadotropins, such as menotropins (e.g., human menopausal gonadotropin or hMG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), are used for controlled ovarian stimulation (COS), and highly purified menotropin (HP-hMG) and recombinant human FSH (rFSH) have been used relatively recently. HP-hMG provides the activity of FSH and exogenous LH mainly in the form of human chorionic gonadotropin (hCG). The effectiveness of ovarian stimulation protocols can be enhanced by using gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists for an extended period for cycle control. See, for example, Devroey et al., Fertility and Sterility 97:561-71 (2012). Ziebe et al., Human Reproduction 22(9)2404-13 (2007) reported that the use of HP-hMG vs rFSH may affect embryo morphology, and observed improved implantation, ongoing pregnancy rates, and live birth rates in the highest quality embryos (based on visual assessment) derived from stimulation with HP-hMG compared to rFSH derived from Chinese hamster ovary cells (CHO cells) (GONAL-F).

[0004] The patient response to ovarian stimulation varies widely, so treatment is often individualized. For example, individualization can be based on the expected ovarian response to gonadotropin stimulation that predicts a poor, normal, or high response. Hyper-responders are typically defined as women who produce a large number of growing follicles following a standard protocol for controlled ovarian stimulation (COS). Such patients are generally considered good candidates for ART, but hyper-response may be associated with relatively low implantation rates and relatively high miscarriage rates, such that the probability of a successful outcome may be reduced compared to a normal ovarian response. Such hyper-responders are also at increased risk of OHSS and associated complications.

[0005] Efforts to develop improved ART methods for expected high responders include consideration of milder stimulation protocols. For example, Rubio et al., Human Reproduction 25(9):2290-97(2010) reported that reducing the gonadotropin dose administered to high responders can improve the fertilization rate and embryo quality, but the lower the dose, the fewer oocytes. In other efforts, it has been examined whether the specific gonadotropin used affects the results. For example, Arce et al., Gyn.Endocrin.30(6):444-50(2014) reported that among expected high responders (subjects with AMH of 5.2 ng / ml or more), the group stimulated with CHO cell-derived rFSH (GONAL-F) recovered significantly more oocytes than the group stimulated with HP-hMG, but the birth rate per cycle was significantly lower (20% vs. 33% in the MERIT "long-acting agonist" clinical trial; 23% vs. 34% in the MEGASET "agonist" trial), see also La Marca et al., Fertility and Sterility O-169(2012)(ibid).

[0006] Women with a regular menstrual cycle typically ovulate or release a mature egg once a month, approximately in the middle of the cycle. Oligo-ovulation refers to the situation where ovulation occurs rarely or irregularly and is usually classified as having 8 or fewer menstrual cycles (periods) in a year. Oligo-ovulation is one of the most common causes of infertility in women. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] In particular, there is a need for improved assisted reproductive technology methods for women who have experienced oligo-ovulation and / or have polycystic ovary syndrome (PCOS) and are expected to have a high ovarian response to controlled ovarian stimulation. MEANS FOR SOLVING THE PROBLEM

[0008] The compositions and methods described herein are derived from the surprising and unexpected finding that patients who have experienced oligo-ovulation (e.g., women who have experienced oligo-ovulation due to PCOS), and who are expected to have a high ovarian response to controlled ovarian stimulation (e.g., are expected to be high responders), and who are undergoing infertility treatment with a controlled ovarian stimulation protocol using hMG as the gonadotropin, have a significantly higher ongoing pregnancy rate compared to patients undergoing infertility treatment with a controlled ovarian stimulation protocol using rFSH as the gonadotropin. In other words, the compositions and methods described herein are for the selection (e.g., selection of patients with high baseline levels of AMH, estradiol, LH and / or testosterone as disclosed herein) of patients diagnosed with oligo-ovulation (e.g., women diagnosed with oligo-ovulation and PCOS), who are expected high responders to controlled ovarian stimulation infertility treatment with HP-hMG (rather than rFSH) as the gonadotropin, and which may be associated with a relatively high ongoing pregnancy rate, which is derived from the surprising and unexpected finding.

[0009] Provided herein is a composition comprising highly purified menotropin (HP-hMG) for use in the treatment of infertility by optionally controlled ovarian stimulation in patients with polycystic ovary syndrome (PCOS), wherein the patient has a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) prior to treatment / stimulation.

[0010] Also provided herein is a composition comprising highly purified menotropin (HP-hMG) for use in the treatment of infertility by optionally controlled ovarian stimulation in patients with oligo-ovulation due to polycystic ovary syndrome (PCOS), wherein the patient has a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) prior to treatment / stimulation.

[0011] In any embodiment, the composition for use may comprise 75 to 450 IU of HP-hMG. In any embodiment, the treatment of infertility may optionally include administering to the patient a daily dose of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day of HP-hMG from the first day of treatment to at least the fifth day of treatment.

[0012] In any embodiment, the treatment of infertility includes identifying (e.g., diagnosing) a patient having (a) serum anti-Müllerian hormone (AMH) levels of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) before treatment / stimulation, and (b) serum estradiol levels of 145 pmol / L or higher (e.g., serum estradiol levels of 150 pmol / L or higher) before treatment / stimulation, and optionally (c) serum testosterone levels of 1.10 nmol / L or higher (e.g., serum testosterone levels of 1.14 nmol / L or higher) before treatment / stimulation, and (d) serum luteinizing hormone (LH) levels of 7 U / L or higher (e.g., serum luteinizing hormone of 7.55 U / L or higher) before treatment / stimulation; and optionally administering to the patient a daily dose of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day of HP-hMG from the first day of treatment to at least the fifth day of treatment.

[0013] Also provided is a composition comprising highly purified menotropins (HP-hMG) for use in the treatment of infertility by optionally controlled ovarian stimulation in patients with polycystic ovary syndrome (PCOS) and having serum anti-Müllerian hormone (AMH) levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, the treatment comprising identifying (e.g., diagnosing) patients with PCOS having serum anti-Müllerian hormone (AMH) levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation; and optionally administering to the patient a daily dose of HP-hMG of 75 - 450 IU / day, preferably 75 - 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day from day 1 of treatment to at least day 5 of treatment.

[0014] Also provided is a composition comprising highly purified menotropins (HP-hMG) for use in the treatment of infertility by optionally controlled ovarian stimulation in patients with oligo-ovulation due to polycystic ovary syndrome (PCOS) and having serum anti-Müllerian hormone (AMH) levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, the treatment comprising identifying (e.g., diagnosing) patients with oligo-ovulation due to PCOS having serum anti-Müllerian hormone (AMH) levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation; and optionally administering to the patient a daily dose of HP-hMG of 75 - 450 IU / day, preferably 75 - 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day from day 1 of treatment to at least day 5 of treatment.

[0015] In any embodiment, the treatment of infertility involves identifying (e.g., diagnosing) patients having (a) serum anti-Müllerian hormone (AMH) levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, and (b) serum estradiol levels of 145 pmol / L or more before treatment / stimulation (e.g., serum estradiol levels of 150 pmol / L or more), and optionally, (c) serum testosterone levels of 1.10 nmol / L or more before treatment / stimulation (e.g., serum testosterone levels of 1.14 nmol / L or more), and (d) serum luteinizing hormone (LH) levels of 7 U / L or more before treatment / stimulation (e.g., serum luteinizing hormone of 7.55 U / L or more); and optionally administering to the patient a daily dose of HP-hMG of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 of treatment to at least day 5 of treatment.

[0016] Regarding the compositions for use disclosed herein, the treatment of infertility disclosed herein increases the ongoing pregnancy rate compared to treatment with recombinant follicle-stimulating hormone (rFSH).

[0017] In any embodiment of the compositions for use disclosed herein, the treatment may further include inducing final follicle maturation by administering hCG or optionally a GnRH agonist supplemented with hCG.

[0018] In any embodiment of the compositions for use disclosed herein, the treatment may be a fresh transfer method that further includes recovering oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally evaluating the quality / morphology of the blastocysts, and transplanting fresh blastocysts (optionally selected, for example, based on a visual evaluation of quality / morphology) into the uterus.

[0019] In any embodiment of the composition for use disclosed herein, the procedure may further be a cryopreservation transfer method that includes recovering an oocyte, fertilizing the oocyte, growing the fertilized oocyte to the blastocyst stage, optionally evaluating the chromosomal quality of the blastocyst, freezing one or more or all of the blastocysts, and transferring the thawed frozen blastocyst (e.g., a euploid blastocyst selected based on chromosomal evaluation) to the uterus.

[0020] In any embodiment of the composition for use disclosed herein, the procedure includes recovering an oocyte, freezing the unfertilized oocyte, then thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocytes to the blastocyst stage, optionally evaluating the quality / morphology of the blastocyst, and transferring the blastocyst (optionally selected, for example, based on a visual evaluation of quality / morphology) to the uterus; or recovering an oocyte, freezing the unfertilized oocyte, then thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocytes to the blastocyst stage, optionally evaluating the chromosomal quality of the blastocyst, freezing one or more or all of the blastocysts, and transferring the thawed frozen blastocyst (e.g., a euploid blastocyst selected based on chromosomal evaluation) to the uterus.

[0021] In any embodiment of the composition for use disclosed herein, the procedure may further include administering a GnRH antagonist starting on the sixth day of the procedure.

[0022] In any embodiment of the composition for use disclosed herein, the patient is not anovulatory, is between 21 and 35 years old, and has a BMI of 18 to 30 kg / m2 at the start of the procedure.

[0023] Also provided is an assisted reproductive technology method for treating a female diagnosed with one or both of oligo-ovulation and PCOS and expected to have a high ovarian response to controlled ovarian stimulation, the method comprising identifying a female diagnosed with one or both of oligo-ovulation and PCOS and having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L (5.0 ± 0.2 ng / ml or higher), and performing controlled ovarian stimulation by administering to the identified female a highly purified menotropin (HP-hMG) in an amount effective to stimulate follicular growth. In some embodiments, the female is identified as being diagnosed with oligo-ovulation. In some embodiments, the female is identified as being diagnosed with oligo-ovulation due to PCOS. In some embodiments, the female is identified as being diagnosed with PCOS. In some embodiments, the female is identified as being diagnosed with both oligo-ovulation and PCOS. The method may further comprise identifying the female as having one or more of (i) a serum luteinizing hormone (LH) level of 7 U / L or higher before treatment / stimulation, (ii) a serum testosterone level of 1.10 nmol / L or higher before treatment / stimulation, and (iii) a serum estradiol level of 145 pmol / L or higher before treatment / stimulation. The method is effective to increase the ongoing pregnancy rate after in vitro fertilization as compared to treatment / controlled ovarian stimulation by administration of recombinant follicle-stimulating hormone (rFSH).

[0024] The HP-hMG may be administered at a dose of 75 to 450 IU of hMG per day. The HP-hMG may be administered, for example, at a dose of 150 IU of hMG per day from day 1 to at least day 5 of treatment.

[0025] The method may further comprise administering a gonadotropin-releasing hormone antagonist (GnRH antagonist) starting on day 6 of treatment / stimulation.

[0026] The method may further comprise inducing final follicular maturation by administering human chorionic gonadotropin (hCG) or, optionally, a gonadotropin-releasing hormone agonist (GnRH agonist) supplemented with hCG.

[0027] The method comprises (a) recovering an oocyte, fertilizing the oocyte, growing the fertilized oocyte to the blastocyst stage, optionally evaluating the quality / morphology of the blastocyst and transplanting a fresh blastocyst (optionally selected, for example, based on a visual evaluation of quality / morphology) into the uterus; or (b) recovering an oocyte, fertilizing the oocyte, growing the fertilized oocyte to the blastocyst stage, optionally evaluating the chromosomal quality of the blastocyst, freezing one or more or all of the blastocysts and transplanting a thawed frozen blastocyst (e.g., a euploid blastocyst selected based on chromosomal evaluation) into the uterus; or (c) recovering an oocyte, freezing the unfertilized oocyte, then thawing one or more of the oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocytes to the blastocyst stage, optionally evaluating the quality / morphology of the blastocyst and transplanting a blastocyst (optionally selected, for example, based on a visual evaluation of quality / morphology) into the uterus; or (d) recovering an oocyte, freezing the unfertilized oocyte, then thawing one or more of the frozen oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocytes to the blastocyst stage, optionally evaluating the chromosomal quality of the blastocyst, freezing one or more or all of the blastocysts and transplanting a thawed frozen blastocyst (e.g., a euploid blastocyst selected based on chromosomal evaluation) into the uterus.

[0028] The female is not anovulatory, is between 21 and 35 years of age, and may have a BMI of 18 to 30 kg / m2 at the start of treatment.

[0029] Also provided herein is the use of HP-hMG in the manufacture of a medicament for the treatment of infertility in women identified as having serum AMH levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) prior to treatment / stimulation, as identified as having oligovulation and / or diagnosed with PCOS, the treatment comprising administering to the identified women an amount of highly purified menotropins (HP-hMG) effective to stimulate follicle growth. This treatment may further comprise, prior to administration, identifying the woman as having one or more of (i) a serum luteinizing hormone (LH) level of 7 U / L prior to treatment / stimulation, (ii) a serum testosterone level of 1.10 nmol / L or more prior to treatment / stimulation, and (iii) a serum estradiol level of 145 pmol / L or more prior to treatment / stimulation. This treatment is effective to increase the ongoing pregnancy rate after in vitro fertilization as compared to treatment / stimulation by administration of recombinant follicle stimulating hormone (rFSH).

[0030] The above summary is illustrative and explanatory and is intended to provide further description of the invention. Refer to the following detailed description for a more thorough understanding of the invention. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description.

Best Mode for Carrying Out the Invention

[0031] Described herein are methods of assisted reproductive technology, such as methods of treating infertility in patients diagnosed with oligovulation and / or PCOS. Specifically, described herein are women diagnosed with oligovulation and / or PCOS (e.g., women experiencing oligovulation due to PCOS or diagnosed with oligovulation and PCOS) and expected to have a high ovarian response to controlled ovarian stimulation (e.g., expected to be high responders) (e.g., women having baseline levels of AMH, estradiol, LH, and / or testosterone as disclosed herein), a controlled ovarian stimulation (COS) method that may be particularly useful. As shown in Example 1, this method is useful for increasing the ongoing pregnancy rate.

[0032] The present invention is based on the unexpected finding by the inventors that the ongoing pregnancy rate is improved by the use of highly purified menotropin (HP-hMG) for the treatment of COS in patients (e.g., women experiencing oligo-ovulation due to PCOS) expected to be good responders diagnosed with oligo-ovulation. As reported in Example 1 below, patients (N = 50) expected to be high responders diagnosed with oligo-ovulation (e.g., women experiencing oligo-ovulation due to PCOS) and treated with HP-hMG as gonadotropin had a 19.2% higher ongoing pregnancy rate (95% confidence interval 1.2% - 37.3%) compared to patients (N = 56) treated with rFSH as gonadotropin. These patients had baseline serum levels of AMH of 35.7 pmol / L or more (5.0 ng / ml or more), LH of 7 U / L or more, testosterone of 1.10 nmol / L or more, and estradiol of 145 pmol / L or more. As discussed in Example 1 below, based on serum levels of, for example, these AMH, estradiol, LH, and testosterone, this patient population appeared to include patients with PCOS, e.g., patients in whom oligo-ovulation was due to PCOS. Based on this finding, the compositions and methods disclosed herein are for the treatment with HP-hMG rather than FSH to achieve a higher ongoing pregnancy rate, and are based on the selection of expected high responder patients diagnosed with oligo-ovulation and / or PCOS, e.g., patients with baseline serum levels of AMH of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more), estradiol of 145 pmol / L or more, LH of 7 U / L or more, and / or testosterone of 1.10 nmol / L or more.

[0033] Definitions As used herein, technical and scientific terms have the meanings commonly understood by those of ordinary skill in the art of assisted reproductive technology to which the present invention pertains, unless otherwise defined. Various methodologies known to those of ordinary skill in the art are cited herein. Unless otherwise specified, any suitable materials and / or methods known to those of ordinary skill in the art may be used in the practice of the present invention. However, specific materials and methods are described. The materials, reagents, and the like mentioned in the following description and examples are available from commercial sources unless otherwise noted.

[0034] As used herein, the singular forms "a", "an", and "the" include both the singular and the plural unless there is a clear stipulation indicating otherwise.

[0035] As used herein, the term "about" means that a number or range is not limited to the exact number or range recited, but includes the range before and after the recited number or range, as would be understood by those of ordinary skill in the art depending on the context in which the number or range is used. Unless otherwise clear from the context or the convention in the art, "about" means plus or minus 10% of a particular term.

[0036] As used herein, the term "oligo-ovulation" refers to sporadic or irregular ovulation (e.g., in women with cycles longer than 31 days) with a total of 8 or fewer menstrual cycles (periods) per year. As used herein, the phrases "identified as oligo-ovulatory" or "diagnosed as oligo-ovulatory" patients and "patients with oligo-ovulation" are used interchangeably to refer to patients with 8 or fewer menstrual cycles (periods) in a year, excluding anovulatory patients. Oligo-ovulation is one of the most common causes of infertility in women.

[0037] As used herein, the term "anovulatory" or "anovulation" refers to patients in whom the ovaries do not release an oocyte during the menstrual cycle. Thus, ovulation does not occur. Chronic anovulation is a common cause of infertility. Generally, the patients of the compositions and methods described herein are not anovulatory patients.

[0038] As used herein, "polycystic ovary syndrome" or "PCOS" refers to a hormonal disorder characterized by two or more of elevated testosterone levels, polycystic ovaries, and ovulatory dysfunction (e.g., infrequent, irregular, and / or long menstrual cycles). PCOS can be diagnosed according to the Rotterdam criteria, excluding other causes of androgen excess or ovulatory dysfunction, based on the presence of at least two of (i) androgen excess, (ii) ovulatory dysfunction, and (iii) polycystic ovaries.

[0039] As used herein, "ongoing pregnancy" refers to a pregnancy with a viable fetus and detectable fetal heart tones at 10 - 11 weeks of gestation (e.g., 8 - 9 weeks after blastocyst / embryo transfer).

[0040] As used herein, "clinical pregnancy" refers to a pregnancy and detectable fetal heart tones at 5 - 6 weeks of gestation (e.g., 3 - 4 weeks after blastocyst / embryo transfer).

[0041] As used herein, "female" refers to an adult female human. Typically, the females treated according to the compositions and methods described herein are 35 years of age or younger and have serum levels of anti - Müllerian hormone (AMH) of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) as measured using the Beckmann - Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644 - 53 (2013) or equivalent AMH levels evaluated by another method and 30 kg / m 2Have the following BMI. In some embodiments, women treated according to the compositions and methods described herein have been identified as being between 21 and 35 years of age prior to treatment. In some embodiments, women treated according to the compositions and methods described herein have been identified as being 35 years of age or younger, or 34 years of age or younger, prior to treatment. In some embodiments, women treated according to the methods described herein have been identified as being between 21 and 34 years of age, or between 21 and 33 years of age, or between 21 and 32 years of age, or between 21 and 31 years of age prior to treatment. In some embodiments, women treated according to the methods described herein have a BMI of 18 - 30 kg / m 2 prior to treatment. In some embodiments, women treated according to the methods described herein have a BMI of 38 kg / m 2 or less, 36 kg / m 2 or less, 34 kg / m 2 or less, 32 kg / m 2 or less, 30 kg / m 2 or less, or 28 kg / m 2 or less, such as a BMI of 18 - 38, 18 - 36, 18 - 34, 18 - 32, 18 - 30, or 18 - 28 kg / m 2 prior to treatment. In some embodiments, women treated according to the methods described herein have a BMI of 18 - 25 kg / m 2 , 18 - 26 kg / m 2 , 18 - 27 kg / m 2 , 18 - 28 kg / m 2 , 18 - 29 kg / m 2 or 18 - 30 kg / m 2 prior to treatment.

[0042] As used herein, a subject classified as "expected to have a high ovarian response to controlled ovarian stimulation" or a "predicted high responder" refers to a female who has the potential to grow a large number of follicles or oocytes according to the standard protocol of controlled ovarian stimulation (COS), for example, a female who has a higher than average likelihood of producing 15 or more oocytes. A female can be identified as a predicted high responder if she has produced 15 or more oocytes in a past ART cycle (e.g., a past COS treatment). Additionally or alternatively, a female can be identified as a predicted high responder if she is considered to be at risk of developing OHSS. Additionally or alternatively, a female can be identified as a predicted high responder if she has serum levels of anti-Müllerian hormone (AMH) of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) as measured using the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013), for example, serum AMH levels of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) or equivalent AMH levels evaluated by another method.

[0043] The term "menotropins" as used herein includes human menopausal gonadotropins such as "highly purified menotropins" or "HP-hMG" or "hMG". As used herein, the terms "highly purified menotropins" and "HP-hMG" refer to highly purified hMG products that contain both follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG)-driven luteinizing hormone (LH) activity, such as hMG products in which most of the LH activity is provided by hCG, such as products in which 90% or more or 95% or more of the LH activity is provided by hCG. See, for example, Foutouh et al., Reproductive BioMed. Online, 14(2):145-47(2007); Wolfenson et al., Reprod. BioMed. Online, 10(4):442-54(2005). In some embodiments, HP-hMG is an HP-hMG product available under the trademark MENOPUR® of Ferring Pharmaceuticals, Inc., which HP-hMG product contains FSH and hCG-driven LH activity and in which, when evaluated by immunoreactivity, 95% or more of the LH activity is provided by hCG (pituitary hCG). See, for example, Arce and Smitz, Human Fertility, 14(3):192-99(2011). When reconstituted for use, one vial (75 IU of HP-hMG) of MENOPUR® contains 75 IU of FSH activity and 75 IU of LH activity, and the hCG contributes approximately 70 IU of LH activity.

[0044] The term "GnRH agonist" as used herein includes gonadotropin releasing hormone (GnRH) agonists such as buserelin (e.g., SUPRECUR®), leuprolide (e.g., leuprolide acetate, e.g., LUPRON®), nafarelin (e.g., SYNAREL®) and triptorelin (e.g., TRELSTAR®).

[0045] As used herein, the term "GnRH antagonist" includes gonadotropin-releasing hormone (GnRH) antagonists, for example ganirelix acetate (e.g. ORGALUTRAN®) and cetrorelix acetate (e.g. CETROTIDE®), which block the action of GnRH by competitively blocking GnRH receptors on gonadotropin-secreting cells of the pituitary gland, thereby preventing the production / release of gonadotropins and preventing the ovulation of immature eggs (release of oocytes).

[0046] As used herein, the phrase "effective amount" refers to an administered amount determined to bring about a particular pharmacological effect for which a drug is administered to a subject in need of such treatment. It is emphasized that a therapeutically effective amount is not necessarily effective in treating the conditions described herein in a given patient, even if one of ordinary skill in the art would consider such an amount to be a therapeutically effective amount. For convenience only, exemplary dosages and therapeutically effective amounts are provided below in relation to adult female human subjects. One of ordinary skill in the art can adjust such amounts according to standard techniques as needed for a particular subject and / or condition / disease.

[0047] Assisted reproductive technology methods The treatment methods described herein are useful for any reproductive technology method involving controlled ovarian stimulation (COS), for example in vitro fertilization, for example in vitro fertilization by intracytoplasmic sperm injection (ICSI), methods involving fresh transfer of fertilized eggs (e.g., blastocysts / embryos), methods involving freezing of fertilized eggs for later transfer, and methods involving freezing of unfertilized oocytes for later fertilization.

[0048] As described above, the present invention provides a composition and method of a reproductive technique involving the use of highly purified menotropin (HP-hMG) as a gonadotropin for controlled ovarian stimulation (COS) in women with oligovulation and / or polycystic ovary syndrome (PCOS) who are expected to have a high ovarian response to COS and who are undergoing COS (e.g., women experiencing oligovulation due to PCOS and women diagnosed with oligovulation and PCOS). Similarly as described above, for the purposes of the compositions and methods disclosed herein, a woman can be identified as expected to have a high ovarian response to COS based on a high ovarian response shown in a past ART cycle (e.g., a past COS treatment), or when measured using the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), having a serum level of anti-Müllerian hormone (AMH) of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher), e.g., a serum AMH level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) or an equivalent AMH level as evaluated by another method, is identified as expected to have a high ovarian response to COS. The serum level of AMH is a surrogate marker of functional follicular reserve, and a positive correlation between the serum level of AMH and ovarian response (e.g., oocyte yield) has been reported (ibid). In accordance with the compositions and methods described herein, a woman is typically identified as an expected hyper-responder based on her serum AMH level.

[0049] In any embodiment of the present invention or any embodiment of the compositions and methods disclosed herein, the step of identifying (e.g., diagnosing) a patient having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) before treatment / stimulation can be replaced by, or enhanced by, the step of identifying a patient who has produced 15 or more oocytes in a past ART cycle (e.g., a past COS treatment) before treatment / stimulation or the step of identifying a patient who is considered to be at risk of developing OHSS before treatment / stimulation, as will be understood.

[0050] The assisted reproductive technology method described herein involves performing controlled ovarian stimulation in women who have been diagnosed with oligo-ovulation and / or PCOS (e.g., women experiencing oligo-ovulation due to PCOS and women diagnosed with both oligo-ovulation and PCOS) and who are expected to have a high ovarian response to controlled ovarian stimulation by stimulating follicular growth using HP-hMG. In any embodiment described herein, HP-hMG can be MENOPUR®.

[0051] The treatment method may include identifying a woman as being diagnosed with oligo-ovulation and / or PCOS (e.g., oligo-ovulation due to PCOS) before performing controlled ovarian stimulation. Thus, in some embodiments, a woman is identified as being diagnosed with oligo-ovulation, in some embodiments, a woman is identified as being diagnosed with oligo-ovulation due to PCOS, in some embodiments, a woman is identified as being diagnosed with PCOS, and in some embodiments, a woman is identified as being diagnosed with both oligo-ovulation and PCOS.

[0052] This treatment method may further include identifying a female as likely to have a high ovarian response to controlled ovarian stimulation before performing the controlled ovarian stimulation. Thus, the assisted reproductive technology method described herein includes selecting a female diagnosed with oligo-ovulation and / or PCOS, and before performing the controlled ovarian stimulation, for example, if this female is measured using the Beckmann-Coulter Gen 2 assay, having a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) or determining an equivalent AMH level measured by another method, identifying the female as likely to have a high ovarian response to the controlled ovarian stimulation. In any embodiment, this female may or may be identified as having a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) when measured using the Beckmann-Coulter Gen 2 assay or an equivalent AMH level measured by another method. In any embodiment, this patient (e.g., female) is not an anovulatory female.

[0053] In addition or alternatively, in any embodiment, the female may or may be identified as having a serum estradiol level of 145 pmol / L or more before treatment / stimulation or a serum estradiol level of 150 pmol / L or more before treatment / stimulation. In addition or alternatively, in any embodiment, the female may or may be identified as having one or more of a serum luteinizing hormone (LH) level of 7 U / L or more (or a serum luteinizing hormone (LH) level of 7.55 U / L or more before treatment / stimulation) and a serum testosterone level of 1.10 nmol / L or more (or a serum testosterone level of 1.14 nmol / L or more before treatment / stimulation) before treatment / stimulation.

[0054] Therefore, in any embodiment, a female may or may be identified as having one or more or all of (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more); (b) a serum estradiol level of 145 pmol / L or more (e.g., a serum estradiol level of 150 pmol / L or more); (c) a serum testosterone level of 1.10 nmol / L or more (e.g., a serum testosterone level of 1.14 nmol / L or more), and (d) a serum luteinizing hormone (LH) level of 7 U / L or more (e.g., a serum luteinizing hormone of 7.55 U / L or more) before treatment / stimulation. In some embodiments, a female may or may be identified as having (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more); and (b) a serum estradiol level of 145 pmol / L or more (e.g., a serum estradiol level of 150 pmol / L or more) before treatment / stimulation. In some embodiments, a female may or may be identified as having (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more), and (b) a serum estradiol level of 145 pmol / L or more (e.g., a serum estradiol level of 150 pmol / L or more), and optionally, (c) a serum testosterone level of 1.10 nmol / L or more (e.g., a serum testosterone level of 1.14 nmol / L or more), and (d) one or both of a serum luteinizing hormone (LH) level of 7 U / L or more (e.g., a serum luteinizing hormone of 7.55 U / L or more) before treatment / stimulation.

[0055] The method involves administering to a subject an effective amount (e.g., from about 75 IU / day to about 450 IU / day, such as 75 IU / day, 150 IU / day, 225 IU / day, 300 IU / day, 375 IU / day or 450 IU / day) of HP-hMG to stimulate follicular growth. Typically, the starting dose of HP-hMG is 150 IU / day, but can range from 75 IU / day to 225 IU / day. Administration of HP-hMG is typically initiated on day 2 or 3 of the patient's menstrual cycle, such that day 1 of treatment (also referred to herein as stimulation day 1) is day 2 or 3 of the patient's menstrual cycle. As noted above, pharmaceutical compositions containing HP-hMG are commercially available (e.g., formulated for subcutaneous injection, sold as the MENOPUR® product from Ferring Pharmaceuticals, Inc.). Administration of HP-hMG is continued daily for a total stimulation period of about 1 to about 20 days, typically a total stimulation period of 8 to 12 days, more specifically typically about 9 to 11 days, such as about 10 days, until a desired level of follicle production is achieved.

[0056] For example, it is known in the art to adjust the administration of gonadotropins during the stimulation period based on the ovarian (follicular) response and serum estradiol levels of a subject that can be evaluated by transvaginal ultrasound examination (TVUS) (e.g., increasing or decreasing the administration of HP-hMG or rFSH). For example, it is known to adjust the administration of gonadotropins during the stimulation period if one or both of the patient's serum estradiol level and the number of follicles greater than 12 mm are excessively low or excessively high. Such evaluation and adjustment can be performed during the stimulation period, typically at any time during the mid-follicular phase of stimulation, typically on the 5th, or 6th, or 7th day of stimulation. Thus, the treatment may include administering a daily dose of HP-hMG (e.g., MENOPUR®) at a starting daily dose of 75 - 450 IU / day (e.g., 150 IU / day) by injection from the first day of treatment (the first day of stimulation) to, for example, at least the 5th day of stimulation (the 5th day of stimulation). Accordingly, the dose can be adjusted up or down (e.g., in increments of 75 IU of hMG) to a maximum daily dose of 300 or 450 IU of hMG or a minimum daily dose of 75 IU of hMG (e.g., depending on the patient's ovarian response).

[0057] As described above, continue the HP-hMG administration daily until the desired level of follicle production is achieved. For example, HP-hMG can be administered until three follicles with a diameter of 17 mm or more are obtained, as determined by TVUS. Typically, the maximum HP-hMG administration period is 20 days, and the typical administration period is 8 - 12 days, more specifically typically about 9 - 11 days, for example about 10 days.

[0058] In some embodiments, the treatment method includes administration of a GnRH antagonist during a part of the gonadotropin (e.g., HP-hMG) administration period. For example, the GnRH antagonist can be administered when the leading follicle reaches 14 mm in diameter and continued throughout the remaining period of gonadotropin (e.g., HP-hMG) administration. For example, the GnRH antagonist can be started and administered on the 5th, or 6th, or 7th day of stimulation (e.g., the 6th day of stimulation) and continued throughout the remaining period of gonadotropin (e.g., HP-hMG) administration. When the GnRH antagonist is ganirelix acetate (e.g., ORGALUTRAN (registered trademark)), a typical dose is 0.25 mg / day administered subcutaneously.

[0059] In other embodiments, the treatment method includes administration of a GnRH agonist before performing controlled ovarian stimulation, for example, administration of triptorelin (typically 0.1 mg / day subcutaneously) or leuprorelin (e.g., leuprolide acetate, e.g., LUPRON (registered trademark)) before performing controlled ovarian stimulation.

[0060] In some embodiments, the treatment method further includes inducing final follicle maturation. For example, when a desired level of follicle production is achieved, the trigger for final follicle maturation can be stimulated by methods known in the art (e.g., a bolus injection of human chorionic gonadotropin (hCG)). For example, in patients with 3 or more follicles each having a diameter of 17 mm or more and typically an estradiol (E2) level of less than 10,000 pmol / mL, the trigger for final follicle maturation can be stimulated. Thus, in some embodiments, the treatment method can include administering hCG to induce final follicle maturation. The dose of hCG can be 5,000 IU to 10,000 IU. A typical dose of recombinant hCG (e.g., OVITRELLE (registered trademark), Merck) is 250 μg (6,500 IU of hCG activity) and is usually administered by a single subcutaneous injection.

[0061] GnRH agonists can be used as an alternative to the use of hCG to induce final follicular maturation. Thus, in some embodiments, the treatment method may include administering a gonadotropin-releasing hormone (GnRH agonist) to induce final follicular maturation. The GnRH agonist can be used to induce final follicular maturation in patients, for example, in cases of overreaction, such as when there are more than 25 follicles with a diameter of 12 mm or more (after COS treatment) or the serum estradiol (E2) level is 5,000 pmol / L or more, or when there are more than 30 follicles with a diameter of 12 mm or more or the serum estradiol (E2) level is 5,000 pmol / L or more, or when the estradiol (E2) level is 10,000 pmol / L or more, or when there are 20 or more follicles with a diameter of 12 mm or more or the estradiol (E2) level is 15,000 pmol / L or more. The GnRH agonist can be leuprolide acetate (e.g., LUPRON®) and is typically used at a dose of, for example, 1 - 4 mg. The GnRH agonist can be triptorelin acetate (e.g., DECAPEPTYL®) and is typically used at a dose of, for example, 0.2 mg. When using a GnRH agonist to induce final follicular maturation, a small amount of hCG, such as 500 - 3000 IU of hCG, can also be used. When using a GnRH agonist to induce final follicular maturation, for example, for safety reasons, it typically follows a "freeze-all" protocol (discussed below).

[0062] In some embodiments, the treatment method further includes recovering the oocytes and fertilizing the oocytes by methods known in the art (e.g., ICSI).

[0063] In some embodiments, the present treatment method is a fresh transfer method. In the fresh transfer method, one or more blastocysts are selected for transfer. The remaining blastocysts can be frozen (including vitrification) by methods known in the art for future transfer. Thus, in the fresh transfer embodiment, the method includes recovering oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, recovering the blastocysts, optionally selecting the blastocysts based on quality / morphology evaluation, and transferring the fresh blastocysts (optionally selected based on, for example, quality / morphology evaluation) to the uterus. In a specific embodiment, the compositions and methods described herein are used in a single blastocyst transfer protocol, and a single blastocyst is selected for fresh transfer. According to this embodiment, the remaining blastocysts can be frozen by methods known in the art for future transfer.

[0064] In some embodiments, the method is a frozen transfer method. In the frozen transfer embodiment, the method includes recovering oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally evaluating the chromosomal quality of the blastocysts, freezing one or more or all of the blastocysts, and transferring the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) to the uterus. In the freezing and "all freezing" methods, the selected blastocysts are frozen by methods known in the art for future implantation / transfer.

[0065] In some embodiments, unfertilized oocytes are frozen. In such embodiments, the method includes recovering oocytes and freezing one or more or all of the recovered oocytes by methods known in the art for future fertilization. In such embodiments, the method then includes thawing one or more frozen oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally selecting blastocysts based on quality / morphology evaluation, and transplanting the (optionally selected, e.g., based on visual evaluation of quality / morphology) blastocysts into the uterus. Alternatively, the method includes recovering oocytes, freezing one or more or all of the recovered oocytes for future fertilization, then thawing one or more frozen oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, performing chromosomal evaluation of the blastocysts, freezing the blastocysts, and transplanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus.

[0066] As described above, in some embodiments, the method includes evaluating the chromosomal quality of blastocysts or selecting blastocysts based on chromosomal evaluation. This can be done by methods known in the art used to examine blastocysts (embryos) for genetic and chromosomal information, such as preimplantation genetic screening (PGT-A, also known as PGS) or preimplantation genetic diagnosis (PGD). When PGS or PGD is used, all chromosomes can be evaluated and only blastocysts identified as having a low risk of chromosomal abnormalities are selected for embryo transfer (transfer into the uterus). This is an alternative to the conventional method of selecting embryos according to their microscopic appearance after growing them in an incubator for 3 to 5 days.

[0067] As described above, the method described herein is useful for increasing the ongoing pregnancy rate as compared to equivalent methods using recombinant follicle stimulating hormone (rFSH) as the gonadotropin. Specifically, the method described herein increases the ongoing pregnancy rate as compared to equivalent methods using rFSH (e.g., GONAL-F) as the gonadotropin. As reported in Example 1, by the method described herein, the ongoing pregnancy rate can be 15% or 19% or higher.

[0068] Accordingly, in some embodiments, there is provided an assisted reproductive technology method for treating a female diagnosed with one or both of oligovulation and PCOS and expected to have a high ovarian response to controlled ovarian stimulation, the method comprising identifying the female as being diagnosed with one or both of oligovulation and PCOS and having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L (5.0 ± 0.2 ng / ml or higher), and performing infertility treatment (e.g., controlled ovarian stimulation) by administering to the identified female a highly purified menotropin (HP-hMG) in an amount effective to stimulate follicular growth. The method may further comprise identifying the female as having one or more of (i) a serum luteinizing hormone (LH) level of, for example, 7 U / L or higher before treatment, (ii) a serum testosterone level of, for example, 1.10 nmol / L or higher before treatment, and (iii) a serum estradiol level of, for example, 145 pmol / L or higher before treatment. HP-hMG may typically be administered at a dose of 75 to 450 IU of hMG per day, for example 150 IU of hMG per day, from day 1 of treatment to at least, for example, day 5 of treatment, wherein the dose may be adjusted up or down (e.g., in increments of 75 IU of HP-hMG) according to the patient's response until the desired level of follicular maturation is achieved for induction of final follicular maturation. The method may further comprise administering a gonadotropin-releasing hormone antagonist (GnRH antagonist), starting, for example, on day 6 of treatment. The method may further comprise inducing final follicular maturation by administering human chorionic gonadotropin (hCG) or optionally a gonadotropin-releasing hormone agonist (GnRH agonist) supplemented with hCG. As discussed above and as shown in Example 1 below, this method is effective in increasing the ongoing pregnancy rate after in vitro fertilization compared to treatment (e.g., controlled ovarian stimulation) by administration of recombinant follicle-stimulating hormone (rFSH).

[0069] In one example, the method comprises identifying a female who has been diagnosed with one or both of oligovulation and PCOS (e.g., oligovulation due to PCOS) and has a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L (5.0 ± 0.2 ng / ml or higher), and performing infertility treatment (e.g., controlled ovarian stimulation) by administering HP-hMG to the identified female at a dose of, for example, 150 IU per day on the first day of treatment to at least, for example, the fifth day of treatment, wherein the dose can be adjusted up or down (e.g., in increments of 75 IU of HP-hMG) according to the patient's response until a desired level of follicular maturation is achieved for the induction of final follicular maturation. In this example, the maximum daily dose is 300 or 450 IU of HP-hMG, and the minimum daily dose is 75 IU of HP-hMG. HP-hMG is administered for a total treatment period (stimulation period) of about 1 to about 20 days, typically an 8- to 12-day total treatment (stimulation) period, more specifically typically about 9 to 11 days, e.g., about 10 days, until a desired level of follicle production is achieved.

[0070] According to the present invention, there is also provided a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in a patient (e.g., a female) with PCOS (e.g., identified or diagnosed with PCOS) having a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation (this patient is not an anovulatory patient). This treatment of infertility can be treatment of infertility by controlled ovarian stimulation. This composition may contain 75 to 450 IU of HP-hMG. This treatment may optionally include administering to the patient a daily dose of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day of HP-hMG from the first day of treatment to at least the fifth day of treatment. This daily dose of HP-hMG is administered over a total treatment period (stimulation period) of about 1 to about 20 days, typically 8 to 12 days, more specifically typically about 9 to 11 days, e.g., about 10 days, until the desired level of follicle production is achieved, e.g., after treatment at the starting dose on the first day of treatment to, e.g., the fifth day, and can be adjusted during this stimulation period, e.g., based on the patient's response.

[0071] According to the present invention, there is also provided a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in a patient (e.g., a female) with oligo-ovulation due to PCOS (e.g., identified or diagnosed as oligo-ovulation due to PCOS), having a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation (this patient is not an anovulatory patient). The treatment of this infertility can be the treatment of infertility by controlled ovarian stimulation. The composition may contain 75 to 450 IU of HP-hMG. The treatment may optionally include administering to the patient a daily dose of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day of HP-hMG from the first day of treatment to at least the fifth day of treatment. The daily dose of this HP-hMG can be adjusted during this stimulation period, for example, based on the patient's response, over a total treatment period (stimulation period) of about 1 to about 20 days, typically 8 to 12 days, more specifically typically about 9 to 11 days, e.g., about 10 days, until the desired level of follicle production is achieved, for example, after treatment with the starting dose on the first day of treatment to, for example, the fifth day of treatment.

[0072] In any embodiment, the composition can be for the treatment of patients having serum AMH levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation and serum estradiol levels of 145 pmol / L or more (e.g., serum estradiol levels of 150 pmol / L or more) before treatment / stimulation. The serum estradiol levels can be measured by methods known in the art, as described in Example 1. In any embodiment, this treatment, when measured using the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013) before treatment / stimulation, can include a further step of identifying patients having serum AMH levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more), e.g., AMH levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) or equivalent AMH levels evaluated by another method.

[0073] In any embodiment, this treatment can include a further step of identifying patients having serum AMH levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) and serum estradiol levels of 145 pmol / L or more (e.g., serum estradiol levels of 150 pmol / L or more) before treatment / stimulation, as disclosed above.

[0074] In any embodiment, the composition can be for the treatment of patients having one or more of a serum luteinizing hormone (LH) level of 7 U / L or more (e.g., a serum luteinizing hormone of 7.55 U / L or more) and / or a serum testosterone level of 1.10 nmol / L or more (e.g., a serum testosterone level of 1.14 nmol / L or more) before treatment / stimulation. The LH level and testosterone level in the serum can be measured by methods known in the art as described in Example 1. Thus, in any embodiment, this treatment can include a further step of identifying patients having a serum luteinizing hormone (LH) level of 7 U / L or more (e.g., a serum luteinizing hormone of 7.55 U / L or more) and / or a serum testosterone level of 1.10 nmol / L or more (e.g., a serum testosterone level of 1.14 nmol / L or more) before treatment / stimulation.

[0075] In any embodiment, this treatment involves: (a) identifying (e.g., diagnosing) a patient having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) and (b) a serum estradiol level of 145 pmol / L or more (e.g., a serum estradiol level of 150 pmol / L or more) before treatment / stimulation, and optionally, (c) a serum testosterone level of 1.10 nmol / L or more (e.g., a serum testosterone level of 1.14 nmol / L or more) and (d) a serum luteinizing hormone (LH) level of 7 U / L or more (e.g., a serum luteinizing hormone of 7.55 U / L or more) before treatment / stimulation; and optionally administering to the patient a daily dose of HP-hMG of 75 - 450 IU / day, preferably 75 - 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day from the first day to at least the fifth day of treatment.

[0076] According to the present invention, a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in patients (non-anovulatory patients, e.g., women) who have PCOS (e.g., are identified or diagnosed as having PCOS) and have a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, wherein the treatment comprises identifying (e.g., diagnosing) patients with PCOS having a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, as measured, for example, using the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or an equivalent AMH level evaluated by another method; optionally administering to the patient a daily dose of 75 to 450 IU, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day of HP-hMG from day 1 of treatment to at least day 5 of treatment; is also provided. The daily dose can be adjusted during this stimulation period, for example, based on the patient's response, until the desired level of follicle production is achieved, over a total stimulation period (treatment period) of about 1 to about 20 days, typically 8 to 12 days, more specifically typically about 9 to 11 days, e.g., about 10 days, starting from the starting dose on day 1 of treatment, e.g., on day 5 of treatment. This treatment of infertility can be treatment of infertility by controlled ovarian stimulation. The composition can contain 75 to 450 IU of HP-hMG.

[0077] According to the present invention, a composition (e.g., a pharmaceutical composition) comprising HP-hMG for use in the treatment of infertility in patients (non-anovulatory patients, e.g., women) who have oligovulation due to PCOS (e.g., are identified or diagnosed as having oligovulation due to PCOS) and have a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, wherein the treatment comprises Before treatment / stimulation, identify (e.g., diagnose) patients with oligo-ovulation due to PCOS having serum AMH levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) or equivalent AMH levels as evaluated by another method, when measured using, for example, the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013); Optionally, administer to such patient a daily dose of 75 to 450 IU, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day of HP-hMG from day 1 of treatment to at least day 5 of treatment; There is also provided a composition comprising. The daily dose may be adjusted during the total stimulation period (treatment period) of about 1 to about 20 days, typically 8 to 12 days, more specifically typically about 9 to 11 days, e.g., about 10 days, until the desired level of follicle production is achieved, e.g., after treatment at the starting dose on day 1 of treatment to, e.g., day 5 of treatment, e.g., based on the patient's response. This infertility treatment may be a treatment for infertility by controlled ovarian stimulation. The composition may contain 75 to 450 IU of HP-hMG.

[0078] In any embodiment, the present procedure identifies (e.g., diagnoses) patients having (a) serum anti-Müllerian hormone (AMH) levels of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, and (b) serum estradiol levels of 145 pmol / L or more (e.g., serum estradiol levels of 150 pmol / L or more) before treatment / stimulation, and optionally, (c) serum testosterone levels of 1.10 nmol / L or more (e.g., serum testosterone levels of 1.14 nmol / L or more) before treatment / stimulation, and (d) serum luteinizing hormone (LH) levels of 7 U / L or more (e.g., serum luteinizing hormone of 7.55 U / L or more) before treatment / stimulation, either or both; and optionally administering to the patient a daily dose of HP-hMG of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 of treatment to at least day 5 of treatment.

[0079] In a further aspect, according to the invention, there is provided the use of HP-hMG in the manufacture of a medicament (e.g., a pharmaceutical composition) for the treatment of infertility in a patient (e.g., a female, e.g., a non-anovulatory female) who is oligovulatory and / or has PCOS (e.g., a female with oligovulation due to PCOS), and who has a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation (e.g., as identified or diagnosed as having oligovulation and / or PCOS). The treatment of this infertility can be treatment of infertility by controlled ovarian stimulation. This composition may contain 75 - 450 IU of HP-hMG. This treatment may include identifying a patient who has a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation (e.g., when measured using the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644 - 53 (2013)) or an equivalent AMH level evaluated by another method. This treatment may further include the step of identifying a patient who has a serum estradiol level of 145 pmol / L or more (e.g., a serum estradiol level of 150 pmol / L or more) before treatment / stimulation. This treatment may further include, in addition, the step of identifying a patient who has a serum luteinizing hormone (LH) level of 7 U / L or more (e.g., a serum luteinizing hormone of 7.55 U / L or more) and / or a serum testosterone level of 1.10 nmol / L or more (e.g., a serum testosterone level of 1.14 nmol / L or more) before treatment / stimulation. The treatment of this infertility may include administering HP-hMG at a dose of 75 - 450 IU of hMG per day until a desired level of follicle production is achieved.

[0080] As described above, the treatment of infertility disclosed herein (i.e., according to each of the various embodiments disclosed herein) is associated with a higher ongoing pregnancy rate compared to equivalent treatment methods using recombinant follicle-stimulating hormone (rFSH) as a gonadotropin.

[0081] As described above, in any embodiment, the composition may comprise 75 - 450 IU of HP-hMG (e.g., MENOPUR®).

[0082] As described above, in any embodiment, the treatment of infertility involves a total stimulation period (treatment period) of about 1 to about 20 days, typically a total stimulation period of 8 - 12 days, more specifically typically about 9 - 11 days, e.g., about 10 days, during which a dose of 75 - 450 IU of HP-hMG per day, such as 75 IU / day, 150 IU / day, 225 IU / day, 300 IU / day, 375 IU / day or 450 IU / day (the dose can be adjusted during this stimulation period, e.g., based on the patient's response, after treatment with an initial dose on, e.g., the first day to, e.g., the fifth day of treatment) is administered to the patient until the desired level of follicle production is achieved. Thus, in any embodiment, the treatment may optionally include administering to the patient a daily dose of 75 - 450 IU / day, preferably 75 - 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day of HP-hMG from the first day of treatment to at least the fifth day of treatment.

[0083] In one example, the treatment includes administering to the patient a dose of 150 IU of HP-hMG per day from the first day to at least the fifth day of treatment. The dose can be adjusted up or down (e.g., in increments of 75 IU of hMG) from, e.g., the sixth day of treatment (e.g., depending on the patient's response). In this example, the maximum daily dose is 300 or 450 IU of hMG and the minimum daily dose is 75 IU of hMG.

[0084] In any embodiment, the treatment may further include the step of administering a GnRH antagonist starting at the time when the leading follicle reaches 14 mm in diameter and / or on the fifth, or sixth, or seventh day of stimulation (e.g., the sixth day of stimulation) and continuing throughout the remaining period of HP-hMG administration.

[0085] In any embodiment, the procedure may further comprise inducing final follicular maturation, as described above. To that end, the procedure may comprise administering hCG (e.g., recombinant hCG) or a GnRH agonist to induce final follicular maturation. As discussed above, when using a GnRH agonist to induce final follicular maturation, a small amount of hCG may also be used.

[0086] In any embodiment, the procedure may further comprise recovering (e.g., harvesting) the oocytes; fertilizing the oocytes (e.g., inseminating); and growing the fertilized oocytes to the blastocyst stage. Fertilization (e.g., insemination) may be in vitro fertilization, optionally intracytoplasmic sperm injection (ICSI).

[0087] In any embodiment, the procedure may be a fresh transfer method comprising recovering the oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, recovering the blastocysts, optionally selecting the blastocysts based on quality / morphology evaluation, and transferring (optionally selected, e.g., based on quality / morphology evaluation) fresh blastocysts to the uterus. The procedure may be a single blastocyst transfer protocol in which a single blastocyst is selected for fresh transfer. Optionally, the remaining blastocysts may be cryopreserved by methods known in the art for future transfer.

[0088] In any embodiment, the procedure can be a cryopreservation transfer method that includes recovering oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally evaluating the chromosomal quality of the blastocysts, freezing one or more or all of the blastocysts, and transferring thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) to the uterus. In cryopreservation and "all freezing" methods, selected blastocysts are frozen by methods known in the art for future implantation / transfer.

[0089] In any embodiment, the method can involve freezing unfertilized oocytes. Thus, the method can include recovering oocytes, freezing one or more or all of the recovered oocytes, then thawing one or more frozen oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally selecting blastocysts based on quality / morphology evaluation, and transferring (optionally selected, e.g., based on visual evaluation of quality / morphology) blastocysts to the uterus. Alternatively, the method can include recovering oocytes, freezing one or more or all of the recovered oocytes, then thawing one or more frozen oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, performing chromosomal evaluation of the blastocysts, freezing the blastocysts, and transferring thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) to the uterus.

[0090] Further aspects of the methods described herein are illustrated in the following examples, which are not limiting in any way.

Examples

[0091] Example 1 - Clinical Trial and Retrospective Analysis of MEGASET HR The following describes a retrospective analysis of data collected in a multi-center, randomized, assessor-blinded comparative non-inferiority trial in 620 women (aged 21 - 35 years) who had received intracytoplasmic sperm injection and single-blastocyst transfer (fresh transfer), had a body mass index (BMI) of 18 - 30 kg / m 2 2 and had serum anti-Müllerian hormone (AMH) levels of 35.7 pmol / L or higher. The trial was named "MENOPUR (registered trademark) in a Gonadotropin-Releasing Hormone (GnRH) Antagonist Cycle With Single-Blastocyst Transfer in a High Responder Subject Population (MEGASET HR)" (ClinicalTrials.gov identifier NCT02554279). Further details can be found at clinicaltrials.gov / ct2 / show / record / NCT02554279 and Witz et al., Fertility and Sterility (in press) (published online March 29, 2020).

[0092] 1. Study Population The main inclusion criteria were women aged 21 - 35 years who had regular ovulatory menstrual cycles of 21 - 45 days and a body mass index (BMI) of 18 - 30 kg 2 2 and who desired pregnancy. Patients / Subjects were defined as expected high responders with serum anti-Müllerian hormone (AMH) levels of 5 ng / mL or higher (35.71 pmol / L) at screening. This population had a documented history of infertility (e.g., unable to conceive for at least 12 months or, if receiving donor sperm, for at least 6 months), and serum FSH levels on cycle day 2 or 3 were 1 - 12 IU / L (inclusive).

[0093] Exclusion criteria were known stage III-IV endometriosis; a history of recurrent miscarriages not leading to birth (recurrent is defined as two or more consecutive miscarriages); and past in vitro fertilization (IVF) or assisted reproductive technology (ART) failures due to poor response to gonadotropins (poor response is defined as growth of two or fewer mature follicles or a history of two past failed cycle cancellations prior to oocyte retrieval due to poor response). Anovulatory women were also excluded.

[0094] 2. Test Protocol This was a multicenter, randomized, assessor-blinded, phase IV clinical trial comparing HP-hMG and rFSH in GnRH antagonist cycles with mandatory single blastocyst transfer (fresh transfer) in a high responder population in the United States. The purpose of this trial was to demonstrate that HP-hMG is at least non-inferior to rFSH with respect to the ongoing pregnancy rate (OPR) in potential high responders undergoing IVF / ICSI procedures.

[0095] Subjects were classified as potential high ovarian responders based on serum levels of AMH of 5.0 ng / ml or greater (e.g., 35.7 pmol / L or greater) by the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), using a single reference laboratory (ReproSource, Inc., Woburn, MA) that utilized materials and reagents from the Beckman Coulter-DSL assay (Chaska, MN).

[0096] The subjects were randomized 1:1 and underwent controlled ovarian stimulation (COS) with either a 150 IU dose of HP-hMG (N = 311; MENOPUR®, Ferring Pharmaceuticals, Inc.) or rFSH (N = 309; GONAL-F, EMD Serono) as gonadotropins in GnRH antagonist cycles. Treatment was initiated on cycle day 2 or 3 with a dose of 150 IU of HP-hMG or rFSH for the first 5 days. After day 6 of stimulation, dosing could be adjusted as needed at 75 IU per adjustment based on follicular response evaluated by TVUS. However, the maximum gonadotropin dose was 300 IU / day. Gonadotropin administration could be continued for up to 20 days, and withholding was prohibited.

[0097] When the leading follicle was >14 mm in diameter, the GnRH antagonist (ganirelix acetate) was initiated at a daily dose of 0.25 mg and continued throughout the gonadotropin treatment period.

[0098] Upon observing 3 follicles ≥17 mm in diameter by TVUS, a single injection of 250 μg of hCG (chorionic gonadotropin alpha) was administered to induce final follicle maturation. However, if the subject exhibited an excessive ovarian response (more than 30 follicles ≥12 mm and / or estradiol (E2) level ≥5,000 pg / mL), a GnRH agonist (4 mg of leuprolide acetate) was administered more than 12 hours after the last GnRH antagonist dose, fresh transfer was cancelled, all blastocysts were biopsied, and viable blastocysts were cryopreserved for use in the next transfer cycle to reduce the risk of OHSS.

[0099] Oocyte retrieval was performed approximately 36 hours after hCG or GnRH agonist administration. Oocytes were fertilized by ICSI using partner sperm within 4 ± 1 hours after retrieval. The quality of oocytes, embryos, and blastocysts was evaluated. The highest quality single blastocyst by morphology (Gardner and Schoolcraft scale) was transferred on day 5 after ICSI (fresh transfer), and all remaining blastocysts were cryopreserved using the vitrification method.

[0100] On the day after oocyte retrieval, vaginal insertion of luteinizing hormone (100 mg twice daily - ENDOMETRIN®; Ferring) for luteal phase support was initiated and continued until the β-hCG test day (10 - 15 days after blastocyst / embryo transfer). Luteal support could be continued until a continuing pregnancy was confirmed.

[0101] Biochemical pregnancy was confirmed by a positive β-hCG test approximately 2 weeks after blastocyst transfer. Clinical pregnancy was confirmed by TVUS showing at least one intrauterine gestational sac with fetal heart tones at 5 - 6 weeks of pregnancy. Continuing pregnancy was confirmed by at least one viable intrauterine fetus at 10 - 11 weeks of pregnancy.

[0102] For subjects who did not have a continuing pregnancy in the fresh cycle, a single frozen blastocyst transfer could be initiated within 6 months of randomization of the subjects in this study. The results of PGS could be used to select euploid blastocysts for frozen transfer. Data on frozen-thawed embryo transfer cycles, including blastocyst transfer information, β-hCG tests, clinical pregnancy, continuing pregnancy, pregnancy loss rate, and births, were collected.

[0103] Post-trial follow-up included collection of delivery information (births and neonatal health status) collected for all subjects who had a continuing pregnancy 1 year after the fresh cycle or randomized frozen-thawed embryo transfer cycle. The birth rate after the fresh cycle and the cumulative birth rate 6 months after the fresh cycle and after the randomized frozen-thawed embryo replacement cycle were evaluated as part of the post-trial follow-up.

[0104] The HP-hMG used was MENOPUR® (provided by Ferring Pharmaceuticals, Inc.), which was provided as vials containing lyophilized HP-hMG (providing 75 IU of HP-hMG, 75 IU of FSH activity, and 75 IU of LH activity, including LH activity provided by hCG) and vials containing solvent for reconstitution. After reconstitution, each vial contained 75 IU of FSH activity and 75 IU of LH activity (including LH activity provided by hCG).

[0105] The FSH used was recombinant FSH (GONAL-F, EMD Serono), which was provided as a solution for injection.

[0106] The other drugs used were as follows: · Ganirelix acetate injection, manufactured by Merck, provided as a prefilled syringe (0.5 mL) delivering 0.25 mg of ganirelix. When the leading follicle was 14 mm or more and / or the serum E2 level was 300 pg / mL or more, ganirelix acetate was started at a daily dose of 0.25 mg and continued throughout the gonadotropin treatment period. · OVIDREL® (chorionic gonadotropin alpha), manufactured by EMD Serono, provided as a prefilled syringe (0.5 mL) delivering 250 μg of chorionic gonadotropin alpha, and administered as a single injection immediately upon observing 3 follicles with a diameter of 17 mm or more by TVUS. · ENDOMETRIN® (progesterone), manufactured by Ferring, provided as an insert for twice-daily vaginal administration, delivering 100 mg (200 mg / day) each.

[0107] The primary endpoint was the ongoing pregnancy rate, and an ongoing pregnancy was defined as the presence of at least one intrauterine pregnancy with a viable fetus accompanied by a detectable fetal heart sound at 10 - 11 weeks of gestation. The secondary endpoints included the following: · Biochemical pregnancy rate (positive β-hCG test) · Clinical pregnancy rate (transvaginal ultrasound examination showing at least one intrauterine gestational sac with fetal heart sounds at 5 - 6 weeks of pregnancy) · Early pregnancy loss (defined as two positive β - hCG tests in a pregnancy at 10 - 11 weeks in a fresh cycle but not a continuing pregnancy) · Birth rate · Follicle growth, follicle levels (total number of follicles, number of follicles less than 9 mm, 10 - 11 mm, 12 - 14 mm, 15 - 16 mm, and 17 mm or more), and target levels (maximum follicle size, mean follicle size, mean size of the three largest follicles, and mean number of follicles 17 mm or more, 15 mm or more, and 12 mm or more) when evaluated by TVUS · Endocrine profile (serum estradiol [E2], progesterone [P4], hCG, LH) · Retrieved oocytes, fertilization rate, and embryo quality.

[0108] 3. Serum assays Blood samples were taken before and throughout the stimulation period (e.g., before stimulation, day 6 of stimulation, and the final day of stimulation). Serum was analyzed for AMH (Beckman Coulter Gen 2), FSH, LH, and hCG using ELISA, for estradiol using two - dimensional high - performance liquid chromatography and tandem mass spectrometry, and for progesterone and testosterone using liquid chromatography and tandem mass spectrometry. The lower limits of detection were as follows: FSH 0.017 mIU / mL; LH 0.005 mIU / mL; βhCG 0.5 mIU / mL; estradiol 1.0 pg / mL, progesterone 10 ng / dL, and testosterone 2.5 ng / dL.

[0109] 4. Results and retrospective analysis The non-inferiority target for the primary endpoint of ongoing pregnancy was achieved. HP-hMG was numerically associated with a higher ongoing pregnancy rate compared to rFSH (35.5% vs 30.7%, P>0.05). The mean number of oocytes per patient in the rFSH group (±SD; 22.2±11.54) was higher than that in the hMG group (15.1±10.12), representing a difference in ovarian response with a statistically significant increase in the rate of OHSS (21.4% vs 9.7%; p<0.05).

[0110] Retrospective analysis in the modified treatment intention population (all randomized subjects who received at least one dose of gonadotropin) included the evaluation of the primary endpoint rate by infertility diagnosis. Retrospective analysis by infertility diagnosis showed no significant difference in the ongoing pregnancy rate between treatment groups in those diagnosed with endometriosis, male factor, tubal infertility, idiopathic or others. However, among those diagnosed with sporadic ovulation, HP-hMG treatment (N = 50) was unexpectedly associated with a 19.2% higher ongoing pregnancy rate compared to rFSH treatment (N = 56) (95% confidence interval 1.2%, 37.3%; ongoing pregnancy rates of 46.0% and 26.8% respectively).

[0111] As shown in the following table, FSH and BMI were similar, but compared to the remaining study populations, the sporadic ovulation study population had a higher mean baseline AMH (60.95 vs 52.10 pmol / L, p<0.001), a higher mean baseline luteinizing hormone (7.55 vs 6.45 U / L, p = 0.007), a higher mean baseline testosterone (1.13 vs 1.00 nmol / L, p = 0.006), and a higher mean baseline estradiol (167.04 vs 135.46 pmol / L, p = 0.001). Comparison between the population with sporadic ovulation and the population without sporadic ovulation was performed using either a t-test (continuous parameter) or Fisher's exact test (discrete parameter).

[0112]

Table 1

[0113] Based on the evaluation of the levels of AMH, LH, testosterone, and estradiol in serum (as well as the tendency of progesterone elevation), the oligoovulatory patient population was likely to include patients with PCOS (for example, patients with oligoovulation caused by PCOS). This is because the elevation of the levels of AMH, LH, testosterone, estradiol, and progesterone is a characteristic of PCOS, and other common causes of oligoovulation (such as ovarian insufficiency, hyperprolactinemia, thyroid dysfunction, and adrenal dysfunction) were considered to be excluded by the selection criteria and exclusion criteria of this study.

[0114]

Table 2

[0115]

Table 3

[0116] Therefore, the inventors surprisingly found that patients who were expected to be high responders, diagnosed with oligoovulation (such as oligoovulation caused by PCOS), and treated with HP-hMG as a gonadotropin for COS (N = 50) had a 19.2% higher ongoing pregnancy rate after fresh embryo transfer (95% confidence interval 1.2% - 37.3%) compared to patients treated with rFSH as a gonadotropin for COS (N = 56). This is large compared to the improvement in the ongoing pregnancy rate associated with HP-hMG treatment in the entire expected high responder population (based on FSH) (35.5% vs. 30.7%, P > 0.05).

[0117] Therefore, the inventors have discovered that the selection of patients predicted to be high responders diagnosed with oligo-ovulation (e.g., oligo-ovulation due to PCOS) for treatment with hMG as the gonadotropin for COS rather than FSH may be associated with a higher ongoing pregnancy rate. Accordingly, the invention described herein relates to a subject selected according to one or more or all of the following criteria: diagnosis of oligo-ovulation; diagnosis of PCOS; serum levels of AMH of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) by the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013) or equivalent serum AMH levels determined by another method; baseline serum estradiol of 145 pmol / L or more, baseline serum LH of 7 U / L or more, and baseline serum testosterone of 1.10 nmol / L or more.

[0118] Example 2 An exemplary method of infertility treatment in oligo-ovulatory and / or PCOS patients (e.g., oligo-ovulation due to PCOS) predicted to be high responders is outlined below. Infertility treatment involving COS with HP-hMG (rather than FSH) as the gonadotropin is associated with a relatively high ongoing pregnancy rate.

[0119] Typically, the treatment of this infertility is supervised by a physician. Typically, the patient is diagnosed or has been diagnosed by a physician with oligo-ovulation and / or PCOS (e.g., oligo-ovulation due to PCOS). This patient is also diagnosed or may be diagnosed as a predicted hyper-responder, for example, based on a serum AMH level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) by a serum AMH test, such as the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or by another method resulting in an equivalent serum AMH level. Additionally or alternatively, this patient is identified or may be identified as having one or more of: (i) a serum luteinizing hormone (LH) level of 7 U / L or more before controlled ovarian stimulation, (ii) a serum testosterone level of 1.10 nmol / L or more before controlled ovarian stimulation, and (iii) a serum estradiol level of 145 pmol / L or more before controlled ovarian stimulation.

[0120] Patients who are diagnosed with oligo-ovulation and / or PCOS (e.g., oligo-ovulation due to PCOS), and have a serum AMH level of 35.7 ± 0.5 pmol / L or more or 5.0 ± 0.2 ng / ml or more before treatment (optionally identified as having), and optionally, one or more of: (i) a serum luteinizing hormone (LH) level of 7 U / L or more before controlled ovarian stimulation, (ii) a serum testosterone level of 1.10 nmol / L or more before controlled ovarian stimulation, and (iii) a serum estradiol level of 145 pmol / L or more before controlled ovarian stimulation, are selected for COS using HP-hMG (e.g., MENOPUR®, available from Ferring Pharmaceuticals) as the gonadotropin. As noted above, when reconstituted for use, each vial of MENOPU® contains 75 IU of FSH activity and 75 IU of LH activity (including hCG-driven LH activity).

[0121] Controlled ovarian stimulation is initiated on day 2 or 3 of the patient's menstrual cycle ("stimulation day 1"). This treatment includes administering a daily dose of MENOPUR® (e.g., 150 IU / day) by injection from day 1 (stimulation day 1) to at least day 5 (stimulation day 5) of the treatment. The dose can be adjusted up or down (e.g., in increments of 75 IU of hMG) to a maximum daily dose of 300 or 450 IU of hMG or a minimum daily dose of 75 IU of hMG (e.g., according to the patient's ovarian response). This treatment can be continued for up to 20 days (up to stimulation day 20), but typically is 8 - 12 days (e.g., about 10 days).

[0122] If the leading follicle is 14 mm or more in diameter as evaluated by TVUS, a GnRH antagonist (ganirelix acetate) can be initiated at a daily dose of 0.25 mg and continued throughout the gonadotropin stimulation treatment period.

[0123] Final follicle maturation is induced by hCG or a GnRH agonist. When 3 follicles with a diameter of 17 mm or more are observed by TVUS, a single injection of 250 μg of hCG (chorionic gonadotropin alpha) can be administered immediately to induce final follicle maturation. Alternatively, for example, in the case of an excessive response to COS (e.g., a patient having more than 30 follicles with a diameter of 12 mm or more or a serum estradiol (E2) level of 5,000 pg / ml or more after COS treatment), a GnRH agonist can be used to induce final follicle maturation. When using a GnRH agonist, this GnRH agonist can be, for example, leuprolide acetate (e.g., LUPRON®) at a dose of, for example, 1 - 4 mg.

[0124] This method further includes oocyte retrieval (generally about 36 hours after induction of final follicle maturation), fertilization, and subsequent procedures (e.g., blastocyst retrieval and transfer of fresh blastocysts to the uterus) according to the protocol described above and variations of this protocol known in the art.

Claims

**Claim 1** A composition for the treatment of infertility by controlled ovarian stimulation in patients with oligo-ovulation, comprising highly purified menotropin (HP-hMG), wherein the patient has a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation. **Claim 2** The composition according to claim 1, comprising 75 to 450 IU of HP-hMG. **Claim 3** The treatment of infertility comprises administering to the patient a daily dose of HP-hMG of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, and most preferably 150 IU / day, the composition according to claim 1 or 2. **Claim 4** The treatment of infertility comprises (a) identifying (e.g., diagnosing) a patient having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) and (b) a serum estradiol level of 145 pmol / L or more (e.g., 150 pmol / L or more) before treatment / stimulation; administering to the patient a daily dose of HP-hMG of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, and most preferably 150 IU / day The composition according to any one of claims 1 to 3. **Claim 5** A composition for the treatment of infertility by controlled ovarian stimulation in patients with oligo-ovulation and having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, comprising highly purified menotropin (HP-hMG), wherein the treatment comprises identifying (e.g., diagnosing) an oligo-ovulatory patient having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation; administering to the patient a daily dose of HP-hMG of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, and most preferably 150 IU / day The composition. **Claim 6** The treatment of infertility comprises Identifying (e.g., diagnosing) a patient having (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or more (e.g., a serum estradiol level of 150 pmol / L or more) before treatment / stimulation; Administering to the patient a daily dose of HP-hMG of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, and most preferably 150 IU / day; The composition according to claim 5, comprising the above.

7. The composition according to any one of claims 1 to 6, wherein the treatment of infertility increases the ongoing pregnancy rate as compared to treatment with recombinant follicle-stimulating hormone (rFSH).

8. The composition according to any one of claims 1 to 7, wherein the treatment further comprises inducing final follicle maturation by administering hCG or a GnRH agonist.

9. The composition according to any one of claims 1 to 8, wherein the treatment is a fresh transfer method further comprising recovering an oocyte, fertilizing the oocyte, growing the fertilized oocyte to the blastocyst stage, and transplanting a fresh blastocyst into the uterus.

10. The composition according to any one of claims 1 to 8, wherein the treatment is a frozen transfer method further comprising recovering an oocyte, freezing the unfertilized oocyte, then thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocyte to the blastocyst stage, and transplanting the blastocyst into the uterus (e.g., a euploid blastocyst selected based on chromosomal evaluation).

11. The treatment is recovering an oocyte, freezing the unfertilized oocyte, then thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocyte to the blastocyst stage, and transplanting the blastocyst into the uterus; or Retrieving oocytes, freezing unfertilized oocytes, then thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and transplanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus The composition according to any one of claims 1 to 8, further comprising

12. The composition according to any one of claims 1 to 11, wherein the treatment further comprises administering a GnRH antagonist starting on the 6th day of the treatment

13. The patient is not anovulatory, is 21 to 35 years old, and has a BMI of 18 to 30 kg / m ２ at the start of treatment, of the composition according to any one of claims 1 to 12.

14. A composition for use in an assisted reproductive technology method for treating a female diagnosed with oligo-ovulation and expected to have a high ovarian response to controlled ovarian stimulation, comprising highly purified menotropin (HP-hMG), wherein the method comprises identifying a female diagnosed with oligo-ovulation and having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or more (5.0 ± 0.2 ng / ml or more) before treatment performing controlled ovarian stimulation by administering to the identified female an effective amount of highly purified menotropin (HP-hMG) to stimulate follicular growth The composition comprising

15. The composition according to claim 14, wherein the method further comprises identifying the female as having one or more of (i) a serum luteinizing hormone (LH) level of 7 U / L or more before treatment / stimulation, (ii) a serum testosterone level of 1.10 nmol / L or more before treatment / stimulation, and (iii) a serum estradiol level of 145 pmol / L or more before treatment / stimulation

16. The composition according to claim 14 or 15, wherein the HP-hMG is administered at a dose of 75 - 450 IU of hMG per day

17. The composition according to claim 14 or 15, wherein the HP-hMG is administered at a dose of 150 IU of hMG per day from the first day to at least the fifth day of the treatment

18. The composition according to any one of claims 14 to 17, wherein the method is effective to increase the ongoing pregnancy rate after in vitro fertilization as compared to controlled ovarian stimulation by administration of recombinant follicle-stimulating hormone (rFSH)

19. The composition according to any one of claims 14 to 18, wherein the method further comprises administering a gonadotropin-releasing hormone antagonist (GnRH antagonist) starting on the 6th day of treatment / stimulation.

20. The composition according to any one of claims 14 to 19, wherein the method further comprises inducing final follicle maturation by administering human chorionic gonadotropin (hCG) or a gonadotropin-releasing hormone agonist (GnRH agonist).

21. The method comprises (a) recovering an oocyte, fertilizing the oocyte, growing the fertilized oocyte to the blastocyst stage, and transferring a fresh blastocyst to the uterus; or (b) recovering an oocyte, fertilizing the oocyte, growing the fertilized oocyte to the blastocyst stage, freezing one or more or all of the blastocysts, and transferring a thawed frozen blastocyst (e.g., a euploid blastocyst selected based on chromosomal evaluation) to the uterus; or (c) recovering an oocyte, freezing an unfertilized oocyte, then thawing one or more of the oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocytes to the blastocyst stage, and transferring the blastocysts to the uterus; or (d) recovering an oocyte, freezing an unfertilized oocyte, then thawing one or more of the frozen oocytes, fertilizing one or more or all of the thawed oocytes, growing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and transferring a thawed frozen blastocyst (e.g., a euploid blastocyst selected based on chromosomal evaluation) to the uterus The composition according to any one of claims 14 to 20, further comprising.

22. The female is not anovulatory, is 21 to 35 years old, and has a BMI of 18 to 30 kg / m ２ at the start of treatment, of the composition according to any one of claims 14 to 21.

23. Use of HP-hMG in the manufacture of a medicament for the treatment of infertility in women having a serum AMH level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) prior to treatment, identified as being diagnosed with oligo-ovulation, wherein the treatment comprises administering to the identified women an amount of highly purified menotropin (HP-hMG) effective to stimulate follicle growth.

24. The use according to claim 23, wherein the female has been identified as having a serum estradiol level of 145 pmol / L or more (for example, a serum estradiol level of 150 pmol / L or more) before the treatment / stimulation before the treatment.

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