HP-hMG for use in the treatment of infertility in patients with polycystic ovary syndrome

Abstract

Described are compositions and methods for assisted reproductive technology that use highly purified menotropins (HP-hMG) to stimulate follicular growth, particularly in women diagnosed with oligoovulation and / or PCOS and who are expected to have a high ovarian response to controlled ovarian stimulation.

Description

[Technical Field]

[0001] The invention described herein relates to assisted reproductive technologies. Specifically, described herein are compositions and methods for treating infertility, including controlled ovarian stimulation methods that may be particularly useful for women who experience oligoovulation and / or have polycystic ovary syndrome (PCOS) and who are expected to have a high ovarian response to controlled ovarian stimulation. [Background technology]

[0002] Assisted reproductive technology (ART) procedures generally involve stimulating egg growth and maturation, retrieving eggs from a woman's ovaries, combining the eggs with sperm in vitro, and implanting them into the woman's uterus (either a donor or another woman). The success of ART is hampered by maternal and renal risks associated with stimulating egg growth and maturation, such as ovarian hyperstimulation syndrome (OHSS) and ectopic pregnancy. Another concern raised with ART is the production of high-quality embryos and euploid blastocysts to support ongoing pregnancy and live birth rates.

[0003] Gonadotropins, such as menotropins (e.g., human menopausal gonadotropin or hMG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), have been used for controlled ovarian stimulation (COS), with highly purified menotropins (HP-hMG) and recombinant human FSH (rFSH) being used more recently. HP-hMG provides the activity of FSH and exogenous LH primarily in the form of human chorionic gonadotropin (hCG). The effectiveness of ovarian stimulation protocols can be enhanced by the long-term use of gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists for cycle control. See, e.g., 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 versus rFSH may affect embryo morphology, and observed improved implantation, ongoing pregnancy, and live birth rates in the highest quality embryos (based on visual assessment) derived from stimulation with HP-hMG compared to Chinese hamster ovary cell (CHO cell)-derived rFSH (GONAL-F).

[0004] Because patient responses to ovarian stimulation vary widely, treatment is often individualized. For example, individualization can be based on the expected ovarian response to gonadotropin stimulation, which predicts a poor, normal, or high response. A high ovarian responder is typically defined as a woman who produces a large number of growing follicles following a standard protocol of controlled ovarian stimulation (COS). While these patients are generally considered good candidates for ART, a high ovarian response may be associated with a relatively low implantation rate and a relatively high miscarriage rate, which may reduce the probability of a successful outcome compared to a normal ovarian response. These high responders are also at increased risk of OHSS and its associated complications.

[0005] Efforts to develop improved ART methods for prospective high responders include examining 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 fertilization rates and embryo quality, but lower doses result in fewer oocytes. Other efforts have examined whether the specific gonadotropin used affects outcome. For example, Arce et al., Gyn. Endocrin. 30(6):444-50 (2014) reported that among expected high responders (subjects with AMH ≥ 5.2 ng / ml), the group stimulated with CHO cell-derived rFSH (GONAL-F) retrieved significantly more oocytes than the group stimulated with HP-hMG, but had a significantly lower live birth rate per cycle (20% vs. 33% in the MERIT "long-term 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] A woman with an average menstrual cycle typically ovulates, or releases, a mature egg once a month, approximately midway through her cycle. Oligovulation refers to infrequent or irregular ovulation and is usually classified as having eight or fewer menstrual cycles (periods) per year. Oligovulation is one of the most common causes of infertility in women. Summary of the Invention [Problem to be solved by the invention]

[0007] In particular, there is a need for improved assisted reproductive technology methods for women who experience oligoovulation and / or have polycystic ovary syndrome (PCOS) and who are expected to have a high ovarian response to controlled ovarian stimulation. [Means for solving the problem]

[0008] The compositions and methods described herein stem from the surprising and unexpected discovery that patients experiencing oligoovulation (e.g., women experiencing oligoovulation due to PCOS) who are predicted to have a high ovarian response to controlled ovarian stimulation (e.g., are predicted to be high responders) and who are undergoing infertility treatment with a controlled ovarian stimulation protocol using hMG as the gonadotropin have significantly higher ongoing pregnancy rates 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 stem from the surprising and unexpected discovery that selecting patients diagnosed with oligoovulation (e.g., women diagnosed with oligoovulation and PCOS) who are predicted to be high responders to controlled ovarian stimulation infertility treatment with HP-hMG (rather than rFSH) as the gonadotropin (e.g., selecting patients who have high baseline levels of AMH, estradiol, LH, and / or testosterone, as disclosed herein) can be associated with a relatively higher ongoing pregnancy rate.

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

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

[0011] In any embodiment, the composition for this use may comprise 75-450 IU of HP-hMG. In any embodiment, treatment of infertility may comprise 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, and most preferably 150 IU / day, optionally from day 1 of treatment through at least day 5 of treatment.

[0012] In any embodiment, treatment of infertility involves having (a) a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) prior to treatment / stimulation, and, optionally, (c) a serum testosterone level of 1.10 nmol / L or greater (e.g., a serum testosterone level of 1.14 nmol / L or greater) prior to treatment / stimulation. and (d) identifying (e.g., diagnosing) a patient who also has one or both of (a) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); and (e) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); 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, and most preferably 150 IU / day, from day 1 of treatment through at least day 5 of treatment.

[0013] Also provided is a composition comprising highly purified menotropins (HP-hMG) for use in the treatment of infertility, optionally by controlled ovarian stimulation, in patients with polycystic ovary syndrome (PCOS) and having a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, wherein the treatment comprises identifying (e.g., diagnosing) a patient with PCOS who has a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation; 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, and most preferably 150 IU / day, from day 1 of treatment through 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 optional controlled ovarian stimulation in patients with oligoovulation due to polycystic ovary syndrome (PCOS) and who have serum anti-Müllerian hormone (AMH) levels of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, wherein the treatment comprises administering to the patient a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation. 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, and most preferably 150 IU / day, from day 1 of treatment through at least day 5 of treatment.

[0015] In any embodiment, treatment of infertility involves having (a) a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) prior to treatment / stimulation, and, optionally, (c) a serum testosterone level of 1.10 nmol / L or greater (e.g., a serum testosterone level of 1.14 nmol / L or greater) prior to treatment / stimulation. and (d) identifying (e.g., diagnosing) a patient who also has one or both of (a) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); and (e) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); 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, and most preferably 150 IU / day, from day 1 of treatment through at least day 5 of treatment.

[0016] With respect to the compositions for use disclosed herein, the infertility treatments disclosed herein increase ongoing pregnancy rates compared to treatment with recombinant follicle-stimulating hormone (rFSH).

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

[0018] In any embodiment of the compositions for use disclosed herein, the treatment may be a fresh transfer method further comprising retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, optionally assessing the quality / morphology of the blastocysts, and transferring the fresh blastocysts (optionally selected, for example, based on visual assessment of quality / morphology) into the uterus.

[0019] In any embodiment of the compositions for use disclosed herein, the treatment may be a cryotransfer method further comprising retrieving oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally assessing 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 the chromosomal assessment) into a uterus.

[0020] In any embodiment of the compositions for use disclosed herein, the treatment may further comprise retrieving oocytes, freezing unfertilized oocytes, thereafter thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, optionally assessing the quality / morphology of the blastocysts, and transferring the blastocysts (optionally selected, for example, based on visual assessment of quality / morphology) into a uterus; or retrieving oocytes, freezing unfertilized oocytes, thereafter thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, optionally assessing 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 assessment) into a uterus.

[0021] In any of the embodiments of the compositions for use disclosed herein, the treatment may further comprise administering a GnRH antagonist starting on the sixth day of treatment.

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

[0023] Also provided is an assisted reproductive technology method for treating a female diagnosed with one or both of oligoovulation and PCOS and predicted to have a high ovarian response to controlled ovarian stimulation, the method comprising: identifying the female as diagnosed with one or both of oligoovulation 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 greater); and administering to the identified female an amount of highly purified menotropin (HP-hMG) effective to stimulate ovarian follicle growth, thereby performing controlled ovarian stimulation. In some embodiments, the female is identified as having been diagnosed with oligoovulation. In some embodiments, the female is identified as having been diagnosed with oligoovulation due to PCOS. In some embodiments, the female is identified as having been diagnosed with PCOS. In some embodiments, the female is identified as having been diagnosed with oligoovulation and PCOS. The method may further include identifying the female as having one or more of: (i) a serum luteinizing hormone (LH) level of 7 U / L or greater before treatment / stimulation, (ii) a serum testosterone level of 1.10 nmol / L or greater before treatment / stimulation, and (iii) a serum estradiol level of 145 pmol / L or greater before treatment / stimulation. The method is effective in increasing ongoing pregnancy rates following in vitro fertilization compared to treatment / controlled ovarian stimulation with 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, for example, at a dose of 150 IU of hMG per day on days 1 through at least 5 of treatment.

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

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

[0027] The method includes (a) retrieving oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally assessing the quality / morphology of the blastocysts, and transferring fresh blastocysts (optionally selected, e.g., based on visual assessment of quality / morphology) into the uterus; or (b) retrieving oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, optionally assessing 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 assessment) into the uterus; or (c) retrieving oocytes, freezing unfertilized oocytes, and 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 assessing the quality / morphology of the blastocysts, and transferring the blastocysts (optionally selected, for example, based on visual assessment of quality / morphology) into a uterus; or (d) oocyte retrieval, freezing unfertilized oocytes, thereafter 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 assessing 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 assessment) into a uterus.

[0028] The women may be non-anovulatory, between 21 and 35 years old, and 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 treating infertility in a woman identified as having oligoovulation and / or PCOS and having a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) before treatment / stimulation, the treatment comprising administering to the identified woman an amount of highly purified menotropin (HP-hMG) effective to stimulate follicle growth. The treatment may further comprise, prior to administration, identifying the woman as having one or more of the following: (i) a serum luteinizing hormone (LH) level of 7 U / L before treatment / stimulation, (ii) a serum testosterone level of 1.10 nmol / L or greater before treatment / stimulation, and (iii) a serum estradiol level of 145 pmol / L or greater before treatment / stimulation. The treatment is effective in increasing ongoing pregnancy rates after in vitro fertilization compared to treatment / stimulation with recombinant follicle-stimulating hormone (rFSH).

[0030] The foregoing summary is exemplary and explanatory and is intended to provide further explanation of the invention. For a full understanding of the invention, reference is made to the following detailed description. Other objects, advantages, and novel features will become readily apparent to those skilled in the art from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

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

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

[0033] definition Unless otherwise defined, technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of assisted reproductive technology to which the present invention pertains. Reference is made herein to various methodologies known to those skilled in the art. Unless otherwise specified, any suitable materials and / or methods known to those skilled in the art may be used in the practice of the present invention. However, specific materials and methods are described. Materials, reagents, and the like referred to 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" refer to both the singular and the plural, unless expressly specified to refer to the singular only.

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

[0036] As used herein, the term "oligoovulation" refers to infrequent or irregular ovulation (e.g., women with cycles of 31 days or more) with a total of eight or fewer menstrual cycles (periods) per year. As used herein, the phrases "patients identified as oligoovulatory" or "diagnosed with oligoovulation" and "patients who are oligoovulatory" are used interchangeably to refer to patients who have eight or fewer menstrual cycles (periods) per year, but exclude anovulatory patients. Oligovulation is one of the most common causes of infertility in women.

[0037] As used herein, the terms "anovulatory" or "anovulatory" refer to a patient whose ovaries do not release oocytes during the menstrual cycle. Thus, ovulation does not occur. Chronic anovulation is a common cause of infertility. Generally, 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 the following: elevated testosterone levels, polycystic ovaries, and ovulatory dysfunction (e.g., infrequent, irregular, and / or prolonged menstrual cycles). PCOS may be diagnosed according to the Rotterdam criteria based on the presence of at least two of the following, excluding other causes of hyperandrogenism or ovulatory dysfunction: (i) hyperandrogenism, (ii) ovulatory dysfunction, and (iii) polycystic ovaries.

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

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

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

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

[0043] The term "menotropin," as used herein, includes human menopausal gonadotropins or "hMG," such as "highly purified menotropins" or "HP-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, e.g., hMG products in which the majority of the LH activity is provided by hCG, e.g., products in which 90% or more or 95% or more of the LH activity is provided by hCG. See, e.g., 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, the HP-hMG is the HP-hMG product available from Ferring Pharmaceuticals, Inc. under the trademark MENOPUR®, which contains FSH- and hCG-driven LH activity, with over 95% of the LH activity coming from hCG (pituitary hCG) as assessed by immunoreactivity. See, e.g., Arce and Smitz, Human Fertility, 14(3):192-99 (2011). When reconstituted for use, one vial of MENOPUR® (75 IU HP-hMG) contains 75 IU of FSH activity and 75 IU of LH activity, with hCG contributing 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®), leuprorelin (e.g., leuprolide acetate, e.g., LUPRON®), nafarelin (e.g., SYNAREL®), and triptorelin (e.g., TRELSTAR®).

[0045] The term "GnRH antagonist," as used herein, includes gonadotropin-releasing hormone (GnRH) antagonists, such as 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 premature ovulation (release of an egg).

[0046] As used herein, the phrase "effective amount" refers to a dosage determined to produce a specific 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 a condition described herein in a given patient, even if one skilled in the art would consider such a dosage to be therapeutically effective. For convenience only, exemplary dosages and therapeutically effective amounts are provided below in relation to adult female human subjects. One skilled in the art can adjust such amounts according to standard techniques as needed to treat 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), such as in vitro fertilization, e.g., 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 compositions and methods of reproductive technology involving the use of highly purified menotropins (HP-hMG) as gonadotropins for COS in women with oligoovulation and / or PCOS who are expected to have a high ovarian response to COS and who are undergoing COS (e.g., women experiencing oligoovulation due to PCOS and women diagnosed with oligoovulation and PCOS). As also noted above, for purposes of the compositions and methods disclosed herein, a woman may be identified as being predicted to have a high ovarian response to COS based on a high ovarian response she demonstrated in a previous ART cycle (e.g., a previous COS treatment), or if she has a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) as measured using the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013), such as a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater), or an equivalent AMH level assessed by another method. Serum AMH levels are a surrogate marker of functional follicular reserve, and a positive correlation between serum AMH levels and ovarian response (e.g., oocyte yield) has been reported (Id.). According to the compositions and methods described herein, women are identified as likely high responders, typically based on serum AMH levels.

[0049] It will be understood that in any example of the present invention or any embodiment of the compositions and methods disclosed herein, the step of identifying (e.g., diagnosing) a patient with a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation may be replaced by or augmented by a step of identifying a patient who has produced 15 or more oocytes in a previous ART cycle (e.g., a previous COS treatment) prior to treatment / stimulation, or a step of identifying a patient who is considered to be at risk for developing OHSS prior to treatment / stimulation.

[0050] The assisted reproductive technology methods described herein include using HP-hMG to stimulate follicular growth to perform controlled ovarian stimulation in women diagnosed with oligoovulation and / or PCOS (e.g., women experiencing oligoovulation due to PCOS and women diagnosed with oligoovulation and PCOS) and who are expected to have a high ovarian response to controlled ovarian stimulation. In any of the embodiments described herein, the HP-hMG can be MENOPUR®.

[0051] The treatment methods may include identifying the woman as having been diagnosed with oligoovulation and / or PCOS (e.g., oligoovulation due to PCOS) prior to performing controlled ovarian stimulation. Thus, in some embodiments, the woman is identified as having been diagnosed with oligoovulation, in some embodiments, the woman is identified as having been diagnosed with oligoovulation due to PCOS, in some embodiments, the woman is identified as having been diagnosed with PCOS, and in some embodiments, the woman is identified as having been diagnosed with oligoovulation and PCOS.

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

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

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

[0055] The method involves administering HP-hMG to a subject in an amount effective to stimulate follicle growth (e.g., about 75 IU / day to about 450 IU / day, e.g., 75 IU / day, 150 IU / day, 225 IU / day, 300 IU / day, 375 IU / day, or 450 IU / day). 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 typically begins on day 2 or 3 of the patient's menstrual cycle, such that treatment day 1 (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., the MENOPUR® product, sold by Ferring Pharmaceuticals, Inc., formulated for subcutaneous injection). Administration of HP-hMG continues daily for a total 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.

[0056] It is known in the art to adjust the administration of gonadotropins (e.g., increasing or decreasing the administration of HP-hMG or rFSH) during the stimulation period based on the subject's ovarian (follicular) response and serum estradiol levels, which can be assessed, for example, by transvaginal ultrasound (TVUS). For example, it is known to adjust the administration of gonadotropins during the stimulation period if a patient's serum estradiol level and / or the number of follicles greater than 12 mm are excessively low or excessively high. Such evaluation and adjustment can occur any time during the stimulation period, typically during the mid-follicular phase of stimulation, typically on day 5, 6, or 7 of stimulation. Thus, treatment can include administering a daily dose of HP-hMG (e.g., MENOPUR®) at a starting daily dose of 75 to 450 IU / day (e.g., 150 IU / day) by injection on day 1 (stimulation day 1) through, for example, at least day 5 (stimulation day 5) of treatment. Thus, the dose may be adjusted up or down (e.g., in increments of 75 IU hMG) to a maximum daily dose of 300 or 450 IU hMG or a minimum daily dose of 75 IU hMG (e.g., depending on the patient's ovarian response).

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

[0058] In some embodiments, the treatment method includes administering a GnRH antagonist during a portion of the gonadotropin (e.g., HP-hMG) administration period. For example, the GnRH antagonist can be administered when the lead follicle reaches 14 mm in diameter and continued throughout the remainder of the gonadotropin (e.g., HP-hMG) administration period. For example, the GnRH antagonist can be administered starting on the fifth, sixth, or seventh day of stimulation (e.g., the sixth day of stimulation) and continued throughout the remainder of the gonadotropin (e.g., HP-hMG) administration period. When the GnRH antagonist is ganirelix acetate (e.g., ORGALUTRAN®), a typical dose is 0.25 mg / day administered subcutaneously.

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

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

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

[0062] In some embodiments, the treatment method further comprises retrieving oocytes and fertilizing the oocytes by methods known in the art (eg, ICSI).

[0063] In some embodiments, the treatment method is a fresh transfer method. In a fresh transfer method, one or more blastocysts are selected for transfer. The remaining blastocysts may be frozen (including vitrification) by methods known in the art for future transfer. Thus, in a fresh transfer embodiment, the method includes oocyte retrieval, fertilization, growing the fertilized oocytes to the blastocyst stage, blastocyst retrieval, optionally selecting blastocysts based on quality / morphology evaluation, and transferring the fresh blastocysts (optionally selected, for example, based on quality / morphology evaluation) into 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 may be frozen by methods known in the art for future transfer.

[0064] In some embodiments, the method is a frozen transfer method. In frozen transfer embodiments, the method includes retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, optionally assessing 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 the chromosomal assessment) into a uterus. In freezing and "whole freeze" methods, selected blastocysts are frozen for future implantation / transfer by methods known in the art.

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

[0066] As noted above, in some embodiments, the methods include assessing the chromosomal quality of blastocysts or selecting blastocysts based on chromosomal assessment. This can be done using methods known in the art, such as preimplantation aneuploidy testing (PGT-A, also known as PGS) or preimplantation genetic diagnosis (PGD), which are used to test blastocysts (embryos) for genetic and chromosomal information. When PGS or PGD is used, all chromosomes can be assessed, and only blastocysts identified as having a low risk of chromosomal abnormalities are selected for embryo transfer (implantation into the uterus). This is an alternative to the traditional method of selecting embryos according to their appearance under a microscope after 3-5 days of growth in an incubator.

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

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

[0069] In one example, the method includes identifying a woman as having been diagnosed with one or both of oligoovulation and PCOS (e.g., oligoovulation due to PCOS) and having a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L (5.0±0.2 ng / ml or greater); and administering HP-hMG to the identified woman for infertility treatment (e.g., controlled ovarian stimulation) at a dose of, for example, 150 IU per day from day 1 of treatment through at least, for example, day 5 of treatment, where the dose can be adjusted up or down depending on the patient's response (e.g., in increments of 75 IU of HP-hMG) until a desired level of follicular maturation is achieved for induction of terminal 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 (stimulation) period of about 1 to about 20 days, typically a total treatment (stimulation) period of 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.

[0070] The present invention also provides a composition (e.g., a pharmaceutical composition) containing HP-hMG for use in treating infertility in a patient (e.g., a woman) with PCOS (e.g., identified or diagnosed with PCOS) who has a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation (the patient is not an anovulatory patient). The infertility treatment may be controlled ovarian stimulation infertility treatment. 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 of HP-hMG per day, preferably 75 to 225 IU per day, more preferably 150 or 225 IU per day, and most preferably 150 IU per day, from day 1 of treatment through at least day 5 of treatment. The daily dose of HP-hMG may be adjusted during the stimulation period, e.g., based on patient response, for a total treatment period (stimulation period) of about 1 to about 20 days, typically a total treatment (stimulation) period of 8 to 12 days, more specifically typically about 9 to 11 days, e.g., about 10 days, until a desired level of follicle production is achieved, e.g., after treatment with a starting dose on day 1 to, e.g., day 5 of treatment.

[0071] The present invention also provides a composition (e.g., a pharmaceutical composition) containing HP-hMG for use in treating infertility in a patient (e.g., a woman) with PCOS-induced oligoovulation (e.g., identified or diagnosed with PCOS-induced oligoovulation) who has a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation (the patient is not an anovulatory patient). The infertility treatment may be controlled ovarian stimulation infertility treatment. 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 of HP-hMG per day, preferably 75 to 225 IU per day, more preferably 150 or 225 IU per day, and most preferably 150 IU per day, from day 1 of treatment through at least day 5 of treatment. The daily dose of HP-hMG may be adjusted during the stimulation period, e.g., based on patient response, for a total treatment period (stimulation period) of about 1 to about 20 days, typically a total treatment (stimulation) period of 8 to 12 days, more specifically typically about 9 to 11 days, e.g., about 10 days, until a desired level of follicle production is achieved, e.g., after treatment with a starting dose on day 1 to, e.g., day 5 of treatment.

[0072] In any embodiment, the composition may be for treating patients with a pre-treatment / stimulation serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) and a pre-treatment / stimulation serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater). Serum estradiol levels may be measured by methods known in the art, such as those described in Example 1. In any embodiment, the treatment may include the further step of identifying patients with serum AMH levels of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, as measured using the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013), e.g., an AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater), or an equivalent AMH level assessed by another method.

[0073] In any embodiment, the treatment may include the further step of identifying patients with serum AMH levels of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) and serum estradiol levels of 145 pmol / L or greater (e.g., serum estradiol levels of 150 pmol / L or greater) prior to treatment / stimulation, as disclosed above.

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

[0075] In any embodiment, the treatment is for a patient having (a) a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) prior to treatment / stimulation, and, optionally, (c) a serum testosterone level of 1.10 nmol / L or greater (e.g., a serum testosterone level of 1.14 nmol / L or greater) prior to treatment / stimulation. and (d) identifying (e.g., diagnosing) a patient who also has one or both of (a) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); and (e) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); 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, and most preferably 150 IU / day, from day 1 of treatment through at least day 5 of treatment.

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

[0077] According to the present invention, there is provided a composition (e.g., pharmaceutical composition) comprising HP-hMG for use in treating infertility in a patient (a non-anovulatory patient, e.g., a woman) who has oligoovulation due to PCOS (e.g., has been identified or diagnosed as having oligoovulation due to PCOS) and who has a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, the treatment comprising: Identifying (e.g., diagnosing) patients with oligoovulation due to PCOS who have a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, as measured using, for example, the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or an equivalent AMH level assessed by another method; optionally administering to said patient a daily dose of HP-hMG of 75 to 450 IU per day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 of treatment through at least day 5 of treatment; Also provided are compositions comprising HP-hMG. The daily dose may be adjusted over a total stimulation period (treatment period) of about 1 to about 20 days, typically 8 to 12 days, more specifically about 9 to 11 days, e.g., about 10 days, until a desired level of follicle production is achieved, e.g., after treatment with a starting dose on day 1 to, e.g., day 5 of treatment, based on, e.g., patient response, during the stimulation period. The infertility treatment may be infertility treatment by controlled ovarian stimulation. The composition may contain 75 to 450 IU of HP-hMG.

[0078] In any embodiment, the treatment is for a patient having (a) a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) prior to treatment / stimulation, and, optionally, (c) a serum testosterone level of 1.10 nmol / L or greater (e.g., a serum testosterone level of 1.14 nmol / L or greater) prior to treatment / stimulation. and (d) identifying (e.g., diagnosing) a patient who also has one or both of (a) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); and (e) a serum luteinizing hormone (LH) level of 7 U / L or greater prior to treatment / stimulation (e.g., a serum luteinizing hormone level of 7.55 U / L or greater); 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, and most preferably 150 IU / day, from day 1 of treatment through at least day 5 of treatment.

[0079] In a further aspect, the present invention provides 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 woman, e.g., a non-anovulatory woman) who has oligoovulation and / or PCOS (e.g., a woman with oligoovulation due to PCOS) (e.g., identified or diagnosed with oligoovulation and / or PCOS) and has a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation. The infertility treatment can be infertility treatment by controlled ovarian stimulation. The composition can contain 75 to 450 IU of HP-hMG. The treatment may include identifying patients with a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation (e.g., as measured using the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013)), or an equivalent AMH level assessed by another method. The treatment may include the further step of identifying patients with a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) prior to treatment / stimulation. This treatment may additionally include the further step of identifying patients with pre-treatment / stimulation serum luteinizing hormone (LH) levels of 7 U / L or greater (e.g., serum luteinizing hormone levels of 7.55 U / L or greater) and / or pre-treatment / stimulation serum testosterone levels of 1.10 nmol / L or greater (e.g., serum testosterone levels of 1.14 nmol / L or greater). This infertility treatment may include administering HP-hMG at a dose of 75-450 IU of hMG per day until the desired level of follicle production is achieved.

[0080] As noted above, the infertility treatments disclosed herein (i.e., according to each of the various embodiments disclosed herein) are associated with higher ongoing pregnancy rates compared to comparable treatment methods using recombinant follicle-stimulating hormone (rFSH) as the gonadotropin.

[0081] As noted above, in any embodiment, the composition may contain 75 to 450 IU of HP-hMG (eg, MENOPUR®).

[0082] As noted above, in any embodiment, treatment of infertility can involve administering to a patient 75 to 450 IU of HP-hMG per day, e.g., at a dose of 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 patient response, after treatment with a starting dose, e.g., on days 1 to 5 of treatment), for a total stimulation period (treatment period) of about 1 to about 20 days, typically 8 to 12 days, more particularly typically about 9 to 11 days, e.g., about 10 days, until a desired level of follicle production is achieved. Thus, in any embodiment, the treatment may include 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, optionally from day 1 of treatment through at least day 5 of treatment.

[0083] In one example, this treatment involves administering (to the patient) a dose of 150 IU of HP-hMG per day on days 1 through at least 5 of treatment. The dose can be adjusted up or down (e.g., in increments of 75 IU of hMG) starting, for example, on day 6 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 include the further step of administering a GnRH antagonist starting when the lead follicle reaches a diameter of 14 mm and / or on the fifth, sixth, or seventh day of stimulation (e.g., day six of stimulation) and continuing throughout the remainder of the HP-hMG administration.

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

[0086] In any embodiment, the treatment may further include retrieving (e.g., harvesting) the oocyte; fertilizing (e.g., inseminating) the oocyte; and developing the fertilized oocyte 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 retrieving oocytes, fertilizing the oocytes, allowing the fertilized oocytes to grow to the blastocyst stage, retrieving the blastocysts, optionally selecting the blastocysts based on a quality / morphology assessment, and transferring the fresh blastocysts (optionally selected, e.g., based on a quality / morphology assessment) into 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 frozen by methods known in the art for future transfer.

[0088] In any embodiment, the procedure may be a frozen transfer method that includes retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, optionally assessing 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 assessment) into the uterus. In the freezing and "whole freeze" methods, selected blastocysts are frozen by methods known in the art for future implantation / transfer.

[0089] In any embodiment, the method may involve freezing unfertilized oocytes. Thus, the method may include oocyte retrieval, freezing one or more or all of the retrieved oocytes, subsequently thawing one or more frozen oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, optionally selecting blastocysts based on a quality / morphology assessment, and transferring the blastocysts (optionally selected, e.g., based on a visual assessment of quality / morphology) into a uterus. Alternatively, the method may include oocyte retrieval, freezing one or more or all of the retrieved oocytes, subsequently thawing one or more frozen oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, performing a chromosomal assessment of the blastocysts, freezing the blastocysts, and transferring the thawed frozen blastocysts (e.g., euploid blastocysts selected based on the chromosomal assessment) into a uterus.

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

[0091] Example 1 – Clinical Trial and Retrospective Analysis of MEGASET HR The following are men with a BMI of 18-30 kg / m who have undergone intracytoplasmic sperm injection and single blastocyst transfer (fresh transfer). 2 We describe a retrospective analysis of data collected in a multicenter, randomized, assessor-blind, controlled, noninferiority trial in 620 women (21-35 years of age) with a history of breast cancer and serum anti-Müllerian hormone (AMH) levels of 35.7 pmol / L or higher. The trial was named "MENOPUR® 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 a regular ovulatory menstrual cycle of 21–45 days and a body mass index (BMI) of 18–30 kg. 2 The study participants were women aged 21-35 years who were seeking pregnancy. Patients / subjects were predicted high responders, defined as those with serum anti-Müllerian hormone (AMH) levels of 5 ng / L or greater (35.71 pmol / L) at screening. These subjects had a documented history of infertility (e.g., failure to conceive for at least 12 months, or at least 6 months if receiving donor sperm), and serum FSH levels of 1-12 IU / L (inclusive) on day 2 or 3 of their menstrual cycle.

[0093] Exclusion criteria were known stage III-IV endometriosis; a history of recurrent miscarriage not resulting in a live birth (recurrent miscarriage defined as two or more consecutive miscarriages); and previous failure of in vitro fertilization (IVF) or assisted reproductive technology (ART) due to poor response to gonadotropins (poor response defined as growth of two or fewer mature follicles or a history of two previous unsuccessful cycle cancellations before 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 forced single blastocyst transfer (fresh transfer) in a high-responder population in the U.S. The objective of this study was to demonstrate that HP-hMG is at least non-inferior to rFSH in terms of ongoing pregnancy rate (OPR) in potential high-responders undergoing IVF / ICSI treatment.

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

[0096] Subjects were randomized 1:1 to receive COS with either HP-hMG (N=311; MENOPUR®, Ferring Pharmaceuticals, Inc.) or rFSH (N=309; GONAL-F, EMD Serono) at a dose of 150 IU as gonadotropin in a GnRH antagonist cycle. Treatment began on day 2 or 3 of the menstrual cycle with a dose of 150 IU of HP-hMG or rFSH for the first 5 days. From day 6 of stimulation onward, administration could be adjusted as needed at 75 IU per adjustment based on follicular response assessed by TVUS. However, the maximum gonadotropin dose was 300 IU / day. Gonadotropin administration could be continued for a maximum of 20 days, with inertia prohibited.

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

[0098] As soon as three follicles measuring 17 mm or greater were observed on TVUS, a single injection of 250 μg hCG (chorionic gonadotropin alfa) was administered to induce final follicular maturation. However, if the subject demonstrated an excessive ovarian response (more than 30 follicles measuring 12 mm or greater each and / or an estradiol (E2) level of 5,000 pg / mL or greater), a GnRH agonist (4 mg leuprolide acetate) was administered 12 hours or more after the last GnRH antagonist dose, the fresh transfer was canceled, all blastocysts were biopsied, and surviving blastocysts were frozen 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 using partner sperm via ICSI 4±1 hours after retrieval. Oocyte, embryo, and blastocyst quality was assessed. Five days after ICSI, a single blastocyst of the highest quality according to morphology (Gardner and Schoolcraft scale) was transferred (fresh transfer), and all remaining blastocysts were frozen using the vitrification method.

[0100] The day after oocyte retrieval, vaginal progestin insertion (100 mg twice daily - ENDOMETRIN®; Ferring) was initiated for luteal phase support and continued until the day of β-hCG testing (10-15 days after blastocyst / embryo transfer). Luteal support was continued until ongoing 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 sounds at 5-6 weeks' gestation. Ongoing pregnancy was confirmed by at least one intrauterine viable fetus at 10-11 weeks' gestation.

[0102] For subjects without an ongoing pregnancy in a fresh cycle, a single frozen blastocyst transfer could be initiated within 6 months of the subject's randomization in this study. PGS results could be used to select euploid blastocysts for frozen transfer. Data on frozen-thawed embryo transfer cycles were collected, including blastocyst transfer information, β-hCG testing, clinical pregnancy, ongoing pregnancy, pregnancy loss rate, and live birth.

[0103] Post-study follow-up included collection of live birth information (birth and neonatal health status) for all subjects with ongoing pregnancies one year after a fresh cycle or a randomized frozen-thawed embryo transfer cycle. Live birth rates after a fresh cycle and cumulative live birth rates six months after a fresh cycle and a randomized frozen-thawed embryo replacement cycle were assessed as part of the post-study follow-up.

[0104] The HP-hMG used was MENOPUR® (provided by Ferring Pharmaceuticals, Inc.) and was provided as a vial containing dry 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 a vial 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) and was provided as a solution for injection.

[0106] Other drugs used were: Ganirelix acetate injection, manufactured by Merck, is supplied as a prefilled syringe (0.5 mL) delivering 0.25 mg of ganirelix. Once the lead follicle was 14 mm or larger and / or serum E2 levels were 300 pg / mL or larger, ganirelix acetate was initiated at a daily dose of 0.25 mg and continued throughout the gonadotropin treatment period. OVIDREL® (chorionic gonadotropin alfa), manufactured by EMD Serono, was provided as a prefilled syringe (0.5 mL) delivering 250 μg of chorionic gonadotropin alfa and was administered as a single injection immediately upon the observation of three follicles measuring 17 mm or greater in diameter on TVUS. ENDOMETRIN® (progestin), manufactured by Ferring, comes as an insert to be administered vaginally twice daily, each delivering 100 mg (200 mg / day).

[0107] The primary endpoint was the ongoing pregnancy rate, defined as the presence of at least one intrauterine pregnancy with a viable fetus with detectable fetal heart sounds at 10-11 weeks' gestation. Secondary endpoints included: Biochemical pregnancy rate (positive β-hCG test) Clinical pregnancy rate (transvaginal ultrasound showing at least one intrauterine gestational sac with fetal heart sounds at 5-6 weeks of gestation) Early pregnancy loss (defined as two positive β-hCG tests at 10-11 weeks of pregnancy in a fresh cycle but without an ongoing pregnancy) ·Birth rate Follicular growth as assessed by TVUS, follicle level (total number of follicles, number of follicles ≤9mm, 10-11mm, 12-14mm, 15-16mm, and ≥17mm), and target level (largest follicle size, mean follicle size, mean size of the three largest follicles, and mean number of follicles ≥17mm, ≥15mm, and ≥12mm) Endocrine profile (serum estradiol [E2], progesterone [P4], hCG, LH) · Quality of retrieved oocytes, fertilization rates and embryos.

[0108] 3. Serum Assay Blood samples were collected before and throughout the stimulation period (e.g., before the start of stimulation, on the sixth day of stimulation, and on 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 detection limits were as follows: FSH 0.017 mIU / mL; LH 0.005 mIU / mL; βhCG 0.5 mIU / mL; estradiol 1.0 pgl / mL; progesterone 10 ng / dL; and testosterone 2.5 ng / dL.

[0109] 4. Results and retrospective analysis The non-inferiority goal for the primary endpoint of ongoing pregnancy was achieved. HP-hMG was associated with a numerically higher ongoing pregnancy rate compared with 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 in the hMG group (15.1±10.12), a difference in ovarian response with a statistically significant increase in the rate of OHSS (21.4% vs. 9.7%; P<0.05).

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

[0111] As shown in the table below, FSH and BMI were similar, but compared to the rest of the study population, the oligoovulatory study population had higher mean baseline AMH (60.95 vs. 52.10 pmol / L, p<0.001), higher mean baseline luteinizing hormone (7.55 vs. 6.45 U / L, p=0.007), higher mean baseline testosterone (1.13 vs. 1.00 nmol / L, p=0.006), and higher mean baseline estradiol (167.04 vs. 135.46 pmol / L, p=0.001). Comparisons between the oligoovulatory and non-oligoovulatory populations were made using either t-tests (continuous parameters) or Fisher's exact tests (fractional parameters).

[0112] [Table 1]

[0113] Based on evaluation of serum AMH, LH, testosterone, and estradiol levels (and a trend toward elevated progesterone), the oligoovulatory patient population was classified as patients with PCOS (e.g., patients whose oligoovulation was due to PCOS). contained This is likely because elevated levels of AMH, LH, testosterone, estradiol, and progesterone are characteristic of PCOS, and other common causes of oligoovulation (e.g., ovarian insufficiency, hyperprolactinemia, thyroid dysfunction, and Adrenal glands functional impairment) would have been excluded by the inclusion and exclusion criteria of this study.

[0114] [Table 2]

[0115] [Table 3]

[0116] Thus, the inventors surprisingly discovered that predicted high-responder patients diagnosed with oligoovulation (e.g., oligoovulation due to PCOS) and treated with HP-hMG as the gonadotropin for COS (N=50) had a 19.2% higher ongoing pregnancy rate (95% CI 1.2%-37.3%) after fresh transfer compared with patients treated with rFSH as the gonadotropin for COS (N=56), which is greater than the improvement in ongoing pregnancy rate (based on FSH) associated with HP-hMG treatment in the entire population of predicted high-responders (35.5% vs. 30.7%, P>0.05).

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

[0118] Example 2 Exemplary methods of infertility treatment for oligoovulatory and / or PCOS patients (e.g., oligoovulation due to PCOS) who are expected to be high responders are outlined below. Infertility treatment, including COS, with HP-hMG (rather than FSH) as the gonadotropin is associated with relatively high ongoing pregnancy rates.

[0119] Typically, the infertility treatment is overseen by a physician. Typically, the patient is or has been diagnosed by a physician with oligoovulation and / or PCOS (e.g., oligoovulation due to PCOS). The patient may also be or have been diagnosed as a predicted high responder, for example, based on a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) using 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 an equivalent serum AMH level determined by another method. Additionally or alternatively, the patient may be identified or have been identified as having one or more of: (i) a serum luteinizing hormone (LH) level of 7 U / L or greater before controlled ovarian stimulation; (ii) a serum testosterone level of 1.10 nmol / L or greater before controlled ovarian stimulation; and (iii) a serum estradiol level of 145 pmol / L or greater before controlled ovarian stimulation.

[0120] Patients who have been diagnosed with oligoovulation and / or PCOS (e.g., oligoovulation due to PCOS) and who have (optionally identified as having) a serum AMH level of 35.7±0.5 pmol / L or greater or 5.0±0.2 ng / ml or greater before treatment, and who are optionally identified as having one or more of the following: (i) a serum luteinizing hormone (LH) level of 7 U / L or greater before controlled ovarian stimulation, (ii) a serum testosterone level of 1.10 nmol / L or greater before controlled ovarian stimulation, and (iii) a serum estradiol level of 145 pmol / L or greater before controlled ovarian stimulation, are selected for COS using HP-hMG (e.g., MENOPUR®, available from Ferring Pharmaceuticals) as a gonadotropin. As described 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 begins on day 2 or 3 of the patient's menstrual cycle ("stimulation day 1"). This treatment involves administering a daily dose of MENOPUR® (e.g., 150 IU / day) by injection on day 1 (stimulation day 1) through at least day 5 (stimulation day 5) of treatment. The dose may be adjusted up or down (e.g., in increments of 75 IU hMG) to a maximum daily dose of 300 or 450 IU hMG or a minimum daily dose of 75 IU hMG (e.g., depending on the patient's ovarian response). This treatment may continue for up to 20 days (up to or including stimulation day 20), but is typically 8 to 12 days (e.g., about 10 days).

[0122] If the lead follicle is 14 mm or larger in diameter as assessed by TVUS, a GnRH antagonist (ganirelix acetate) may be initiated at a daily dose of 0.25 mg and continued throughout the gonadotropin-stimulating treatment period.

[0123] Final follicular maturation is induced with hCG or GnRH agonists. A single injection of 250 μg of hCG (chorionic gonadotropin alpha) can be administered immediately upon observation of three follicles measuring 17 mm or greater in diameter by TVUS to induce final follicular maturation. Alternatively, in cases of an exaggerated response to COS (e.g., patients with more than 30 follicles measuring 12 mm or greater in diameter or serum estradiol (E2) levels of 5,000 pg / ml or greater after COS treatment), a GnRH agonist can be used to induce final follicular maturation. When a GnRH agonist is used, it can be, for example, leuprolide acetate (e.g., LUPRON®) at a dose of 1 to 4 mg.

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

Claims

1. A composition for the treatment of infertility by controlled ovarian stimulation in patients with polycystic ovary syndrome (PCOS), comprising highly purified menotropin (HP-hMG), wherein the patients have serum anti-Müllerian hormone (AMH) levels of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation.

2. A composition for the treatment of infertility by controlled ovarian stimulation in patients with oligoovulation due to polycystic ovary syndrome (PCOS), comprising highly purified menotropin (HP-hMG), wherein the patients have serum anti-Müllerian hormone (AMH) levels of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation.

3. 3. The composition according to claim 1, comprising 75 to 450 IU of HP-hMG.

4. 4. The composition according to any one of claims 1 to 3, wherein 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, most preferably 150 IU / day.

5. The treatment of infertility comprises: (a) identifying (e.g., diagnosing) patients with a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) before treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) before treatment / stimulation; administering to said 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; The composition of any one of claims 1 to 4, comprising:

6. A composition for the treatment of infertility by controlled ovarian stimulation in patients with polycystic ovary syndrome (PCOS) and having a serum anti-Mullerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, comprising highly purified menotropins (HP-hMG), said treatment comprising: Identifying (e.g., diagnosing) a patient with PCOS who has a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) before treatment / stimulation; administering to said 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; A composition comprising:

7. A composition for the treatment of infertility by controlled ovarian stimulation in patients with oligoovulation due to polycystic ovary syndrome (PCOS) and having a serum anti-Mullerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment / stimulation, comprising highly purified menotropin (HP-hMG), said treatment comprising: Identifying (e.g., diagnosing) patients with oligoovulation due to PCOS who have a serum anti-Mullerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) before treatment / stimulation; administering to said 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; A composition comprising:

8. The treatment of infertility comprises: (a) identifying (e.g., diagnosing) patients with a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) before treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) before treatment / stimulation; administering to said 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; 8. The composition of claim 6 or 7, comprising:

9. 9. The composition of any one of claims 1 to 8, wherein the treatment of infertility increases the ongoing pregnancy rate compared to treatment with recombinant follicle-stimulating hormone (rFSH).

10. The composition of any one of claims 1 to 9, wherein the treatment further comprises inducing terminal follicular maturation by administering an hCG or GnRH agonist.

11. 11. The composition of any one of claims 1 to 10, wherein the treatment is a fresh transfer method further comprising retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, and transferring the fresh blastocyst into the uterus.

12. 11. The composition of any one of claims 1 to 10, wherein the treatment is a cryotransfer method further comprising retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and transferring the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into a uterus.

13. The treatment comprises: Retrieving oocytes, freezing unfertilized oocytes, then thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, and implanting the blastocysts 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, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and transferring the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus. The composition of any one of claims 1 to 10, further comprising:

14. The composition of claim 1, wherein the treatment further comprises administering a GnRH antagonist starting on the sixth day of treatment.

15. The patients were non-anovulatory, aged 21-35 years, and had a weight of 18-30 kg / m at the start of treatment. ２ The composition according to any one of claims 1 to 14, wherein the composition has a BMI of 16. A composition comprising highly purified menotropins (HP-hMG) for use in an assisted reproductive technology method for treating a female diagnosed with oligoovulation due to polycystic ovary syndrome (PCOS) and expected to have a high ovarian response to controlled ovarian stimulation, the method comprising: Identifying women as having been diagnosed with oligoovulation due to polycystic ovary syndrome (PCOS) and having a pre-treatment serum anti-Mullerian hormone (AMH) level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater); and administering to the identified woman an amount of highly purified menotropin (HP-hMG) effective to stimulate follicular growth, thereby effecting controlled ovarian stimulation. A composition comprising:

17. The composition of claim 16, wherein the method further comprises identifying the woman as having one or more of: (i) a serum luteinizing hormone (LH) level of 7 U / L or greater before treatment / stimulation, (ii) a serum testosterone level of 1.10 nmol / L or greater before treatment / stimulation, and (iii) a serum estradiol level of 145 pmol / L or greater before treatment / stimulation.

18. The composition of claim 16 or 17, wherein the HP-hMG is administered at a dose of 75 to 450 IU of hMG per day.

19. 18. The composition of claim 16 or 17, wherein the HP-hMG is administered at a dose of 150 IU of hMG per day on days 1 through at least 5 of treatment.

20. A composition described in any one of claims 16 to 19, wherein the method is effective in increasing the rate of ongoing pregnancy after in vitro fertilization compared to controlled ovarian stimulation by administration of recombinant follicle-stimulating hormone (rFSH).

21. A composition described in any one of claims 16 to 20, wherein the method further comprises administering a gonadotropin-releasing hormone antagonist (GnRH antagonist) starting on the sixth day of treatment / stimulation.

22. A composition described in any one of claims 16 to 21, wherein the method further comprises inducing final follicle maturation by administering human chorionic gonadotropin (hCG) or a gonadotropin-releasing hormone agonist (GnRH agonist).

23. The method comprising: (a) retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, and implanting a fresh blastocyst into the uterus; or (b) retrieving oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and transferring the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into a uterus; or (c) oocyte retrieval, freezing unfertilized oocytes, then thawing one or more oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, and implanting the blastocysts into the uterus; or (d) oocyte retrieval, freezing unfertilized oocytes, then thawing one or more frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, freezing one or more or all of the blastocysts, and transferring the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into a uterus. The composition of any one of claims 16 to 22, further comprising:

24. The women were non-anovulatory, aged 21-35 years, and had a weight of 18-30 kg / m at the start of treatment. ２ The composition according to any one of claims 16 to 23, having a BMI of

25. Use of HP-hMG in the manufacture of a pharmaceutical for the treatment of infertility in women who have been identified as having oligoovulation due to polycystic ovary syndrome (PCOS) and who have a serum AMH level of 35.7±0.5 pmol / L or greater (5.0±0.2 ng / ml or greater) prior to treatment, wherein the treatment comprises administering to the identified women an amount of highly purified menotropin (HP-hMG) effective to stimulate follicle growth.

26. 26. The use of claim 25, wherein the woman is identified prior to treatment as having a serum estradiol level of 145 pmol / L or greater (e.g., a serum estradiol level of 150 pmol / L or greater) prior to treatment / stimulation.

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