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

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

[0003] Gonadotropins, such as menotropin (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 menotropin (HP-hMG) and recombinant human FSH (rFSH) being used more recently. HP-hMG primarily provides FSH and exogenous LH activity in the form of human chorionic gonadotropin (hCG). The effectiveness of ovarian stimulation protocols can be enhanced over time by using gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists for cyclical control. See, for example, Devroey et al., Fertility and Sterility 97:561-71 (2012). Ziebe et al., Human Reproduction 22(9)2404-13(2007) reported that the use of HP-hMG versus rFSH may affect embryonic morphology, and observed improvements in implantation, ongoing pregnancy rates, and live birth rates in the highest quality embryos (based on visual evaluation) derived from HP-hMG stimulation compared to rFSH (GONAL-F) derived from Chinese hamster ovary cells (CHO cells).

[0004] Because patient responses to ovarian stimulation vary considerably, treatment is often individualized. For example, individualization may be based on the expected ovarian response to gonadotropin stimulation, which may predict a poor, normal, or high response. High-ovarian response women are typically defined as women who produce a large number of developing follicles following a standard controlled ovarian stimulation (COS) protocol. While these patients are generally considered good candidates for ART, high-ovarian response may be associated with relatively low implantation rates and relatively high miscarriage rates, thus reducing the probability of a successful outcome compared to a normal ovarian response. These high-responder women also have a higher risk of OHSS and its associated complications.

[0005] Efforts to develop improved ART methods for expected high-responders include exploring milder stimulation protocols. For example, Rubio et al., Human Reproduction 25(9):2290-97 (2010) reported that reducing the dose of gonadotropins administered to high-responders may improve fertilization rates and embryo quality, but lower doses resulted in fewer oocytes. Other efforts are investigating whether the specific gonadotropins used affect the outcome. For example, Arce et al., Gyn. Endocrin. 30(6):444-50 (2014) reported that among expected high-responders (subjects with AMH levels of 5.2 ng / ml or higher), the group stimulated with CHO cell-derived rFSH (GONAL-F) retrieved significantly more oocytes compared to the group stimulated with HP-hMG, but the birth rate per cycle was significantly lower (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] Women with average menstrual cycles typically ovulate or release a mature egg once a month, roughly in the middle of the cycle. Ovulatory ovulation refers to cases where ovulation occurs infrequently or irregularly, usually classified as having eight or fewer menstrual cycles per year. Ovulatory ovulation is one of the most common causes of infertility in women. [Overview of the Initiative] [Problems that the invention aims to solve]

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

[0008] The compositions and methods described herein stem from the surprising and unexpected finding that patients experiencing oligoovulation (e.g., women experiencing oligoovulation due to PCOS), who are expected to have a high ovarian response to controlled ovarian stimulation (e.g., expected 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 finding that the selection of patients diagnosed with oligoovulation (e.g., women diagnosed with oligoovulation and PCOS) who are expected to be high responders to controlled ovarian stimulation infertility treatment with HP-hMG (instead of rFSH) as the gonadotropin (e.g., the selection of patients with high baseline levels of AMH, estradiol, LH, and / or testosterone, as disclosed herein) may be associated with relatively high ongoing pregnancy rates.

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

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

[0011] In any embodiment, the composition for use may contain 75 to 450 IU of HP-hMG. In any embodiment, treatment for infertility may optionally include administering to the patient a daily dose of 75 to 450 IU / day, preferably 75 to 225 IU / day, more preferably 150 or 225 IU / day, and most preferably 150 IU / day of HP-hMG, from day 1 to at least day 5 of treatment.

[0012] In any embodiment, the treatment for infertility involves (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) prior to treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or higher (e.g., a serum estradiol level of 150 pmol / L or higher) prior to treatment / stimulation, and optionally, (c) a serum testosterone level of 1.10 nmol / L or higher (e.g., a serum testosterone level of 1.14 nmol / L or higher) prior to treatment / stimulation. This may include (e.g., diagnosing) patients who have either or both of the following conditions prior to treatment / stimulation: (d) a high strontosterone level, and (f) a serum luteinizing hormone (LH) level of 7 U / L or higher (e.g., serum luteinizing hormone of 7.55 U / L or higher); and optionally administering to patients a daily dose of HP-hMG of 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 to at least day 5 of treatment.

[0013] Also provided is a composition comprising highly purified menotropin (HP-hMG) for use in the treatment of infertility by optional 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 higher (5.0±0.2 ng / ml or higher) prior to treatment / stimulation, wherein the treatment comprises: identifying (e.g., diagnosing) patients with PCOS who have a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or higher (5.0±0.2 ng / ml or higher) prior to treatment / stimulation; and optionally administering a daily dose of HP-hMG to the patient at a dose of 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 to at least day 5 of treatment.

[0014] Also provided is a composition comprising highly purified menotropin (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 a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / L or higher (5.0±0.2 ng / ml or higher) prior to treatment / stimulation, wherein the treatment is performed with a serum anti-Müllerian hormone (AMH) level of 35.7±0.5 pmol / The composition comprises: identifying (e.g., diagnosing) patients with oligoovulation due to PCOS who have serum anti-Müllerian hormone (AMH) levels of L or higher (5.0 ± 0.2 ng / ml or higher); and optionally administering to the patients 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 to at least day 5 of treatment.

[0015] In any embodiment, the treatment for infertility involves (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) prior to treatment / stimulation, and (b) a serum estradiol level of 145 pmol / L or higher (e.g., a serum estradiol level of 150 pmol / L or higher) prior to treatment / stimulation, and optionally, (c) a serum testosterone level of 1.10 nmol / L or higher (e.g., a serum testosterone level of 1.14 nmol / L or higher) prior to treatment / stimulation. This may include (e.g., diagnosing) patients who have either or both of the following conditions prior to treatment / stimulation: (d) a high strontosterone level, and (f) a serum luteinizing hormone (LH) level of 7 U / L or higher (e.g., serum luteinizing hormone of 7.55 U / L or higher); and optionally administering to patients a daily dose of HP-hMG of 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 to at least day 5 of treatment.

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

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

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

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

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

[0021] In any embodiment of the composition for use disclosed herein, the procedure may further include administering a GnRH antagonist starting on the 6th day of the procedure.

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

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

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

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

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

[0027] This method involves (a) collecting oocytes, fertilizing these oocytes, developing the fertilized oocytes to the blastocyst stage, selectively evaluating the quality / morphology of the blastocysts, and implanting the fresh blastocysts (selected selectively, for example, based on visual evaluation of quality / morphology) into the uterus; or (b) collecting oocytes, fertilizing these oocytes, developing the fertilized oocytes to the blastocyst stage, selectively evaluating the chromosomal quality of the blastocysts, freezing one or more or all of the blastocysts, and implanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus; or (c) collecting oocytes, freezing unfertilized oocytes, and then thawing one or more oocytes. (d) fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, selectively evaluating the quality / morphology of the blastocysts and implanting the blastocysts (selected selectively, for example, based on visual evaluation of quality / morphology) into the uterus; or (d) retrieving oocytes, freezing unfertilized oocytes, then thawing one or more of the frozen oocytes, fertilizing one or more or all of the thawed oocytes, developing the fertilized oocytes to the blastocyst stage, selectively evaluating the chromosomal quality of the blastocysts, freezing one or more or all of the blastocysts and implanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus.

[0028] This woman is not anovulatory, is between 21 and 35 years old, and may have a BMI of 18-30 kg / m2 at the start of treatment.

[0029] Similarly, provided herein is the use of HP-hMG in the manufacture of a pharmaceutical product for the treatment of infertility in women having a serum AMH level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml) prior to treatment / stimulation, wherein the treatment comprises administering to the identified woman a highly purified amount of menotropin (HP-hMG) effective in stimulating follicular 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 prior to treatment / stimulation, (ii) a serum testosterone level of ≥1.10 nmol / L prior to treatment / stimulation, and (iii) a serum estradiol level of ≥145 pmol / L prior to treatment / stimulation. The treatment is effective in increasing the rate of continued pregnancy after in vitro fertilization compared to treatment / stimulation with recombinant follicle-stimulating hormone (rFSH).

[0030] The above summary is illustrative and descriptive and is intended to provide a further explanation of the invention. For a detailed understanding of the invention, please refer to the detailed description below. Other objectives, advantages, and novel features will be readily apparent to those skilled in the art from the detailed description below. [Modes for carrying out the invention]

[0031] Described herein are assisted reproductive technologies, 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 experiencing oligoovulation due to PCOS or diagnosed with oligoovulation and PCOS) and who are expected to have a high ovarian response to controlled ovarian stimulation (e.g., women expected to be high responders) (e.g., women having baseline levels of AMH, estradiol, LH, and / or testosterone, as disclosed herein). As shown in Example 1, this method is useful in increasing the rate of continued pregnancy.

[0032] This invention is based on the unexpected discovery by the inventors that the use of highly purified menotropin (HP-hMG) for the treatment of patients with COS who are expected to be highly responsive and diagnosed with oligoovulation (e.g., women experiencing oligoovulation due to PCOS) improves the rate of continuing pregnancy. As reported in Example 1 below, patients who were expected to be highly responsive and diagnosed with oligoovulation (e.g., women experiencing oligoovulation due to PCOS) and treated with HP-hMG as the gonadotropin (N=50) had a 19.2% higher rate of continuing pregnancy (95% confidence interval 1.2%~37.3%) compared to patients treated with rFSH as the gonadotropin (N=56). These patients had baseline serum AMH levels of ≥35.7 pmol / L (≥5.0 ng / ml), baseline serum LH levels of ≥7 U / L, baseline serum testosterone levels of ≥1.10 nmol / L, and baseline serum estradiol levels of ≥145 pmol / L. As discussed in Example 1 below, based on, for example, these serum levels of AMH, estradiol, LH, and testosterone, this patient population appears to have included patients with PCOS, e.g., patients whose oligoovulation is due to PCOS. Based on this finding, the compositions and methods disclosed herein are based on the selection of highly responsive patients diagnosed with oligoovulation and / or PCOS, e.g., patients having a baseline serum level of AMH ≥ 35.7 ± 0.5 pmol / L (≥ 5.0 ± 0.2 ng / ml), a baseline serum level of estradiol ≥ 145 pmol / L, a baseline serum level of LH ≥ 7 U / L, and / or a baseline serum level of testosterone ≥ 1.10 nmol / L, for treatment with HP-hMG rather than FSH in order to achieve a higher rate of continued pregnancy.

[0033] definition The technical and scientific terms used herein have the meanings generally understood by those skilled in the art of assisted reproductive technology, to which the present invention relates, unless otherwise defined. Various methodologies known to those skilled in the art are referenced herein. Unless otherwise specified, any suitable materials and / or methods known to those skilled in the art may be used in the execution of the present invention. However, certain materials and methods are described. The materials, reagents and similar materials mentioned in the following description and examples are available from commercial sources unless otherwise noted.

[0034] As used herein, the singular forms "a," "an," and "that" refer to both singular and plural, unless otherwise explicitly stated.

[0035] As used herein, the term “about” means that the number or range is not limited to the exact number or range specified, but encompasses the range before and after the number or range enumerated, as understood by those skilled in the art in the context in which the number or range is used. Unless otherwise evident from the context or convention of the art, “about” means up to 10 percent plus or minus 10 percent of the particular term.

[0036] As used herein, the term “oligoovulation” refers to infrequent or irregular ovulation (e.g., in women with a cycle of 31 days or longer) resulting in a total of eight or fewer menstrual cycles per year. As used herein, the terms “patients identified with oligoovulation” or “diagnosed with oligoovulation” and “patients who are oligoovulating” are used interchangeably to refer to patients with eight or fewer menstrual cycles per year, but anovulatory patients are excluded. 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 in whom the ovaries do not release oocytes during the menstrual cycle; therefore, ovulation does not occur. Chronic anovulation is a common cause of infertility. Generally, the patients for whom the compositions and methods described herein are used 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, after excluding other causes of androgen excess or ovulatory dysfunction, on the basis of the presence of at least two of the following according to the Rotterdam criteria: (i) androgen excess, (ii) ovulatory dysfunction, and (iii) polycystic ovaries.

[0039] As used herein, “continuing pregnancy” refers to a pregnancy of 10–11 weeks (e.g., 8–9 weeks after blastocyst / embryo transfer) with a viable fetus and detectable fetal heartbeat.

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

[0041] As used herein, “female” refers to an adult female human. Typically, the females treated according to the compositions and methods described herein are 35 years of age or younger and have a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) 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 as assessed by another method, and a weight of 30 kg / m². 2Have the following BMI. In some embodiments, women treated according to the compositions and methods described herein are identified as being 21 to 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 less or 34 years old or less prior to treatment. In some embodiments, women treated according to the methods described herein are identified as being 21 to 34 years old, or 21 to 33 years old, or 21 to 32 years old, or 21 to 31 years old prior to treatment. In some embodiments, women treated according to the methods described herein have a BMI of 18 to 30 kg / m 2 prior to treatment. In some embodiments, women treated according to the methods described herein have a BMI of 38 kg / m 2 or less, 36 kg / m 2 or less, 34 kg / m 2 or less, 32 kg / m 2 or less, 30 kg / m 2 or less or 28 kg / m 2 or less, such as a BMI of 18 to 38, 18 to 36, 18 to 34, 18 to 32, 18 to 30 or 18 to 28 kg / m 2 prior to treatment. In some embodiments, women treated according to the methods described herein have a BMI of 18 to 25 kg / m 2 , 18 to 26 kg / m 2 , 18 to 27 kg / m 2 , 18 to 28 kg / m 2 ​​​​​​​​As used herein, a person classified as “expected to have a high ovarian response to controlled ovarian stimulation” or “expected high responder” refers to a woman who is capable of developing a large number of follicles or oocytes according to a standard controlled ovarian stimulation (COS) protocol, for example, a woman who is more likely than average to produce 15 or more oocytes. A woman may be identified as an expected high responder if she has produced 15 or more oocytes in a previous ART cycle (e.g., a previous COS treatment). In addition, or instead, a woman may be identified as an expected high responder if she is considered to be at risk of developing OHSS. In addition, or alternatively, a woman may be identified as a highly expected responder if she has a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) as measured using the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013), for example, a serum AMH level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) or an equivalent AMH level as assessed by another method.

[0043] The term “menotropin” as used herein includes human menopausal gonadotropin or “hMG,” such as “highly purified menotropin” or “HP-hMG.” As used herein, the terms “highly purified menotropin” and “HP-hMG” refer to highly purified hMG products containing both follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG)-driven luteinizing hormone (LH) activity, for example, hMG products in which the majority of LH activity is provided by hCG, for example, products in which 90% or more or 95% or more of LH activity is provided by hCG. See, for example, Foutouh et al., Reproductive BioMed. Online, 14(2):145-47 (2007); Wolfenson et al., Reprod. BioMed. Online, 10(4):442-54 (2005). In some embodiments, HP-hMG is the HP-hMG product available under the trademark MENOPUR® of Ferring Pharmaceuticals, Inc., which contains FSH and hCG-driven LH activity, with over 95% of the LH activity being provided by hCG (pituitary hCG) as assessed by immunoreactivity. See, for example, 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] As used herein, the term "GnRH agonist" 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] When used herein, the term “GnRH antagonist” includes gonadotropin-releasing hormone (GnRH) antagonists, such as ganirelix acetate (e.g., ORGALUTRAN®) and cetrorelic 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 thus preventing ovulation (release of an immature oocyte).

[0046] Where used herein, the term “effective dose” refers to the dosage determined to produce a particular pharmacological effect (for which the drug is administered to a subject requiring such treatment). It is emphasized that a therapeutically effective dose is not necessarily effective in treating the conditions described herein in a given patient, even if a person skilled in the art considers such a dose to be therapeutically effective. For convenience only, exemplary doses and therapeutically effective doses are provided below in relation to adult female human subjects. A person skilled in the art may adjust such doses according to standard techniques as necessary to treat a particular subject and / or condition / disease.

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

[0048] As described above, the present invention provides compositions and methods for reproductive technologies that involve using highly purified menotropin (HP-hMG) as a gonadotropin for COS in women with oligoovulation and / or PCOS who are expected to have a high ovarian response to COS and who are experiencing COS (for example, women who are experiencing oligoovulation due to PCOS and women who have been diagnosed with oligoovulation and PCOS). Similarly, as described above, for the purposes of the compositions and methods disclosed herein, women can be identified as having a high ovarian response to COS based on the high ovarian response they have shown in previous ART cycles (e.g., previous COS treatments), or they can be identified as having a high ovarian response to COS if they have a serum anti-Müllerian hormone (AMH) level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) as measured using the Beckmann-Coulter Gen 2 assay described in Arce et al., Fertility and Sterility 99:1644-53 (2013), for example, a serum AMH level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) or an equivalent AMH level as 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 (ibid.). According to the compositions and methods described herein, women are identified as expected high-responders, typically based on serum AMH levels.

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

[0050] The assisted reproductive technology methods described herein include stimulating follicular growth using HP-hMG to perform controlled ovarian stimulation in women who have been 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 embodiment described herein, HP-hMG may be MENOPUR®.

[0051] This procedure may include identifying the woman as diagnosed with oligoovulation and / or PCOS (e.g., oligoovulation due to PCOS) before performing controlled ovarian stimulation. Therefore, in some embodiments, the woman is identified as diagnosed with oligoovulation; in some embodiments, the woman is identified as diagnosed with oligoovulation due to PCOS; in some embodiments, the woman is identified as diagnosed with PCOS; and in some embodiments, the woman is identified as diagnosed with oligoovulation and PCOS.

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

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

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

[0055] This method involves administering HP-hMG to a target in an amount effective in stimulating follicular growth (e.g., approximately 75 IU / day to approximately 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 may range from 75 IU / day to 225 IU / day. Administration of HP-hMG is typically initiated on the second or third day of the patient's menstrual cycle, so that Day 1 of treatment (also referred to herein as Day 1 of stimulation) is the second or third day of the patient's menstrual cycle. As described above, pharmaceutical compositions containing HP-hMG are commercially available (e.g., MENOPUR® products sold by Ferring Pharmaceuticals, Inc., formulated for subcutaneous injection). HP-hMG is administered daily for a total stimulation period of approximately 1 to 20 days, typically 8 to 12 days, more specifically typically 9 to 11 days, for example, about 10 days, until the desired level of follicular production is achieved.

[0056] For example, it is known in the art to adjust gonadotropin administration during the stimulation period (e.g., increasing or decreasing the administration of HP-hMG or rFSH) based on the target ovarian (follicular) response and serum estradiol levels, which can be assessed by transvaginal ultrasound (TVUS). For example, it is known to adjust gonadotropin administration during the stimulation period if either or both of the patient's serum estradiol levels and / or the number of follicles greater than 12 mm are excessively low or excessively high. Such assessments and adjustments may be made during the stimulation period, typically at any time during the intermediate follicular phase, typically on day 5, or day 6, or day 7 of stimulation. Therefore, the procedure may include administering a daily dose of HP-hMG (e.g., MENOPUR®) by injection at an initial daily dose of 75-450 IU / day (e.g., 150 IU / day) from day 1 (day 1 of stimulation) to, for example, at least day 5 (day 5 of stimulation). Therefore, the dose can be adjusted up or down (for example, in increments of 75 IU of hMG) to a maximum daily dose of 300 or 450 IU of hMG or a minimum daily dose of 75 IU of hMG, depending on the patient's ovarian response.

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

[0058] In some embodiments, the treatment method includes the administration of a GnRH antagonist during a portion of the gonadotropin (e.g., HP-hMG) administration period. For example, the GnRH antagonist may be administered when the lead follicle reaches a diameter of 14 mm and continued throughout the remainder of the gonadotropin (e.g., HP-hMG) administration. For example, the GnRH antagonist may be initiated on day 5, 6, or 7 of stimulation (e.g., day 6 of stimulation) and continued throughout the remainder of the gonadotropin (e.g., HP-hMG) administration. 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 the administration of a GnRH agonist prior to controlled ovarian stimulation, for example, the administration of triptorelin (typically 0.1 mg / day subcutaneously) or leuprorelin (e.g., leuprolide acetate, e.g., LUPRON®) prior to controlled ovarian stimulation.

[0060] In some embodiments, the treatment method further includes inducing terminal follicular maturation. For example, once a desired level of follicular production is achieved, the trigger for terminal follicular maturation may be stimulated by methods known in the art (e.g., a bolus injection of human chorionic gonadotropin (hCG)). For example, the trigger for terminal follicular maturation may be stimulated in patients with three or more follicles, each with a diameter of 17 mm or more, and typically with an estradiol (E2) level of less than 10,000 pmol / mL. Therefore, in some embodiments, the treatment method may include administering hCG to induce terminal follicular maturation. The dose of hCG may 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 agonists can be used as an alternative to hCG to induce final follicular maturation. Therefore, in some embodiments, the treatment method may include administering gonadotropin-releasing hormone (GnRH agonists) to induce final follicular maturation. GnRH agonists can be used to induce final follicular maturation in patients, for example, in cases of hyperresponse, such as (after COS treatment) having more than 25 follicles with a diameter of 12 mm or more or a serum estradiol (E2) level of 5,000 pmol / L or higher, or more than 30 follicles with a diameter of 12 mm or more or a serum estradiol (E2) level of 5,000 pmol / L or higher, or an estradiol (E2) level of 10,000 pmol / L or higher, or 20 or more follicles with a diameter of 12 mm or more or an estradiol (E2) level of 15,000 pmol / L or higher. GnRH agonists may include leuprolide acetate (e.g., LUPRON®) and are typically used in doses of, for example, 1–4 mg. GnRH agonists may also include triptorelin acetate (e.g., DECAPEPTYL®) and are typically used in doses of, for example, 0.2 mg. When inducing final follicular maturation with a GnRH agonist, small amounts of hCG, such as 500–3000 IU, may also be used. When inducing final follicular maturation with a GnRH agonist, a “total freezing” protocol (discussed below) is typically followed, for example, for safety reasons.

[0062] In some embodiments, the procedure further includes collecting oocytes and fertilizing these oocytes by a method known in the art (e.g., ICSI).

[0063] In some embodiments, the procedure is a fresh transplantation method. In the fresh transplantation method, one or more blastocysts are selected for transplantation. The remaining blastocysts may be frozen (including vitrification) by methods known in the art for future transplantation. Thus, in the fresh transplantation embodiment, the method includes retrieving oocytes, fertilizing these oocytes, growing the fertilized oocytes to the blastocyst stage, retrieving blastocysts, selectively selecting blastocysts based on quality / morphological evaluation, and transplanting the fresh blastocysts (selected selectively, for example, based on quality / morphological evaluation) into the uterus. In specific embodiments, the compositions and methods described herein are used in a single blastocyst transplantation protocol to select a single blastocyst for fresh transplantation. According to this embodiment, the remaining blastocysts may be frozen by methods known in the art for future transplantation.

[0064] In some embodiments, the method is a cryopreservation method. In the cryopreservation embodiment, the method includes retrieving oocytes, fertilizing the oocytes, growing the fertilized oocytes to the blastocyst stage, selectively evaluating the chromosomal quality of the blastocysts, freezing one, more, or all of the blastocysts, and implanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus. In the freezing and "total freezing" methods, the selected blastocysts are frozen for future implantation / transfer using 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 using methods known in the art. In such embodiments, the method may then include thawing one or more of the frozen oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, selectively selecting blastocysts based on quality / morphological evaluation, and implanting the blastocysts (selected selectively, for example, based on visual evaluation of quality / morphology) into the uterus. Alternatively, this method may include retrieving oocytes, freezing one or more or all of the retrieved oocytes for future fertilization, then thawing one or more of the frozen oocytes, fertilizing the oocytes, developing the fertilized oocytes to the blastocyst stage, performing chromosomal evaluation of the blastocysts, freezing the blastocysts, and implanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus.

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

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

[0068] Therefore, according to some embodiments, there is a method for assisted reproductive technology to treat a woman who has been diagnosed with oligoovulation and / or PCOS and is expected to have a high ovarian response to controlled ovarian stimulation, the method comprising: identifying the woman as having been diagnosed with oligoovulation and / or PCOS and having a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L (≥ 5.0 ± 0.2 ng / ml); and performing infertility treatment (e.g., controlled ovarian stimulation) by administering to the identified woman a quantity of highly purified menotropin (HP-hMG) effective in stimulating follicular growth. The method may further include identifying the woman as having one or more of the following prior to treatment: (i) a serum luteinizing hormone (LH) level of, for example, ≥ 7 U / L; (ii) a serum testosterone level of, for example, ≥ 1.10 nmol / L; and (iii) a serum estradiol level of, for example, ≥ 145 pmol / L. HP-hMG may typically be administered at a dose of 75-450 IU per day, for example, 150 IU per day, from day 1 to at least day 5 of the procedure, where the dose may be adjusted up or down according to the patient's response (e.g., in increments of 75 IU of HP-hMG) until the desired level of follicular maturation is achieved for induction of final follicular maturation. This method may further include administering a gonadotropin-releasing hormone antagonist (GnRH antagonist), for example, starting on day 6 of the procedure. This method may further include inducing final follicular maturation by administering human chorionic gonadotropin (hCG) or a gonadotropin-releasing hormone agonist (GnRH agonist) supplemented with hCG in an optional manner. As discussed above and as shown in Example 1 below, this method is effective in increasing the rate of continued pregnancy 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 who has been diagnosed with either or both oligoovulation and PCOS (e.g., oligoovulation due to PCOS) and has a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L (≥ 5.0 ± 0.2 ng / ml), and performing infertility treatment (e.g., controlled ovarian stimulation) by administering HP-hMG to the identified woman at a dose of, for example, 150 IU per day from day 1 to at least, for example, day 5 of the treatment, wherein the dose can be adjusted up or down according to 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 final follicular maturation. In this example, the maximum daily dose is 300 or 450 IU of HP-hMG, and the minimum daily dose is 75 IU of HP-hMG. HP-hMG is administered for a total treatment (stimulation) period of approximately 1 to 20 days, typically a total treatment (stimulation) period of 8 to 12 days, more specifically typically 9 to 11 days, for example, over about 10 days, until the desired level of follicular production is achieved.

[0070] The present invention also provides a composition (e.g., a pharmaceutical composition) containing HP-hMG for use in the treatment of infertility in patients (e.g., women) with PCOS (e.g., identified or diagnosed with PCOS) who have a serum AMH level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) before treatment / stimulation (these patients are not anovulatory patients). This treatment of infertility may be treatment of infertility by controlled ovarian stimulation. This composition may contain 75 to 450 IU of HP-hMG. This treatment may optionally include administering a daily dose of HP-hMG to the patient 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 to at least day 5 of treatment. The daily dose of HP-hMG may be adjusted during the stimulation period, for example, based on the patient's response, after treatment with an initial dose on day 1 to day 5, until the desired level of follicular production is achieved, over a total treatment (stimulation) period of approximately 1 to 20 days, typically 8 to 12 days, more specifically typically 9 to 11 days, for example, about 10 days.

[0071] The present invention also provides a composition (e.g., a pharmaceutical composition) containing HP-hMG for use in the treatment of infertility in patients (e.g., women) with PCOS-induced oligoovulation (e.g., identified or diagnosed with PCOS-induced oligoovulation) who have a serum AMH level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) before treatment / stimulation (these patients are not anovulatory patients). This infertility treatment may be treatment of infertility by controlled ovarian stimulation. This composition may contain 75 to 450 IU of HP-hMG. This treatment may optionally include administering a daily dose of HP-hMG to the patient 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 to at least day 5 of treatment. The daily dose of HP-hMG may be adjusted during the stimulation period, for example, based on the patient's response, after treatment with an initial dose on day 1 to day 5, until the desired level of follicular production is achieved, over a total treatment (stimulation) period of approximately 1 to 20 days, typically 8 to 12 days, more specifically typically 9 to 11 days, for example, about 10 days.

[0072] In any embodiment, the composition may be for the treatment of patients having a serum AMH level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) and a serum estradiol level of 145 pmol / L or higher (e.g., a serum estradiol level of 150 pmol / L or higher) before treatment / stimulation. The serum estradiol level may be measured by methods known in the art, as described in Example 1. In any embodiment, the procedure may include a further step of identifying patients who, prior to the procedure / stimulation, have a serum AMH level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml), for example, an AMH level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) 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 as assessed by another method.

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

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

[0075] In any embodiment, the treatment is provided that (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) and (b) a serum estradiol level of 145 pmol / L or higher (e.g., a serum estradiol level of 150 pmol / L or higher) before treatment / stimulation, and optionally, (c) a serum testosterone level of 1.10 nmol / L or higher (e.g., a serum testosterone level of 1.14 nmol / L or higher) before treatment / stimulation. This may include (e.g., diagnosing) patients who have either or both of the following conditions prior to treatment / stimulation: (d) a tosterone level, and (f) a serum luteinizing hormone (LH) level of 7 U / L or higher (e.g., serum luteinizing hormone level of 7.55 U / L or higher); and optionally administering to patients a daily dose of HP-hMG of 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 to at least day 5 of treatment.

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

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

[0078] In any embodiment, the treatment is provided that (a) a serum anti-Müllerian hormone (AMH) level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) and (b) a serum estradiol level of 145 pmol / L or higher (e.g., a serum estradiol level of 150 pmol / L or higher) before treatment / stimulation, and optionally, (c) a serum testosterone level of 1.10 nmol / L or higher (e.g., a serum testosterone level of 1.14 nmol / L or higher) before treatment / stimulation. This may include (e.g., diagnosing) patients who have either or both of the following conditions prior to treatment / stimulation: (d) a tosterone level, and (f) a serum luteinizing hormone (LH) level of 7 U / L or higher (e.g., serum luteinizing hormone level of 7.55 U / L or higher); and optionally administering to patients a daily dose of HP-hMG of 75-450 IU / day, preferably 75-225 IU / day, more preferably 150 or 225 IU / day, most preferably 150 IU / day, from day 1 to at least day 5 of treatment.

[0079] In a further embodiment, the present invention provides for the use of HP-hMG in the manufacture of a pharmaceutical product (e.g., a pharmaceutical composition) for the treatment of infertility in patients (e.g., women, e.g., non-anovulatory women) who are oligoovulatory and / or PCOS (e.g., women with oligoovulation due to PCOS) (e.g., identified or diagnosed with oligoovulation and / or PCOS) and have a serum AMH level of 35.7 ± 0.5 pmol / L or higher (5.0 ± 0.2 ng / ml or higher) before treatment / stimulation. This treatment of infertility may be treatment of infertility by controlled ovarian stimulation. The composition may contain 75 to 450 IU of HP-hMG. This procedure may include identifying patients who have a serum anti-Müllerian hormone (AMH) level of ≥35.7 ± 0.5 pmol / L (≥5.0 ± 0.2 ng / ml) or an equivalent AMH level as assessed by other means prior to treatment / stimulation (for example, when measured using the Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013)). This procedure may include a further step of identifying patients who have a serum estradiol level of ≥145 pmol / L (e.g., a serum estradiol level of ≥150 pmol / L) prior to treatment / stimulation. This procedure may also include the further step of identifying patients who have a serum luteinizing hormone (LH) level of 7 U / L or higher (e.g., serum luteinizing hormone level of 7.55 U / L or higher) and / or a serum testosterone level of 1.10 nmol / L or higher (e.g., serum testosterone level of 1.14 nmol / L or higher) before the procedure / stimulation. This infertility treatment may include administering HP-hMG at a dose of 75-450 IU of hMG per day until the desired level of follicular production is achieved.

[0080] As described 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 equivalent treatment methods using recombinant follicle-stimulating hormone (rFSH) as the gonadotropin.

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

[0082] As described above, in any embodiment, treatment for infertility may involve administering to the patient a dose of 75 to 450 IU of HP-hMG per day, for example 75 IU / day, 150 IU / day, 225 IU / day, 300 IU / day, 375 IU / day, or 450 IU / day (the dose may be adjusted during this stimulation period, for example, based on the patient's response, after treatment with an initial dose, for example, on day 1 to day 5 of treatment) for a total stimulation period (treatment period) of about 1 to about 20 days, typically a total stimulation period of 8 to 12 days, more specifically typically about 9 to 11 days, for example, about 10 days, until a desired level of follicular production is achieved. Therefore, in any embodiment, the treatment may optionally include 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, from day 1 to at least day 5 of the treatment.

[0083] In one example, this treatment involves administering a dose of 150 IU of HP-hMG per day to the patient from day 1 to at least day 5 of the treatment. The dose may be adjusted up or down (for example, in increments of 75 IU of hMG) (for example, depending on the patient's response) from day 6 of the treatment. 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 procedure may further include administering a GnRH antagonist, starting when the lead follicle reaches a diameter of 14 mm and / or on day 5, 6, or 7 of stimulation (e.g., day 6 of stimulation), and continuing throughout the remainder of HP-hMG administration.

[0085] In any embodiment, the procedure may further include inducing terminal follicular maturation, as described above. Therefore, the procedure may include inducing terminal follicular maturation by administering hCG (e.g., recombinant hCG) or a GnRH agonist. As discussed above, when inducing terminal follicular maturation using a GnRH agonist, a small amount of hCG may also be used.

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

[0087] In any embodiment, the procedure may be a fresh transplantation method comprising: retrieving oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; retrieving blastocysts; optionally selecting blastocysts based on quality / morphological evaluation; and transplanting the fresh blastocysts (optionally selected, for example, based on quality / morphological evaluation) into the uterus. The procedure may be a single blastocyst transplantation protocol in which a single blastocyst is selected for fresh transplantation. Optionally, the remaining blastocysts may be frozen for future transplantation by methods known in the art.

[0088] In any embodiment, the procedure may be a cryopreservation method comprising: collecting oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; selectively evaluating the chromosomal quality of the blastocysts; freezing one, more, or all of the blastocysts; and implanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus. In the freezing and "total freezing" methods, the selected blastocysts are frozen for future implantation / transfer using methods known in the art.

[0089] In any embodiment, the method may involve freezing unfertilized oocytes. Therefore, the method may include: retrieving oocytes; freezing one or more or all of the retrieved oocytes; then thawing one or more of the frozen oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; optionally selecting blastocysts based on quality / morphological evaluation; and implanting the blastocysts (optionally selected, for example, based on visual evaluation of quality / morphology) into the uterus. Alternatively, the method may include: retrieving oocytes; freezing one or more or all of the retrieved oocytes; then thawing one or more of the frozen oocytes; fertilizing the oocytes; developing the fertilized oocytes to the blastocyst stage; performing chromosomal evaluation of the blastocysts; freezing the blastocysts; and implanting the thawed frozen blastocysts (e.g., euploid blastocysts selected based on chromosomal evaluation) into the uterus.

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

[0091] Example 1 - Clinical trials and retrospective analysis of MEGASET HR The following are patients who have undergone intracytoplasmic sperm injection and single blastocyst transfer (fresh transfer), with a BMI of 18-30 kg / m². 2 This paper describes a retrospective analysis of data collected in a multicenter, randomized, evaluator-blind, controlled, non-inferiority trial in 620 women (21–35 years old) who had 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 in Witz et al., Fertility and Sterility (in press) (published online on March 29, 2020).

[0092] 1. Test group The main selection criteria are a regular ovulatory menstrual cycle of 21-45 days and a body mass index (BMI) of 18-30 kg. 2 The subjects were women aged 21–35 years who desired to become pregnant. Patients / subjects were defined as expected high-response subjects with a serum anti-Müllerian hormone (AMH) level of ≥5 ng / L (35.71 pmol / L) at the time of screening. These subjects had a documented history of infertility (e.g., inability to conceive for at least 12 months or at least 6 months if receiving donor sperm) and serum FSH levels on day 2 or 3 of the menstrual cycle were 1–12 IU / L (inclusive).

[0093] Exclusion criteria included known stage III-IV endometriosis; a history of recurrent miscarriages that did not result in live birth (recurrent is defined as two or more consecutive miscarriages); and past failures of in vitro fertilization (IVF) or assisted reproductive technology (ART) due to poor response to gonadotropins (poor response is defined as the development of two or fewer mature follicles or a history of two previous failed cycle cancellations prior to oocyte retrieval due to poor response). Women with anovulation were also excluded.

[0094] 2. Test Protocol This was a multicenter, randomized, evaluator-blind phase IV clinical trial comparing HP-hMG and rFSH in a GnRH antagonist cycle with forced single blastocyst transfer (fresh transfer) in a high-response population in the United States. The objective of this trial was to demonstrate that HP-hMG is at least non-inferior to rFSH in terms of ongoing pregnancy rate (OPR) in potential high-response patients undergoing IVF / ICSI treatment.

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

[0096] Participants were randomized in a 1:1 ratio to receive cohort stimulant stimulation (COS) in a GnRH antagonist cycle with either 150 IU of HP-hMG (N=311; MENOPUR®, Ferring Pharmaceuticals, Inc.) or rFSH (N=309; GONAL-F, EMD Serono) as the gonadotropin. Treatment was initiated on day 2 or 3 of the menstrual cycle with 150 IU of HP-hMG or rFSH for the first 5 days. From day 6 of stimulation onward, the dose could be adjusted as needed, up to 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 up to 20 days, with inertia prohibited.

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

[0098] When three follicles with a diameter of 17 mm or more were observed by TVUS, a single injection of 250 μg of hCG (human chorionic gonadotropin alfa) was immediately administered to induce final follicular maturation. However, if a subject showed an excessive ovarian response (more than 30 follicles, each 12 mm or larger, and / or estradiol (E2) levels of 5,000 pg / mL or higher), a GnRH agonist (4 mg of leuprolide acetate) was administered more than 12 hours after the last GnRH antagonist dose, the fresh transfer was canceled, all blastocysts were biopsied, and the viable blastocysts were frozen for use in the next transfer cycle to reduce the risk of OHSS.

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

[0100] The day after oocyte retrieval, progesterone was inserted vaginally (100 mg twice daily - ENDOMETRIN®; Ferring) to support the luteal phase, and this was continued until the day of the β-hCG test (10-15 days after blastocyst / embryo transfer). Luteal support was continued until continued pregnancy was confirmed.

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

[0102] For subjects who had not achieved a continuing pregnancy in a fresh cycle, single frozen blastocyst transfer could be initiated within 6 months of randomization to subjects in this study. Euploidy could be selected for frozen transfer using PGS results. Data from the frozen-thawed embryo transfer cycle, including blastocyst transfer information, β-hCG testing, clinical pregnancy, continuing pregnancy, pregnancy loss rate, and live births, were collected.

[0103] Post-trial follow-up included the collection of birth information (birth and neonatal health status) for all subjects who were still pregnant one year after a fresh cycle or randomized frozen-thawed embryo transfer cycle. The birth rate after the fresh cycle and the cumulative birth rate six months after the fresh cycle and randomized frozen-thawed embryo replacement cycle were evaluated as part of the post-trial follow-up.

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

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

[0106] Other drugs used were as follows: • Ganirelix acetate injection, manufactured by Merck, is supplied as a pre-filled syringe (0.5 mL) delivering 0.25 mg of ganirelix. When the lead follicle was 14 mm or larger and / or the serum E2 level was 300 pg / mL or larger, ganirelix acetate was initiated at a daily dose of 0.25 mg and continued throughout the entire gonadotropin-releasing period. • OVIDREL® (Human Cholangiogonadotropin Alpha), manufactured by EMD Serono, was provided as a pre-filled syringe (0.5 mL) containing 250 μg of human chorionic gonadotropin alfa. It was administered as a single injection immediately after observing three follicles with a diameter of 17 mm or more using TVUS. • ENDOMETRIN® (progestin), manufactured by Ferring, is supplied as an insert for vaginal administration twice daily, delivering 100 mg (200 mg / day) each time.

[0107] The primary endpoint was the rate of continuing pregnancy, defined as the presence of at least one intrauterine pregnancy with a viable fetus and detectable fetal heartbeat at 10–11 weeks of 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 heartbeat at 5-6 weeks of gestation) • Early pregnancy loss (defined as a pregnancy of 10-11 weeks in a fresh cycle with two positive β-hCG tests, but not a continuing pregnancy) ·Birth rate • Follicle growth, follicular levels (total number of follicles, number of follicles ≤9mm, 10-11mm, 12-14mm, 15-16mm, and ≥17mm) as evaluated by TVUS, and target levels (maximum follicular size, average follicular size, average size of the three largest follicles, and average number of follicles ≥17mm, ≥15mm, and ≥12mm). • Endocrine profile (serum estradiol [E2], progesterone [P4], hCG, LH) • Retrieved oocytes, fertilization rate, and embryo quality.

[0108] 3. Serum assay Blood samples were collected before and throughout the stimulation period (e.g., before the start of stimulation, on day 6, 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 limits of detection 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 Non-inferiority targets for the primary endpoint of continuing pregnancy were achieved. HP-hMG was associated with numerically higher continuing pregnancy rates compared to rFSH (35.5% vs. 30.7%, P>0.05). The mean number of oocytes per patient in the rFSH group (±SD; 22.2±11.54) was higher than in the hMG group (15.1±10.12), representing a difference in ovarian response with a statistically significant increase in the rate of OHSS (21.4% vs. 9.7%, p<0.05).

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

[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 population and the non-oligoovulatory population were made using either a t-test (continuous parameters) or Fisher's exact test (fragmentary parameters).

[0112] [Table 1]

[0113] Based on the assessment of serum AMH, LH, testosterone, and estradiol levels (and the tendency toward elevated progesterone), the oligoovulation patient population was likely included in the PCOS patient population (e.g., patients whose oligoovulation was due to PCOS). This is because elevated levels of AMH, LH, testosterone, estradiol, and progesterone are characteristic of PCOS, and other common causes of oligoovulation (e.g., ovarian dysfunction, hyperprolactinemia, thyroid dysfunction, and renal dysfunction) were likely excluded by the inclusion and exclusion criteria of this study.

[0114] [Table 2]

[0115] [Table 3]

[0116] Therefore, the inventors surprisingly found that patients expected to be high responders, diagnosed with oligoovulation (e.g., oligoovulation due to PCOS), and treated with HP-hMG as a gonadotropin for COS (N=50) had a 19.2% higher (95% confidence interval 1.2%~37.3%) continuing pregnancy rate after fresh embryo transfer compared to patients treated with rFSH as a gonadotropin for COS (N=56). This is larger than the improvement in continuing pregnancy rate associated with HP-hMG treatment in the entire population of expected high responders (referenced to FSH) (35.5% vs. 30.7%, P>0.05).

[0117] Therefore, the inventors have found that the selection of expected high-response patients diagnosed with oligoovulation (e.g., oligoovulation due to PCOS) for treatment with hMG as a gonadotropin for COS, rather than FSH, may be associated with a higher continued pregnancy rate. Accordingly, the present invention as described herein relates to subjects selected according to one or more or all of the following criteria: diagnosis of oligoovulation; diagnosis of PCOS; serum AMH level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) 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, baseline serum LH of ≥7 U / L, and baseline serum testosterone of ≥1.10 nmol / L.

[0118] Example 2 Below is an overview of exemplary methods for treating infertility in patients with oligoovulation and / or PCOS (e.g., oligoovulation due to PCOS), who are expected to be highly responsive. Infertility treatment including COS with HP-hMG (rather than FSH) as a gonadotropin has been associated with relatively high continuing pregnancy rates.

[0119] Typically, the treatment of this infertility is supervised by a physician. Typically, the patient is diagnosed or has been diagnosed by a physician with oligoovulation and / or PCOS (e.g., oligoovulation due to PCOS). The patient may also be diagnosed or has been diagnosed as a high-responder, for example, based on a serum AMH level of ≥35.7±0.5 pmol / L (≥5.0±0.2 ng / ml) by serum AMH testing, e.g., Beckmann-Coulter Gen 2 assay as described in Arce et al., Fertility and Sterility 99:1644-53 (2013), or a comparable serum AMH level determined by other means. In addition, or instead, this patient may be identified or have been identified as having one or more of the following conditions prior to controlled ovarian stimulation: (i) a serum luteinizing hormone (LH) level of 7 U / L or higher, (ii) a serum testosterone level of 1.10 nmol / L or higher, and (iii) a serum estradiol level of 145 pmol / L or higher.

[0120] Patients diagnosed with oligoovulation and / or PCOS (e.g., oligoovulation due to PCOS), who have a serum AMH level of ≥35.7±0.5 pmol / L or ≥5.0±0.2 ng / ml prior to treatment (as selectively identified), and who are selectively identified to have one or more of the following: (i) a serum luteinizing hormone (LH) level of ≥7 U / L prior to controlled ovarian stimulation, (ii) a serum testosterone level of ≥1.10 nmol / L prior to controlled ovarian stimulation, and (iii) a serum estradiol level of ≥145 pmol / L prior to controlled ovarian stimulation, are selected for COS using HP-hMG (e.g., MENOPUR®, available from Ferring Pharmaceuticals) as the 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 is initiated on day 2 or 3 of the patient's menstrual cycle ("Stimulation Day 1"). This procedure involves administering a daily dose of MENOPUR® (e.g., 150 IU / day) by injection from day 1 (Stimulation Day 1) to at least day 5 (Stimulation Day 5). The dose may be adjusted up or down (e.g., in increments of 75 IU of hMG) to a maximum daily dose of 300 or 450 IU of hMG or a minimum daily dose of 75 IU of hMG (depending on the patient's ovarian response). This procedure may be continued for up to 20 days (not more than 20 days of stimulation), 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 evaluated by TVUS, GnRH antagonist (ganirelix acetate) may be initiated at a daily dose of 0.25 mg and continued throughout the entire gonadotropin stimulation period.

[0123] Final follicular maturation is induced by hCG or a GnRH agonist. If three follicles with a diameter of 17 mm or more are observed by TVUS, a single injection of 250 μg of hCG (human chorionic gonadotropin alfa) may be administered immediately to induce final follicular maturation. Alternatively, in cases of excessive response to COS (e.g., patients with more than 30 follicles with a diameter of 12 mm or more after COS treatment, or with serum estradiol (E2) levels of 5,000 pg / ml or higher), final follicular maturation may be induced using a GnRH agonist. When using a GnRH agonist, this GnRH agonist may be, for example, leuprolide acetate (e.g., LUPRON®) in doses of 1-4 mg.

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

Claims

1. 1. 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 said 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. 1. A composition comprising highly purified menotropins (HP-hMG) for use in the treatment of infertility, optionally by controlled ovarian stimulation, in patients with oligoovulation due to polycystic ovary syndrome (PCOS), wherein said 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 for use according to claim 1 or 2, comprising 75 to 450 IU of HP-hMG.

4. 4. The composition for use 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, optionally from day 1 of treatment to at least day 5 of treatment.

5. The treatment of infertility comprises: identifying (e.g., diagnosing) patients who have (a) 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, 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, and optionally also one or both of: (c) 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), and (d) 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); optionally 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, from day 1 of treatment through at least day 5 of treatment; A composition for use according to any one of claims 1 to 4, comprising:

6. 1. 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 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) prior to treatment / stimulation, 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; optionally 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, from day 1 of treatment through at least day 5 of treatment; A composition comprising:

7. 1. 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) and 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) prior to treatment / stimulation, 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; optionally 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, from day 1 of treatment through at least day 5 of treatment; A composition comprising:

8. The treatment of infertility comprises: identifying (e.g., diagnosing) patients who have (a) 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, 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, and optionally also one or both of: (c) 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), and (d) 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); optionally 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, from day 1 of treatment through at least day 5 of treatment; 8. A composition for use according to claim 6 or 7, comprising:

9. 9. The composition for use according to 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. 10. The composition for use according to any one of claims 1 to 9, wherein the treatment further comprises inducing final follicular maturation by administering hCG or a GnRH agonist optionally supplemented with hCG.

11. 11. The composition for use according to any one of claims 1 to 10, wherein the treatment is a fresh transfer method further comprising retrieving oocytes, fertilizing the oocytes, allowing the fertilized oocytes to develop to the blastocyst stage, optionally assessing the quality / morphology of the blastocysts, and transferring fresh blastocysts (optionally selected, for example, based on visual assessment of quality / morphology) into the uterus.

12. 11. The composition for use according to 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, 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.

13. The treatment comprises: retrieving oocytes, freezing unfertilized oocytes, subsequently 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 based on, for example, visual assessment of quality / morphology) 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, 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. The composition for use according to any one of claims 1 to 10, further comprising:

14. The composition for use according to any one of claims 1 to 13, further comprising 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 for use according to any one of claims 1 to 14, wherein the patient has a BMI of

16. 1. An assisted reproductive technology method for treating a female who has been diagnosed with one or both of oligoovulation and PSCOS and who is expected to have a high ovarian response to controlled ovarian stimulation, comprising: Identifying women as having been diagnosed with oligoovulation and / or PCOS and having a serum anti-Mullerian hormone (AMH) level of 35.7±0.5 pmol / L (5.0±0.2 ng / ml or greater) prior to treatment; and administering to the identified woman an amount of highly purified menotropin (HP-hMG) effective to stimulate follicular growth, thereby effecting controlled ovarian stimulation. Assisted reproductive technology methods, including:

17. 17. The method of claim 16, further comprising 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.

18. 18. The method of claim 16 or 17, wherein the female has been identified as being diagnosed with oligoovulation.

19. 19. The method of any one of claims 16 to 18, wherein the HP-hMG is administered at a dose of 75 to 450 IU of hMG per day.

20. 19. The method of any one of claims 16 to 18, 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.

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

22. 22. The method of any one of claims 16 to 21, further comprising administering a gonadotropin-releasing hormone antagonist (GnRH antagonist) starting on day 6 of treatment / stimulation.

23. 23. The method of any one of claims 16 to 22, further comprising inducing final follicular maturation by administering human chorionic gonadotropin (hCG) or a gonadotropin-releasing hormone agonist (GnRH agonist) optionally supplemented with hCG.

24. (a) retrieving oocytes, fertilizing the oocytes, allowing the fertilized oocytes to develop 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 a uterus; or (c) oocyte retrieval, freezing unfertilized oocytes, subsequently 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, e.g., based on visual assessment of quality / morphology) into the uterus; or (d) oocyte retrieval, freezing the unfertilized oocytes, subsequently 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. The method of any one of claims 16 to 23, further comprising:

25. 25. The method of any one of claims 16 to 24, wherein the woman 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.

26. 1. Use of HP-hMG in the manufacture of a medicament for the treatment of infertility in a woman who has been identified as having 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, said treatment comprising administering to said identified woman an amount of highly purified menotropin (HP-hMG) effective to stimulate follicle growth.

27. 27. The use of claim 26, wherein the female 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, and optionally also having one or both of 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 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) prior to treatment / stimulation.