FIELD

The methods described herein relate to assisted reproductive technology. In particular, described herein are methods for treating infertility, including controlled ovarian stimulation methods that may be particularly useful for women at risk of a high ovarian response thereto.

BACKGROUND

Assisted reproductive technology (ART) procedures generally involve stimulating egg production, harvesting eggs from a woman's ovaries, combining them with sperm in vitro, and transferring them to a woman's uterus (the donor or another woman). Success of ART is hampered by maternal and perinatal risks associated with the stimulation of egg production, such as ovarian hyperstimulation syndrome (OHSS) and ectopic pregnancy. Other concerns that arise in ART are the production of quality embryos and euploid blastocysts to support ongoing pregnancy rates and live birth rates.

Gonadotropins, such as menotropin (e.g., human menopausal gonadotropin, or hMG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), have been widely used for controlled ovarian stimulation (COS), and highly purified menotropin (HP-hMG) and recombinant human FSH (r-hFSH) have been used more recently. The efficacy of ovarian stimulation protocols may be enhanced using long gonadotropin hormone releasing hormone (GnRH) agonists or GnRH antagonists for cycle control. See, e.g., Devroey et al.Fertility and Sterility97: 561-71 (2012).

Because patient responses to ovarian stimulation vary widely, treatments often are individualized. For example, individualization may be based on predicted ovarian response to gonadotropin stimulation, which forecasts poor, normal or high response. High ovarian responders usually are defined as women who produce high numbers of developing follicles following a standard protocol of controlled ovarian stimulation (COS). Although these patients are generally considered good candidates for ART, high ovarian response may be associated with lower implantation rates and higher miscarriage rates, and thus a decreased chance of successful outcome as compared with a normal ovarian response. These high responders also are at greater risk for OHSS and the complications associated therewith.

It has been hypothesized that ovarian stimulation may have a general negative impact on embryo quality, as assessed by morphological parameters and/or chromosomal analysis (e.g., euploidy vs. aneuploidy). See, e.g., Hamdine et al., “Ovarian Stimulation for IVF: Mild Approaches” in Human Fertility: Methods and Protocols, Methods in Molecular Biology, Vol. 1154, Springer Science+Business Media, N.Y. (2014). Additionally, Haaf et al.,Fertility and Sterility91(3): 733-38 (2009), reported that a high oocyte yield is associated with an increased chromosome error rate. However, Fatemi et al.,Human Reproduction28(2) 442-52 (2013), reported that high ovarian response does not jeopardize ongoing pregnancy rates, but rather increases cumulative pregnancy rates.

Efforts to develop improved ART methods have involved exploring milder stimulation protocols. For example, Rubio et al.,Human Reproduction25(9): 2290-2010 (2010), reported that decreasing the gonadotrophin dose administered to high responders could improve fertilization rates and embryo quality, although the lower doses resulted in a decreased number of oocytes. Other efforts have considered whether the specific gonadotrophin used impacts the results. For example, Ziebe et al.,Human Reproduction22(9) 2404-13 (2007), reported that the use of HP-hMG versus rFSH could impact the morphology of embryos, and observed improved implantation, ongoing pregnancy and live birth rates among the top-quality embryos derived from stimulation with HP-hMG compared with rFSH. However, Ziebe's findings were based on a visual assessment of oocyte/embryo morphology on day three following retrieval, not based on chromosomal analysis, and morphology at day three is not correlated with aneuploidy. Along the same lines, La Marca et al.,Fertility and SterilityO-169 (2012), reported that among predicted high responders (subjects having an AMH≥5.2 ng/ml) the group stimulated with rFSH group had significantly more oocytes retrieved, but a significantly lower live birth rate per cycle as compared to the group stimulated with HP-hMG.

There remains a need, therefore, for improved assisted reproductive technology methods, particularly for women at risk of a high response to controlled ovarian stimulation.

SUMMARY

In accordance with some embodiments, there are provided assisted reproductive technology methods useful for women at risk of a high response to controlled ovarian stimulation, comprising selecting a woman at risk of a high ovarian response to controlled ovarian stimulation having a serum anti-Müllerian hormone (AMH) level greater than or equal to 5.0±0.5 ng/ml, when measured using a Beckmann-Coulter Gen 2 assay or a comparable AMH level measured by a different method, and administering to the selected woman an amount of highly purified menotropin (HP-hMG) effective to stimulate follicle development. In accordance with some embodiments, the methods are for improving the quality of an embryo produced by in vitro fertilization after controlled ovarian stimulation in a woman at risk of a high ovarian response thereto. In accordance with other embodiments, the methods are for increasing the proportion of euploid blastocysts produced by in vitro fertilization after controlled ovarian stimulation in a woman at risk of a high ovarian response thereto. In accordance with other embodiments, the methods are for treating infertility in a woman at risk of a high ovarian response to controlled ovarian stimulation. In accordance with other embodiments, the methods are for effecting controlled ovarian stimulation in a woman at risk of a high ovarian response thereto. In accordance with other embodiments, the methods are for increasing ongoing pregnancy rates. In accordance with other embodiments, the methods are for increasing live birth rates. In accordance with other embodiments, the methods are for promoting the development of euploid blastocysts, such as for future blastocyst transfer, in a woman at risk of a high ovarian response to controlled ovarian stimulation.

In accordance with other embodiments, there are provided assisted reproductive technology methods useful for women at risk of a high response to controlled ovarian stimulation, comprising administering an amount of highly purified menotropin (HP-hMG) effective to stimulate follicle development to a woman selected as being at risk of a high ovarian response to controlled ovarian stimulation, wherein the selected woman has a serum anti-Müllerian hormone (AMH) level greater than or equal to 5.0±0.5 ng/ml, when measured using a Beckmann-Coulter Gen 2 assay or a comparable AMH level measured by a different method. In accordance with some embodiments, the methods are for improving the quality of an embryo produced by in vitro fertilization after controlled ovarian stimulation in a woman at risk of a high ovarian response thereto. In accordance with other embodiments, the methods are for increasing the proportion of euploid blastocysts produced by in vitro fertilization. In accordance with other embodiments, the methods are for treating infertility in a woman at risk of a high ovarian response to controlled ovarian stimulation. In accordance with other embodiments, the methods are for effecting controlled ovarian stimulation in a woman at risk of a high ovarian response thereto. In accordance with other embodiments, the methods are for increasing ongoing pregnancy rates. In accordance with other embodiments, the methods are for increasing live birth rates. In accordance with other embodiments, the methods are for promoting the development of euploid blastocysts, such as for future blastocyst transfer, in a woman at risk of a high ovarian response to controlled ovarian stimulation.

In specific embodiments of any of these methods, the woman may have an antral follicle count (AFC) of greater than or equal to 10, or greater than or equal to 15, in both ovaries combined, prior to stimulation.

In specific embodiments of any of these methods, the method may result in an increased proportion of euploid blastocysts, and/or an increased proportion/percentage of euploid blastocysts versus aneuploid blastocysts, and/or a reduced aneuploidy rate, and/or an increased ongoing pregnancy rate, and/or an increased live birth rate, each as compared to a comparable method using recombinant follicle-stimulating hormone (rFSH) as the gonadotropin. In further specific embodiments of any of these methods, the method may result in an increased proportion of euploid blastocysts, and/or an increased proportion/percentage of euploid blastocysts versus aneuploid blastocysts, and/or a reduced aneuploidy rate, and/or an increased ongoing pregnancy rate, and/or an increased live birth rate, each as compared to a comparable method using recombinant follicle-stimulating hormone (rFSH) as the gonadotropin.

In specific embodiments of any of these methods, the amount of HP-hMG administered may be from 100-300 IU per day for from about 1 to about 20 days, or from 100-200 IU per day for from about 1 to about 20 days.

In specific embodiments of any of these methods, the HP-hMG may be administered for at least 5 days.

In specific embodiments of any of these methods, the methods may further comprise administering a gonadotropin hormone releasing hormone (GnRH) agonist or a GnRH antagonist.

In specific embodiments of any of these methods, the methods may further comprise one or more of administering an amount of hCG effective to trigger ovulation, harvesting oocytes from the woman, and in vitro fertilization of harvested oocytes (optionally, by intra-cytoplasmic sperm injection (ICSI)).

In specific embodiments of any of these methods, the methods may further comprise assessing the chromosomal quality of blastocysts obtained from the woman after in vitro fertilization of oocytes harvested from the woman. In further specific embodiments, the methods may further comprise transfer of a blastocyst determined to be a euploid blastocyst. In specific embodiments, the transfer may be fresh transfer. In further specific embodiments, the methods may further comprise freezing a blastocyst determined to be a euploid blastocyst.

The foregoing general description and the detailed description are exemplary and explanatory and are intended to provide further explanation of the invention. For detailed understanding of the invention, reference is made to the following detailed description of specific embodiments, taken in conjunction with the accompanying figures. Other objects, advantages and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.

