How to individualize fertility treatment for women with low functional ovarian reserve (LFOR)

#1 in a series on DOR/LFOR

With CHR, likely being an extreme example (median age 43 years), patient populations in many fertility centers are aging, leading to surges in donor egg cycles, in most IVF centers, unfortunately, pretty automatically considered the remedy of choice for age above 42-43 years. Though pregnancy chances with autologous (own) eggs are, of course, significantly lower, most women, nevertheless, prefer own eggs over donor eggs. Standing pretty much alone in that regard, CHR, therefore, considers the need to recommend egg donation to a patient a “treatment failure,” though for patients who really have no other choice to experience physical motherhood, it then becomes an excellent second choice.

Considering the substantial changes in ovarian physiology with advancing female age, one would intuitively presume that IVF treatments of older women are appropriately adjusted. Likely because of limited research, this has, however, not been the case in most IVF centers. Consequently, outcomes of IVF cycles in older women have remained relatively poor and, in addition, are, however, generally even underestimated in their potential by colleagues as well as the general public.

Ovarian physiology in women with premature ovarian aging (POA),also called occult primary ovarian insufficiency (oPOI), in many features mimics ovarian aging. Younger women with POA/oPOI, therefore, often require similar treatments as older women. Both of these patient groups are in the medical literature often combined under acronyms, like poor/low responderslow (functional) ovarian reserve (LFOR) or poor-prognosis patients. They share a need for individualized treatments, which we in this installment of a series of articles will attempt to describe.

Introduction

Because studies of older and, otherwise, unfavorable patients going through in vitro fertilization (IVF) treatments with own (autologous) oocytes are sparse, we here present to a large degree thesubjective experience of CHR, which as of this point, likely, contributed a majority of relevant published studies on this subject to the literature. As U.S. national IVF data registries by the Center for Disease Control and Prevention (CDC)and the Society for Assisted Reproductive Technologies (SART)demonstrate, this centerserves the by-far oldest patient population among over 500 reporting U.S. IVF centers and, therefore, likely the oldest patient population of any IVF center in the world. While the median age of all U.S. centers reporting to the CDCin 2016 was 36 years, this center’s median age was 42 years in 2016 and 43 years in 2017-2019. Over 90% of the center’ new patients in recent years reported prior failed IVF cycles, often at multiple centers. Over half of the center’s patients are so-called “long-distance” patients from outside the larger New York City Tri-State area, many from Canada and overseas. Finally, in excess of 95% percent of the center’s patients suffer from LFOR, which means that even younger patients usually demonstrate abnormally high age-specific follicle stimulating hormone (FSH) and abnormally low anti-Müllerian hormone (AMH). This center, thus, overall, likely, serves the poorest-prognosis patient population of any IVF center in the world.

Poor response to ovarian stimulation is a very subjective diagnosis: It can be caused by many treatment-independent factors, like wrong medication dosing, poor quality medications, poor absorption of medication, patient errors, etc. The definition of poor response also changes with advancing age. We, therefore, do not favor the diagnostic terminology of “poor response,”as expressed by the so-called Bologna Criteria and, instead, prefer to define patients objectively by their functional ovarian reserve (FOR), also called the growing follicle pool (Box 1). Objectively poor responders, will usually, of course, demonstrate LFOR. These two patient definitions, therefore, to a degree overlap. Utilizing the idiom LFOR rather than poor response as diagnostic term, also offers the opportunity of a prospective diagnosis, while poor response always represents a post-factum diagnosis after a usually unsatisfactory IVF cycle. 

Background 

As women are, likely, born with at least the vast majority of their lifelong available eggs, their ovarian reserve (OR) represents all remaining follicles/eggs a woman still maintains in her ovaries. Their OR, thus, declines with advancing age. It is made up of resting follicles, also called primordial follicles, and so-called growing follicles, which start the growth and maturation process after recruitment from the resting pool. We here describe the growing follicle pool as a patient’s FOR because the resting pool is not available to clinical interventions (Box 1).

For the longest time, the growing follicle pool was also considered out of therapeutic reach. Over the last 60 years, infertility practice, indeed, concentrated practically exclusively only on the last two weeks of follicle maturation, the so-called gonadotropin-dependent stage of follicle maturation, when follicles become sensitive to gonadotropin stimulation. Only during those two weeks, do follicles respond to traditional fertility medications, including exogenously administered gonadotropins. By the time follicles reach this developmental stage, most of their fate must already have been determined. Effects on egg and, therefore, embryo quality during those two weeks will, therefore, at most only be marginal. This conclusion explains why “embryo selection,” almost an obsession of the IVF community since the inception of IVF, has been rather unsuccessful overall of those years.

Most older mothers-to-be need to restore their androgen levels for better chance of pregnancy. Image by Alexander Dumer via Unsplash.

An underreported conceptual breakthrough, however, happened almost 15 years ago, when the importance of androgen levels for follicle maturation at small growing follicle stages became apparent in animal models and clinical studies, mostly performed at CHR. Though by some still considered controversial, widely overlooked, androgen supplementation of selected infertile women represented the first extension of fertility treatments from the last two weeks of follicle maturation into earlier stages of follicle maturation in 60 years of modern infertility care.

With oocytes contributing ca. 95% of embryo quality, potential importance of this development cannot be overemphasized because, the more upstream interventions will occur, the more will they beneficially impact oocyte quality and, ultimately, embryo quality. An important goal of modern infertility research, therefore, must be a switch from 40 years of not very successful attempts at embryo selection toward improving embryo quality through earlier interventions into recruitment and oocyte maturation.

Observations surrounding androgen supplementation also significantly contributed to a better understanding of ovarian aging. There is consensus that ovarian aging concomitantly means a number of different things: With advancing age, women, for example, persistently lose follicles/oocytes. How many follicles/oocytes a woman’s ovaries still contain, therefore, defines her “ovarian age.” In ca. 90% of women, chronological and ovarian ages are the same; in the remaining 10%, however, remaining follicles/oocytes numbers are below normal. So-affected women are generally described as suffering from POA/oPOI and, clinically, they often behave in their infertility treatments like much older women.

Ovarian aging is, however, not only a quantitative but also a qualitative problem. Remarkably, even if age, AMH and FSH are controlled for, and if identical numbers of embryos are transferred, infertile women who produce more embryos suitable for transfer, will demonstrate better pregnancy and live birth chances in IVF. This correlation, however, is only maintained until a peak in AMH levels is reached, beyond which, implantation rates start to reverse, and miscarriage rates progressively increase. Until this AMH peak at very high levels), quantity and quality of oocytes and embryos, therefore, usually coincide. There is only one infertility diagnosis where this does not happen, the so-called hypo-androgenic PCOS-like phenotype (H-PCOS) which will be discussed in further detail later.

The modified CHR hypothesis of ovarian aging

Declining egg quality with advancing age has, traditionally, been quantitatively as well as qualitatively linked to the natural aging process of primordial follicles in ovaries. CHR’S experience with androgen supplementation, however, led to a modified hypothesis: It proposes that, due to the almost complete isolation of primitive primordial follicles from their surrounding stroma, aging-induced environmental damage of primordial follicles is only limited. Some evidence is provided by the observation that some even highly toxic chemotherapeutic agents do not damage primordial follicles, though others, of course, do. Once recruited into small growing follicle stages, follicles, however, almost uniformly are severely damaged by chemo- as well as radiation therapy and quickly undergo apoptosis. CHR’s revised aging hypothesis, therefore, suggests that much, if not most, damage that occurs to follicles of women at advanced ages does not happen before recruitment but after recruitment because of the aging process affecting the ovarian microenvironment in which recruited follicles then must mature.

Future installments in the DOR/LFOR series

  • How to select patients for individualized fertility treatments
  • Individualized treatments
  • Preparation of ovaries
  • Ovarian stimulation
  • Highly individualized egg retrieval (HIER)
  • Treatments of associated conditions
  • Conclusions and the future

Conflict statement

CHR and some of CHR’s scientists are listed as co-owners of a number of already awarded and still pending U.S. patents, some claiming benefits from androgen supplementation in women with low ovarian reserve, a topic addressed in this series of manuscripts. They also are co-owners of a number of U.S. patents relating to other fertility issues, unrelated to here discussed topics, including diagnostic importance of the FMR1gene and potential diagnostic and/or therapeutic functions of AMH. CHR and some of its scientists are shareholder in a number of start-ups, including Fertility Nutraceuticals, LLC, which produces a DHEA product and pays CHR and some of its scientists royalties. CHR and individual scientists have in the past received research support, travel funds and/or speaker honoraria from different Pharma companies as well as medical device corporation – none, however, in any way related to here discussed subjects. 

This is a part of the May 2020 CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.