2.1.1 Background

As women are, likely, born with all of their eggs. OR represents all remaining follicles/eggs a woman still maintains in her ovaries. OR, thus, declines with advancing age. It is made up of resting follicles, also called primordial follicles, and the so-called growing follicles 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 2.1).

For the longest time, the growing follicle pool was also considered outside of therapeutic reach. Infertility practice, indeed, over the last 60 years 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, it, however, appears reasonable to assume that most of a follicle’s fate has already been determined. That during those two weeks effects on egg and, therefore, embryo quality at most will only be marginal, has in recent years been increasingly recognized and, likely, represents a main contributing factor why over 40 years the concept of “embryo selection” has only been marginally successful at best.

An underreported conceptual breakthrough, however, occurred over 10 years ago, when the importance of appropriate androgen levels for follicle maturation became apparent in animal models at small-growing follicle stages (3) and in concomitant clinical androgen supplementation studies (4). Though by some still considered a controversial issue (5), what has been widely overlooked is the fact that androgen supplementation of selected infertile women represented in 60 years of modern infertility treatment the first extension of fertility treatments from the last two weeks of follicle maturation in the gonadotropin-dependent stage into earlier stages of folliculogenesis.

With the oocyte believed to contribute ca. 95 percent of embryo quality, the importance of this revolutionary step for modern infertility care cannot be overemphasized because, the more upstream interventions occur, the more will they beneficially impact oocyte quality and, ultimately, embryo quality. An important goal of modern infertility research, therefore, must be to switch from 40 years of, understandably, not very successful attempts at embryo selection, toward attempting to improve embryo quality through interventions into earlier stages of recruitment and oocyte maturation.

Observations surrounding androgen supplementation of selected infertile women also significantly contributed to a better understanding of what, likely, represents 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 percent of women, chronological and ovarian ages are the same; in the remaining 10 percent, however, remaining follicles/oocytes numbers are below normal. So-affected women are generally described to suffer from POA/oPOI and, as will be further discussed in more detail below, clinically and physiologically, they often behave 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 with progressively more embryos available for transfer will demonstrate progressively better and better pregnancy and live birth chances in IVF until a peak in AMH levels is reached, implantation rates start to reverse and miscarriage rates progressively increase (6). Until this AMH peak is reached (at usually very high levels), quantity and quality of oocytes and embryos, therefore, usually coincide, except in one only recently described condition, the so-called hypoandrogenic PCOS-like phenotype (H-PCOS) (7, 8), further discussed below.

Traditionally, with advancing female age, declining egg quality has been linked to the natural aging process of primordial follicles in ovaries. Though aging of primordial follicles, not only quantitatively but, likely, also qualitatively, plays an important part in ovarian aging, the center’s experience with androgen supplementation led to a revised hypothesis. It proposes that, due to the almost complete isolation of primitive primordial follicles from their surrounding stroma, aging-induced environmental damage on primordial follicles over time is only limited. Good evidence in support can be found in the observation that some even highly toxic chemotherapeutic agents do not damage primordial follicles (9), while others, of course, do (10). Once recruited into small-growing follicle stages, follicles, however, almost uniformly are severely damaged by chemo- as well as radiation therapy and undergo apoptosis.

This new ovarian aging hypothesis builds on these observations by making the argument that primordial follicles cannot be too badly damaged by advanced female age if, postrecruitment, androgen supplementation can still significantly improve IVF cycle outcomes (4). Like chemotherapy damage, at least some age-dependent damage to follicles, therefore, must happen postrecruitment. Assuming this, indeed, to be the case, this damage to follicles/oocytes must happen postrecruitment, at early stages of follicle maturation, and not prerecruitment at primordial stages, as current dogma holds. Granulosa cells of small-growing follicle stages are characterized by greatest density of androgen receptors (Figure 2.1) (3, 4). The culprit, therefore, must be the ovarian microenvironment in which these maturation stages take place: a hypoandrogenic ovarian microenvironment.

Figure 2.1 FSH and androgen receptors during small-growing follicle stages.

Modified from Gleicher et al. (13), with permission.

This new hypothesis of ovarian aging, therefore, not only explains how androgen supplementation can beneficially affect female infertility but opens the field to much wider potential treatment horizons in establishing that oocyte quality can be beneficially affected through early intervention into folliculogenesis (in itself, a major innovation in the treatment of female infertility) and, second, by concentrating research efforts on the ovarian microenvironment of older ovaries.

If treatment of androgen deficiencies can lead to better egg quality, there must be innumerable, yet to be discovered, additional deficiencies in the ovarian microenvironment that occur with advancing female age. Further improvements in the ovarian microenvironment can, therefore, be expected to yield similar incremental improvements, witnessed with androgen supplementation (4). Within this context, it is also of interest that worldwide popularity of human growth hormone (HGH) supplementation in IVF cycles has recently significantly increased, even though HGH may only increase oocyte yields, without improving pregnancy and live birth chances (11). Achieving its effectiveness via IGF-1, HGH, like androgens, primarily improves FSH activity on granulosa cells at small-growing follicle stages.

Follicles enter the growing follicle pool after recruitment and require at least additional 6–8 weeks to reach the gonadotropin-dependent stage, where they become available to exogenous gonadotropin stimulation in IVF cycles. Appropriate timing of supplementation of the ovarian microenvironment is, therefore, crucial: Exerting effects primarily at small-growing follicle stages (Figure 2.1), supplementation of androgens and HGH must, therefore, be started at least 6–8 weeks prior to IVF cycle start (12, 13). If supplementation is offered only during IVF cycles (as, unfortunately, is practice at many IVF centers), follicles stimulated in that cycle will get hardly any benefits, though recent reports raised the possibility of positive androgen and HGH supplementation effects also on the implantation process (14, 15).

2.1.2 How to Select Patients for Individualized Fertility Treatments

For decades, most IVF centers have been following specific treatment protocols, which only rarely diverge from established baselines. To maintain consistency of results, such an approach made sense, as long as patient populations were relatively cohesive. With IVF outcomes till ca. 2010 steadily improving (16), initially uniform patient populations started, however, increasingly to diverge into better- and poorer-prognosis patients. Better-prognosis patients conceived quicker, thus rapidly exiting fertility treatments. Poorer-prognosis patients, however, lingered and, over time, increased in absolute numbers as well as in proportions of total patients in treatment.

Poorer-prognosis patients were mostly older women, desirous of conceptions at ever-increasing ages, but also younger women with POA/oPOI and, therefore, almost equally poor pregnancy and live birth chances. Both of these patient populations were in obvious need of distinctively different treatment algorithms and more individualized infertility treatments. In many treatment aspects both groups also overlapped and, therefore, shared the fate of, often, being given no choice but third-party egg donation cycles rather than individualized cycles with autologous oocytes. The IVF field, therefore, largely missed out on the rapidly evolving concept of “personalized medicine” that swept medical practice in most specialty areas over the last decade. This kind of individualized personalized medicine is, however, exactly what is required if the dramatic declines in live birth rates observed all over the world since 2010 (16, 17) are to be reversed.

Though these developments seemed too obvious to be overlooked, they did not lead to reassessments of mostly uniform and universal protocols in favor of more individualized approaches, but to rapidly growing utilization of third-party egg donation cycles, which, indeed, in 2010 in parallel with live birth rates peaked (16, 17). As a consequence, the IVF field really never learned to treat poor-prognosis patients with individualized treatment protocols because most, instead, ended up in third-party donor egg cycles.

Returning to our preferred patient classification of good, average, and poor prognoses based on age-specific FOR, female patients can at all ages be classified into these categories quite easily. The reason is in IVF’s above noted almost universal interdependence of quantity and quality of oocyte yields. Embryo numbers available for transfer, therefore, ultimately determines prognosis (6). But FOR is, of course, age-dependent and declines as women age. What represents a favorable FOR, associated with good prognosis, therefore, also changes, as do determinations of average and poor prognoses.

FOR is clinically traditionally determined through FSH, AMH and in some centers via antral follicle counts (AFCs). Theoretically, they should correlate, but some distinct differences exist. Many centers, for example, consider AFCs a more subjective FOR parameter than FSH and AMH levels and, therefore, do not use them as objective parameters in daily patient assessments. Others, on the other hand, use AFCs as primary assessment tools in order to avoid blood draws. Also, at extremely low levels, AMH loses its clinical predictability, while evaluations of FSH are, of course, cycle-day-dependent (should be drawn on days 2/3 of cycle) and easily influenced by estradiol levels (FSH, therefore, must be drawn in association with estradiol).

A study performed a number of years ago investigated various FSH/AMH combinations and their respective outcomes in clinical IVF practice (18). Surprisingly, best pregnancies were achieved in women with high-FSH/high-AMH patterns. When originally reported, the authors had no good explanation for these findings. They, however, since, were able to explain them after discovering a new diagnostic entity in infertile women (named H-PCOS; see below for further detail) (7, 8). Though FSH and AMH in general correlate in the inverse, there are exceptions with potentially significant diagnostic relevance.

Since FOR changes with age, FSH, AMH, and AFC must be evaluated in age-specific ways. Remarkably, this, however, happens only in a small minority of IVF centers. IVF practitioners who do not consider FSH, AMH, and/or AFCs in age-specific ways will fail to diagnose in timely fashion those with abnormally LFOR in POA/oPOI and older patients or those with excessively high FOR – mostly cases of PCOS.

Since many laboratories consider FSH levels up to 10.0 or even 12.0 mIU/mL as “normal range,” many women with POA/oPOI do not necessarily present with “abnormal” FSH. For example, an FSH of 9.9 mIU/mL in a 25-year-old cannot be considered normal, even if still in “normal” laboratory range. The same level in a 46-year-old, on the other hand, may actually denote unusually good FOR considering her age. In reverse, an AMH of 1.0 ng/mL at age 25 is strongly suggestive of POA/oPOI but at age 45 would actually denote exceptionally good FOR.

Table 2.1 summarizes diagnoses mandating special attention and, therefore, individualized IVF protocols. As already noted, one population that automatically qualifies are women of advanced age. Because in early IVF days, age 38 represented the upper age limit for IVF treatments, advanced female age has in association with IVF historically been defined as age above 38 years. With improved abilities to achieve pregnancies in older women, the definition of advanced female age moved to age 40. Based on contemporary IVF practice, in which women above age 42 are mostly referred into third-party egg donations (16, 17), it can now be considered to start at roughly age 42.

Though in the US IVF with autologous oocytes is rare above age 42–43, we have been advocating treatments of older women with autologous oocytes with the argument that outcomes can be better than has been widely perceived (19). Outcomes, of course, cannot approach treatment successes achieved with young third-party donor eggs. Genetic maternity does, however, represent a principal desire and goal of most female infertility patients, and must be respected under a patient’s right to self-determination.

Young women with POA/oPOI, as previously noted, mimic older women in many physiologic as well as clinical observations. Consequently, treatments often are quite similar. Because diagnostic terminologies can at times be confusing, a clear understanding of which patient populations should be given specific treatments is of utmost importance. So, for example, a recent systematic review in a reputable medical journal claimed to address pregnancy following premature ovarian insufficiency (20). It further defined this condition by criteria of the European Society of Human Reproduction and Embryology (ESHRE) as primary or secondary amenorrhea for more than 4 months, onset before age 40 and FSH over 25 mIU/mL (21). One of the two references the authors cited, however, referred to a diagnosis of primary rather than premature ovarian insufficiency (22), a more commonly used terminology. Though both terminologies can be abbreviated as POI and are defined by similar criteria, they are substantially different because primary ovarian insufficiency is defined by FSH levels above 40.0 mIU/mL, rather than 25 mIU/mL (23).

This is a crucially important differentiation because POA/oPOI, the precursor condition to POI, is often defined by abnormally elevated FSH between 10.0 and 12.0 mIU/ml up to 40.0 mIU (though, as noted before, should really be determined in age-specific ways). Premature ovarian insufficiency, as defined in the above-referenced review and by ESHRE criteria, is, therefore, a very different condition from POI, a distinction, unfortunately, lost in the above-cited review and in much of the infertility literature. Box 2.2 defines terminologies, and with it, patient populations, as they are described in this chapter.

Box 2.2 Terminology of Ovarian Failure Diagnoses Used in This Chapter

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Related posts:

1. Chapter 6 – Individualized Fertilization Technique in the IVF Laboratory
2. Chapter 7 – Individualized Genetic Testing
3. Chapter 1 – Individualized Ovarian Stimulation for Normal and High Responders
4. Chapter 11 – Individualized Embryo Transfer

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