PCOS' effects on egg quality are age-dependent

Posted on Mar 29, 2019

Whether PCOS negatively affects egg quality is a complex question, in part due to the diversity within a PCOS diagnosis

Whether PCOS adversely affects egg quality in IVF has remained a highly controversial issue, with many authors claiming yes and similar numbers of investigators claiming no. The reason for this discrepancy is, likely, the same problem that has prevented the field of infertility from making significant progress in understanding PCOS over many decades: What is currently defined as PCOS is really a basket of very different conditions, with different causes, etiologies and pathophysiologies. Throwing them all together in the “PCOS” moniker does not make any sense; yet, this is exactly what has been happening in the PCOS literature for decades, even though different PCOS phenotypes have been described and characterized.

Though a large recent conference once again tried to bring some order to the subject, disagreement still rules. For some years, CHR investigators have, however, been following a different track, and have made some interesting discoveries. All the world agrees that the two most frequent phenotypes of PCOS are the so-called “classical” and “lean” phenotypes. Though each represent roughly 40% of PCOS, it is only the “classical” phenotype, characterized by hyper-androgenism, anovulation, irregular menses, truncal obesity, hirsutism, acne and metabolic syndrome later in life, that even the most experienced investigators see in front of their eyes when thinking about PCOS.

These “classical” PCOS phenotype has attracted most of the attention for many reasons, and to some degree rightly so, because they represent a life-long phenotype with serious medical consequences, not only for fertility at young ages but for general health later in life.

Because “classical” phenotypes had a typical appearance, menstrual problems and often other medical issues, they were traditionally considered the “more difficult” PCOS cases to treat in infertility practices. They were also more noticeable in contrast to "lean" PCOS phenotypes, usually young and lean women, mostly with regular menses and no obvious later sequalae in life. That is, until CHR investigators one day realized that practically all of CHR’s PCOS patients had the "lean" phenotypes. This unexpected finding initiated a brand-new research effort at CHR: Trying to understand this surprising discovery, CHR’s investigators concluded that only a self-selection process of patients could explain why no “classical” and only “lean” PCOS phenotypes sought fertility care at CHR.

As an IVF center of last resort, CHR almost exclusively serves patients who previously had, often multiple, failed IVF cycles elsewhere. The only possible explanation for not finding “classical” PCOS patients at CHR was, therefore, that they conceived before reaching CHR. In contrast, the “lean” PCOS patients sought CHR in quite surprising numbers, by extension suggesting that they had been unable to conceive at other IVF centers before seeking tertiary-level fertility care at CHR.

pcos wp

The pearl-like appearance of follicles is one of the few PCOS characteristics common to both classical and lean PCOS phenotypes.

This observation, of course, contradicted the fertility field’s decades-long understanding that “classical” PCOS patients were the more “severe” cases. The new observations at CHR now, suddenly, appeared to suggest exactly the opposite, namely that “lean” PCOS women, at least when it came to conception at more advanced ages, were more challenging infertility patients than “classical” PCOS women. Further investigations, published in two manuscripts in the medical endocrinology literature, then described the ontogeny of this “lean” PCOS phenotype in considerable detail, confirming that “classical” and “lean” phenotypes, likely, represent very different disease entities, having little in common besides a PCOS-like ovarian phenotype on ultrasound and hyper-androgenism (high testosterone) at younger ages. While the ovarian phenotype remained a common feature into older ages, women with “lean” phenotype between mid-20s and -30s lost their hyperandrogenism, becoming instead hypo-androgenic.

Adrenal glands 300W

Zona renticularis in the adrenal gland produces about half the androgens in a woman's body.

It would exceed the framework of this section to go into too much further details regarding the “lean” hypo-androgenic PCOS-like phenotype; the interested reader is referred to a more detailed discussion in a recent issue of the VOICE. As it turned out, the above-noted difference in status of hyper-androgenism both PCOS phenotypes shared at younger ages, but between mid 20s and -30 started to differ when “lean” PCOS women, suddenly, lost the adrenal component of their androgen production, and testosterone levels, therefore, plummeted, was identified as the principal reason why these “lean” PCOS women had not been able to conceive before seeking more advanced care at CHR.

As is now widely accepted, ovaries must have good testosterone levels in their ovarian micro-environment in order to produce good quality eggs. Therefore, these, usually older, women only started conceiving once CHR’s practice of androgen supplementation via DHEA of women with low testosterone levels improved their egg and embryo quality.

The answer to the question whether PCOS affects egg quality is, therefore, a complex one but can be answered as follows: At younger ages (approximately till age 35), PCOS, whether of “classical” or “lean” phenotype, does _not _affect egg quality. In “classical” PCOS patients, there also appears to be no effect at older ages. However, in older “lean” PCOS women, who by this time usually have become hypo-androgenic, egg quality is, indeed, negatively affected, unless androgen levels are appropriately pre-supplemented, starting at least 6-8 weeks prior to IVF cycle start.

One final comment: CHR investigators also presented evidence that loss of adrenal androgen production in lean PCOS patients, likely, is the consequence of an autoimmune attack on the zona reticularis of the adrenals. “Lean” PCOS patients, indeed, demonstrate a very high prevalence of a large variety of autoimmune problems which, of course, also have the potential of negatively affecting a woman’s fertility and increasing her miscarriage risks.

This is a part of the March 2019 CHR VOICE.

Norbert Gleicher, MD, FACOG, FACS

Norbert Gleicher, MD, FACOG, FACS

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.

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