You must have heard of “Ovarian Rejuvenation”

Having a significant presence on the Internet here, CHR receives a large number of inquiries daily about all kinds of fertility-related subjects. One such subject has been floating toward increasing prominence over the recent months. The subject can be summarized under the term “Ovarian Rejuvenation.”

The idea of “rejuvenating ovaries” is nothing new. This concept has been under consideration since modern infertility treatments started in the late 50s and early 60s with initiation of gonadotropin therapy. It is based on the recognition that ovaries “age” as women advance in age. “Rejuvenation” of ovaries, therefore, implies the ability to reverse this ovarian aging process. To better understand whether such rejuvenation is really possible, it is essential to understand the physiological basics of ovarian aging.

What is ovarian aging?

The ovarian age is determined by the ovaries’ principal product, their oocytes (eggs). Since women are, likely, born with all of their eggs in ovaries, and since these eggs are constantly lost in large numbers, the total number of eggs (i.e., the ovarian reserve) declines with advancing female age. Concomitantly, egg quality also declines. As woman grow older, they, therefore, experience in parallel two independent declines, in egg quantity and quality, leading to age-related infertility.

The decline in egg quality is still widely attributed to the fact that eggs are in ovaries from birth and, therefore, age. In contrast, males constantly produce fresh sperm into advanced ages, which, therefore, remains “fresh.”

While environmental aging over time may play some role in oocyte aging, CHR investigators have questioned this concept of ovarian aging. They proposed a number of years ago the hypothesis (the “CHR hypothesis of ovarian aging”) that increasingly poor oocyte quality with advancing female age may not be due to aging of oocytes but actually due to aging of the ovarian micro-environment, in which follicles and eggs mature after recruitment. Under this hypothesis, primordial follicles, which contain the most primitive and immature eggs prior to recruitment into maturation cycles, sit in the outermost layer of ovaries, the so-called ovarian capsule. Their extremely immature state and minuscule size mean that those follicles have almost no metabolic needs and, practically, live in total isolation, and mostly without nutritional needs. In a way, they, therefore, can be considered “frozen in time,” like frozen eggs, sperm or embryos are, once they are cryopreserved. Consequently, these very immature eggs are well protected from environmental influences.

This changes immediately, however, once such primordial follicles are “recruited,” and start their weeks- to months-long journeys of maturation, during which they literally travel from the outer capsule toward the innermost parts of the ovary (the medulla), while rapidly growing in size. During that journey of maturation, follicles become extremely dependent on nutrition from their environment (stroma) and, therefore, do become exposed to influences from the ovarian micro-environment in which they mature.

The modified ovarian aging hypothesis developed by CHR investigators, therefore, suggests that the age of this ovarian-microenvironment, likely, greatly affects oocyte quality. In other words, while sitting in ovaries, often for decades, at very primitive primordial stages may have some negative impact, it, likely, is relatively small. A much larger impact can be expected during weeks and months of follicle maturation after recruitment, when the ovarian micro-environment really can negatively affect follicles and eggs and, therefore, produce poorer egg quality.

Differences between these two theories of ovarian aging are of great theoretical and practical importance because, under the traditional theory of long-term damage, follicles and eggs recruited into maturation are already damaged. Their ultimate fate, therefore, is already determined and no medical treatment will, likely, be able to improve already damaged eggs.

Under the CHR hypothesis of aging, however, the assumption is that eggs enter maturation after recruitment mostly undamaged. Consequently, if the ovarian micro-environment, in which they will mature, can be therapeutically improved, their maturation will take place under improved environmental conditions, and egg quality will be better at the end of folliculogenesis. In other words, under the CHR hypothesis of ovarian aging, ovaries, indeed, can be medically rejuvenated by reconstituting the ovarian micro-environment  as close as possible to where those micro-environments used to be at younger ages.

Rejuvenating the ovarian micro-environment

That the ovarian micro-environment changes with advancing female age is well documented. Surprisingly, however, only very little is known about what changes and at what ages. What actually lead CHR investigators to the CHR hypothesis of ovarian aging was the recognition that androgen levels (i.e., male hormone levels) rapidly decline in the ovarian micro-environment after age 40. Since small growing follicles need good androgen levels in these very early stages of follicle and egg maturation, CHR investigators started reconstituting older women with androgens (in that case with dehydroepiandrosterone, DHEA, from which our bodied make testosterone). With improving testosterone levels, ovaries started producing better eggs; better eggs led to better embryos and higher pregnancy rates.

It was this observation that then led CHR investigators to develop their hypothesis of ovarian aging because it did not appear probable to them that better androgen levels would be able to reverse existing long-term damage to oocytes. The only remaining alternative explanation for outcome improvements observed in older women and younger women with premature ovarian aging (POA) after DHEA supplementation was, therefore, that improvements in the ovarian micro-environment had led to better egg quality.

The success of DHEA supplementation can, therefore, be viewed as the first and, unfortunately, so far the only successful clinical attempt at ovarian rejuvenation. It is, however, reasonable to assume that, like androgens, other important ingredients of the ovarian micro-environment also change with advancing female age. It now would behoove us to learn what those are. The better we reconstitute the micro-environment in older women, the better will our fertility treatments fare.

Legitimate trials

This is, however, not the kind of “rejuvenation” the Internet has been buzzing about in recent months. There were, of course, some legitimate reports of other potential approaches. For example, investigators in Japan and San Francisco reported a few years ago a form of ovarian rejuvenation, in which they removed ovarian tissue from women who had entered menopause prematurely (premature ovarian failure, POF, also called primary ovarian insufficiency, POI), treated that tissue in the laboratory with biologically active ingredients known to activate a certain pathway (i.e. the Hippo signaling pathway) in primordial follicles, and then surgically re-implanted the treated tissue into the patient. Primordial follicles activated by this treatment, in some cases, started growing and a very small number of so-treated women ended up conceiving, because even women in menopause still have follicles and eggs in their ovaries. The problem with those follicles is, however, that they no longer grow in response to fertility drugs (gonadotropins). The in vitro treatment of these women’s ovarian tissue, thus, in a way “rejuvenated” the ovarian tissues removed and reinserted.

Requiring surgery twice, this treatment did not prove very practical and does not appear destined for wide clinical application. It, nevertheless, generated considerable interest because it, of course, raised the potential of learning how to activate these dormant follicles in vivo (i.e., in the body). Because the Hippo pathway can be mechanically induced, investigators at CHR have started to investigate such an approach in a preliminary fashion. Unfortunately, others have not been as measured in their approach (see below).

Watch out for snake oil

OvaScience, Inc. (NASDAQ:OVAS) is a biotechnology company, which presents itself as a “global fertility company, dedicated to improving treatment options for women around the world.” Its motto is “improving fertility through science.” After reaching an extravagant market cap in the hundreds of millions of dollars based on alleged treatments that could “rejuvenate” ovaries through “proprietary technology that leverages the breakthrough discovery of egg precursors cells,” OvaScience returned to a much lower market reality even more quickly, and now operates under new management. Its first treatment, called AUGMENT™, initially got wide publicity, but was never offered in the U.S. for regulatory reasons. Now, after years of being sold in Canada and the Middle East, the treatment still has no evidence of efficacy.

Indeed, the company has mostly moved on from this initial product line, and is now offering a successor product, called OvaPrime™. While AUGMENT™ was designed “to improve IVF outcomes,” the company claims that OvaPrime™ “could increase a woman’s egg reserve.” Whether it really does so is, of course, unknown, and a healthy degree of skepticism appears appropriate. The company is also developing OvaTure™, “a potential next-generation in vitro (IVF) fertilization treatment that could help a woman produce healthy, young, fertilized eggs without hormone injections.” That would be a very welcome addition to the currently available fertility treatment offerings, but we, again, advise caution in paying for unvalidated products.

Above, we noted the interesting work of Japanese and West Coast colleagues regarding the Hippo pathway, and noted that there was a scientific rationale for exploring the possibility of trying to activate this pathway in vivo in order to avoid the double surgery required under our colleagues’ protocol. Though the purpose was not activation of the Hippo pathway in ovaries (at least they did not describe their practice as such), the Internet has recently been flooded by reports, where women with POF/POI have, with allegedly favorable results, all kinds of biological substances injected into their ovaries.

A center in a Middle Eastern country reported success in POF/POI patients through injections of the patients’ own white blood cells into ovaries. Though this approach was first reported over two years ago, the claim has, still, not been formally reported in the medical literature. It, therefore, cannot be verified and/or duplicated. Nevertheless, at least one center in NYC picked up on the report and has been offering this treatment to patients (of course, with full charges). We advise utmost caution!

Even more attention has been given on the Internet and in some articles on the Web to injection of platelet-enriched plasma into ovaries. This approach was first reported by a center in Athens, Greece, and was picked up by at least two centers in NYC and others on the West Coast, who have started offering these treatments, of course, for appropriate fees. Once again, we advise great caution because no validation studies on any of these products have so far been offered.

Platelet-enriched human plasma has gained notoriety in sports medicine, where well known athletes have been allegedly cured from joint and other skeletal problems by such injections. The hypothesis behind these treatments is that platelet-enriched plasma contains many immunologically active substances (which is true), which exert anti-inflammatory and other beneficial effects (which, at least as of this time, is unproven).

Our friends and steady readers of the VOICE, of course, know how interested we are here at CHR in research that advances fertility care and allows quick translational applications. We, therefore, would strongly hope that all of here described attempts at ovarian “rejuvenation” will be properly researched and reported. Unfortunately, this is currently not the case. Most of these “products” are introduced to the market without any prior validation. We consider this inappropriate, potentially dangerous and often misleading because uninformed patients often believe these to be established procedures.

They are not! And this is why we felt we had to write about them.

This is a part of the July 2017 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.