The CHR celebrates the important 20th anniversary of introducing dehydroepiandrosterone (DHEA) to worldwide infertility practice
By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction (CHR) in New York City. He can be contacted though The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu
It is now exactly 20 years since my colleague David Barad, MD, MS, and I published our first paper reporting on the potential fertility benefits of supplementing selected patients with DHEA (dehydroepiandrosterone). This and several quickly following papers on the same subject ended up changing infertility practice in many – maybe most – fertility clinics in the world (1). It was a paper reporting on a CHR patient in her early 40s who – completely unknown to us at the CHR – had started self-supplementing with DHEA because a first IVF cycle had yielded only one egg and embryo, she had been advised that, assuming a similar second cycle, further repeat IVF cycles with use of her own eggs would not make much sense. She then, however, made us scratch our heads - wondering what was going on - in subsequent back-to-back cycles, as the patient from cycle to cycle produced more and more oocytes and embryos. Only after her 6th consecutive cycle, did she finally clarify what was going on, when disclosing that she - completely on her own – had started supplementing with DHEA. It was this disclosure that then initiated years of DHEA-related research at the CHR, resulting in a large number of published studies in several leading peer-reviewed medical journal and – to this day – the only U.S. patents approved for claims of treatment benefits for androgens (including DHEA) supplementation in selected infertile women. On the occasion of this 20th anniversary, this article presents an update on the subject of androgen supplementation in selected infertile women, with special emphasis on DHEA supplementation.
BEFORE CONTINUING TO READ, PLEASE NOTE THE FOLLOWING CONFLICT STATEMENT
The author of this article is a co-owner of several U.S. user patents which claim clinical benefits in hypo-androgenic female infertile women from supplementation with androgens. He and the CHR receive royalty payments for these patents from companies producing androgen supplements, including a company called Fertility Nutraceuticals, LLC, of which he is also a shareholder.
Introduction
There are few issues in infertility practice as controversial as androgen supplementation. Though this article is meant to offer a general overview of androgen supplementation in selected female infertility patients, it is primarily geared at trying to explain why androgen supplementation has remained so controversial and why, as of this time point, it really no longer should be considered that at all.
What is the rational for androgen supplementation in selected women?
I am always surprised to still regularly confirm in my discussions with patients and colleagues that a majority in both groups (yes, physician colleagues as well!) – whether proponents or opponents of androgen supplementation - usually lack even minimal knowledge of why androgen supplementation is indicated in selected infertile women. Let us, therefore, discuss this issue first.
For us at the Center for Human Reproduction (CHR) in NYC and for most of the infertility field, androgen supplementation arose as a serious research issue around 2004. Though several small studies had been before published suggesting that various drugs may in some women increase oocyte yields in IVF cycles– among them only one study reporting on use of the mild androgen, dehydroepiandrosterone, DHEA), the real study of androgens in female infertility only started in ca, 2004 at the CHR in NYC, because of a single patient who wanted to cryopreserve her eggs: This then 42-year old female patient with extremely low functional ovarian reserve (LFOR) – unknown to the center’s physicians – initiated self-supplementation with DHEA. She decided on supplementing with this hormone after researching the literature for compounds that might improve the dismal one oocyte yield she had produced in her first IVF cycle at the CHR. Other drugs she identified in her literature search for their alleged ability to improve oocyte yields, required prescriptions. DHEA, under an obscure U.S. law considered a food supplement (even though in many other countries, because of abuse by athletes and body builders, DHEA is considered a controlled substance), she could purchase over the counter without prescription and without having to tell anybody at the CHR.
Going back-to-back month after month in consecutive IVF cycles, she demonstrated steadily improving oocyte yields and increasing numbers of cryo-preservable embryos, until her gonadotropin dosage had even to be reduced because she had developed a typical ovarian PCOS phenotype which – paradoxically - even put her at risk for ovarian hyperstimulation. After her sixth cycle – with everybody at the CHR scratching their head in search of an explanation – she, smiling - revealed her secret: she had secretly started to self-supplement with 75mg of dehydroepiandrosterone (DHEA) daily, because I had advised her that we would not start additional IVF cycles if her oocyte yield remained that small (1).
The year was 2004 and, like other IVF clinics, the CHR had absolutely no idea why and how DHEA might improve oocyte yields in older women with low FOR (LFOR). The observations in this index patients were, so surprising and – yet – so obvious that our hands-on observations of a single female patient in her 40s gave us confidence enough regarding the potential beneficial effects of DHEA on older ovaries to intensely start investigating DHEA in women with LFOR.
We quickly discovered that available DHEA products were extremely uneven in potency and, often, did not even contain the alleged dose of DHEA. Serious studies, therefore, were impossible with these products. A DHEA product of consistent quality, including consistent absorption (dependent on particle size during micronation), and overall production quality consequently became an essential prerequisite. We, therefore, contracted a pharmacy in NYC to compound such a special DHEA product under highly specific production criteria. This DHEA was then, without exception, used by the CHR’s patients over the initial years of the study of DHEA supplementation at the CHR. On last count, the CHR’s investigators have since published 36 peer reviewed publications on DHEA supplementation, a large majority in efforts to improve infertility treatment outcomes and in a small minority in efforts to improve hypo-androgenic loss of libido.
In initial studies, we very quickly confirmed the beneficial effects of DHEA supplementation on several outcome parameters in infertile women with low androgen levels, we made only slow progress in our understanding of how these outcome improvements came about. But that changed very quickly when Aritro Sen PhD and Stephen R. Hammes MD in 2010 reported a mouse study in which they had knocked out androgen receptors on granulosa cells and oocytes and noticed that the knockouts on granulosa cells severely interrupted follicle maturation, while receptor knock out on oocytes showed hardly any effects (2).
Not only did this paper instantly explain our observation with DHEA, but this paper also initiated years of a highly effective collaboration between Sen, Hammes, and the CHR that allowed us to further our understanding of androgen effects on ovaries by going back and forth between mouse and human studies in explaining things. Concomitantly, not least due to the CHR’s publications, the popularity of DHEA supplementation in infertility continued to increase. An internet survey conducted after several years suggested that approximately half of the world’s IVF clinics had started supplementing patients with androgens, while clinical research also expanded worldwide.
Not all studies, however, confirmed the effectiveness of DHEA the CHR had reported, and study results in humans became quite contradictory. Animal studies in contrast, however, uniformly confirmed the initial mouse data of Sen and Hames which, of course, fully corresponded with the clinical data the CHR’s investigators had reported. The animal data was not only restricted to mouse models but also included larger animal models, including sheep and monkey models. All uniformly confirmed that good/normal testosterone levels were essential during small follicle-growing stages (i.e., between secondary and small antral follicles) in – synergistically with FSH – supporting follicle growth and maturation. Too low androgens reduced egg numbers as well as egg quality. Proper supplementation of abnormally low androgens leading to normal testosterone levels, then, however, reconstituted more and better-quality oocyte yields, leading to more pregnancies and fewer miscarriages.
And these small as well as large animal data - in contrast to clinical human data – have to this day remained undisputed.
Then why is androgen supplementation in female infertility still so controversial?
That is exactly the main question this communication is attempting to answer. Considering the overwhelming and consistent animal experience explaining in detail the benefits of androgen supplementation in hypo-androgenic females, we have great difficulties in finding a single valid explanation because, in our opinion (which, of course, possibly may be biased considering above posted Conflict Statement) the resistance to selective androgen supplementation to this day found in many peer-reviewed publications does not make logical sense. This is especially the case, if one considers that the same skeptics regarding androgen supplementation often proclaim full support for a plethora of equally (or even more) controversial but do not have any/or comparable animal data in support. Moreover, many of these treatments (often called “add-ons” to IVF; think, for example PGT-A, etc.) add significant costs to fertility treatments, while the costs of androgen supplementation with DHEA are in comparison only a pittance.
One principal argument one always hears from skeptics of androgen supplementation is that there are no properly conducted prospectively randomized clinical trials in the literature that would support such androgen supplementation, and this is, of course, correct. But most of routine medical practice - and not only in infertility – is lacking support from such trials. And many of these practices exist with much less or, at times, no animal data in support at all. Moreover, even a majority of randomized clinical trials to guide clinical practice in various medical areas have features which disqualify them from meeting their purpose (3)
Infertility practice in addition has an excellent excuse for not producing enough prospectively randomized studies in comparison to other medical practice areas as - understandably - infertile women are often not willing to be randomized to placebo because, especially when the problem is LFOR, the potential loss in time may harm their overall pregnancy chances. We know this concern from personal experience because the CHR in early years of DHEA research secured generous funding for a prospectively randomized clinical trial, - but had to abandon it because we were unable to recruit sufficient numbers of willing patients. We then, after representation that they would have no problems with patient recruitment, indeed, transferred the funding to a European group of IVF clinics, only to find out that they, too, had misread their recruitment chances.
All of this, of course, did not prevent investigators from conducting androgen supplementation studies using either small prospectively randomized studies with inadequate statistical power or study designs of lower evidence levels. Not even one of them – to the best of our knowledge – moreover ever noted specifics regarding the DHEA they used in their studies. That those studies often produced contradictory results, to no ones surprise. But there were major additional problems with many of these studies: Likely the most important one was that – once again to the best of our knowledge – not even a single one of those studies ever evaluated androgen levels in infertile women before starting them on DHEA supplementation. Consequently, when colleagues reported on androgen supplementation with DHEA or testosterone in the literature, they either conducted non-randomized studies or supplemented patients without knowing whether they were hypo-androgenic.
And this, of course, introduces a fatal error into any clinical study because it is akin to investigating whether treating a headache with aspirin in individuals who don’t have a headache makes sense — which, of course, it does not. Similarly, supplementing an infertile women who has normal androgen levels does not make sense. As any prospectively randomized headache study of aspirin, of course, would have to be restricted to patients with headaches, every DHEA supplementation study in infertile women, of course, would also have to be restricted to hypo-androgenic infertile women.
In other words, the contradictory findings of DHEA and/or direct testosterone supplementation in female infertility – to a large degree – can be traced to incorrect study designs. Studies that showed positive DHEA/testosterone effects in concordance with the CHR’s results and animal experiments, likely, had simply more hypo-androgenic participants than studies that showed no effects from DHEA/testosterone supplementation.
Related, the same error in study design – also explains similarly contradictory findings reported in the literature for pretreatment of infertile women with growth hormone (GH). Since GH works through insulin growth factor -1 (IGF-1), GH supplementation makes sense only if IGF-1 levels are abnormally low. Most fertility clinics, however, do not test IGF-1 levels in their patients and – once again – we are unfamiliar with even a single GH study in the medical literature in infertile females that preselected their study participants based on predetermination of IGF-1 levels. And low IGF-1 levels are significantly rarer than low androgen levels. Even in a very aged female infertile populations like the CHR is serving, the percentage of low IGF-1 is less than 5%.
But this is not yet the end of the story why androgen supplementation data in literature has been so contradictory. Another point of crucial misunderstanding has been in almost all studies the timing of DHEA (and GH) supplementation. We previously noted that androgen effects on follicles are especially important during the so-called small growing follicle stages between secondary follicle and small antral follicle stages and that, after that stage, follicles still need at least 6-8 weeks to reach gonadotropin sensitivity, when they become reactive to gonadotropin treatments.
In practical terms this means that DHEA/testosterone supplementation must start at least 6-8 weeks before IVF cycle start. If treatments start later, later generations of follicles will receive most of the supplementation benefits, - but not the planned IVF cycle. And, once again, a review of the DHEA/ testosterone supplementation literature clearly demonstrates that in a majority of published studies androgen supplementation before IVF cycle start was much shorter than required. Indeed, in many studies androgen supplementation was started only with the IVF cycle start. Once again, one cannot be surprised that androgen supplementation in so many studies has not shown clinical effectiveness.
DHEA or testosterone supplementation?
Patients often ask why we prefer DHEA supplementation over direct testosterone administration. The principal reason is the difference in treatment risk: Testosterone is usually given transdermal by gel. This must be done very carefully because everybody who comes in touch with the gel will instantly absorb the hormone. This means that, if mom has testosterone gel on her arm, she better does not come close to any of her children. Moreover, testosterone floods the whole body, producing identical testosterone levels in every organ. It, therefore, is very easy to overdose androgen levels with direct testosterone supplementation; and too high androgens can be worse for fertility treatments than too low androgens.
Oral DHEA, in contrast, as the precursor of testosterone (i.e., our bodies make testosterone from DHEA), for several reasons hardly ever can overdose a patient. A first reason is that DHEA has – what is called – very low “binding-affinity” to the androgen receptor on granulosa cells (and elsewhere). This means that even if DHEA levels are too high, it does not have significant androgenic effects. Moreover, since most organs produce their testosterone locally and often have different baseline testosterone levels, each organ -including ovaries – will take out of circulation only as much circulating DHEA as this organ needs to reach its desired testosterone level. For both reasons, overdosing and complications from too much DHEA are, therefore, practically almost impossible.
Side effects and other potential dangers of DHEA and/or testosterone, including cancer risk
We already in the preceding paragraph noted that too high testosterone levels may be worse for fertility than too low levels. Once androgen supplementation is initiated it, therefore, is important to continue monitoring androgen levels at regular intervals. At the CHR, this means ca. 30 days after initiation - and then usually roughly every three months – and androgen panel including sex hormone binding globulin (SHBG) is obtained. The typical androgen screen involves DHEA, DHEA-S, free testosterone, total testosterone and SHBG, which usually goes the opposite way from testosterone: if testosterone is low, SHBG will be elevated. We, therefore, use SHBG to determine the effectiveness of androgen supplementation.
A concern often expressed by patients and colleagues is increased cancer risk, especially breast cancer risk, and to a lesser degree ovarian cancer risk. And while understandable, such concern is really not warranted, and here is why: It stems primarily from the fact that a small fraction of a woman’s testosterone is converted to estrogen and estrogen can make breast cancers with estrogen receptors grow quicker. Whether estrogen also induces fresh breast cancers is more controversial.
But even assuming it does (which by no means is certain), that – in itself – would not be a reason to withhold androgen supplementation either via DHEA or testosterone, and here is, again, why: The rise in estrogen caused by conversion from testosterone is much smaller than the rise of estrogen after a woman conceives. In other words, the estrogen exposure from being pregnant is substantially bigger and usually longer (over nine months of pregnancy) than it would be from DHEA and/or testosterone supplementation during infertility treatments.
In practical terms this, therefore, means that, if a woman is cleared for pregnancy, this automatically also means she is cleared for androgen supplementation.
This issue arises, of course, especially in women with a history of prior breast cancer or with a history of genetic predisposition toward breast cancers, as is, for example, the case in women who are carriers of BRCA1/2 gene mutations or other cancer genes which increase breast cancer risk. And the rule then is very simple: if a patient under cancer surveillance by her oncologist has been cleared for pregnancy, she can also be pretreated with androgens, whether DHEA or testosterone directly.
Other side effects are usually even milder with DHEA than with testosterone. The reason is, once more, the fact that DHEA itself is a very “mild” androgen in contrast to testosterone. Consequently, other side effects of DHEA, like oily skin, acne, rarely mild hirsutism (usual primarily facial hair growth) and, rarely, mild hair loss, are usually immediately reversible when treatments are stopped or even if medication dosages are just reduced.
Which DHEA product should be used in infertility?
Before we address this question, we once again want to point out our above noted Conflict Statement. We above also already noted that, because of uneven and often poor-quality DHEA products on the market, we over several years conducted initial DHEA studies at the CHR exclusively using DHEA compounded for CHR patients by a pharmacy in NYC according to our specification with special attention paid to particle size which is responsible for absorption rates. They, of course, must be stable in order to provide stable dosing to patients.
This arrangement over several years worked well but medication costs for patient were obviously quite high. The CHR by that time had earned several U.S. user patents for the use of androgens (DHEA as well as testosterone) in selected infertile women. We, therefore, contacted most major pharma companies active in the infertility field and tried to interest them in developing a DHEA pharma product (in contrast to an over-the-counter product) with quality parameters identical to the compounded product we had used in our initial DHEA studies. Unfortunately, none of the companies was interested because they – likely correctly – considered the market as too small for such an effort which would – at very high development costs - have required formal FDA-approval for such a DHEA product.
The CHR, therefore, decided to start production of a DHEA product as a food supplement for its patients on its own (which, of course, required much less front-up investment), with initially the only purpose, of being able to offer the CHR’s patients a DHEA product with identical characteristics to the originally compounded DHEA, - though at lower and more affordable costs.
This is how Fertinatal® was born, which over the years has won a worldwide following [produced by Ovaterra, a Fertility Nutraceuticals LLC, subsidiary, New York, N.Y.]. Concomitantly, we started licensing other companies under our patents to sell their DHEA for fertility purposes, though only if we were convinced of the quality of their product and of their quality assurance process.
While the CHR out of principle does not make specific product recommendation for any medication or supplement, including Fertinatal® and/or any other product of Ovaterra, a large majority of DHEA products on the market – as will be obvious – do not claim any effects from their products on female fertility. Only those licensed by Fertility Nutraceuticals LLC, have the ability to make such representations. Licensure of products to point toward female fertility effects, therefore, has its values.
Other beneficial effects of androgens in hypo-androgenic women
Hypo-androgenism is not only associated with lowered female fertility and poorer fertility treatment outcomes, but also with lower general energy levels in women, decreased sex drive, libido, and often especially perimenopausal and menopausal, with dry vaginas. One company several years ago received a patent for local vaginal DHEA treatments and the CHR’s investigators more recently reported that oral DHEA treatment in infertile women with low androgen levels also improved their sexual function (patent pending) (4).
References
1. Barad DH, Gleicher N. Fertil Steril 2005;84(3): 756
2. Sen A, Hammes SR. Mol Endocrinol 2010;24(7):1339-1403
3. Hutchinson et al., eLife 2022;11:e79491
4. Kushnir et al. Endocrine 2018;63:632-638