Does DHEA cause cancer?

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 really 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 controversial 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 only around 2004. Though there were several small studies in the literature before that suggested that supplementation with various drugs – among them only one study reporting on an androgen (dehydroepiandrosterone, DHEA ) - may in some women increase oocyte yields in IVF cycles, the study of androgens in female infertility only started at the CHR in 2004 after a 42-year old patient with extremely low functional ovarian reserve (FOR) – unknown to the center’s physicians – initiated self-supplementing with DHEA. She decided on using DHEA after researching the literature for compounds that might improve the dismal one oocyte yield she 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 even considered a controlled substance) she could purchase without telling 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 -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 to me that she had started to self-supplement with 25mg of dehydroepiandrosterone (DHEA) daily, after I had agreed to only one more stimulation cycle after her first cycle that had yielded only one oocyte and one embryo.1

The year was 2004 and we at the CHR had absolutely no idea why and how DHEA might improve oocyte yields in older women with low FOR (LFOR); but our observations in this single patient was reason enough to start investigating DHEA. 

We, however, quickly discovered that the DHEA being sold by many different companies was extremely uneven in potency and often did not even reflect the recommended dosing indicated on the product. It, therefore, was impossible to conduct serious studies of DHEA without having a DHEA product of consistent quality, including consistent absorption (dependent on particle size during micronation), and overall production quality. We, therefore, convinced Metro Pharmacy in NYC to compound a special DHEA product for the CHR’s patients under specific production criteria we had investigated. This DHEA was then used by the CHR’s patients without exception 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.

Though 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 in IVF came about. But that changed very quickly when Sen and Hammes 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 highly effective collaboration between Sen and 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, as the popularity of DHEA supplementation in infertility practice – not the least because of the CHR’s publications  - continued to increase (an internet survey after several years suggested that ca. half of the world’s IVF clinics had started to supplement patients with androgens), clinical research also expanded worldwide. 

It, however, quite quickly became apparent that not all studies confirmed the effectiveness of DHEA CHR had reported. Clinical study results, indeed, started to be contradictive. Animal studies however, in contrast, 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. And these animal data were not only restricted to mouse models but also included larger animal models, including sheep and monkeys and, uniformly, demonstrated 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, indeed, have great difficulties in finding a single valid explanation because – in our opinion (which possibly is biased – please consider above posted Conflict Notice), the resistance to selective androgen supplementation one to this day finds in many peer-reviewed publications not only does not make any logical sense, - but is also contradicted by a plethora of widely accepted fertility treatments which may or may not be equally controversial based on clinical study findings 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 only a pittance in comparison. 

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 in various medical areas designed to guide clinical practice have features which disqualify them from meeting this purpose.3

Infertility practice has in addition an excellent excuse for not producing enough prospectively randomized studies in comparison to other medical practice areas: Infertile women – rightly – are simply not willing to be randomized because, especially when the problem is LFOR, the potential loos in time from randomization to placebo may harm their pregnancy chances. We know the impact of this concern from experience because we in those early years of DHEA supplementation secured funding for such a prospectively randomized clinical trial of DHEA, - but had to abandon it because we were unable to recruit enough patients. We then transferred the funding to a European group of IVF clinics after they represented that they would have no problems with recruitment. But they were wrong and had to abandon the study as well.

All of this, of course, did not prevent investigators to conduct androgen supplementation studies using either small prospectively randomized studies with inadequate statistical power or study designs of lower evidence levels. And those, in contrast to above noted animal studies, often produced contradictory results; and here is why: Likely the most important reason why androgen supplementation results in clinical infertility have remained contradictory is the fact that – to the best of our knowledge  - the evaluation of androgen levels is practically never part of a female’s basic testing schedule when presenting to fertility centers (it, of course, has been routine at the CHR for over 20 years!). Consequently, when colleagues reported in the literature on androgen supplementation with DHEA or testosterone, even in small, randomized studies, they either did or -randomized – did not supplement patients without knowing whether they were hypo-androgenic or not. 

We several years ago reviewed the literature of DHEA supplementation and, except for the CHR’s studies, were unable to find even a single other study were androgen levels of the study population before DHEA supplementation start were even tested.

But - if we treat a headache with aspirin in individuals who don’t have a headache, aspirin will, of course, not work. And since in unselected infertile women, at any given moment only very few will have a headache, aspirin will definitely show no effect in a so-randomized study population. A prospectively randomized study of aspirin, of course, would have to be restricted to patients with headache; and the same applies to DHEA supplementation: DHEA will only work if the patient’s testosterone levels are abnormally low and need to be reconstituted; and, if every infertile patient is given DHEA, the treatment’s effectiveness will be significantly diluted  because many, if not most, random infertility patients, of course, will not be hypo-androgenic, especially if still relatively young.

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 more hypo-androgenic participants than studies that showed no DHEA/testosterone supplementation effects. 

The same error – apropos – 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 only sense if IGF-1 levels are abnormally low. Since most fertility clinics – like testosterone levels - also do not test IGF-1 levels, those who believe in GH supplementation will treat everybody. And, like the literature – except for CHR studies – shows no studies with patient selection being based on women with low testosterone levels, so does, to the best of our knowledge, the GH literature not contain even a single study in which the patient population was pre-evaluated for IGF-1 levels. And low IGF-1 levels are even much rarer than low androgen levels (even in a very aged population like the CHR’s, less than 5%). 

And then there is one additional reason why the clinical literature on androgen supplementation has been so contradictory, which we before already allude to when we noted that androgen effects of follicles are especially important during the so-called small growing follicle stages between secondary follicle and small antral follicle stages and that, after that, these 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 because, if treatment is started later, the next generation of follicle in the following month will receive most of the supplementation benefits but not the planned IVF cycle. Yet, once again, a review of the DHEA/testosterone supplementation literature demonstrates that in a majority of published studies androgen supplementation was much shorter than required. Indeed, in many studies androgen supplementation was started only with IVF cycle start. Once again, one therefore cannot be surprised if androgen supplementation did not show clinical effectiveness in such cases.

DHEA or testosterone supplementation?

Patients always ask why we prefer DHEA supplementation and not directly testosterone. The principal reason is the difference in treatment risk: Testosterone is usually given transdermal by gel and must be done extremely carefully because everybody who comes in touch with the gel will be affected. 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; and too high androgens can be worse for fertility 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 much androgenic effects. Moreover, since most organs produce their testosterone locally and often have different “best” testosterone levels, each organ -including ovaries – will take out only as much circulating DHEA as it 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. The typical androgen screen involves DHEA, DHEA-S, free testosterone, total testosterone and sex hormone binding globulin (SHBG), which usually goes the opposite way from testosterone: if testosterone is low, SHBG will be elevated. We, therefore, use SHBG to determine 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, it really is not warranted, - and here is why: The concern comes 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, 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. In practical terms this 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 – usually rather mild 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, 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. Especially DHEA is usually very well tolerated.

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 of many DHEA products on the market, we over several years conducted initial DHEA studies at the CHR  exclusively using DHEA compounded by Metro Pharmacy in NYC according to our specification with special attention paid to particle size which is responsible for absorption rates, which, therefore, must be stable in order to provide stable dosing. 

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. 

The CHR, therefore, decided to start production on its own, 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, 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 female fertility effects from their products.

Only those licensed by Fertility Nutraceuticals LLC, the current patent holder, 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

Barad DH, Gleicher N. Fertil Steril 2005;84(3): 756

Sen A, Hammes SR. Mol Endocrinol 2010;24(7):1339-1403

Hutchinson et al., eLife 2022;11:e79491

Kushnir et al. Endocrine 2018;63:632-638