Supplementing ANDROGENS - DEHYDROEPIANDROSTERONE (DHEA) or TESTOSTERONE - in selected infertile women | *Advertisement*
By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He can be contacted though The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu.
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
Few issues in infertility practice are as controversial as androgen supplementation. While this article aims to offer a general overview of androgen supplementation in selected female infertility patients, it is primarily focused on explaining why androgen supplementation has remained so controversial and why, as of now, it should no longer be considered controversial.
What is the rationale for androgen supplementation in selected women?
I am often surprised to find that, in discussions with patients and colleagues, the majority of both groups (yes, even physician colleagues!)—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.
At the Center for Human Reproduction (CHR) in NYC, as well as in most of the infertility field, androgen supplementation became a serious research issue only around 2004. Although several small studies before that suggested that supplementation with various drugs—among them a single study reporting on an androgen (dehydroepiandrosterone, DHEA)—may, in some women, increase oocyte yields in IVF cycles, the study of androgens in female infertility began in earnest at CHR in 2004, when a 42-year-old patient with extremely low functional ovarian reserve (FOR)—unknown to the center’s physicians—initiated self-supplementing with DHEA. She chose DHEA after researching the literature for compounds that might improve the dismal one-oocyte yield she produced in her first IVF cycle at CHR. Other drugs she identified in her search, which were alleged to improve oocyte yields, required prescriptions. However, DHEA, considered a food supplement under an obscure U.S. law (though it is a controlled substance in many other countries due to abuse by athletes and bodybuilders), could be purchased without telling anyone at CHR.
Month after month, in consecutive IVF cycles, she demonstrated steadily improving oocyte yields and increasing numbers of cryopreserved embryos, to the point where her gonadotropin dosage had to be reduced because she developed a typical ovarian PCOS phenotype, which paradoxically put her at risk for ovarian hyperstimulation. After her sixth cycle, with everyone at CHR scratching their heads in search of an explanation, she, smiling, revealed her secret: she had started self-supplementing with 25mg of DHEA daily after I had agreed to one more stimulation cycle, following her first cycle that had yielded only one oocyte and one embryo (1).
The year was 2004, and we at CHR had no idea why or how DHEA might improve oocyte yields in older women with low FOR (LFOR). However, our observations in this single patient provided enough reason to begin investigating DHEA.
We quickly discovered that the DHEA being sold by many different companies was extremely inconsistent in potency and often did not even reflect the recommended dosing indicated on the product label. It, therefore, became impossible to conduct serious studies of DHEA without a product of consistent quality, including consistent absorption (dependent on particle size during micronization) and overall production quality. We convinced Metro Pharmacy in NYC to compound a special DHEA product for CHR’s patients, adhering to the specific production criteria we had investigated. This DHEA was then used exclusively by CHR patients during the initial years of our study on DHEA supplementation. To date, CHR investigators have published 36 peer-reviewed publications on DHEA supplementation, the majority of which aim to improve infertility treatment outcomes, with a small minority focused on improving hypo-androgenic loss of libido.
Although initial studies quickly confirmed the beneficial effects of DHEA supplementation on several outcome parameters in infertile women with low androgen levels, we made slow progress in understanding how these improvements came about. That changed rapidly in 2010, when Sen and Hammes reported a mouse study in which they knocked out androgen receptors on granulosa cells and oocytes. They found that knocking out androgen receptors on granulosa cells severely disrupted follicle maturation, while knocking out receptors on oocytes had hardly any effect (2).
Not only did this study immediately explain our observations with DHEA, but it also initiated years of highly productive collaboration between Sen, Hammes, and CHR, helping us further our understanding of androgen effects on ovaries through a combination of mouse and human studies. At the same time, the popularity of DHEA supplementation in infertility practice—largely driven by CHR’s publications—continued to grow. An internet survey conducted after several years suggested that about half of the world’s IVF clinics had started to supplement patients with androgens, and clinical research expanded globally.
However, it quickly became apparent that not all studies confirmed the effectiveness of DHEA as CHR had reported. In fact, clinical study results started to show contradictory findings. Animal studies, on the other hand, consistently confirmed the initial mouse data from Sen and Hammes, which aligned with the clinical data CHR’s investigators had reported. These animal studies were not limited to mouse models but also included larger animal models, such as sheep and monkeys, and uniformly demonstrated that normal testosterone levels are essential during the small follicle-growing stages (i.e., between secondary and small antral follicles). In synergy with FSH, normal testosterone levels support follicle growth and maturation. Too low androgens reduce egg numbers and quality, while proper supplementation of abnormally low androgens restores more and better-quality oocyte yields, leading to more pregnancies and fewer miscarriages.
These animal data—both small and large models—have, to date, remained undisputed.
Why is androgen supplementation in female infertility still so controversial?
This is the central question this communication seeks to address. Despite the overwhelming and consistent animal evidence explaining the benefits of androgen supplementation in hypo-androgenic females, we have difficulty finding a valid explanation for the resistance to selective androgen supplementation that is still found in many peer-reviewed publications. In our opinion (which may be biased—please consider the conflict notice above), the resistance to androgen supplementation makes no logical sense and contradicts a plethora of widely accepted fertility treatments. These treatments, which may or may not be equally controversial based on clinical study findings, do not have any comparable animal data to support them. Moreover, many of these treatments (often referred to as "add-ons" to IVF, such as PGT-A) significantly increase the costs of fertility treatments, while the costs of androgen supplementation with DHEA are minimal by comparison.
One common argument from skeptics of androgen supplementation is that there are no properly conducted prospective randomized clinical trials supporting it. This is true, but most routine medical practice—especially in infertility—lacks support from such trials. Many practices exist with little or no animal data in support. Furthermore, even a majority of randomized clinical trials in various medical areas designed to guide clinical practice often have features that disqualify them from meeting this purpose (3).
Infertility practice has a good reason for not producing enough prospective randomized studies: Infertile women—rightly—are simply not willing to be randomized. Especially when the problem is LFOR, the potential loss of time from randomization to placebo could harm their pregnancy chances. We know the impact of this concern from experience, as we secured funding for a prospective randomized clinical trial of DHEA in those early years but had to abandon it due to difficulty recruiting enough patients. We then transferred the funding to a European group of IVF clinics, who also struggled with recruitment and ultimately had to abandon the study.
This did not prevent investigators from conducting androgen supplementation studies, but most used small, underpowered randomized trials or study designs with lower levels of evidence. These often produced contradictory results. The most important reason for this is likely that, to the best of our knowledge, the evaluation of androgen levels is almost never part of a woman's basic testing schedule when presenting to fertility centers. (It has, of course, been routine at CHR for over 20 years.) Consequently, when colleagues reported on androgen supplementation with DHEA or testosterone—even in small randomized studies—they either did not test for hypo-androgenism or failed to randomize patients accordingly.
Several years ago, we reviewed the literature on DHEA supplementation and, except for CHR’s studies, could not find a single study where the androgen levels of the study population were tested before starting supplementation.
If we treat a headache with aspirin in individuals who don’t have a headache, aspirin will, of course, not work. Since, in unselected infertile women, only a small percentage will have low androgen levels at any given time, DHEA supplementation will be ineffective in a randomized study population. A properly designed randomized study of DHEA would have to be restricted to patients with low testosterone levels. If every infertile patient is given DHEA, the treatment’s effectiveness will be significantly diluted because many, if not most, random infertility patients will not be hypo-androgenic, especially if they are relatively young.
In other words, the contradictory findings of DHEA and/or direct testosterone supplementation in female infertility can largely be traced to incorrect study designs. Studies that showed positive DHEA/testosterone effects, in concordance with CHR’s results and animal experiments, likely included more hypo-androgenic participants than studies that showed no effects.
The same issue explains similarly contradictory findings in the literature for the pretreatment of infertile women with growth hormone (GH). Since GH works through insulin-like growth factor 1 (IGF-1), GH supplementation is only effective if IGF-1 levels are abnormally low. However, most fertility clinics—like those that don't test for testosterone levels—do not test for IGF-1 levels. Thus, those who believe in GH supplementation often treat every patient, without regard to IGF-1 levels. And, as with testosterone, the literature—except for CHR studies—contains no studies in which patient populations were pre-evaluated for IGF-1 levels. Furthermore, low IGF-1 levels are much rarer than low androgen levels, with less than 5% of the CHR’s population affected.
Another reason the clinical literature on androgen supplementation has been so contradictory is the timing of supplementation. Androgen effects on follicles are especially important during the small growing follicle stages, between secondary and small antral follicles. After that, these follicles still need 6–8 weeks to reach gonadotropin sensitivity. This means that DHEA/testosterone supplementation must start at least 6–8 weeks before an IVF cycle to be effective. Yet, many published studies started androgen supplementation only at the start of the IVF cycle, which often led to disappointing results.
DHEA or testosterone supplementation?
Patients frequently ask why we prefer DHEA supplementation rather than directly administering testosterone. The primary reason is the difference in treatment risk. Testosterone is usually given transdermally (via gel) and must be applied carefully because anyone who comes into contact with the gel will be affected. For instance, if a mother has testosterone gel on her arm, she should avoid close contact with her children. Moreover, testosterone floods the entire body, producing uniform testosterone levels in every organ, making it easy to overdose. Excessive testosterone can be worse for fertility than low testosterone levels.
Oral DHEA, on the other hand, is the precursor to testosterone, meaning that the body converts DHEA into testosterone. Due to DHEA’s low "binding affinity" to the androgen receptor, it rarely leads to an overdose. Even if DHEA levels are too high, it does not cause significant androgenic effects. Additionally, since most organs produce their testosterone locally, each organ—including the ovaries—only takes as much DHEA as it needs to reach its desired testosterone level. As a result, overdosing on DHEA and experiencing complications from excessive DHEA are practically impossible.
Side effects and other potential dangers of DHEA and/or testosterone, including cancer risk
We already mentioned that excessively high testosterone levels can be more harmful to fertility than low levels. Once androgen supplementation is started, it is essential to monitor androgen levels regularly. At CHR, we measure androgen levels approximately 30 days after starting treatment, followed by monitoring every three months. A typical androgen screen includes DHEA, DHEA-S, free testosterone, total testosterone, and sex hormone-binding globulin (SHBG). SHBG usually increases when testosterone levels are low, and we use SHBG to determine the effectiveness of supplementation.
A concern often raised by patients and colleagues is the increased risk of cancer, particularly breast cancer, and to a lesser degree, ovarian cancer. While this concern is understandable, it is not warranted. The primary concern stems from the fact that a small fraction of a woman’s testosterone is converted to estrogen, which can stimulate the growth of estrogen-receptor-positive breast cancer cells. However, the rise in estrogen caused by testosterone conversion is much smaller than the increase in estrogen levels during pregnancy, which is much longer in duration. In practical terms, if a woman is cleared for pregnancy, this automatically means she can also safely use androgen supplementation.
This issue is particularly relevant for women with a history of breast cancer or genetic predisposition to breast cancer, such as those with BRCA1/2 gene mutations. The rule is simple: if a patient has been cleared for pregnancy by her oncologist, she can also be pretreated with androgens, whether DHEA or testosterone.
Other side effects, such as oily skin, acne, mild hirsutism (primarily facial hair), and mild hair loss, are typically mild and reversible when treatment is stopped or when the medication dose is reduced. DHEA is generally well tolerated.
Which DHEA product should be used in infertility?
Before addressing this question, we reiterate the conflict notice mentioned earlier. As noted, many DHEA products on the market vary greatly in quality. Over several years, CHR conducted initial DHEA studies exclusively using a compounded DHEA product from Metro Pharmacy in NYC, which met our stringent production criteria. This product worked well but came with a high cost.
Afterward, CHR decided to produce its own DHEA product, Fertinatal®, to offer more affordable options for patients. Fertinatal® has gained worldwide recognition and is produced by Ovaterra, a Fertility Nutraceuticals LLC in New York. We have also licensed other companies under our patents to sell DHEA for fertility, provided they meet our quality standards.
While CHR does not make specific product recommendations, only those licensed by Fertility Nutraceuticals LLC can make claims regarding female fertility effects.
Other beneficial effects of androgens in hypo-androgenic women
Hypo-androgenism is not only associated with lower fertility and poorer fertility treatment outcomes but also with reduced energy levels, decreased libido, and often vaginal dryness, particularly in perimenopausal and menopausal women. One company has even received a patent for local vaginal DHEA treatments. CHR’s investigators have also reported that oral DHEA treatment improves sexual function in infertile women with low androgen levels (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