We appreciate the interest of Kunicki and colleagues in our Review (Genetics of androgen metabolism in women with infertility and hypoandrogenism. Nat. Rev. Endocrinol. 11, 429–441; 2015),1 and are pleased to respond to their comments (DHEA in women with hypoandrogenism—debate remains open. Nat. Rev. Endocrinol. doi:10.1038/nrendo.2015.107).2 We fully agree with our Polish colleagues that what actually constitutes abnormally low levels of androgens in women with infertility has not yet been fully defined. This lack of clarity, however, is not only a problem in assessing androgen levels but, also, in assessing levels of all fertility-related hormones, which in their normal ranges are age-dependent.3,4
Kunicki and colleagues2 also do not differentiate between age-specific and functional hypoandrogenism. At certain advanced ages, testosterone or dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) levels of 8.68 nmol/l and 40.74 nmol/l, respectively, might, indeed, be normal on an age-specific basis; yet functionally, they might represent hypoandrogenism. We know this on the basis of a number of observations. Firstly, women with infertility who have normal age-specific androgen levels often present with increased levels of sex hormone-binding globulin (SHBG). When these women are given androgen supplements, their SHBG levels normalize in parallel with improving testosterone levels. This pattern is often most profoundly visible in young women under the age of 35 years with a history of polycystic ovary syndrome at an earlier age, when ovaries, it seems, have 'become used' to especially high levels of androgens. Secondly, women with low functional ovarian reserve almost universally have lower testosterone levels than women with normal ovarian function.5 Thirdly, androgen supplementation statistically relates to pregnancy success.6
We fully agree with Kunicki and colleagues2 that age-specific androgen ranges should be determined, and that such determinations should only be made using tandem mass spectrometry and liquid chromatography. They, however, misunderstood our comments on the duration of DHEA supplementation as we have repeatedly demonstrated that statistical efficacy of DHEA supplementation is first observed after ∼6 weeks of supplementation but that efficacy continues to improve up to 4–5 months.7 We now, however, no longer recommend preset time periods of DHEA supplementation but, instead, recommend evaluations of androgen and SHBG levels as a criteria for initiation of in vitro fertilization cycles.
As we discussed in our Review,1 the commonly used daily dosage of 50 mg is unlikely to increase testosterone levels to supraphysiological levels even in women with normal baseline androgen levels, as individual organs will use only as much DHEA and/or DHEAS as necessary to achieve the desired testosterone levels. This caveat is exactly the reason why supplementation with DHEA seems superior to supplementation with testosterone and results in fewer adverse effects.
Kunicki and colleagues are also not the only investigators to report that DHEA and/or DHEAS levels are not predictive of pregnancy. We reported this fact, indeed, quite some time ago.6,7 They are, however, incorrect in reaching conclusions based on this observation alone in women with normal ovarian reserve, because, as we discussed in our Review,1 what seems to be relevant for ovarian function is not the level of the testosterone precursor DHEA or the level of its precursor storage form DHEAS but, rather, the level of their downstream effector metabolite, testosterone. In women with low baseline levels of testosterone, the conversion of the precursor DHEA to testosterone becomes substantial and is associated with pregnancy rates, as we have demonstrated.5,6,7 Clinical assessment of this conversion is currently limited to studies of precursor supplementation and resulting metabolite levels. Indeed, the importance of DHEA and/or DHEAS metabolism to testosterone was the principal motivation for writing our Review.1
Shohat-Tal, A., Sen, A., Barad, D. H., Kushnir, V. & Gleicher, N. Genetics of androgen metabolism in women with infertility and hypoandrogenism. Nat. Rev. Endocrinol. 11, 429–441 (2015).
Kunicki, M., Łukaszuk, K. & Liss, J. DHEA in women with hypoandrogenism—debate remains open. Nat. Rev. Endocrinol. http://dx.doi.org/10.1038/nrendo.2015.107.
Barad, D. H., Weghofer, A. & Gleicher, N. Age-specific levels for basal follicle-stimulating hormone assessment of ovarian function. Obstet. Gynecol. 109, 1404–1410 (2007).
Barad, D. H., Weghofer, A. & Gleicher, N. Utility of age-specific serum anti-Müllerian hormone concentrations. Reprod. Biomed. Online 22, 284–291 (2011).
Gleicher, N. et al. Hypoandrogenism in association with diminished functional ovarian reserve. Hum. Reprod. 28, 1084–1091 (2013).
Gleicher, N. et al. Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR). J. Assist. Reprod. Genet. 30, 49–62 (2013).
Gleicher, N. & Barad, D. H. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod. Biol. Endocrinol. 9, 67 (2011).
N.G. and D.H.B. are listed as co-inventors on four awarded US patents, which claim therapeutic benefits of DHEA and other androgens in women with low functional ovarian reserve (US 7,615,544: 'Method of improving cumulative embryo score and quantity of fertilized oocytes, increasing euploidy rate and of normalizing ovarian function using an androgen such as dehydroepiandrosterone'; US 8,067,400: 'Androgen treatment in females'; US 8,501,719: 'Androgen treatment in females'; and US 8,501,718: 'Androgen treatment in females'). N.G. and D.H.B. are also listed as co-inventors on two awarded US patents, which are not related to the subject of this Review (US 8,629,120: 'Method of treatment related to the FMR1 gene'; and US 8,951,724: 'Detection of infertility risk and premature ovarian aging, addressing various claimed effects and diagnostic functions of the FMR1 gene on ovaries and female fertility'). N.G. owns shares in Fertility Nutraceuticals, a company that sells DHEA products, and both N.G. and D.H.B. receive patent royalties from this company. N.G. is also the owner of The Centre for Human Reproduction, New York, NY, USA. A.S.-T., A.S. and V.A.K. declare no competing interests.
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Shohat-Tal, A., Sen, A., Barad, D. et al. More on the conversion of DHEA to testosterone. Nat Rev Endocrinol 11, 521 (2015). https://doi.org/10.1038/nrendo.2015.108