More on the Conversion of DHEA to Testosterone Aya Shohat-Tal, Aritro Sen, David H

CORRESPONDENCE

Nature Reviews Endocrinology published online 14 July 2015; doi:10.1038/nrendo.2015.108

REPLY More on the conversion of DHEA to testosterone Aya Shohat-Tal, Aritro Sen, David H. Barad, Vitaly A. Kushnir and Norbert Gleicher

We appreciate the interest of Kunicki should be determined, and that such metabolite levels. Indeed, the importance and colleagues in our Review (Genetics determinations should only be made using of DHEA and/or DHEAS metabolism to of androgen metabolism in women tandem mass spectrometry and liquid testosterone was the principal motivation with infertility and hypoandrogen- chromatography. They, however, mis for writing our Review.1 ism. Nat. Rev. Endocrinol. 11, 429–441; understood our comments on the dura- 2015),1 and are pleased to respond to tion of DHEA supplementation as we have Center for Human Reproduction, 21 East th their comments (DHEA in women with repeatedly demonstrated that statistical 69 Street, New York, NY 10021, USA (A.S.-T., hypoandrogenism—debate remains efficacy of DHEA supplementation is first D.H.B., V.A.K., N.G.). Department of Internal Medicine, Division of Endocrinology and open. Nat. Rev. Endocrinol. doi:10.1038/ observed after ~6 weeks of supplementa- Metabolism, University of Rochester Medical nrendo.2015.107).2 We fully agree with our tion but that efficacy continues to improve Center, 601 Elmwood Avenue, Rochester, Polish colleagues that what actually consti- up to 4–5 months.7 We now, however, no NY 14642, USA (A.S.). tutes abnormally low levels of androgens longer recommend preset time periods Correspondence to: A.S.‑T. in women with infertility has not yet been of DHEA supplementation but, instead, [email protected] fully defined. This lack of clarity, however, recommend evaluations of androgen and Competing interests is not only a problem in assessing andro- SHBG levels as a criteria for initiation of N.G. and D.H.B. are listed as co-inventors on four gen levels but, also, in assessing levels of all in vitro fertilization cycles. awarded US patents, which claim therapeutic fertility-related hormones, which in their As we discussed in our Review,1 the com benefits of DHEA and other androgens in women normal ranges are age-dependent.3,4 monly used daily dosage of 50 mg is unlikely with low functional ovarian reserve (US 7,615,544: ‘Method of improving cumulative embryo score and 2 Kunicki and colleagues also do not to increase testosterone levels to supra- quantity of fertilized oocytes, increasing euploidy differentiate between age-specific and physiological levels even in women with rate and of normalizing ovarian function using an functional hypoandrogenism. At certain normal baseline androgen levels, as indi- androgen such as dehydroepiandrosterone’; US 8,067,400: ‘Androgen treatment in females’; advanced ages, testosterone or dehydro- vidual organs will use only as much DHEA US 8,501,719: ‘Androgen treatment in females’; epiandrosterone (DHEA) and dehydro- and/or DHEAS as necessary to achieve the and US 8,501,718: ‘Androgen treatment in epiandrosterone sulphate (DHEAS) levels desired testosterone levels. This caveat is females’). N.G. and D.H.B. are also listed as co-inventors on two awarded US patents, which of 8.68 nmol/l and 40.74 nmol/l, respec- exactly the reason why supplementation are not related to the subject of this Review tively, might, indeed, be normal on an age- with DHEA seems superior to supplemen- (US 8,629,120: ‘Method of treatment related to specific basis; yet functionally, they might tation with testosterone and results in fewer the FMR1 gene’; and US 8,951,724: ‘Detection represent hypoandrogenism. We know adverse effects. of infertility risk and premature ovarian aging, addressing various claimed effects and diagnostic this on the basis of a number of observa- Kunicki and colleagues are also not the functions of the FMR1 gene on ovaries and female tions. Firstly, women with infertility who only investigators to report that DHEA fertility’). N.G. owns shares in Fertility have normal age-specific androgen levels and/or DHEAS levels are not predictive of Nutraceuticals, a company that sells DHEA products, and both N.G. and D.H.B. receive patent often present with increased levels of sex pregnancy. We reported this fact, indeed, royalties from this company. N.G. is also the owner 6,7 hormone-binding globulin (SHBG). When quite some time ago. They are, however, of The Center for Human Reproduction, New York, these women are given androgen supple- incorrect in reaching conclusions based NY, USA. A.S.‑T., A.S. and V.A.K. declare no ments, their SHBG levels normalize in on this observation alone in women with competing interests. parallel with improving testosterone levels. normal ovarian reserve, because, as we 1 1. Shohat-Tal, A., Sen, A., Barad, D. H., This pattern is often most profoundly discussed in our Review, what seems to be Kushnir, V. & Gleicher, N. Genetics of androgen visible in young women under the age of relevant for ovarian function is not the level metabolism in women with infertility and 35 years with a history of polycystic ovary of the testosterone precursor DHEA or the hypoandrogenism. Nat. Rev. Endocrinol. 11, syndrome at an earlier age, when ovaries, level of its precursor storage form DHEAS 429–441 (2015). 2. Kunicki, M., Łukaszuk, K. & Liss, J. DHEA in it seems, have ‘become used’ to especially but, rather, the level of their downstream women with hypoandrogenism—debate high levels of androgens. Secondly, women effector metabolite, testosterone. In women remains open. Nat. Rev. Endocrinol. http:// with low functional ovarian reserve almost with low baseline levels of testosterone, dx.doi.org/10.1038/nrendo.2015.107. 3. Barad, D. H., Weghofer, A. & Gleicher, N. Age- universally have lower testosterone levels the conversion of the precursor DHEA to specific levels for basal follicle-stimulating than women with normal ovarian func- testosterone becomes substantial and is hormone assessment of ovarian function. tion.5 Thirdly, androgen supplementation associated with pregnancy rates, as we have Obstet. Gynecol. 109, 1404–1410 (2007). 6 5–7 4. Barad, D. H., Weghofer, A. & Gleicher, N. Utility statistically relates to pregnancy success. demonstrated. Clinical assessment of this of age-specific serum anti-Müllerian hormone We fully agree with Kunicki and col- conversion is currently limited to studies concentrations. Reprod. Biomed. Online 22, leagues2 that age-specific androgen ranges of precursor supplementation and resulting 284–291 (2011).

5. Gleicher, N. et al. Hypoandrogenism in supplementation determine at all ages 7. Gleicher, N. & Barad, D. H. association with diminished functional ovarian in vitro fertilization (IVF) pregnancy rates Dehydroepiandrosterone (DHEA) reserve. Hum. Reprod. 28, 1084–1091 (2013). in women with diminished ovarian reserve supplementation in diminished ovarian 6. Gleicher, N. et al. Starting and resulting (DOR). J. Assist. Reprod. Genet. 30, 49–62 reserve (DOR). Reprod. Biol. Endocrinol. 9, testosterone levels after androgen (2013). 67 (2011).