Androgen pre-treatment in poor responders undergoing controlled ovarian stimulation and IVF treatment

To the Editor:

We updated our meta-analysis (1) following the recent publication of a randomized controlled trial (RCT) evaluating the effect of testosterone pre-treatment in poor responders undergoing IVF treatment (2).

Our updated meta-analysis of RCTs of adjuvant androgens [DHEA (dehydroepiandrosterone) and testosterone] in poor responders showed a significant improvement in the ongoing pregnancy/ live birth rates (RR 2.08; 95% CI: 1.10, 3.93; p = 0.002, Figure 1). Meta-analysis for the outcome of total dose of gonadotrophin consumption showed a significantly lower gonadotrophin consumption in the androgen supplementation group compared to the control group (WMD -464.66; 95% CI: – 612.90 to -312.42; p < 0.01, Figure 2).

Figure 1: Meta-analysis of the trials of androgen supplementation in poor responders undergoing IVF treatment for outcome of ongoing pregnancy rate

Figure 2: Meta-analysis of the trials of androgen supplementation in poor responders undergoing IVF treatment for outcome of total gonadotropin consumption

Despite the four RCTs of adjuvant androgens in poor responders (2-5), it is important to highlight the small sample sizes employed by the four published trials with only 127 women treated with androgens (testosterone or DHEA) even when the trials were combined in a meta-analysis. The quality of the studies was poor, with only one out of the four studies using a placebo in the control group (3). The studies varied in their inclusion criteria (i.e., definition of poor ovarian response), type of androgen supplementation (testosterone gel/patches or oral DHEA) and the duration of androgen supplementation.

Nonetheless, the existing evidence presents a powerful reason to proceed with a trial of adjuvant androgens in poor responders undergoing IVF treatment. DHEA is a pro-hormone processed in a tissue-specific fashion which promotes local steriodogenesis to either androgens or estrogens based on the steriodogenic enzymes present in the target cells. DHEA supplementation is therefore more likely to result in physiological circulating androgen levels compared to testosterone treatment. This sets the prospect for an adequately powered well-designed multicentered RCT of DHEA supplementation for poor responders undergoing IVF treatment.

Sesh Kamal Sunkara, M.R.C.O.G.
Assisted Conception Unit
Guy’s and St Thomas’ Foundation Trust
King’s College London
London, United Kingdom

Arri Coomarasamy, M.D., M.R.C.O.G.
Academic Department
Birmingham Women’s Hospital
Birmingham University
Birmingham, United Kingdom

References
1. Effect of androgen supplementation or modulation on ovarian stimulation outcome in poor responders: a meta-analysis. Sunkara SK, Pundir J, Khalaf Y. Reprod Biomed Online. 2011 Feb 17. [Epub ahead of print]

2. Kim CH, Howles CM, Lee HA. The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders. Fertil Steril. 2011;95:679-83.

3. Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf J.P, Hugues J.-N. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique – A prospective, randomized, double-blind study; Human Reprod. 2006;21:1204-11.

4. Fabregues F, Penarrubia J, Creus M, Manau D, Casals G, Carmona F, Balasch J. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: A randomized, clinical trial; Human Reprod. 2009;24:349-59.

5. Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman AAddition of dehydroepiandrostereone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: A randomized prospective study; Human Reprod. 2010; 25:2496-500.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.04.083

The Authors Respond:

We thank Dr. Sunkara and Dr. Coomarasamy for their comments on our article and meta-analysis including our data. We agree with them that we should have used placebo for control group. Our preliminary study showed that transdermal testosterone gel (TTG) treatment for 3 weeks resulted in a significant increase of antral follicle count (AFC) and significant decreases of mean follicular diameter (MFD) and resistance index (RI) value of ovarian stromal artery compared with baseline values. Therefore, positive effect of TTG pretreatment in our study is most unlikely a placebo effect, and unused placebo is unlikely to affect the results of our randomized controlled trial (RCT).

We used TTG for androgen priming in low responders. Administration of testosterone (T) or 5-alpha-dihydrotestosterone (DHT) to rhesus monkeys promotes initiation of primordial follicle growth, accumulation of primary follicles and follicle survival, suggesting a folliculotropic action (1, 2). Also, these studies showed that androgen receptors are abundant in granulosa cells of healthy preantral and antral follicles. Based on these studies, we used TTG as a folliculotropic agent rather than as a pro-hormone. Dehydroepiandrosterone (DHEA) supplementation is more likely to result in physiological circulating androgen levels compared to T treatment. However, T treatment is likely to be more potent and effective folliculotropic agent for low responders. Moreover, androgen treatment using TTG is safe, easy and convenient.

We agree with the assertion that sample size employed by RCT was small and well designed multicenter RCT of androgen treatment for low responders is required. Despite some drawbacks, updated meta-analysis by Dr. Sunkara and Dr. Coomarasamy showed a significant improvement in the ongoing pregnancy and live birth rates as well as a significant decrease in a total dose of gonadotropin used in the androgen treatment group compared to the control group. In our opinion, androgen treatment is one of promising strategies for improvement of ovarian response to controlled ovarian stimulation in low responders.

Chung-Hoon Kim, M.D., Ph.D.
Division of Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
University of Ulsan College of Medicine
Asan Medical Center
Seoul, Korea

References
1. Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, et al. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab 1998;83:2479–85.

2. VendolaKA, Zhou J,AdesanyaOO,Weil SJ, BondyCA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 1998;101:2622–9.

3. Vendola KA, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod 1999;61:353–7.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.04.084