Letters to the editor |
Reply: Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study
Reproductive Biomedicine Unit, Jean Verdier Hospital: Bondy, University Paris XIII, Bondy, France
E-mail: jean-noel.hugues{at}jvr.ap-hop-paris.fr
Sir,
We express our best thanks to N. Gleicher and D.H. Barad for their interest in our newly published study. We agree with their statement that caution must be exercised before drawing any firm conclusions on the impact of medical interventions on IVF outcomes from studies performed with a limited number of patients.
We also agree with the authors of this letter that a longer duration of androgen administration should have been more effective, and this issue has been extensively discussed in our article.
Nevertheless, we emphasize that similar caution should be exercised when the authors conclude from their own data on the beneficial effects of dehydroepiandrosterone (DHEA) administration. Major drawbacks of their reports came from methodological aspects. The first publication described a case report in 43-year-old woman. In this unique case, both acupuncture and DHEA interventions have been assumed to improve ovarian response in nine consecutive cycles. However, conclusions from this study are entirely speculative. The second study, presented in an abstract form at the American Society of Reproductive Medicine (ASRM) meeting in 2005, assessed the effects of DHEA in elderly women. However, several methodological flaws could have led the authors to misleading conclusion.
- First, this study was not prospectively randomized and did not include any placebo control group. Interestingly, our placebo-controlled study demonstrated a similar improvement in the number of follicles and oocytes in patients without any androgen supplementation. These data emphasize that valuable data can be only obtained from strictly designed, randomized and placebo-controlled clinical trials. This rule is particularly relevant in a population of poor-responder women whose intercycle variability in the ovarian response to FSH is huge.
- Second, the duration of DHEA administration was different between individuals. Therefore, no clear relationship between DHEA intake and improvement in the number of retrieved oocytes could be eventually demonstrated.
As regards the choice of androgen, it has been well established that DHEA has a weak androgenic activity as compared with testosterone, when assessed on peripheral tissues. To our knowledge, no informative data are yet available on the intraovarian conversion of DHEA to testosterone. It is therefore speculative to conclude that DHEA may be a potential precursor of active androgen within the ovary. Further studies are required to conclude on this issue.
Although we strongly believe that intraovarian androgens play a critical role in the process of folliculogenesis in primates, our study could not demonstrate the clinical relevance of adding androgen in a selected population of poor responders with ovarian deficiency. These data do not exclude any positive effect in patients with a less-severe ovarian deficiency. However, this potential effect of androgen supplementation, clearly demonstrated in monkeys, is strictly limited to an improvement in the number of follicles in relation to a strong reduction in granulosa cell apoptosis. To our knowledge, there is no evidence so far that aneuploidy, a hallmark of oocyte quality in elderly women, might be improved by androgen supplementation.
Consequently, additional well-designed, randomized, placebo-controlled clinical trials are needed to validate our hypothesis that androgen supplementation might be effective at stimulating follicular recruitment in humans. These studies should be performed in a selected population whose both oocyte quantity and quality are likely to be improved. One of the most challenging issues for clinicians is to identify predictive factors of response to androgen. Further work-up of theca cell function might be helpful to better identify the subgroup of women responsive to androgen supplementation. We do believe that this new approach is promising for some women who are often excluded from any assisted reproduction technique (ART) programmes.
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