Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial

Description

Studies in primates showed that treatment with testosterone increased the number of growing follicles, lead to proliferation of granulosa and theca cells, while finally reduced the apoptosis of granulosa cells (Vendola et al., 1999; Weil et al., 1999). These studies further suggest that androgens may have a specific action in pre-antral and small antral follicles, prior to serving as substrate for estradiol synthesis in larger follicles and in this regard influence the responsiveness of the ovaries to gonadotropins and amplify the effects of FSH on the ovary.

Despite the available evidence, only 3 small RCTs evaluated the effect of transdermal testosterone on infertile patients with poor ovarian response to stimulation. A pooled analysis of these studies demonstrated a benefit in clinical and ongoing pregnancy rates for testosterone pre-treated patients (Gonzlez-Comadran et al., 2012). However, two of these trials were considerably small, whereas all of them restricted testosterone administration between 5 and 21 days prior ovarian stimulation. Evidence from basic research and early trials suggest that androgens should be administered for at least 2 months before initiation of ovarian stimulation (Casson PR, 2000), in order affect preantral follicles and equip them with more FSH receptors in an attempt to have a larger cohort of follicles surviving to the recruitable antral stage.

Taking into account the promising results from recently conducted small RCTS, the investigators decided to perform a double blind placebo controlled randomized controlled trial, with adequate sample size, in order to test the effect of administration of transdermal testosterone in poor ovarian responders fulfilling the Bologna criteria, for 2 months prior ovarian stimulation in a long agonist protocol. The daily dose of transdermal testosterone gel (TTG) will be 0.55gr (5.5mg testosterone/day). The specific dose was selected based on previous pharmacokinetic studies in women according to which daily application of 5 mg of transdermal testosterone cream (Fooladi, 2014) or TTG (Singh et al. 2006, Nathorst-Bs et al., 2005) is likely to restore fT levels to the premenopausal reference range. Although no side effects had been described after pre-treatment with higher doses of 12.5mg TTG for 21 days in a previous randomized controlled trial (Kim et al., 2011), it is likely that higher doses will result in supraphysiological TT and fT levels. Therefore the dose of 0.55gr TTG (5.5mg testosterone/day) has been selected for the T-TRANSPORT trial since this will restore TT and fT levels to levels above and within the upper normal reference range.

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