Androgens and diminished ovarian reserve: the long road from basic science to clinical implementation. A comprehensive and systematic review with meta-analysis

This study aimed to present a narrative review regarding androgen production, androgens’ role in folliculogenesis, and the available therapeutic approaches for androgen supplementation, and to perform a systematic review and meta-analysis regarding the impact of androgens (dehydroepiandrosterone/testosterone) compared with placebo or no treatment on ovarian response and pregnancy outcomes in patients with diminished ovarian reserve and/or poor ovarian responders. An electronic search of MEDLINE, Embase, Cochrane Library, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, the ISRCTN registry, and the World Health Organization International Clinical Trials Registry, was conducted for studies published until September 2021. Randomized controlled trials that compared ovarian response and/or pregnancy outcomes between the different in vitro fertilization protocols using androgens (ie, dehydroepiandrosterone and testosterone) and conventional in vitro fertilization stimulation in patients with diminished ovarian reserve and/or poor ovarian responders were included. The quality of each study was evaluated with the revised Cochrane risk-of-bias tool for randomized trials (RoB 2). The meta-analysis used random-effects models. All results were interpreted on the basis of intention-to-treat analysis (defined as the inclusion of all randomized patients in the denominator). Risk ratios and 95% confidence intervals were used and combined for meta-analysis. No significant differences were found regarding the number of oocytes retrieved (mean difference, 0.76; 95% confidence interval, −0.35 to 1.88), mature oocytes retrieved (mean difference, 0.25; 95% confidence interval, −0.27 to 0.76), clinical pregnancy rate (risk ratio, 1.17; 95% confidence interval, 0.87–1.57), live-birth rate (risk ratio, 0.97; 95% confidence interval, 0.47–2.01), or miscarriage rate (risk ratio, 0.80; 95% confidence interval, 0.29–2.22) when dehydroepiandrosterone priming was compared with placebo or no treatment. Testosterone pretreatment yielded a higher number of oocytes retrieved (mean difference, 0.94; 95% confidence interval, 0.46–1.42), a higher clinical pregnancy rate (risk ratio, 2.07; 95% confidence interval, 1.33–3.20), and higher live-birth rate (risk ratio, 2.09; 95% confidence interval, 1.11–3.95). Although dehydroepiandrosterone did not present a clear effect on outcomes of assisted reproductive techniques, we found a potentially beneficial effect of testosterone priming on ovarian response and pregnancy outcomes. However, results should be interpreted with caution, taking into account the low to moderate quality of the available evidence.