Therapeutic management in women with a diminished ovarian reserve: a systematic review and meta-analysis of randomized controlled trials

Importance: The clinical management of women with diminished ovarian reserve (DOR) is a challenge in the field of medically assisted reproduction. Several therapeutic strategies have been proposed, but with mixed results, mainly because the definition of DOR used was inconsistent among trials. Objective: To investigate adjuvant treatments and protocols involving only women with DOR according to POSEIDON criteria. Data sources: We conducted a systematic search using the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases to identify relevant studies published up to June 2024. The review protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42022346117). Study selection and synthesis: After duplication removal, the titles and abstracts of 4,806 articles were scrutinized, and 124 full-text articles were assessed for eligibility. In total, 38 randomized controlled trials were included in the qualitative/quantitative analysis. The following interventions were evaluated: dehydroepiandrosterone (n = 1,336), testosterone (n = 418), high- versus low-dose gonadotropin (n = 957), delayed-start protocol with GnRH antagonist (n = 398), letrozole (n = 612), clomiphene citrate (1,113), growth hormone (311), luteal phase stimulation (n = 57), dual triggering (n = 139), dual stimulation (168), luteinizing hormone (979), oestradiol pre-treatment (n = 552), and corifollitropin alfa (n = 561). Results: Testosterone supplementation is associated with higher live birth rates compared with non-supplemented women among all interventions evaluated (OR 2.19, 95% CI 1.11-4.32, 4 studies, 368 patients; p = 0.02). Testosterone (WMD 0.88, 95% CI 0.03-1.72; 4 studies, n = 368 patients; p = 0.04), DHEA (WMD 0.60, 95% CI 0.07-1.13; 4 studies, n = 418 patients; p = 0.03), high-dose gonadotropin regimen (WMD -1.57, 95% CI -2.12 to -1.17; 2 studies, n = 905 patients; p < 0.0001) and delayed started protocol (WMD 1.32, 95% CI 0.74 to 1.89; 3 studies, n = 398 patients; p < 0.00001) significantly improved the total number of eggs collected. The other interventions did not produce significant improvements. Conclusion and relevance: Specific interventions such as testosterone seem to correlate with a better live birth rate in women with diminished ovarian reserve; these findings should be further explored in randomized trials.