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Meta-Analysis
. 2025 Mar;123(3):457-476.
doi: 10.1016/j.fertnstert.2024.09.038. Epub 2024 Sep 26.

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

Alessandro Conforti  1 , Luigi Carbone  2 , Raffaella Di Girolamo  3 , Giuseppe Gabriele Iorio  2 , Maurizio Guida  2 , Maria Rosaria Campitiello  4 , Filippo Maria Ubaldi  5 , Laura Rienzi  6 , Alberto Vaiarelli  5 , Danilo Cimadomo  5 , Carlo Ronsini  7 , Salvatore Longobardi  8 , Thomas D'Hooghe  9 , Sandro C Esteves  10 , Carlo Alviggi  3
Affiliations
Free article
Meta-Analysis

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

Alessandro Conforti et al. Fertil Steril. 2025 Mar.
Free article

Abstract

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 (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) 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- vs. low-dose gonadotropin (n = 957); delayed-start protocol with gonadotropin hormone-releasing hormone 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 pretreatment (n = 552); and corifollitropin alfa (n = 561).

Main outcomes: The primary outcome was live birth rate or ongoing pregnancy if data on live birth were unavailable. Secondary outcomes were number of oocytes retrieved, number of metaphase II oocytes, clinical pregnancy rate and miscarriage rate.

Results: Testosterone supplementation is associated with higher live birth rates compared with nonsupplemented women among all interventions evaluated (odds ratio: 2.19, 95% confidence interval [CI]: 1.11-4.32, four studies, 368 patients). Testosterone (weighted mean difference [WMD] 0.88, 95% CI: 0.03-1.72; 4 studies, n = 368 patients), dehydroepiandrosterone (WMD 0.60, 95% CI: 0.07-1.13; 4 studies, n = 418 patients), and delayed started protocol (WMD 1.32, 95% CI: 0.74 to 1.89; 3 studies, n = 398 patients) significantly improved the total number of eggs collected. Lower number of oocytes retrieved is achieved in women undergoing low dose gonadotropin regimen vs high dose (WMD: -1.57, 95% CI: -2.12 to -1.17; 2 studies, n = 905 patients), 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 DOR; these findings should be further explored in randomized trials.

Keywords: ART; IVF; Ovarian reserve; POSEIDON criteria; diminished ovarian reserve; poor ovarian reserve; poor responders; poor response.

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Conflict of interest statement

Declaration of Interests C.A. reports honoraria from Merck, Serono, Medea, Event Planet, and IBSA outside the submitted work. D.C. reports honoraria from IBSA, Merck KGaA, Organon, and Fairtility; leadership, positions: ESHRE SIG implantation and Early Pregnancy, SIERR, Associate Editor Human Reproduction Update outside the submitted work. A.C. reports honoraria from Merck, Serono, Medea, and Event Planet outside the submitted work. S.C.E. reports honoraria from Merck outside the submitted work. L.R. reports honoraria from Merck KGaA, MSD, Ferring, IBSA, Gedeon Richter, Cooper Surgical, and Cook; leadership positions: Nterilizer and Editor of Reproductive BioMedicine Online outside the submitted work. F.M.U. reports honoraria from Merck KGaA, MSD, Ferring, IBSA, Gedeon Richter, Cooper Surgical, and Cook; President of SIFES-MR outside the submitted work. A.V. reports honoraria from Meck, MSD- Organon, Gedeon Richer, and Ferring; travel support from Ferring, Theramex, and Merck; advisory board Scientific Seminars outside the submitted work. A.C., F.M.U., L.R., A.V., S.C.E., and C.A. report personal fees and honoraria outside the submitted work. S.L. is Senior Medical Director Fertility, Clinical Development, Merck KGaA, Darmstadt, Germany. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development, Merck Healthcare KGaA, Darmstadt, Germany. L.C. has nothing to disclose. R.D.G. has nothing to disclose. G.G.I. has nothing to disclose. M.G. has nothing to disclose. M.R.C. has nothing to disclose. C.R. has nothing to disclose.

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