Purpose To evaluate the efficacy and safety of oral L-ergothioneine (EGT) in improving ovarian reserve and clinical symptoms in women with diminished ovarian reserve (DOR). As a proof-of-concept study, we explored correlations between hormonal shifts and symptom amelioration.

Methods This single-center, open-label trial enrolled 40 women (aged 35–45 years) with DOR (baseline AMH: 1.0–3.0 ng/mL) and menstrual disorders. Participants received oral EGT (120 mg/day) for three consecutive menstrual cycles. The primary outcome was the change in serum AMH. Secondary outcomes included sex hormones (FSH, E2), antral follicle count, and validated clinical questionnaires (modified Kupperman Index [KI], PSQI, SF-36, and Menstrual Symptom Score).

Results Thirty-six participants completed the intervention without product-related adverse events. EGT significantly improved core ovarian markers: mean AMH increased from 1.79 ± 0.71 to 2.47 ± 1.52 ng/mL (p = 0.029). Concurrently, basal FSH decreased (8.22 ± 2.93 to 7.05 ± 2.47 mIU/mL, p = 0.032) and E2 increased (46.00 ± 22.70 to 63.46 ± 50.10 pg/mL, p = 0.030). Clinical assessments showed progressive reductions in KI (5.42 ± 3.66 to 1.90 ± 2.16, p < 0.0001) and PSQI scores (6.89 ± 1.82 to 5.50 ± 1.40, p < 0.0001), alongside improved menstrual and SF-36 scores (p < 0.001). Subgroup analysis revealed upward AMH trends across both the 35–39 and 40–45 age cohorts. Crucially, endocrine restoration (ΔFSH) significantly correlated with improvements in sleep quality (ΔPSQI, r = 0.43, p < 0.05) and E2 increases (r = -0.46, p < 0.05), linking hormonal stabilization directly to systemic relief.

Conclusion Oral EGT safely enhances serum AMH and optimizes the FSH/E2 balance in women with DOR, yielding substantial relief from peri-menopausal and sleep disturbances. This pilot proof-of-concept study provides the first clinical evidence supporting EGT’s systemic benefits in reproductive aging, laying the groundwork for future placebo-controlled trials.

Trial Registration ChiCTR2500104484; Prospectively registered on 2025-06-18.

The authors have declared no competing interest.

ChiCTR2500104484

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocol complied with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines and was formally approved by the Institutional Ethics Committee of Qingdao Central Hospital (Approval No.: SY202502202). Written informed consent was obtained from all participants prior to screening.

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