Oral Chinese herbal formulas for premature ovarian insufficiency: a systematic review, meta-analysis, and exploratory therapeutic-principle subgroup analysis

Introduction Premature ovarian insufficiency (POI) is characterized by impaired ovarian endocrine function and reduced ovarian reserve. Methods We searched eight bibliographic databases, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and the Chinese Clinical Trial Registry (ChiCTR) from inception to May 30, 2026, for parallel-group randomized controlled trials comparing HRT-based regimens with pure oral Chinese herbal formulas within three prespecified therapeutic-principle categories. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251234457). Results Menstrual return or resumption was designated as the patient-important outcome, while follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) were designated as primary surrogate biomarkers. Forty-one HRT-controlled trials met the prespecified therapeutic-principle criteria. No clear between-group difference was detected for menstrual return or resumption (4 studies, 266 participants; odds ratio [OR] 1.523, 95% confidence interval [CI] 0.315 to 7.371; I 2 = 86.16%). Point estimates favored oral herbal formulas for FSH (37 studies; mean difference [MD] −5.563, 95% CI −8.230 to −2.896; I 2 = 99.13%) and AMH (12 studies; MD 0.167, 95% CI 0.035 to 0.299; I 2 = 98.17%), but both were surrogate outcomes and their prediction intervals crossed the null. Directionally favorable estimates were also observed for luteinizing hormone (LH), estradiol (E2), antral follicle count (AFC), and peak systolic velocity (PSV), although these were surrogate or exploratory outcomes with substantial uncertainty. Fewer adverse events were reported with oral herbal formulas, but safety remained unestablished because ascertainment and reporting were incomplete. Therapeutic-principle analyses yielded an exploratory subgroup signal only for FSH and did not establish comparative superiority among kidney-tonifying alone (PK), kidney-tonifying and liver-soothing (KL), and kidney-tonifying and blood-activating (KB) categories. All assessed outcomes were rated as very low-certainty evidence. Discussion Current evidence does not support the routine use of any specific Chinese herbal formula or therapeutic-principle category. Guideline-based management, including HRT when clinically appropriate, should remain standard care, and rigorously designed multicenter trials using patient-important outcomes and standardized safety reporting are needed. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251234457.