Data-driven subtypes of polycystic ovary syndrome and their association with clinical outcomes

Xueying Gao; Shigang Zhao; Yanzhi Du; Ziyi Yang; Ye Tian; Junli Zhao; Xi Yuan; Betania R Santos; Daimin Wei; Linlin Cui; Junhao Yan; Yingying Qin; Yuhua Shi; Rong Tang; Yun Sun; Jingmei Hu; Lingling Ding; Xueru Song; Lingxia Ha; Jingyu Li; China Women’s Reproductive Metabolic Network; Heping Zhang; Poli Mara Spritzer; Bulent O Yildiz; Elisabet Stener-Victorin; Eu-Leong Yong; Xiang-Hong Ou; Richard S Legro; Han Zhao; Zi-Jiang Chen

doi:10.1038/s41591-025-03984-1

PMOS / PCOS · Long Term Health

Data-driven subtypes of polycystic ovary syndrome and their association with clinical outcomes

Gao X, Zhao S, Du Y, Yang Z, Tian Y, Zhao J, Yuan X, Santos BR, Wei D, Cui L, Yan J, Qin Y, Shi Y, Tang R, Sun Y, Hu J, Ding L, Song X, Ha L, Li J, China Women’s Reproductive Metabolic Network, Zhang H, Spritzer PM, Yildiz BO, Stener-Victorin E, Yong EL, Ou XH, Legro RS, Zhao H, Chen ZJ

Published December 2025 Nature Medicine, 31(12), 4214-4224

DOI 10.1038/s41591-025-03984-1 PMID 41162652 PMC PMC12705455

RRM Academy Synopsis

PCOS sorts into four subtypes with different health outcomes

A study of 11,908 women with PMOS, formerly PCOS, found four subtypes. Each subtype had different pregnancy and metabolic outcomes. All 11,908 came from one Chinese center. Five other groups of women showed the same four subtypes.

Key Findings

Nine clinical measurements sorted women with polyendocrine metabolic ovarian syndrome (PMOS / PCOS) into four subtypes: hyperandrogenic (25%), obesity (26%), high sex hormone-binding globulin (26%) and high LH-AMH (23%).
At a median follow-up of 6.5 years, 523 women had physical exams. Of these, 50.9% in the obesity subtype and 74.8% in the high LH-AMH subtype still met the Rotterdam criteria.
Follow-up incidence was highest for dyslipidemia in the hyperandrogenic subtype (24.4%) and for type 2 diabetes in the obesity subtype (16.0%).
Among women who had IVF, live birth rates were 48.9% in the obesity subtype and 56.3% in the high sex hormone-binding globulin subtype, against 53.8% in the control group.
Versus controls, second trimester pregnancy loss was highest in the hyperandrogenic subtype (OR 7.32, 95% CI 4.94–10.85), moderate or severe ovarian hyperstimulation in the high LH-AMH subtype (OR 7.44, 95% CI 4.63–11.96).

Interpretation

The authors built the subtypes in a single Chinese reproductive center and followed a subset by telephone, with physical exams for 523 women. Most cohorts came from specialized reproductive centers, which may favor certain subtypes, and the validation cohorts were smaller. Menstrual cycle regularity was left out of the clustering. Fertility comparisons come from women having IVF, measured against IVF patients with tubal or male-partner causes. The paper has no data on lifestyle changes or ovulation induction, and the control group was not followed. The design shows associations only.

RRM Context

Sorting PMOS / PCOS by hormone and metabolic patterns fits the cause-based logic of restorative reproductive medicine: find the drivers behind each woman's presentation. The authors name objective cycle data, such as digital tracking apps, as an input future subtype work should include. Cycle charting is one source of that record. Diagnosis in the paper uses the Rotterdam criteria.

Our editorial summary of this paper, not the article's abstract.

Abstract

Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine disorder that affects 11%-13% of women worldwide, with profound implications for fertility and long-term metabolic health. Here we identify four reproducible subtypes-PCOS with hyperandrogen, with obesity, with high-sex hormone-binding globulin and with high-luteinizing hormone-anti-Müllerian hormone-through unsupervised clustering of 9 clinical variables in 11,908 affected women, validated across 5 international cohorts. Prospective 6.5-year follow-up and in vitro fertilization treatment data revealed distinct reproductive and metabolic trajectories: hyperandrogenic PCOS showed the highest risk of second trimester pregnancy loss and dyslipidemia incidence; PCOS with obesity exhibited the most severe metabolic complications, lowest live birth rates and highest PCOS remission rate; PCOS with high-sex hormone-binding globulin demonstrated favorable reproductive outcomes and the lowest incidence of diabetes and hypertension; and PCOS with high-luteinizing hormone-anti-Müllerian hormone had the greatest risk of ovarian hyperstimulation and the lowest PCOS remission rate. These findings advance understanding of PCOS heterogeneity and provide a framework for subtype-based risk stratification and personalized management.

Topics

PMOS / PCOS › Long Term Health › Metabolic Risk · Reproductive Endocrinology › Ovarian Hormones › Androgens · Menstrual Cycle › Cycle Disorders › Ovulatory Disturbances

Xueying Gao, Shigang Zhao, Yanzhi Du, Ziyi Yang, Ye Tian, Junli Zhao, Xi Yuan, Betania R Santos, Daimin Wei, Linlin Cui, Junhao Yan, Yingying Qin, Yuhua Shi, Rong Tang, Yun Sun, Jingmei Hu, Lingling Ding, Xueru Song, Lingxia Ha, Jingyu Li, Heping Zhang, Poli Mara Spritzer, Bulent O Yildiz, Elisabet Stener-Victorin, Eu-Leong Yong, Xiang-Hong Ou, Richard S Legro, Han Zhao, Zi-Jiang Chen

X Gao, S Zhao, Y Du, Z Yang, Y Tian, J Zhao, X Yuan, B Santos, D Wei, L Cui, J Yan, Y Qin, Y Shi, R Tang, Y Sun, J Hu, L Ding, X Song, L Ha, J Li, H Zhang, P Spritzer, B Yildiz, E Stener-Victorin, E Yong, X Ou, Rick Legro, Dick Legro, Rich Legro, R Legro, H Zhao, Z Chen

PMID 41162652 41162652 DOI 10.1038/s41591-025-03984-1 10.1038/s41591-025-03984-1 Gao et al. 2025, Gao 2025

Correction published 2025

Data-driven subtypes of polycystic ovary syndrome and their association with clinical outcomes

PCOS sorts into four subtypes with different health outcomes

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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