Researchers have delineated four distinct subgroups within polycystic ovary syndrome (PCOS), offering new avenues for personalized management. The subtypes are hyperandrogenic PCOS (HA-PCOS), overweight-obesity PCOS (OB-PCOS), SHBG-dominant PCOS (SHBG-PCOS), and a LH-AMH–driven phenotype (LH-PCOS).
The findings, published in Nature Medicine, demonstrate meaningful differences in pregnancy rates, live births, and complications across subtypes, suggesting that clinicians could tailor in vitro fertilization (IVF) strategies to a patient’s specific PCOS category.
The study aimed to identify clinical features capable of reliably distinguishing PCOS subtypes. Participants were cisgender women aged 20 to 45 years diagnosed with PCOS using broader Rotterdam criteria, which require at least two of the following: cycle lengths shorter than 21 days, hyperandrogenism, and polycystic-appearing ovaries. Therapy for PCOS at enrollment was an exclusion criterion. Twenty-nine baseline features were evaluated, with items showing weak associations excluded.
The final analysis incorporated nine continuous variables: body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), antimüllerian hormone (AMH), fasting insulin, and fasting glucose.
Blood samples were collected at the initial consultation, and reproductive steroid hormone levels were measured on days 1 to 3 of the menstrual cycle. AMH and other biochemical parameters were quantified using enzyme-linked immunosorbent assays. Participants diagnosed between 2014 and 2018 were followed up by telephone from March 2021 to August 2024, with a median follow-up of 6.5 years. During follow-up, researchers tracked current height and weight, menstrual status, pregnancies and births, IVF treatments, and disease status, along with periodic physical examinations.
Prevalence and characteristics of each PCOS subtype were reported as follows:
- HA-PCOS: 25%
- OB-PCOS: 26%
- SHBG-PCOS: 26%
- LH-PCOS: 23%
Each subtype exhibited distinct clinical constellations. HA-PCOS showed elevated DHEA-S with only mild metabolic disturbances. OB-PCOS was defined by higher BMI, fasting glucose, and fasting insulin. SHBG-PCOS was marked by the highest SHBG levels and the lowest BMI among the four groups. LH-PCOS demonstrated elevated LH, FSH, and AMH levels.
To validate these subtypes, the investigators analyzed five independent cohorts from China, the United States, Europe, Singapore, and Brazil. The same four subtypes emerged in all cohorts, and predictive accuracy, measured by the area under the curve, ranged from 0.82 to 0.98 across cohorts (0.82–0.98 in the respective studies).
Follow-up data showed differential persistence of Rotterdam criteria across subtypes: 67.2% in HA-PCOS continued to meet Rotterdam criteria, compared with 50.9% in OB-PCOS, 52.8% in SHBG-PCOS, and 74.8% in LH-PCOS, underscoring the heterogeneity within PCOS and the potential for subtype-specific disease trajectories.
Implications for practice
The identification of four PCOS subtypes with unique clinical and biochemical signatures supports a move toward more personalized therapy. The researchers propose that understanding a patient’s PCOS subtype could inform not only diagnostic clarity but also the selection of IVF protocols and follow-up strategies tailored to the subtype’s biology.
“This international collaboration provides robust evidence that could change how we diagnose, treat, and monitor women with PCOS,” commented Elisabet Stener-Victorin, PhD, of Karolinska Institutet. “Treatments can be aligned with PCOS subtypes to better capture the biological variation and optimize outcomes.”
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