Current concepts of polycystic ovary syndrome pathogenesis
Open accessAbstract
Purpose of review: This review provides a model for understanding polycystic ovary syndrome (PCOS) pathophysiology and updates the evidence on which it is based. Then, it highlights complimentary molecular genetic and epigenetic advances in understanding PCOS cause. Recent findings: Important studies into PCOS cause built on the 2014 discovery of a novel regulatory protein variant that underlies the typical PCOS steroidogenic abnormalities: DENND1A.V2 (differentially expressed in normal and neoplastic development, isoform 1A, variant 2). Over 30 DENND1A gene variants have been found, the vast majority upstream of the coding sequence and potentially regulatory. These variants are individually uncommon but collectively plausibly cause 50% of PCOS. Anti-Müllerian hormone (AMH)/AMH receptor variants with decreased function possibly cause 6.7% of PCOS. DENNND1A was recently reported to belong to a signaling network that upregulates luteinizing hormone receptor expression and insulin mitogenic signaling. Prenatal androgen administration has proven to be a potent epigenetic regulator that causes transgenerational epigenomic changes in a mouse PCOS model with similarities to those in human PCOS and PCOS daughters. Summary: In addition to finding how gene variants contribute to PCOS pathogenesis, better understanding of androgen epigenetic mechanisms of action in diverse tissues can be expected to expand our understanding of PCOS pathogenesis.
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Compensatory hyperinsulinemia caused by insulin resistance may lead to excessive activation of IGF-1 and directly stimulate theca cells to produce androgens, exacerbating hyperandrogenism and inhibiting follicular development and ovulation.
“Additionally, compensatory hyperinsulinemia caused by IR may lead to excessive activation of IGF-1 and it can directly stimulate theca cells to produce androgens, exacerbating hyperandrogenism and inhibiting follicular development and ovulation, thus worsening the symptoms associated with PCOS15,16.”
From Efficacy and safety of GLP-1 receptor agonists on weight management and metabolic parameters in PCOS women: a meta-analysis of randomized controlled trials (2025) · cites this paper as [15]
The PCOS Pathophysiology section, under “Insulin-resistant hyperinsulinism” (page not provided), says compensatory hyperinsulinemia increases thecal LH receptors and CYP17 activity, aggravates ovarian hyperandrogenism, and disrupts follicle maturation and ovulation. It does not describe excessive IGF-1 activation or say that insulin directly stimulates theca cells to produce androgens; those specific mechanisms are unsupported by this copy. (LLM, conf=0.88)
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Lin, S., Deng, Y., Huang, J., Li, M., Sooranna, S. R., Qin, M., & Tan, B. (2025) · Scientific Reports · doi:10.1038/s41598-025-99622-4 · Cited by 35 · see citing works
- Authors
- Rosenfield, R. L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Rosenfield, Robert L.
- Venue
- Current Opinion in Pediatrics
- Published
- 2020-09-03
- Volume
- 32
- Issue
- 5
- Pages
- 698-706
- ISSN
- 1040-8703 (ISSN-L)
- 1531-698X
- PMC
- PMC7774867
- OpenAlex
- W3083316467
- Cited by
- 77
- References
- 60
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 15 · 2023: 13 · 2022: 17 · 2021: 2 · 2020: 2
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Current Opinion in Pediatrics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Research Resources (UL1RR024999, M01RR000055)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD041859)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- polycystic ovary syndrome, PCOS pathogenesis, DENND1A, anti-Müllerian hormone, luteinizing hormone receptor, insulin signaling, prenatal androgen exposure, transgenerational epigenetic inheritance, epigenetics, genetic variants
- MeSH terms
- Androgens, Female, Humans, Insulin, Polycystic Ovary Syndrome, Signal Transduction, Guanine Nucleotide Exchange Factors, Death Domain Receptor Signaling Adaptor Proteins, Anti-Mullerian Hormone
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