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Cited by 504Ovarian function and disordersReproductive Biology and FertilitySexual Differentiation and Disorders

Developmental origin of polycystic ovary syndrome—a hypothesis

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Abbott, DH, Dumesic, DA, Franks, S·2002·Journal of Endocrinology
DOI 10.1677/joe.0.1740001
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Abstract

Polycystic ovary syndrome (PCOS) is a common but complex endocrine disorder and is a major cause of anovulation and consequent subfertility. It is also associated with a metabolic disturbance, characterized by hyperinsulinaemia and insulin resistance that carries an increased risk of type 2 diabetes in later life. Despite its prevalence little is known about its aetiology, but there is increasing evidence for an important genetic involvement. On the basis of experimental observations in the prenatally androgenized sheep and rhesus monkey, and supported by data from human studies, we propose that the clinical and biochemical features of PCOS can arise as a consequence of genetically determined hypersecretion of androgens by the ovary during, or very likely long before, puberty. The resulting hyperandrogenism results in 'programming' of the hypothalamic-pituitary unit to favour excess LH secretion, and encourages preferential abdominal adiposity that predisposes to insulin resistance. The severity of hyperinsulinaemia and insulin resistance (which has a profound influence on the phenotype of PCOS) is further influenced by both genetic factors (such as polymorphism in the insulin gene regulatory region) and environmental factors, notably obesity. This hypothesis therefore suggests a unifying, 'linear' model to explain the aetiology of the heterogeneous phenotype.

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  • Dietary and environmental factors have an impact on developmental programming of susceptible gene variants in women with PCOS.

    “Dietary and environmental factors are hypothesized to have an impact on developmental programming of susceptible gene variants in women with PCOS [41,42,43].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [42]

    The Introduction and “Prenatal androgen excess provides the developmental origin for PCOS” section (page not specified in our copy) hypothesize that dietary and other environmental factors interact with genetic factors and modify the PCOS phenotype. They attribute developmental programming primarily to androgen excess, however, and do not say that diet or environmental factors program susceptible gene variants. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Multiple lines of evidence suggest that inherited PCOS gene variants are developmentally programmed in a way that primes them for activation by nutritional and environmental factors in postnatal life.

    “In keeping with this model, multiple lines of evidence suggest that inherited PCOS gene variants are developmentally programmed in a way that primes them for activation by nutritional and environmental factors in postnatal life [41,42,98].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [42]

    The Introduction and ‘Prenatal androgen excess provides the developmental origin for PCOS’ describe a genetic contribution, developmental programming by early androgen excess, and later modification of the PCOS phenotype by environmental factors, particularly diet. They do not say that inherited gene variants themselves are developmentally programmed or primed for postnatal activation; the proposed programming acts on developing physiological systems. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Fetal, neonatal, prepubertal, and/or pubertal ovaries may be genetically predisposed to increased androgen secretion.

    “Fetal, neonatal, prepubertal, and/or pubertal ovaries may be genetically predisposed to increased androgen secretion [100, 101].”

    From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [100]

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Authors
Abbott, D., Dumesic, D., & Franks, S.
Affiliations
  • University of Wisconsin–Madison (US)
  • University of London (GB)
ORCID
Franks, S
Venue
Journal of Endocrinology
Publisher
Bioscientifica
Published
2002-07-01
Volume
174
Issue
1
Pages
1-5
ISSN
  • 0022-0795 (ISSN-L)
  • 1479-6805
DOI
10.1677/joe.0.1740001
OpenAlex
W2130933461
Cited by
504
References
51
Citations by year
2026: 13 · 2025: 9 · 2024: 13 · 2023: 12 · 2022: 17 · 2021: 17 · 2020: 15 · 2019: 24 · 2018: 20 · 2017: 21 · 2016: 24 · 2015: 23 · 2014: 22 · 2013: 30 · 2012: 23
FWCI
3.96
Type
journal article
Language
en
Open access
Locations
  • Journal of Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
polycystic ovary syndrome, etiology, developmental programming, prenatal androgen exposure, hyperandrogenism, ovary, luteinizing hormone secretion, insulin resistance, hyperinsulinemia, type 2 diabetes, obesity, anovulation, subfertility, sheep, rhesus monkeys
MeSH terms
Androgens, Animals, Female, Humans, Insulin, Insulin Resistance, Luteinizing Hormone, Macaca mulatta, Ovarian Diseases, Polycystic Ovary Syndrome, Pregnancy, Prenatal Exposure Delayed Effects, Sheep

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