The DOI matches its Crossref record; 549 of the 549 references it cites were found in a registry or an index.
The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited
Open accessAbstract
Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989 -1995.Subsequent studies have supported and amplified this hypothesis.When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation.Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production.About 3% of PCOS have a related isolated functional adrenal hyperandrogenism.The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS.Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects.Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH.These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17.Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro.A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism.PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors.Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects.Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor.The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome.Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.(Endocrine Reviews 37: 467-520, 2016) I. Historical Perspective II.Definition of Polycystic Ovary Syndrome (PCOS) III.Normal Androgen Physiology A. Biochemical and molecular overview of steroidogenesis B. Regulation of ovarian function 1. Regulation of gonadotropin secretion 2. Regulation of ovarian steroidogenesis a. Homologous desensitization to LH b.Modulation of LH action 3. Folliculogenesis and its regulation C. Regulation of adrenal androgen production D. Regulation of peripheral androgen production E. Summary of normal androgen physiology IV.Source of Androgen Excess in PCOS A. Testing to determine the source of androgen in PCOS B. Functional Ovarian Hyperandrogenism (FOH) in PCOS 1. Spectrum of ovarian androgenic function in PCOS: Typical and atypical FOH 2. Spectrum of ovarian androgenic function in asymptomatic women with polycystic ovarian morphology (PCOM)
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“Elevated ovarian androgen production is a core feature of PCOS and results in PCOS symptoms including hair loss, acne, oily skin, and accumulation of abdominal fat (Rosenfield & Ehrmann, 2016).”
From Endometriosis and polycystic ovary syndrome are diametric disorders (2021) · cites this paper as Rosenfield & Ehrmann, 2016
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“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 [43]
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“Insulin resistance (IR) is not the leading cause of obesity, although obesity really does worsen the insulin resistance of polycystic ovarian syndrome (PCOS) and hyperandrogenemia.”
From Nutritional and herbal interventions for polycystic ovary syndrome (PCOS): a comprehensive review of dietary approaches, macronutrient impact, and herbal medicine in management (2025) · cites this paper as [63]
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“This research has resulted in a proposed “two hit” hypothesis for the development of PCOS phenotypes [43,45].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [43]
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“Hyperinsulinism can appear due to insulin resistance and be caused by the production of chemical substances that are metabolically active by the visceral adipose tissue [63].”
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“Visceral adiposity in PCOS is associated with increased IR, leading to exacerbation of reproductive and metabolic abnormalities [23].”
From PCOS and nutritional approaches: Differences between lean and obese phenotype (2021) · cites this paper as [23]
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“Additionally, obesity significantly impacts the PCOS phenotype since it is associated with a higher prevalence of menstrual irregularity, hyperandrogenemia, and hirsutism [23].”
From PCOS and nutritional approaches: Differences between lean and obese phenotype (2021) · cites this paper as [23]
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“In turn, androgens promote visceral fat accumulation and IR by inhibiting lipolysis and promoting lipogenesis.”
From PCOS and nutritional approaches: Differences between lean and obese phenotype (2021) · cites this paper as [23]
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The Diagnosis of Polycystic Ovary Syndrome during Adolescence
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Self-citation
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Sorted by citations
Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment
Escobar-Morreale, H. F. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2018.24 · Cited by 2,083
Ibáñez, L., Oberfield, S. E., Witchel, S., Auchus, R. J., Chang, R. J., Codner, E., Dabadghao, P., Darendeliler, F., Elbarbary, N. S., Gambineri, A., et al. (2017) · Hormone Research in Paediatrics · doi:10.1159/000479371 · Cited by 463
GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects
Zhao, X., Wang, M., Wen, Z., Lu, Z., Cui, L., Fu, C., Xue, H., Liu, Y., & Zhang, Y. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.721135 · Cited by 463
Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics
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Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing
Sadeghi, H. M., Adeli, I., Calina, D., Docea, A. O., Mousavi, T., Daniali, M., Nikfar, S., Tsatsakis, A., & Abdollahi, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020583 · Cited by 445
Metadata
- Authors
- Rosenfield, R. L., & Ehrmann, D. A.
- Affiliations
- University of Chicago (US)
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2016-07-26
- Volume
- 37
- Issue
- 5
- Pages
- 467-520
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC5045492
- OpenAlex
- W2528009933
- Cited by
- 1,603
- References
- 549
- Citations by year
- 2026: 201 · 2025: 234 · 2024: 207 · 2023: 229 · 2022: 224 · 2021: 191 · 2020: 137 · 2019: 87 · 2018: 56 · 2017: 33 · 2016: 2
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Chicago (UL1 RR024999)
- National Institutes of Health (P60 DK20595)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60DK020595, P30DK020595)
- National Institute of Child Health and Human Development
- National Center for Research Resources (RR-00055, UL1RR024999, M01RR000055)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD057796)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- polycystic ovary syndrome, androgen secretion, theca cells, P450c17, insulin resistance, hyperinsulinemia, metabolic syndrome, obesity, prenatal androgen exposure, fetal growth restriction, hyperandrogenemia
- MeSH terms
- Androgens, Animals, Female, Humans, Hyperinsulinism, Insulin Resistance, Ovary, Polycystic Ovary Syndrome, Hyperandrogenism, Genome-Wide Association Study
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