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Most PCOS results from a \u201cfunctionally typical\u201d form of ovarian hyperandrogenism characterized by a unique pattern of ovarian steroidogenic hyperresponsiveness to gonadotropin stimulation that seems explainable by gene variants that cause overexpression of an activating variant of DENND1A (differentially expressed in normal and neoplastic development). However, one-third of PCOS is \u201cfunctionally atypical,\u201d lacking this ovarian response. These 2 forms of PCOS share clinical traits with the respective \u201creproductive\u201d and \u201cmetabolic\u201d subtypes of PCOS that have been recently distinguished by cluster analysis, with DENND1A gene variants present in significantly more of the former. This review suggests that severe adiposity causes \u201cmetabolic\/functionally atypical\u201d PCOS by enhancing ovarian steroidogenesis through hyperinsulinism and adipose- and gut-dependent proinflammatory adipokines in genetically predisposed individuals, plus amplifying the ability of adipose tissue to generate testosterone and adrenal-derived 11\u00df-hydroxytestosterone from circulating precursors. This review furthermore indicates that preferential abdominal fat accumulation, often subclinical, is a central feature of PCOS that also affects metabolic function. The hyperandrogenic environment created within adipose tissue by adiposity-dependent and independent insulin-resistant hyperinsulinism, intra-adipose steroidogenesis, and PCOS-related hyperandrogenemia also appears to restrict the capacity of subcutaneous adipose to safely store fat, predisposing to ectopic fat deposition and lipotoxicity with weight gain. We conclude that excess total and\/or abdominal fat seems to be a nearly constant feature of PCOS, either as the cause of hyperandrogenism or as the result of hyperandrogenism contributing to the adipogenic endocrine milieu.<\/jats:p>","DOI":"10.1210\/clinem\/dgaf527","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T11:45:26Z","timestamp":1758627926000},"page":"11-23","source":"Crossref","is-referenced-by-count":10,"title":["On the Intimate Relationship of Adiposity to Polycystic Ovary Syndrome"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8043-5693","authenticated-orcid":false,"given":"Robert L","family":"Rosenfield","sequence":"first","affiliation":[{"name":"Pediatrics and Medicine, The University of Chicago , Chicago, IL 60637 ,","place":["USA"]},{"name":"Pediatrics, The University of California , San Francisco, CA 94143 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0387-1277","authenticated-orcid":false,"given":"Daniel A","family":"Dumesic","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of California Los Angeles , Los Angeles, CA 90095-1740 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"issue":"1","key":"2025121807421590500_dgaf527-B1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.fertnstert.2003.10.004","article-title":"Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome","volume":"81","author":"Rotterdam ESHRE\/ASRM-Sponsored PCOS Consensus Workshop Group","year":"2004","journal-title":"Fertil 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