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The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology, insulin resistance, hyperinsulinism, type 2 diabetes mellitus, folliculogenesis, androgen secretion, obesity, phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large-scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicate that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and proinflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in 40 percent of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.<\/jats:p>","DOI":"10.1210\/endrev\/bnae007","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T07:54:25Z","timestamp":1709884465000},"page":"553-592","source":"Crossref","is-referenced-by-count":14,"title":["The Search for the Causes of Common Hyperandrogenism, 1965 to Circa 2015"],"prefix":"10.1210","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8043-5693","authenticated-orcid":false,"given":"Robert L","family":"Rosenfield","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Medicine, The University of Chicago , Chicago, IL 94109 , USA"},{"name":"Department of Pediatrics, The University of California, San Francisco , San Francisco, CA 94143 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2024,3,11]]},"reference":[{"issue":"6","key":"2024071216314826000_bnae007-B1","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1210\/endrev\/bnab009","article-title":"Normal and premature adrenarche","volume":"42","author":"Rosenfield","year":"2021","journal-title":"Endocr Rev"},{"issue":"4","key":"2024071216314826000_bnae007-B2","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1542\/peds.99.4.505","article-title":"Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network","volume":"99","author":"Herman-Giddens","year":"1997","journal-title":"Pediatrics"},{"issue":"12","key":"2024071216314826000_bnae007-B3","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1093\/humrep\/dew218","article-title":"The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis","volume":"31","author":"Bozdag","year":"2016","journal-title":"Hum Reprod"},{"issue":"11","key":"2024071216314826000_bnae007-B4","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1210\/jc.2018-01865","article-title":"Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline","volume":"103","author":"Speiser","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2024071216314826000_bnae007-B5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1210\/endrev\/bnac019","article-title":"History of adrenal research: from ancient anatomy to contemporary molecular biology","volume":"44","author":"Miller","year":"2023","journal-title":"Endocr Rev"},{"issue":"1","key":"2024071216314826000_bnae007-B6","first-page":"153","article-title":"The blood vessels, angiogenesis, organogenesis, reticulum, and histology of the adrenal","volume":"9","author":"Flint","year":"1900","journal-title":"Johns Hopkins Hosp Rep"},{"key":"2024071216314826000_bnae007-B7","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/BF01979887","article-title":"Ein Beitrag zu der feineren Structur und dem Chemismus der Nebennieren (a contribution to the finer structure and chemistry of the adrenal glands","volume":"35","author":"Arnold","year":"1866","journal-title":"Virchows Arch"},{"issue":"5","key":"2024071216314826000_bnae007-B8","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1097\/00000441-194211000-00001","article-title":"A syndrome characterized by primary ovarian insufficiency and decreased stature. 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