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The Pathogenesis of Polycystic Ovary Syndrome (PCOS): the Hypothesis of PCOS As Functional Ovarian Hyperandrogenism Revisited

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The Pathogenesis of Polycystic Ovary Syndrome (PCOS): the Hypothesis of PCOS As Functional Ovarian Hyperandrogenism Revisited REVIEW The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited Robert L. Rosenfield and David A. Ehrmann Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637 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 hy- pothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimula- tion. 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 re- maining 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 mor- phology (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 steroid- ogenic 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. Environmen- tal 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 B. Functional Ovarian Hyperandrogenism (FOH) in II. Definition of Polycystic Ovary Syndrome (PCOS) PCOS III. Normal Androgen Physiology 1. Spectrum of ovarian androgenic function in A. Biochemical and molecular overview of steroidogenesis PCOS: Typical and atypical FOH B. Regulation of ovarian function 2. Spectrum of ovarian androgenic function in 1. Regulation of gonadotropin secretion asymptomatic women with polycystic ovarian morphology (PCOM) 2. Regulation of ovarian steroidogenesis a. Homologous desensitization to LH Abbreviations: AE-PCOS, Androgen Excess-PCOS Society; AMH, anti-Müllerian hormone; b. Modulation of LH action BMI, body mass index; BMP, bone morphogenetic protein; CYP17, cytochrome P450c17; 3. Folliculogenesis and its regulation DAST, dexamethasone androgen-suppression test; DENND, differentially expressed in nor- C. Regulation of adrenal androgen production mal and neoplastic development; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; DM, diabetes mellitus; FAH, functional adrenal hyperandrogenism; FOH, functional ovar- D. Regulation of peripheral androgen production ian hyperandrogenism; GDF, growth differentiation factor; GnRHag, GnRH agonist; GTT, E. Summary of normal androgen physiology glucose tolerance test; GWAS, genome-wide association studies; hCG, human chorionic IV. Source of Androgen Excess in PCOS gonadotropin; Hippo, hippopotamus; HOMA-IR, insulin resistance by homeostatic model ␤ ⌬ ␤ A. Testing to determine the source of androgen in assessment; 3 HSD2, 5-isomerase-3 -hydroxysteroid dehydrogenase type 2; IGT, im- paired glucose tolerance; MNC, mononuclear cell; NGF, nerve growth factor; NIH criteria, PCOS National Institutes of Health 1990 conference diagnostic criteria; NOM, normal ovarian mor- phology; 17OHP, 17-hydroxyprogesterone; OSA, obstructive sleep apnea; PCOM, polycystic ISSN Print 0163-769X ISSN Online 1945-7189 ovarian morphology; PCOS, polycystic ovary syndrome; PCOS-A, functionally atypical PCOS; Printed in USA PCOS-T, functionally typical PCOS; POR, cytochrome P450-oxidoreductase; RD, reductase; Copyright © 2016 by the Endocrine Society SDAST, short DAST; SHBG, sex hormone-binding globulin; SNS, sympathetic nervous system; Received September 17, 2015. Accepted July 20, 2016. SULT2A1, steroid sulfotransferase; VEGF, vascular endothelial growth factor; V-NOM, volun- First Published Online July 26, 2016 teer with NOM. doi: 10.1210/er.2015-1104 Endocrine Reviews, October 2016, 37(5):467–520 press.endocrine.org/journal/edrv 467 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 December 2016. at 03:46 For personal use only. No other uses without permission. All rights reserved. 468 Rosenfield and Ehrmann PCOS as FOH Endocrine Reviews, October 2016, 37(5):467–520 C. Functional adrenal hyperandrogenism (FAH) in found to be variably associated with the signs and symp- PCOS toms that characterize the disorder (5). D. Other sources of androgen in PCOS Seminal contributions to our understanding of PCOS E. Summary pathogenesis began with the 1958 report that urinary LH V. Pathophysiology of PCOS: Abnormal Regulation of Steroidogenesis and Ovarian Function was elevated by bioassay in the 4 cases studied (6). The A. Dysregulation of ovarian function in PCOS 1970 documentation by RIA that serum LH and the ratio 1. Dysregulation of steroidogenesis in PCOS of LH to FSH were typically high (7) led both to the adop- a. Intrinsic theca cell dysfunction tion of altered gonadotropin secretion as an alternative b. Adrenocortical androgenic dysfunction in diagnostic tool and to a focus of research on the putative PCOS neuroendocrine genesis of the syndrome. Shortly thereaf- 2. Granulosa cell dysfunction and disordered ter, plasma free testosterone was recognized as a marker folliculogenesis a. Granulosa cell dysfunction contributes to the- for hyperandrogenism in hirsute amenorrheic women; cal androgen excess subsequent studies suggested the hyperandrogenemia was b. Disordered folliculogenesis and PCOM of ovarian origin (8). During the 1980s, administration of 3. Summary testosterone to female-to-male transsexuals was found to B. Relationship of metabolic syndrome to PCOS cause polycystic ovaries (9), and ultrasonographic criteria 1. Role of insulin-resistant hyperinsulinism in for the identification of polycystic ovarian morphology PCOS pathogenesis a. Insulin resistance and ovarian dysfunction (PCOM) were developed (10). b. Insulin resistance and adipose tissue biology Meanwhile, significant insulin resistance was recog- 2. Role of obesity in PCOS pathogenesis nized to be related to hyperandrogenism and acanthosis a. Obesity and insulin resistance nigricans (11) and to occur independently of obesity in the b. Obesity and gonadotropins syndrome (12, 13). In vitro studies subsequently showed C. Relationship of LH excess to PCOS that insulin stimulates ovarian androgen production (14), D. Modulation of androgen action in PCOS particularly in synergy with LH (15, 16). These studies E. Summary: Unified model of PCOS pathophysiology VI. Etiology of PCOS: A Complex Trait raised the possibility that hyperinsulinemia contributes to A. Heritable traits and genetic linkages ovarian androgen excess. 1. Maternal PCOS In 1989, we published evidence that a GnRH agonist 2. Polycystic ovarian morphology (GnRHag) test, which stimulates the coordinated function 3. Hyperandrogenemia of the ovarian follicle in response to endogenous LH and 4. Metabolic syndrome and diabetes mellitus (DM) FSH release, disclosed a previously unrecognized form of 5. Gene variants hyperandrogenism in women with classic PCOS: general- B. Intrauterine environment 1. Congenital virilization ized ovarian steroidogenic hyperresponsiveness (17). 17- 2. Disturbed fetal nutrition Hydroxyprogesterone (17OHP), and to a lesser extent C. Postnatal environment androstenedione, responses were most consistently abnor- 1. Insulin resistance mal, and there was no evidence of a steroidogenic block. This 2. Hyperandrogenism suggested abnormal regulation (dysregulation) of 17-hy- 3. Other precipitants and risk factors droxylase and 17,20-lyase activities, which are 2 activities of D. Implications for evolutionary origin of PCOS E. Summary the single enzyme cytochrome P450c17 (CYP17) encoded by VII. Conclusions and Implications for Future Research CYP17A1 (17, 18). We then found that most hyperandrogenic women (two-thirds of those with oligo-amenorrhea, 30% of eu- I. Historical Perspective menorrheic ones) had this type of androgenic ovarian dys- function and that this was independent of serum LH ele- olycystic ovary syndrome (PCOS) is the most common vation or PCOM in about half of cases (19, 20). This P endocrine disorder in reproductive aged women, abnormality was termed functional ovarian hyperandro- with a prevalence between 5% and
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