Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

Daniel A Dumesic, Sharon E Oberfield, Elisabet Stener-Victorin, John C Marshall, Joop S Laven, Richard S Legro, Daniel A Dumesic, Sharon E Oberfield, Elisabet Stener-Victorin, John C Marshall, Joop S Laven, Richard S Legro

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown.

Figures

Figure 1.
Figure 1.
Meta-analysis of stroke and coronary heart disease (CHD) in women with PCOS. This figure includes a forest plot comparing the risk of nonfatal stroke in women with PCOS compared to controls in the older age group (mean > 45 y) (top) and a forest plot comparing risk of nonfatal CHD in women with PCOS compared to controls in the older age group (bottom) (mean > 45 y). CI, confidence interval; M-H, Mantel-Haenszel. [Adapted from S. A. Anderson et al: Risk of coronary heart disease and risk of stroke in women with polycystic ovary syndrome: a systematic review and meta-analysis. Int J Cardiol. 2014;176:486–487 (173), with permission. © Elsevier.]
Figure 2.
Figure 2.
Pathophysiology of PCOS—a vicious circle. Several theories have been proposed to explain the pathogenesis of PCOS. One of these is that neuroendocrine defects lead to increased pulse frequency and amplitude of LH and relatively low FSH. This causes intrinsic defects in ovarian androgen production. Also, there may be an alteration in cortisol metabolism and excessive adrenal androgen production. Insulin resistance with compensatory hyperinsulinemia further increases ovarian androgen production both directly and indirectly via the inhibition of hepatic SHBG production. Obesity, insulin resistance, and high circulating androgens are associated with increased sympathetic nerve activity. E, estradiol.
Figure 3.
Figure 3.
Day/night changes in GnRH pulse frequency in normal (open) and obese hyperandrogenemic (closed) girls through pubertal maturation. The shaded area indicates the range of pulse frequency during sleep and is unchanged throughout puberty. *, P < .05; **, P < .001, obese (a) vs controls. [Adapted from C.R. McCartney et al: Maturation of luteinizing hormone (gonadotropin-releasing hormone) secretion across puberty: evidence for altered regulation in obese peripubertal girls. J Clin Endocrinol Metab. 2009;94:56–66 (224), with permission. © The Endocrine Society.]
Figure 4.
Figure 4.
Excessive production of sex steroids by human thecal PCOS cells from women with PCOS in response to forskolin stimulation (mimicking gonadotropin action). [Adapted from V. L. Nelson et al: Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol. 1999;13(6):946–957 (262), with permission. © The Endocrine Society.]
Figure 5.
Figure 5.
Overexpression of DENND1A isoforms leading to increased androgen production. Forced expression of DENND1A.V2 in normal theca cells results in augmented androgen and progestin production. A, DHEA production after infection of normal theca cells, with 0.3, 1.0, 3.0, and 10 pfu per cell of either empty (Null) or DENND1A.V2 (DENN.V2) adenovirus, treated in the absence (C) or presence (F) of 20 μm forskolin for 72 hours. B, Quantitative Western analysis after the infection of normal theca cells with 3 pfu Null or DENND1A.V2 adenovirus to confirm DENND1A.V2 protein expression. C—F, DHEA (C), 17OHP4 (D), T (E), and progesterone (F) biosynthesis in normal theca cells infected with either 3 pfu per cell of DENND1A.V2 or control (Null) adenovirus and treated in the absence (C) or presence (F) of 20 μm forskolin for 72 hours. DENND1A.V2 infection increased basal 17OHP4 (*, P < .01), T (*, P < .05), and P4 (*, P < .05) accumulation compared with control (Null) adenovirus. DENND1A.V2 infection also increased forskolin-stimulated DHEA (*, P < .001), 17OHP4 (**, P < .001), and P4 (**, P < .001) compared with control (Null) adenovirus. 17OHP4, 17-hydroxyprogesterone; P4, vaginal progesterone. [Adapted from J. M. McAllister et al: Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci USA. 2014;111(15):E1519–E1527 (425), with permission. © National Academy of Sciences, USA.]
Figure 6.
Figure 6.
Genome-wide Manhattan plot for the GWAS meta-analysis. Shown are the −log10P values for the SNPs that passed quality control. The solid horizontal line indicates P < 1 × 10−5. Markers with 50 kb of a SNP associated with PCOS are marked in red for those identified in a previous GWAS and replicated here and in blue for those first identified in the current study. Associations at THADA, LHCGR, and DENND1A were also reported in a previous GWAS. [Adapted from Y. Shi et al: Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012;44(9):1020–1025 (416), with permission. © Nature Publishing Group.]
Figure 7.
Figure 7.
Median FSH levels in women with PCOS, stratified according to the number of allelic variants in the FSH receptor [FSHR (Ser680)] and LH receptor [LHR (Asn312)], ie, carriers of zero to four polymorphic alleles. The total number of variant alleles was significantly associated with increasing FSH levels. [Adapted from O. Valkenburg et al: Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Hum Reprod. 2009;24(8):2014–2022 (432), with permission. © European Society of Human Reproduction and Embryology.]
Figure 8.
Figure 8.
Manhattan plots for LH levels in women with PCOS. Alternating blue and red colors indicate genotyped SNPs, and accompanying black and grey colors indicate imputed variants, on odd and even chromosomes, respectively. The red horizontal red line indicates genomewide significance. QQ plots and lGC/ lGC1000 are inset in the upper right corner of the plot. For LH levels, P values are from sample-size weighted two-strata meta-analysis of strata-specific linear regression P values. (Stage 1: 645 PCOS cases; Stage 2: 399 PCOS cases). (Adapted from Hayes MG, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun. 2015;6:7502.) (431)

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