Diagnosis, phenotype, and prevalence of polycystic ovary syndrome

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Nonclassic Congenital Adrenal Hyperplasia

Nonclassic congenital adrenal hyperplasia (NCAH) due to P450c21 (21-hydroxylase deficiency) is a common autosomal recessive disorder. This disorder is due to mutations in the CYP21A2 gene which is located at chromosome 6p21. The clinical features predominantly reflect androgen excess rather than adrenal insufficiency leading to an ascertainment bias favoring diagnosis in females. Treatment goals include normal linear growth velocity and “on-time” puberty in affected children. For adolescent and adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and fertility. This paper will review key aspects regarding pathophysiology, diagnosis, and treatment of NCAH

A Brief History of Androgen Excess

SUMMARY Male-like hair growth and masculinization of women and the ambiguity of genders has fascinated mankind for millennia, frequently appearing in mythology and the arts. The earliest reports of androgen excess, beginning 400 years BC, focused on the appearance of male-like hair growth and features in women, often accompanied by menstrual cessation. The first etiologies identified as a cause of androgenization in the female were adrenal disorders, primarily adrenocortical neoplasms, but also eventually adrenal hyperplasia. The first report of a patient with nonclassic adrenal hyperplasia (NCAH) was made in 1957. The Achard-Thiers syndrome, which was originally reported in 1921 and was felt to primarily affect postmenopausal women, included the development of diabetes mellitus, hirsutism, and menstrual irregularity or amenorrhea in conjunction with adrenocortical disease. Androgen production by the ovary was not recognized until the early 1900s, with the first case of a patient with glucose intolerance, hirsutism, and ovarian pathology reported by Tuffier in 1914. As early as the mid-18th century, the presence of sclerocystic or multicystic ovaries was recognized, although this pathology was felt to be primarily associated with pelvic pain and/or menorrhagia. It was not until the seminal report of Drs. Stein and Leventhal of 1935 that the association of polycystic ovaries and amenorrhea, and possibly obesity and/or hirsutism, was noted. Subsequent investigations have elucidated the ovarian source of the androgens the gonadotropic abnormalities, the insulin resistance, and the high prevalence of the disorder, currently known as the polycystic ovary syndrome (PCOS). This syndrome was initially treated by ovarian wedge resection, but subsequent ovulatory therapies, including clomiphene citrate, menopausal gonadotropins, and most recently insulin sensitizers, have replaced this surgery as the treatment of choice for fertility improvement in PCOS. Notwithstanding, laparoscopic ovarian drilling retains a place in our current therapeutic armamentarium for these patients

Epigenetic Mechanism Underlying the Development of Polycystic Ovary Syndrome (PCOS)-Like Phenotypes in Prenatally Androgenized Rhesus Monkeys

The pathogenesis of polycystic ovary syndrome (PCOS) is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA) of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT) harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD), testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD P<0.05). Among these two sets of genes, we identified several significant pathways, including the antiproliferative role of TOB in T cell signaling and transforming growth factor-β (TGF-β) signaling. Our results suggest PA may modify DNA methylation patterns in both infant and adult VAT. This pilot study suggests that excess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans

Socioeconomic status and polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common metabolic-endocrine disorder in women and is associated with a number of metabolic morbidities. We examined the association of PCOS and its components with socioeconomic status (SES) over the life course to explore the role of the environment on the development of PCOS. METHODS: Participants included 1163 women, aged 34-39, from the Coronary Artery Risk Development in Young Adults (CARDIA) Women\u27s Study, examined at year 16 of the CARDIA study (2001). PCOS was defined according to the 1990 National Institutes of Health (NIH) criteria. RESULTS: Logistic regression models, adjusted for age, body mass index (BMI), waist circumference, and oral contraceptive (OC) use, demonstrated a statistically significant association between those women with low parental education/high personal education and PCOS (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4-4.4). CONCLUSIONS: Our results indicate that women who experienced low childhood SES are at increased risk of PCOS, but this risk is limited to those who have personally attained a high level of education. More research is needed to determine the childhood socioeconomic factors that might influence this risk and whether conditions associated with upward life mobility play a role or if this group of at-risk women is simply more likely to recall the symptoms that define PCOS

FTO and MC4R Gene Variants Are Associated with Obesity in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ2 = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism

A Summary of the Endocrine Society Clinical Practice Guidelines on Congenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency

Steroid 21-hydroxylase deficiency accounts for about 95% of cases of congenital adrenal hyperplasia (CAH). Newborns are currently being screened for the classical forms of this disease throughout the United States and in 12 other countries. As such, it seems important to develop the best practice guidelines for treating not only infants and children, but affected adults as well. This report gives a brief overview of the most recent expert opinion and clinical practice guidelines for CAH as formulated by The Endocrine Society Task Force

Harnessing Expression Data to Identify Novel Candidate Genes in Polycystic Ovary Syndrome

Novel pathways in polycystic ovary syndrome (PCOS) are being identified in gene expression studies in PCOS tissues; such pathways may contain key genes in disease etiology. Previous expression studies identified both dickkopf homolog 1 (DKK1) and DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) as differentially expressed in PCOS tissue, implicating them as candidates for PCOS susceptibility. To test this, we genotyped a discovery cohort of 335 PCOS cases and 198 healthy controls for three DKK1 single nucleotide polymorphisms (SNPs) and four DNAJB1 SNPs and a replication cohort of 396 PCOS cases and 306 healthy controls for 1 DKK1 SNP and 1 DNAJB1 SNP. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. We found that no single nucleotide polymorphisms were associated with PCOS risk; however, the major allele of rs1569198 from DKK1 was associated with increased total testosterone (discovery cohort P = 0.0035) and dehydroepiandrosterone sulfate (replication cohort P = 0.05). Minor allele carriers at rs3962158 from DNAJB1 had increased fasting insulin (discovery cohort P = 0.003), increased HOMA-IR (discovery cohort P = 0.006; replication cohort P = 0.036), and increased HOMA-%B (discovery cohort P = 0.004). Carriers of haplotype 2 at DNAJB1 also had increased fasting insulin, HOMA-IR, and HOMA-%B. These findings suggest that genetic variation in DKK1 and DNAJB1 may have a role in the hyperandrogenic and metabolic dysfunction of PCOS, respectively. Our results also demonstrate the utility of gene expression data as a source of novel candidate genes in PCOS, a complex and still incompletely defined disease, for which alternative methods of gene identification are needed