Basis Of Polycystic Ovary Syndrome Research Articles

Androgen signaling pathways driving reproductive and metabolic phenotypes in a PCOS mouse model.

As the mechanistic basis of polycystic ovary syndrome (PCOS) remains unknown, current management relies on symptomatic treatment. Hyperandrogenism is a major PCOS characteristic and evidence supports it playing a key role in PCOS pathogenesis. Classically, androgens can act directly through the androgen receptor (AR) or, indirectly, following aromatization, via the estrogen receptor (ER). We investigated the mechanism of androgenic actions driving PCOS by comparing the capacity of non-aromatizable dihydrotestosterone (DHT) and aromatizable testosterone to induce PCOS traits in WT and Ar-knockout (ARKO) mice. DHT and testosterone induced the reproductive PCOS-like features of acyclicity and anovulation in WT females. In ARKO mice, DHT did not cause reproductive dysfunction; however, testosterone treatment induced irregular cycles and ovulatory disruption. These findings indicate that direct AR actions and indirect, likely ER, actions of androgens are important mediators of PCOS reproductive traits. DHT, but not testosterone, induced an increase in body weight, body fat, serum cholesterol and adipocyte hypertrophy in WT mice, but neither androgen induced these metabolic features in ARKO mice. These data infer that direct AR-driven mechanisms are key in driving the development of PCOS metabolic traits. Overall, these findings demonstrate that differing PCOS traits can be mediated via different steroid signaling pathways and indicate that a phenotype-based treatment approach would ensure effective targeting of the underlying mechanisms.

Genetic basis of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with obesity and manifests with reproductive, hyperandrogenic and metabolic features. Although the etiology of PCOS is complex and incompletely understood, genetics plays an important role (heritability: ∼70%). Potential problems with studying the genetics of PCOS include the heterogeneity of the condition and associated sub-fertility. A candidate gene approach has been used in over 70 published studies on PCOS, most of which have been inadequately powered to detect a statistically meaningful association. Furthermore, these studies often fail to replicate prior published studies on the same candidate gene in different populations. The first genome-sequence variant (identified from a genome-wide association study in subjects with Type 2 diabetes mellitus) to be studied in PCOS (FTO gene) has been shown by our group to associate with susceptibility for the development of PCOS. This is the first genetic corroboration of a link between PCOS and obesity. Future directions include a genome-wide association study in PCOS.

Is There a Genetic Basis for Polycystic Ovary Syndrome?

Clinical evidence indicates that polycystic ovary syndrome (PCOS) has a heritable basis (1, 2), at least in part, which could result from a genetic etiology, epigenetic changes, or an admixture of the two causes. The apparent heritable nature of the syndrome has led investigators to search for the gene (or genes) that contribute to development of the PCOS phenotype. One impetus for genetic studies of PCOS was to unravel the etiology of the syndrome and provide greater precision to the diagnosis. Unfortunately, the phenotypic variability of the syndrome represents a major hindrance to that goal because the PCOS phenotype is based on criteria marked by a constellation of features, currently defined by the Rotterdam criteria (3). Thus, the PCOS phenotype is not a clearly delineated disease entity, and there is imprecision of diagnosis. Patients diagnosed with PCOS may satisfy the diagnostic criteria by having different features of the disease. Stated differently, PCOS can be conceptualized as a pathophysiological state of acyclic ovarian function rather than a single distinct disorder. This imprecision in diagnosis raises the strong possibility that PCOS with different root causes will be lumped into the same “diseased category” for comparison with normal controls. Genetic studies of PCOS are also confounded by variability between different investigators, especially if the study design or diagnostic criteria used across studies are not the same. The group of Ewens et al. (4) has used standard diagnostic criteria throughout their studies (oligomenorrhea and increased testosterone levels) to distinguish cases from controls. A potential problem is that any variability in diagnostic criteria between investigators may impact the ability of putative candidate genes identified in one population to be replicated in other populations if the initial population studied was phenotypically dissimilar, as a result of different diagnostic criteria. Investigators conducting genetic studies of PCOS have used several different approaches in different populations. Some have used a candidate gene approach. Other investigators have used linkage studies, either of case-control or family-based sib pairs. Association studies have also been conducted. Another approach is the transmission disequilibrium test—briefly, a family-based test of association designed to minimize error due to population stratification (5). Despite a decade of collaborative efforts, including analysis of 37 candidate genes (6), efforts to identify loci associated with PCOS have been plagued by a lack of replication between association and linkage studies (reviewed in Ref. 7). It seems clear that neither follistatin (8) nor lamin a/c (9) is a critical PCOS gene. So what genes are associated with PCOS? Surprisingly, in 2010 the best evidence of an association of a single gene (locus) with PCOS is the dinucleotide repeat microsatellite marker D19S884 (4, 6, 10–13). The D19S884 marker lies within intron 55 of the fibrillin-3 gene (FBN3, NM_032447). Allele 8 of the D19S884 marker contains 17 “GT” repeats and has been associated with PCOS. In contrast, allele 9 containing 18 GT repeats and allele 13 with 22 GT repeats show no association with PCOS. Fibrillin is a large extracellular matrix protein that forms microfibrils and contains epidermal growth factorlike modules, some of which have a calcium binding consensus sequence (calcium binding-epidermal growth factor-like modules). Related fibrillin family members regulate TGF action, but the reason as to why fibrillin-3 hasbeenassociatedwithPCOSremainsunclear, especially

The Polycystic Ovary Unraveled

In 1964, I suggested that the pathophysiologic basis for polycystic ovary syndrome was a decreased conversion of androgen to estrogen ( 1. Gabrilove J.L. Diseases associated with some enzymic defects in the gonads and adrenal cortex; a classification based on a theory of the biogenesis of the feminizing and virilizing syndromes. J Mt Sinai Hosp N Y. 1964; 31: 449-456 PubMed Google Scholar ). This view was based in large measure on the report of Short and London of an increased ratio of androstenedione to estradiol in the follicular fluid obtained from polycystic ovaries ( 2. Short R.V. London D.R. Defective biosynthesis of ovarian steroids in the Stein-Leventhal syndrome. Br Med J. 1961; 1: 1724-1727 Crossref PubMed Scopus (55) Google Scholar , 3. Gabrilove J.L. The pathogenesis of the polycystic ovary syndrome: a hypothesis. Endocr Pract. 2002; 8: 127-132 Abstract Full Text Full Text PDF PubMed Google Scholar ).

The genetic basis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The disorder is characterized by clinical features of hyperandrogenism, menstrual irregularities and often central obesity and hyperinsulinaemia. PCOS may increase the risk for infertility, type 2 diabetes mellitus, dyslipidaemia, cardiovascular disease and endometrial cancer, emphasizing the need for early diagnosis of the syndrome. The genetic basis of PCOS is unknown. There is a strong familial component but the mode of inheritance is uncertain and several candidate genes have been proposed to contribute to susceptibility. Not only genes involved in steroid hormone biosynthesis have been studied but also genes associated with the regulation of insulin secretion and action since hyperinsulinaemia is a characteristic of PCOS. So far there is evidence that INS VNTR (insulin variable number of tandem repeats) or CYP11alpha (cholesterol side chain cleavage) genes are associated with this syndrome. PCOS appears, however, to be an oligogenic disorder and more studies are necessary to define the genetic basis.

Polycystic ovary syndrome: a single gene mutation or an evolving set of symptoms.

Polycystic ovary syndrome is one of the most common endocrinopathies among women. Nevertheless, there is no one single acceptable definition for this syndrome, its pathophysiology is not completely understood and its etiology remains an enigma. Several studies have examined the genetic basis of polycystic ovary syndrome with varying results, probably caused by the different criteria used to define the syndrome. These studies, together with studies that deal with reclassification of polycystic ovary syndrome, are described in the following review. Furthermore, a simplified alternative approach to this symptom complex is proposed.

The genetic basis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Familial clustering of cases suggests that genetic factors play an important part in its aetiology. A number of studies of families with several cases of PCOS have produced results suggesting an autosomal dominant trait. Detailed analysis of a large number of affected families has, however, cast some doubt about the mode of inheritance. An autosomal dominant trait remains possible but a more complex aetiology seems more likely. The results of our recent studies support the concept of an oligogenic disorder in which genes affecting metabolic pathways in glucose homeostasis and steroid biosynthesis are both involved. We review evidence for an important role for the insulin gene minisatellite in the aetiology of anovulatory PCOS and for the gene coding for P450 cholesterol side chain cleavage (CYP11a) in the mechanism of excessive androgen secretion in women with polycystic ovaries. We propose that the heterogeneity of clinical and biochemical features in PCOS can be explained by the interaction of a small number of key genes with environmental, particularly nutritional, factors.

Genetic basis of human reproductive endocrine disorders.

Disturbed human reproductive function may be caused by environmental and/or genetic factors. Much information related to single gene defects underlying reproductive failure has become available in recent years due to advances in molecular biology. In this review, techniques currently applied for deoxyribonucleic acid (DNA) analysis are addressed. We also highlight underlying molecular mechanisms and the corresponding clinical presentation of single gene defects affecting (i) the hypothalamic-pituitary-gonadal axis, resulting in disturbed gonadotrophin-releasing hormone (GnRH) neuron migration, or leading to defective gonadotrophins, gonadotrophin receptors and the Gs alpha protein; (ii) gonadal and adrenal steroid biosynthesis and (iii) steroid and insulin receptors. The potential genetic basis of polycystic ovary syndrome is also discussed. Although disease states caused by well-defined genetic abnormalities appear to represent only a small proportion of those found in the patient population, it should be considered that these affected individuals represent only the most severe cases in a wide spectrum of genetic abnormalities underlying disturbed fertility. Comprehension of these extreme cases will provide the basis for the elucidation of more common reproductive disorders as the result of subtle genetic changes or increased susceptibility to environmental factors.

Pituitary-Ovarian Responses to Nafarelin Testing in the Polycystic Ovary Syndrome

To investigate the basis of polycystic ovary syndrome, we examined the responses of patients to nafarelin, a specific gonadotropin-releasing-hormone agonist, given to stimulate pituitary and gonadal secretion. We compared 16 normal women in the follicular phase, 5 normal men, 8 women with polycystic ovary syndrome, and 1 woman with polycystic ovary syndrome caused by a 3 beta-hydroxysteroid dehydrogenase deficiency. After 100 micrograms of nafarelin was given subcutaneously, serum follicle-stimulating hormone and luteinizing hormone increased rapidly to peak levels within four hours. The women with polycystic ovary syndrome had a pattern similar to that of the men, with greater early luteinizing-hormone responses (30 minutes to 1 hour) and lower peak follicle-stimulating-hormone responses than normal women (P less than 0.05). Patients with polycystic ovary syndrome responded to gonadotropin stimulation with normal to increased production of plasma estrogens and increased levels of androstenedione at 16 to 24 hours (P less than 0.05). Elevated production of 17 alpha-hydroxyprogesterone was found in all the women with polycystic ovary syndrome and in the men. These abnormal responses were unchanged by pretreatment with dexamethasone to suppress adrenal function. In the patient with the 3 beta-hydroxysteroid dehydrogenase deficiency, both basal and stimulated plasma levels of delta 5-3 beta-hydroxysteroids before the enzymatic block were elevated, whereas plasma levels of 17 alpha-hydroxyprogesterone and androstenedione--the steroids immediately beyond the block--were low. We conclude that women with polycystic ovary syndrome have masculinized pituitary and ovarian responses to stimulation by nafarelin. Our findings suggest that the regulation of the ovarian 17-hydroxylase and C-17,20-lyase activities is abnormal in such women.

Pituitary-Ovarian Responses to Nafarelin Testing in the Polycystic Ovary Syndrome

To investigate the basis of polycystic ovary syndrome, we examined the responses of patients to nafarelin, a specific gonadotropin-releasing-hormone agonist, given to stimulate pituitary and gonadal secretion. We compared 16 normal women in the follicular phase, 5 normal men, 8 women with polycystic ovary syndrome, and 1 woman with polycystic ovary syndrome caused by a 3 beta-hydroxysteroid dehydrogenase deficiency. After 100 micrograms of nafarelin was given subcutaneously, serum follicle-stimulating hormone and luteinizing hormone increased rapidly to peak levels within four hours. The women with polycystic ovary syndrome had a pattern similar to that of the men, with greater early luteinizing-hormone responses (30 minutes to 1 hour) and lower peak follicle-stimulating-hormone responses than normal women (P less than 0.05). Patients with polycystic ovary syndrome responded to gonadotropin stimulation with normal to increased production of plasma estrogens and increased levels of androstenedione at 16 to 24 hours (P less than 0.05). Elevated production of 17 alpha-hydroxyprogesterone was found in all the women with polycystic ovary syndrome and in the men. These abnormal responses were unchanged by pretreatment with dexamethasone to suppress adrenal function. In the patient with the 3 beta-hydroxysteroid dehydrogenase deficiency, both basal and stimulated plasma levels of delta 5-3 beta-hydroxysteroids before the enzymatic block were elevated, whereas plasma levels of 17 alpha-hydroxyprogesterone and androstenedione--the steroids immediately beyond the block--were low. We conclude that women with polycystic ovary syndrome have masculinized pituitary and ovarian responses to stimulation by nafarelin. Our findings suggest that the regulation of the ovarian 17-hydroxylase and C-17,20-lyase activities is abnormal in such women.