Genetic polymorphisms of the glucocorticoid receptor may affect the phenotype of women with anovulatory polycystic ovary syndrome

Valkenburg, Olivier; Uitterlinden, André G.; Themmen, Axel P. N.; Jong, Frank H. de; Hofman, Albert; Fauser, B. C. J. M.; Laven, Joop S.E.

doi:10.1093/humrep/der222

Cited by 21 publications

(23 citation statements)

References 41 publications

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“…The H6PD SNP rs668832 has been examined extensively but has demonstrated a consistent lack of association with CRD/ACRD, hyperandrogenism, or PCOS (40,(42)(43)(44)58). Only 2 small case-control studies suggest that rs668832 is associated with PCOS (45,59).…”

Section: Genetic Variation In the H6pd Gene And Influence On 11␤-hsd1mentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects

et al. 2013

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11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.

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Section: Genetic Variation In the H6pd Gene And Influence On 11␤-hsd1mentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects

et al. 2013

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“…Despite PCOS prevalence and health implications, there is no gold standard for long-term treatment of women with PCOS and the etiology of PCOS remain unclear. Interestingly, it has also been demonstrated that PCOS is a multifactorial disease with polygenic nature, and this heterogeneity complicates the effort to investigate additional genetic components of its pathogenesis (3). The DENN domain containing 1a (DENND1A) gene, a member of a family of 18 human genes termed “connecdenns”, has gained recognition as a strong PCOS susceptibility gene in several studies (4,5).…”

Section: Introductionmentioning

confidence: 99%

Association of DENND1A Gene Polymorphisms with Polycystic Ovary Syndrome: A Meta-Analysis

Bao¹,

Cai²,

Yang³

et al. 2016

Jcrpe

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Objective: The rs2479106 and rs10818854 polymorphisms in the DENND1A gene have been reported to be extensively associated with risk of polycystic ovary syndrome (PCOS). However, the results from these studies remained inconclusive and conflicting. To detect a true association of rs2479106 and rs10818854 polymorphisms with PCOS risk, a single study may be underpowered, particularly for those studies with inadequate sample size. Therefore, we performed a meta-analysis of all available studies to explore this association.Methods: All studies published up to March 2015 on the association were identified by searching electronic databases PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure. Studies containing available genotype frequencies of those 2 polymorphisms were chosen, and the odds ratios and associated 95% confidence intervals were calculated using fixed- or random- effects models.Results: A total of 8 studies about s2479106 polymorphism (8185 cases and 28675 controls) and 5 studies about rs10818854 polymorphism (6638 cases and 27443 controls) met the inclusion criteria for the meta-analysis. Overall, significant increase of PCOS risk was found between DENND1A-rs10818854 and PCOS susceptibility. In addition, we also found an increased risk of PCOS in rs2479106 allele model, heterozygote variant genetic model, and dominant genetic model.Conclusion: This meta-analysis suggested that rs2479106 and rs10818854 polymorphisms in the DENND1A gene were associated with increased risk of PCOS. To validate the association between these polymorphisms and PCOS susceptibility, further large and well-designed studies are needed.

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“…Not surprisingly, other studies (Ewens et al, 2010;Qin and Rosenfield, 2011;Valkenburg et al, 2011) have not replicated our published association between R453Q and PCOS , since the emerging picture of PCOS is that of a complex multigenic trait in which modifying environmental factors play an important role in the expression of the hyperandrogenic phenotype. Differences in these environmental factors, especially those pertaining to diet and life-style, could contribute to explain the discrepancies among our previous and present results and those of other studies conducted in women from the United States and Northern Europe (Ewens et al, 2010;Qin and Rosenfield, 2011;Valkenburg et al, 2011). Additionally, the pathogenesis of PCOS probably differs among the different phenotypes of the syndrome, as has been proposed by others (Gambineri et al, 2006).…”

Section: Discussionmentioning

confidence: 67%