CYP11A, the gene encoding P450scc, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that ...have examined CYP11A for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of CYP11A promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies.
Context: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent ...and all studies have featured small sample sizes.
Objective: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility.
Design: Case-control, family-based association and quantitative trait analyses.
Setting and Participants: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the −23HphI variant.
Intervention(s): None.
Main Outcome Measure(s): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype.
Results: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis χ2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58).
Conclusions: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.
Summary
Objective There are close phenotypic similarities between cortisone reductase deficiency (CRD), a rare abnormality of cortisone metabolism, and polycystic ovary syndrome (PCOS). As there is ...evidence that CRD results from digenic mutations involving the genes encoding 11β‐hydroxysteroid dehydrogenase type 1 (HSD11B1) and hexose‐6‐phosphate dehydrogenase (H6PD), we sought to establish whether CRD‐associated variants in these genes, individually or in combination, influence susceptibility to PCOS.
Design Case‐control, family‐based association and quantitative‐trait analyses.
Patients A UK case sample comprising 256 nuclear families ascertained from a PCOS offspring and 213 singleton PCOS cases plus 549 control subjects.
Measurements All subjects were genotyped for CRD‐related variants in HSD11B1 (rs12086634) and H6PD (rs6688832). Testosterone was measured with an in‐house radioimmunoassay using ether extraction and dextran‐coated charcoal separation.
Results Case‐control analyses revealed no differences in genotype distribution between PCOS and controls for rs12086634 or rs6688832 (both P = 0·84). Three per cent of cases and 2·4% of controls had genotype combinations (three or more variant alleles at the two sites) considered characteristic of CRD (P = 0·73). There were no departures from expectation in the family‐based association studies, and no significant associations between genotypes (individually or in combination) and BMI, WHR or testosterone.
Conclusions The variants in HSD11B1 and H6PD typed, though implicated in causation of CRD, do not influence susceptibility to PCOS. It seems likely that additional variants within these genes are required for the development of CRD.
Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in ...several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43–19-63) was 0.84 (95% confidence intervals, 0.40–1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.
Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in ...several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43-19-63) was 0.84 (95% confidence intervals, 0.40-1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.
To report the case of a female who presented in childhood with symptoms and signs of hyperandrogenism secondary to an extraovarian steroid cell tumor.
Case report.
Endocrine investigation unit of a ...university teaching hospital.
An 11-year-old female presented with symptoms and signs of hyperandrogenism.
Ultrasonography, MRI imaging, bilateral adrenal and ovarian venous sampling, laparoscopy, and laparotomy.
Ultrasonography, laboratory tests.
Hyperandrogenism was due to an extraovarian steroid cell tumor located in the broad ligament. The tumor was successfully removed at laparotomy with biochemical and clinical resolution of the hyperandrogenism.
Extraovarian steroid cell tumor is a rare cause of hyperandrogenism.
PDF
