The aim of the present study was to investigate the role of CAG repeat polymorphism and X-chromosome Inactivation (XCI) pattern in Recurrent Spontaneous Abortions among Indian women which has not been hitherto explored. 117 RSA cases and 224 Controls were included in the study. Cases were recruited from two different hospitals - Lakshmi Fertility Clinic, Nellore and Fernandez Maternity Hospital, Hyderabad. Controls were roughly matched for age, ethnicity and socioeconomic status. The CAG repeats of the Androgen Receptor gene were genotyped using a PCR-based assay and were analysed using the GeneMapper software to determine the CAG repeat length. XCI analysis was also carried out to assess the inactivation percentages. RSA cases had a significantly greater frequency of allele sizes in the polymorphic range above 19 repeats (p = 0.006), which is the median value of the controls, and in the biallelic mean range above 21 repeats (p = 0.002). We found no evidence of abnormal incidence of skewed X-inactivation. We conclude that longer CAG repeat lengths are associated with increased odds for RSA with statistical power estimated to be ∼90%.
Polycystic ovary syndrome (PCOS), one of the most common and complex endocrine disorders affecting up to 15 % of reproductive age women, is considered a predominantly hyperandrogenic syndrome according to the Androgen Excess Society. It is generally accepted that androgens determine the characteristic features of PCOS; in this context, a hyperactive androgen receptor (AR) at the levels of the GnRH pulse generator in the hypothalamus and at the granulosa cells in the ovary, skeletal muscle or adipocytes senses initially normal testosterone and dihydrotestosterone as biochemical hyperandrogenism and might be a crucial connection between the vicious circles of the PCOS pathogenesis.
Polymorphism of the AR gene has been associated with different androgen pattern diseases. Several studies have demonstrated an association between AR with increased activity encoded by shorter CAG repeat polymorphism in the exon 1 of the AR gene and PCOS, although there are conflicting results in this field. The phenomenon is more complex because the AR activity is determined by the epigenetic effect of X chromosome inactivation (XCI). Moreover, we must evaluate the AR as a dynamic heterocomplex, with a large number of coactivators and corepressors that are essential to its function, thus mediating tissue-specific effects. In theory, any of these factors could modify the activity of AR, which likely explains the inconsistent results obtained when this activity was quantified by only the CAG polymorphism in PCOS.
CAG repeat polymorphism; AR; PCOS
Polycystic Ovary Syndrome (PCOS) is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63) with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p = 0.007) with highly significant odds ratio when compared to TC (OR = 2.51, p = 0.003, 95% CI = 1.37–4.61) as well as TT (OR = 1.94, p = 0.016, 95% CI = 1.13–3.34). While the haplotype carrying the SNP-44 and SNP-19 variants (21121) exhibited a 2 fold increase in the risk for PCOS (OR = 2.37, p = 0.03), the haplotype containing SNP-56 and SNP-19 variants (11221) seems to have a protective role against PCOS (OR = 0.20, p = 0.004). Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS.
The majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.
We examined XCI profiles of females affected with RA (n = 106), AITDs (n = 145) and age-matched healthy women (n = 257). XCI analysis was performed by enzymatic digestion of DNA with a methylation sensitive enzyme (HpaII) followed by PCR of a polymorphic CAG repeat in the androgen receptor (AR) gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X-chromosome.
Skewed XCI was observed in 26 of the 76 informative RA patients (34.2%), 26 of the 100 informative AITDs patients (26%), and 19 of the 170 informative controls (11.2%) (P < 0.0001; P = 0.0015, respectively). More importantly, extremely skewed XCI, defined as > 90% inactivation of one allele, was present in 17 RA patients (22.4%), 14 AITDs patients (14.0%), and in only seven controls (4.1%, P < 0.0001; P = 0.0034, respectively). Stratifying RA patients according to laboratory profiles (rheumatoid factor and anti-citrullinated protein antibodies), clinical manifestations (erosive disease and nodules) and the presence of others autoimmune diseases did not reveal any statistical significance (P > 0.05).
These results suggest a possible role for XCI mosaicism in the pathogenesis of RA and AITDs and may in part explain the female preponderance of these diseases.
Polycystic ovarian syndrome (PCOS) refers to an inheritable androgen excess disorder characterized by multiple small follicles located at the ovarian periphery. Hyperandrogenism in PCOS, and inverse correlation between androgen receptor (AR) CAG numbers and AR function, led us to hypothesize that CAG length variations may affect PCOS risk.
CAG repeat region of 169 patients recruited following strictly defined Rotterdam (2003) inclusion criteria and that of 175 ethnically similar control samples, were analyzed. We also conducted a meta-analysis on the data taken from published studies, to generate a pooled estimate on 2194 cases and 2242 controls.
CAG bi-allelic mean length was between 8.5 and 24.5 (mean = 17.43, SD = 2.43) repeats in the controls and between 11 and 24 (mean = 17.39, SD = 2.29) repeats in the cases, without any significant difference between the two groups. Further, comparison of bi-allelic mean and its frequency distribution in three categories (short, moderate and long alleles) did not show any significant difference between controls and various case subgroups. Frequency distribution of bi-allelic mean in two categories (extreme and moderate alleles) showed over-representation of extreme sized alleles in the cases with marginally significant value (50.3% vs. 61.5%, χ2 = 4.41; P = 0.036), which turned insignificant upon applying Bonferroni correction for multiple comparisons. X-chromosome inactivation analysis showed no significant difference in the inactivation pattern of CAG alleles or in the comparison of weighed bi-allelic mean between cases and controls. Meta-analysis also showed no significant correlation between CAG length and PCOS risk, except a minor over-representation of short CAG alleles in the cases.
CAG bi-allelic mean length did not differ between controls and cases/case sub-groups nor did the allele distribution. Over-representation of short/extreme-sized alleles in the cases may be a chance finding without any true association with PCOS risk.
Polycystic ovary syndrome (PCOS) is a heterogenic, complex common genetic disease. Multiple pathways are involved in its pathogenesis, including the androgen signaling pathway and insulin signaling pathway. Small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA) is a putative member of the androgen receptor-chaperone-cochaperone complex, and may play a role in androgen signaling as a co-chaperone. Polymorphisms in the SGTA gene have not been evaluated for a role in PCOS.
Women with and without PCOS (287 cases, 187 controls) were genotyped for three single nucleotide polymorphisms (SNPs) in SGTA. SNPs and haplotypes were determined and tested for association with PCOS and component traits of PCOS.
For SNP rs1640262, homozygotes for the minor allele were protected against PCOS (P=0.009). Haplotype 1 (G-A-T) was associated with increased risk of PCOS (P=0.015). In women with PCOS, haplotype 2 (A-G-C) was associated with increased insulin resistance (P=0.013), consequently resulting in increased insulin secretion (P=0.014).
This study presents genetic evidence suggesting a potential role of SGTA in the pathogenesis of PCOS. SGTA may provide a connection between multiple pathways in PCOS.
Polycystic ovary syndrome; small glutamine-rich tetratricopeptide repeat-containing; alpha; single nucleotide polymorphism; haplotype; association
An increased frequency of skewed X-chromosome inactivation (XCI) is found in clinically overt autoimmune thyroid disease (AITD) compared with controls. Whether skewed XCI is involved in the pathogenesis of autoantibodies to thyroid peroxidase (TPOAb) in euthyroid subjects is unknown. To examine the impact of XCI on the serum concentration of TPOAb, we studied whether within-cohort and within-twin-pair differences in XCI are associated with differences in serum concentrations of TPOAb. A total of 318 euthyroid female twin individuals distributed in 159 pairs were investigated. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. TPOAb concentrations were measured using a solid-phase time-resolved fluoroimmunometric assay. Overall (within cohort), there was a significant association between XCI and serum concentrations of TPOAb; regression coefficient (β)=1.45 (95% confidence interval, 0.52–2.38), P=0.003. The association remained significant in the within-pair analysis; β=1.74 (0.79–2.69), P<0.001. The relationship was nonsignificant within the 82 monozygotic pairs (β=0.57 (−0.78–1.92), P=0.405), whereas the association was significant in the 77 dizygotic pairs (β=2.17 (0.81–3.53), P=0.002). This preliminary finding of a significant association between TPOAb concentrations and XCI within cohort and within dizygotic but not within monozygotic twin pairs may indicate that XCI per se does not have a major role in the pathogenesis of TPOAb. More likely, XCI and TPOAb are influenced by shared genetic determinants.
X-chromosome inactivation; thyroid peroxidase antibodies; thyroid autoantibodies; thyroid autoimmunity; twins; epigenetics
Objective: Androgen receptor (AR) was detected in leiomyoma. AR gene has a polymorphic microsatellite encoding cytosine, adenine, and guanine (CAG) repeats. We aimed to investigate the association between the AR gene CAG repeats and leiomyoma.
Methods: Women were divided into two groups: (1) leiomyoma (n=159); (2) non- leiomyoma groups (n=129). Their CAG repeats were detected by polymerase chain reaction. The CAG repeats ranged in length from 168 bp (9 CAG repeats, genotype A) to 234 bp (31 CAG repeats, genotype W). Distributions of CAG repeats in both groups were compared.
Results: Genotype proportions of different CAG repeats for AR gene in both groups were significantly different. The genotype S (27 CAG repeats) is associated with higher susceptibility of leiomyoma. Distribution of CAG repeats in both groups appeared mono-peak distributions. Percentages of genotypes K-S (19–27 CAG repeats) in leiomyoma and non-leiomyoma groups were: (1) 5, 11, 19.5, 10.4, 12.9, 8.8, 7.5, 5.7, 4.4%; (2) 5.4, 14.3, 16.7, 12.8, 12.4, 5.8, 9.3, 7, 1.2%.
Conclusions: AR trinucleotide polymorphism is associated with leiomyoma susceptibility. The 27 CAG repeats is related with higher risk of leiomyoma.
Androgen receptor; leiomyoma; multiallele polymorphism; trinucleotide repeat polymorphism
The length of the polymorphic CAG repeat in the N-terminal of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Some studies have indicated that short CAG repeats are related to higher risk of prostate cancer. We performed a case–control study to investigate relations between CAG repeat length and prostate cancer risk, tumour grade, tumour stage, age at diagnosis and response to endocrine therapy. The study included 190 AR alleles from prostate cancer patients and 186 AR alleles from female control subjects. All were whites from southern Sweden. The frequency distribution of CAG repeat length was strikingly similar for cases and controls, and no significant correlation between CAG repeat length and prostate cancer risk was detected. However, for men with non-hereditary prostate cancer (n = 160), shorter CAG repeats correlated with younger age at diagnosis (P = 0.03). There were also trends toward associations between short CAG repeats and high grade (P = 0.07) and high stage (P = 0.07) disease. Furthermore, we found that patients with long CAG repeats responded better to endocrine therapy, even after adjusting for pretreatment level of prostate-specific antigen and tumour grade and stage (P = 0.05). We conclude that short CAG repeats in the AR gene correlate with young age at diagnosis of prostate cancer, but not with higher risk of the disease. Selection of patients with early onset prostate cancer in case–control studies could therefore lead to an over-estimation of the risk of prostate cancer for men with short CAG repeats. An association between long CAG repeats and good response to endocrine therapy was also found, but the mechanism and clinical relevance are unclear. © 1999 Cancer Research Campaign
prostatic neoplasms; cancer risk; androgen receptor; genetics; epidemiology
A number of studies focusing on the association between the exon 1 CAG repeat polymorphism of the androgen receptor (AR) gene and polycystic ovary syndrome (PCOS) have revealed conflicting results. The current systematic review and meta-analysis was conducted to quantify the strength of the association and to explore potential sources of heterogeneity that may have influenced the results. Studies matched to search terms from PubMed, EMBASE and HuGE Navigator published through to 31 January 2012 were retrieved. Data extraction from the included studies was carried out by two authors independently. Weighted mean differences (WMDs) of biallelic mean and odds ratios (ORs) of alleles and genotypes were pooled for meta-analysis. Sixteen articles reporting on 17 studies were included. In continuous data analysis, the summary WMD was −0.06 (95% confidence interval −0.29 to 0.16). In dichotomous data analysis, we divided the alleles into short and long alleles and calculated the summary ORs. No statistically significant results were identified by different comparison models or different cut-off point definitions. No publication bias was observed in continuous and dichotomous data analysis. In summary, the current systematic review and meta-analysis found that the AR CAG microsatellite repeat polymorphism is unlikely to be a major determining factor in the development of PCOS.
androgen receptor; CAG repeat; genetic polymorphism; meta-analysis; polycystic ovary syndrome
We investigated the cellular mechanisms of the unique disorder of insulin action found in the polycystic ovary syndrome (PCOS). Approximately 50% of PCOS women (PCOS-Ser) had a significant increase in insulin-independent beta-subunit [32P]phosphate incorporation (3.7-fold, P < 0.05 vs other groups) in skin fibroblast insulin receptors that was present in serine residues while insulin-induced tyrosine phosphorylation was decreased (both P < 0.05 vs other groups). PCOS skeletal muscle insulin receptors had the same abnormal phosphorylation pattern. The remaining PCOS women (PCOS-n1) had basal and insulin-stimulated receptor autophosphorylation similar to control. Phosphorylation of the artificial substrate poly GLU4:TYR1 by the PCOS-Ser insulin receptors was significantly decreased (P < 0.05) compared to control and PCOS-n1 receptors. The factor responsible for excessive serine phosphorylation appeared to be extrinsic to the receptor since no insulin receptor gene mutations were identified, immunoprecipitation before autophosphorylation corrected the phosphorylation defect and control insulin receptors mixed with lectin eluates from affected PCOS fibroblasts displayed increased serine phosphorylation. Our findings suggest that increased insulin receptor serine phosphorylation decreases its protein tyrosine kinase activity and is one mechanism for the post-binding defect in insulin action characteristic of PCOS.
Polycystic ovary syndrome (PCOS), the most common endocrine disease among premenopausal women, is caused by both genes and environment. We and others previously reported association between single nucleotide polymorphisms (SNPs) in the DENND1A gene and PCOS. We therefore sequenced the DENND1A gene in white patients with PCOS to identify possible alterations that may be implicated in the PCOS pathogenesis. Patients were referred with PCOS and/or hirsutism between 1998 and 2011 (n = 261). PCOS was diagnosed according to the Rotterdam criteria (n = 165). Sequence analysis was performed in 10 patients with PCOS. Additional patients (n = 251) and healthy female controls (n = 248) were included for SNP genotyping. Patients underwent clinical examination including Ferriman-Gallwey score (FG-score), biochemical analyses and transvaginal ultrasound. Mutation analysis was carried out by bidirectional sequencing. SNP genotyping was tested by allelic discrimination in real-time PCR in the additional patients and controls. Sequencing of the DENND1A gene identified eight SNPs; seven were not known to be associated with any diseases. One missense SNP was detected (rs189947178, A/C), potentially altering the structural conformation of the DENND1A protein. SNP genotyping of rs189947178 showed significantly more carriers among patients with PCOS and moderate hirsutism compared to controls. However, due to small sample size and lack of multiple regression analysis supporting an association between rs189947178 and FG-score or PCOS diagnosis, this could be a false positive finding. In conclusion, sequence analysis of the DENND1A gene of patients with PCOS did not identify alterations that alone could be responsible for the PCOS pathogenesis, but a missense SNP (rs189947178) was identified in one patient and significantly more carriers of rs189947178 were found among patients with PCOS and moderate hirsutism vs. controls. Additional studies with independent cohort are needed to confirm this due to the small sample size of this study.
Given the high rate of pregnancy and perinatal complications recently observed in patients with polycystic ovary syndrome (PCOS) and the lack of data on the serum variations in androgens and insulin sensitivity indexes in pregnant women with PCOS, the current study was aimed to assess these changes and their potential effect on pregnancy outcomes in a population of women with PCOS.
Forty-five pregnant patients with ovulatory PCOS (PCOS group) and other 42 healthy pregnant women (control group) were studied assaying serum androgen levels and insulin sensitivity indexes throughout pregnancy serially, and recording obstetrical outcomes.
Serum androgen levels and insulin resistance indexes were significantly (p < 0.05) higher in PCOS than in control group at study entry, these differences were sustained throughout pregnancy, and their changes resulted significantly (p < 0.05) different between PCOS and control group. In PCOS patients, women who had a complicated pregnancy showed serum androgen levels and insulin sensitivity indexes significantly (p < 0.05) worse in comparison to subjects without any pregnancy and/or neonatal complications.
PCOS patients have impaired changes in serum androgen levels and insulin sensitivity indexes during pregnancy. These alterations could be implicated in the pregnancy and neonatal complications frequently observed in women affected by PCOS.
To investigate associations between the androgen receptor (AR) polymorphisms as CAG repeats, GGC repeats and c.211G>A polymorphism and the risk of preeclampsia.
The AR polymorphisms were experienced in 184 preeclamptic patients and 190 normal pregnancies and analyzed by multiple logistic regression.
Women with GGC repeats>16 were more frequently observed in preeclampsia, compared to those with GGC repeats≤16 [adjOR (95% CI): 3.64 (1.71–6.23)]. However, no significant differences were observed between the two groups with respect to CAG repeats. The genotypic and allelic frequencies of c.211G>A variant were significantly higher in cases than in controls (P < 0.05 for both). In the combined distribution of these polymorphisms, the highest risk of preeclampsia was found among women with the haplotype as CAG > 20/GA/GGC>16 [adjOR (95% CI): 4.26 (1.92–12.23)].
Our findings suggest that longer GGC repeats and c.211G>A variant in the AR gene are associated with increased susceptibility to the risk of preeclampsia.
Androgen receptor; CAG repeats; GGC repeats; c.211G>A polymorphism; Preeclampsia
Anogenital distance (AGD) is used to define degree of virilization of genital development, with shorter length being associated with feminization and male infertility. The first exon of the androgen receptor (AR) consists of a polymorphic sequence of cytosine–adenine–guanine (CAG) repeats, with longer CAG repeat lengths being associated with decreased receptor function. We sought to determine if there is an association between AGD and AR CAG repeat length. A cross-sectional, prospective cohort of men evaluated at a urology clinic at a single institution was recruited. AGD (the distance from the posterior scrotum to the anal verge) and penile length (PL) were measured. Sanger DNA sequence analysis was used to define CAG repeat length. AGD and CAG repeat lengths in 195 men were determined. On unadjusted analysis, there was no linear relationship between CAG repeat length and PL (P=0.17) or AGD (P=0.31). However, on sub-population analyses, those men with longer CAG repeat lengths (>26) had significantly shorter AGDs compared to men with shorter CAG repeat lengths. For example, the mean AGD was 41.9 vs. 32.4 mm with a CAG repeat length ≤26 vs. >26 (P=0.01). In addition, when stratifying the cohort based on AGD, those with AGD less than the median (i.e. 40 mm) had a longer CAG repeat length compared to men with an AGD >40 mm (P=0.02). In summary, no linear relationship was found between AGD and AR CAG repeat length overall.
androgen receptor (AR); anogenital distance (AGD); genitalia; penile length (PL); perineum
Adrenal androgen excess is frequently observed in PCOS. The aim of the study was to determine whether adrenal gland function varies among PCOS phenotypes, women with hyperandrogenism (H) only and healthy women.
The study included 119 non-obese patients with PCOS (age: 22.2 ± 4.1y, BMI:22.5 ± 3.1 kg/m2), 24 women with H only and 39 age and BMI- matched controls. Among women with PCOS, 50 had H, oligo-anovulation (O), and polycystic ovaries (P) (PHO), 32 had O and H (OH), 23 had P and H (PH), and 14 had P and O (PO). Total testosterone (T), SHBG and DHEAS levels at basal and serum 17-hydroxprogesterone (17-OHP), androstenedione (A4), DHEA and cortisol levels after ACTH stimulation were measured.
T, FAI and DHEAS, and basal and AUC values for 17-OHP and A4 were significantly and similarly higher in PCOS and H groups than controls (p < 0.05 for all) whereas three groups did not differ for basal or AUC values of DHEA and cortisol. Three hyperandrogenic subphenotypes (PHO, OH, and PH) compared to non-hyperandrogenic subphenotype (PO) had significantly and similarly higher T, FAI, DHEAS and AUC values for 17-OHP, A4 and DHEA (p < 0.05). All subphenotypes had similar basal and AUC values for cortisol.
PCOS patients and women with H only have similar and higher basal and stimulated adrenal androgen levels than controls. All three hyperandrogenic subphenotypes of PCOS exhibit similar and higher basal and stimulated adrenal androgen secretion patterns compared to non-hyperandrogenic subphenotype.
Adrenal androgen; PCOS; ACTH; DHEAS
To study the risk for obstructive sleep apnea (OSA) in a group of non-obese and obese PCOS and control women. Women with polycystic ovary syndrome (PCOS) are at high risk for obstructive sleep apnea (OSA). Whether this risk is independent of obesity is not clear.
Design/Patients/Interventions/Main Outcome Measures
In a prospective study, 44 women with PCOS and 34 control women completed the Berlin questionnaire for assessment of OSA risk. All women underwent fasting determination of androgens, glucose and insulin.
Women with PCOS were more obese compared to control women (p=0.02). However, there were no differences in BMI once subjects were divided into non-obese (PCOS n=17 and control n=26) and obese (PCOS n=26 and control n=8) groups. Women with PCOS had higher prevalence of high risk OSA compared to control women on the Berlin questionnaire (47% vs. 15%, P<0.01). However, none of the non-obese PCOS and control women screened positive for high risk OSA. Among the obese group, the risk did not differ between groups (77% vs. 63%, P= 0.65).
Our findings indicate that even though the risk for OSA in PCOS is high, it is related to the high prevalence of severe obesity. The risk for OSA among non-obese women with PCOS is very low. However, our findings are limited by lack of polysomnographic confirmation of OSA.
Berlin questionnaire; Obesity; Insulin resistance; Body mass index
Women affected by polycystic ovary syndrome (PCOS) are known to be at higher risk of cardiovascular disease. The aim of this study was to identify the artery that first is affected by early pre-atherosclerotic changes in PCOS.
Twenty-nine women with PCOS aged 17 to 27 years and 26 healthy nonhyperandrogenic volunteers with regular menses (control women) aged 16 to 28 years were enrolled. All PCOS patients were overweight or obese (body mass index [BMI] ≥ 25). Diagnosis of PCOS was performed in line with the 2003 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Accordingly, PCOS was defined when at least two of the following three features were present after exclusion of other etiologies: 1) oligomenorrhea and or anovulation; 2) hyperandrogenism and/or hyperandrogenemia; and 3) polycystic ovaries visible at ultrasound. Androgen excess or related disorders were excluded. The intima-media thickness (IMT) of common carotid arteries and common femoral arteries and the anteroposterior diameter of the infrarenal abdominal aorta were measured by ultrasound. Lutenizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, total testosterone, androstenedione, and sex hormone-binding globulin (SHBG) serum levels were measured between the 3rd and the 6th day of spontaneous or progestin-induced menstrual cycle. Our study was performed in the absence of any medical treatment.
Women with PCOS showed a higher LH to FSH ratio (p < 0.01), increased fasting insulin (p < 0.001), total testosterone (p < 0.001), and androstenedione (p < 0.001) levels, and lower SHBG concentrations (p < 0.001) compared to control women. BMI and waist-to-hip ratio were also higher in women with PCOS (p < 0.000 and p < 0.001, respectively). Women with PCOS also showed increased total cholesterol (p < 0.001), triglyceride (p < 0.001), and apolipoprotein B (p < 0.001) levels. Vascular data showed women with PCOS had a higher anteroposterior diameter than control women (p < 0.005). However, when analysis of covariance was performed and BMI was entered into the model as a covariate, anteroposterior diameter did not maintain a significant association with PCOS.
This study shows that anteroposterior diameter of the infrarenal abdominal aorta, but not IMT of common carotid arteries or common femoral arteries, is higher in women with PCOS than in women without this disease. This represents the earliest atherosclerotic change in women with PCOS. However, this alteration seems to be due to body weight secondary to PCOS and not due to PCOS per se.
polycystic ovary syndrome; antero-posterior diameter; infrarenal abdominal aorta; intimia-media thickness
Genetic variation in the androgen receptor gene (AR) may be associated with endometrial cancer risk based on the androgen receptor’s role in regulating androgen levels. However, endometrial cancer studies reported inconsistent associations for a CAG repeat polymorphism in exon 1. Only one of these studies measured haplotype-tagging single nucleotide polymorphisms (htSNPs) in AR, and found statistically non-significant, decreased associations with endometrial cancer risk. In a population-based case-control study of 497 cases and 1024 controls, we examined the CAG repeat polymorphism and six htSNPs (rs962458, rs6152, rs1204038, rs2361634, rs1337080, and rs1337082), which cover an estimated 80% of the known common variation in AR among Caucasian populations. CAG repeat length was not significantly associated with endometrial cancer (OR (95%CI) per unit increase in the average number of repeats =1.02 (0.97 – 1.08); P-trend=0.29). Minor alleles in three correlated htSNPs (rs6152, rs1204038, and rs1337082; r2≥0.6) were associated with increased risk for endometrial cancer. The strongest association was observed for rs6152: the ORs (95% CIs) were 1.13 (0.89–1.44) for heterozygous and 2.40 (1.28–4.51) for homozygous minor genotypes (P-trend=0.02), compared to homozygous major allele genotype. However, these associations were not statistically significant after permutation adjustment for multiple comparisons (P-trend ≥ 0.09). Haplotype analyses did not reveal any additional associations with endometrial cancer. Results from our study taken together with previously published studies provide little evidence of a consistent association between common genetic variation in AR and endometrial cancer risk.
genetics; endometrial cancer; androgen receptor
Cytochrome P450-C17 enzyme (CYP17) is an important component of the androgen synthesis pathway, a pathway that is dysfunctional in polycystic ovary syndrome (PCOS). Variation in 11-beta hydroxysteroid dehydrogenase (HSD11B1) is associated with cortisone reductase deficiency, a condition with a phenotype similar to PCOS. Both CYP17 and HSD11B1 genes have been previously studied for their possible relationship with PCOS, yielding inconsistent results. In this study, we evaluated the association between variation in these genes and PCOS. Two-hundred and eighty-seven Caucasian PCOS women and 187 Caucasian controls were genotyped for single nucleotide polymorphisms (SNPs) that were specifically chosen to allow full coverage of CYP17 and HSD11B1, including four SNPs in CYP17 and eight SNPs in HSD11B1. SNP and haplotype association analyses were conducted. Our results indicate that variants in the two genes are not associated with PCOS, or with the quantitative traits characteristic of PCOS, suggesting that these genes are not major risk factors for the syndrome.
CYP17; haplotype; HSD11B1; polycystic ovary syndrome; single nucleotide polymorphism
It is estimated that as many as 1.4 million Canadian women may be afflicted with polycystic ovary syndrome (PCOS). Although PCOS is heralded as one of the most common endocrine disorders occurring in women, its diagnosis, management, and associated long-term health risks remain controversial. Historically, the combination of androgen excess and anovulation has been considered the hallmark of PCOS. To date, while these symptoms remain the most prevalent among PCOS patients, neither is considered an absolute requisite for the syndrome. Inclusion of ultrasonographic evidence of polycystic ovaries as a diagnostic marker has substantially broadened the phenotypic spectrum of PCOS, yet much debate surrounds the validity of these newly identified milder variants of the syndrome. Difficulty in resolving the spectrum of PCOS stems from the continued use of inconsistent and inaccurate methods of evaluating androgen excess, anovulation, and polycystic ovaries on ultrasound. At present, there is no clear-cut definition of biochemical hyperandrogenemia, particularly since we depend on poor laboratory standards for measuring androgens in women. Clinical signs of hyperandrogenism are ill-defined in women with PCOS, and the diagnosis of both hirsutism and polycystic ovarian morphology remains alarmingly subjective. Lastly, there is an inappropriate tendency to assign ovulatory status solely on the basis of menstrual cycle history or poorly timed endocrine measurements. In this review, we elaborate on these limitations and propose possible resolutions for clinical and research settings. By stimulating awareness of these limitations, we hope to generate a dialogue aimed at solidifying the evaluation of PCOS in Canadian women.
PMID: 18786289 CAMSID: cams574
Polycystic ovary syndrome; hyperandrogenism; hirsutism; menstruation disturbances; ultrasonography
Insulin resistance and glucose dysmetabolism in polycystic ovary syndrome (PCOS) are related with the polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, especially Gly972Arg/Ala513Pro polymorphism being reported to be associated with type-2 diabetes and PCOS. We intended to assess the prevalence of abnormal glucose tolerance (AGT) and insulin resistance in Taiwanese PCOS women. We also tried to assess whether the particular identity of Gly972Arg/Ala513Pro polymorphic alleles of the IRS-1 gene mutation can be used as an appropriate diagnostic indicator for PCOS.
We designed a prospective clinical study. Forty-seven Taiwanese Hoklo and Hakka women, diagnosed with PCOS were enrolled in this study as were forty-five healthy Hoklo and Hakka women as the control group. Insulin resistance was evaluated with fasting insulin, fasting glucose/insulin ratio, and homeostasis model assessment index for insulin resistance (HOMAIR). The genomic DNA of the subjects was amplified by PCR and digested by restriction fragmented length polymorphism (RFLP) with Bst N1 used for codon 972 and Dra III for codon 513.
AGT was found in 46.8% of these PCOS patients and was significantly related to high insulin resistance rather than the low insulin resistance. Those patients with either insulin resistance or AGT comprised the majority of PCOS affected patients (AGT + fasting insulin ≥17: 83%, AGT + glucose/insulin ratio ≥6.5: 85.1%, AGT + HOMAIR ≥ 2: 87.2%, and AGT + HOMAIR ≥ 3.8: 72.3%). None of the tested samples revealed any polymorphism due to the absence of any Dra III recognition site or any Bst N1 recognition site in the amplified PCR fragment digested by restriction fragmented length polymorphism.
There is significantly high prevalence of AGT and insulin resistance in PCOS women, but Gly972Arg and Ala513Pro polymorphic alleles of IRS-1 are rare and are not associated with the elevated risk of PCOS amongst Taiwanese subjects. This is quite different from the similar study in phylogenetically diverged Caucasian subjects.
Prostate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5′ end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 ± 2.65, in controls 22.28 ± 2.86 (p = 0.009) and in BPH patients 22.1 ± 2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men.
Prostrate cancer (PC); Androgen receptor (AR) gene; CAG repeat; Benign prostatic hyperplasia (BPH)
High circulating luteinizing hormone (LH) level is a typical biochemical feature of polycystic ovary syndrome (PCOS) whose pathophysiology is still unclear. Certain mutations of LH and LH receptor (LHR) may lead to changes in bioactivity of these hormones. The aim of this study was determine the role of the LH and LHR polymorphisms in the pathogenesis of PCOS using a genetic approach.
315 PCOS women and 212 controls were screened for the gene variants of LH G1052A and LHR rs61996318 polymorphisms by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).
PCOS patients had significantly more A allele frequency of LH G1052A mutations than controls (p=0.001). Within PCOS group, carriers of LH 1052A allele had lower LH (p=0.05) and higher fasting glucose levels (p=0.04). No subjects were identified with LHR rs61996318 polymorphisms. A new LHR single nucleotide polymorphism (SNP) was found without clear association with PCOS.
Results suggested LH G1052A mutation might influence PCOS susceptibility and phenotypes.
Luteinizing hormone; Luteinizing hormone receptor; Polycystic ovary syndrome; Gene polymorphism
Polymorphisms in PPARG implicated in previous studies of metabolic traits do not appear to influence component phenotypes of PCOS, but do affect androgens and insulin resistance in the general population.
To investigate the relationship of the PPARG Pro12Ala and silent exon 6 (His447His) polymorphisms with the clinical features of polycystic ovary syndrome (PCOS).
PCOS and control subjects were genotyped for Pro12Ala and His447His; associations between genotype, diagnosis, and hormonal/metabolic parameters were assessed.
Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the surrounding community. Genotyping was performed at Cedars-Sinai Medical Center in Los Angeles.
Participants included 285 White women with PCOS and 187 controls.
Main Outcome Measure(s)
Pro12Ala and His447His genotype, hormonal and metabolic phenotypes.
Pro12Ala and His447His did not influence risk of PCOS or its component phenotypes in PCOS patients. In controls, Pro12Ala did not influence measures of insulin resistance or androgen production; however, carriers of the His447His T allele had significantly decreased free and total testosterone levels and HOMA-IR. Furthermore, haplotypes in controls bearing the His447His T allele were also associated with decreased testosterone.
does not appear to be an important modifier gene in PCOS. In controls, however, the His447His T allele may be in linkage disequilibrium with a functional variant that influences insulin resistance and testosterone production.
peroxisome proliferator activated receptor gamma; polycystic ovary syndrome; single nucleotide polymorphism; testosterone; insulin resistance