Estrogen receptor alpha single nucleotide polymorphism as predictor of diabetes type 2 risk in hypogonadal men.

Abstract Estradiol (E2) is, apart from its role as a reproductive hormone, also important for cardiac function and bone maturation in both genders. It has also been shown to play a role in insulin production, energy expenditure and in inducing lipolysis. The aim of the study was to investigate if low circulating testosterone or E2 levels in combination with variants in the estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) genes were of importance for the risk of type-2 diabetes. The single nucleotide polymorphisms rs2207396 and rs1256049, in ESR1 and ESR2, respectively, were analysed by allele specific PCR in 172 elderly men from the population-based Tromsø study. The results were adjusted for age. In individuals with low total (≤11 nmol/L) or free testosterone (≤0.18 nmol/L) being carriers of the variant A-allele in ESR1 was associated with 7.3 and 15.9 times, respectively, increased odds ratio of being diagnosed with diabetes mellitus type 2 (p = 0.025 and p = 0.018, respectively). Lower concentrations of E2 did not seem to increase the risk of being diagnosed with diabetes. In conclusion, in hypogonadal men, the rs2207396 variant in ESR1 predicts the risk of type 2 diabetes

Exposure to persistent organic pollutants and sperm sex chromosome ratio in men from the Faroe Islands

People in the Arctic as well as fishermen on the polluted Swedish east coast are highly exposed to persistent organic pollutants (POPs). These compounds have been shown to affect the sperm Y:X chromosome ratio. In present study, the aim was to investigate whether polychlorinated biphenyl (PCB) congeners and 1,1,-dichloro-2,2,-bis(p-chlorophenyl)ethane (p,p′-DDE) influence sperm sex chromosome ratio in Faroese men, and whether these men differ regarding Y:X ratio compared to Greenland Inuit and Swedish fishermen. The study population (n = 449) consisted of young men from the general population (n = 276) as well as proven fertile men (n = 173). The Y:X ratio was assessed by fluorescent in situ hybridization. Serum concentrations of POPs were measured using gas chromatography. Associations between POP concentrations and Y:X ratio were calculated using linear and non-linear regression models as well as trend analysis and pairwise comparison of exposure data categorized into quartiles. The selected POPs were associated with Y:X ratio in fertile Faroese men, but not in the total population; p,p′-DDE (95% CI for B = − 0.005 to − 0.001, p = 0.005) and ΣPCB (95% CI for B = − 0.005 to − 0.001, p = 0.012). Since p,p′-DDE and ΣPCB correlated significantly (r = 0.927, p < 0.001), the results involving the exposure variables can be regarded as a single finding. The Y:X ratio for the total Faroese population was 0.500 ± 0.018, which was statistically significantly lower than in both Inuit and Swedish fishermen (0.512 for both). In conclusion, Faroese men presented with lower Y:X ratio than Greenland Inuit and Swedish fishermen. Although no direct health effects are expected due to the lower Faroese Y:X ratio, it could be indicative of adverse effects on the reproductive system

Impact of PCB and p,p′-DDE Contaminants on Human Sperm Y:X Chromosome Ratio: Studies in Three European Populations and the Inuit Population in Greenland

OBJECTIVE: Recent studies indicate that persistent organohalogen pollutants (POPs) may contribute to sex ratio changes in offspring of exposed populations. Our aim in the present study was to investigate whether exposure to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153) and dichlorodiphenyldichloroethene (p,p′-DDE) affects sperm Y:X chromosome distribution. SUBJECTS AND METHODS: We obtained semen and blood for analysis of PCB-153 and p,p′-DDE levels from 547 men from Sweden, Greenland, Poland (Warsaw), and Ukraine (Kharkiv), with regionally different levels of POP exposure. The proportion of Y- and X-chromosome–bearing sperm in the semen samples was determined by two-color fluorescence in situ hybridization analysis. RESULTS: Swedish and Greenlandic men had on average significantly higher proportions of Y sperm (in both cohorts, 51.2%) and correspondingly higher lipid-adjusted concentrations of PCB-153 (260 ng/g and 350 ng/g, respectively) compared with men from Warsaw (50.3% and 22 ng/g) and Kharkiv (50.7% and 54 ng/g). In the Swedish cohort, log-transformed PCB-153 and log-transformed p,p′-DDE variables were significantly positively associated with Y-chromosome fractions (p-values 0.04 and < 0.001, respectively). On the contrary, in the Polish cohort PCB-153 correlated negatively with the proportion of Y-bearing fraction of spermatozoa (p = 0.008). CONCLUSIONS: The present study indicates that POP exposure might be involved in changing the proportion of ejaculated Y-bearing spermatozoa in human populations. Intercountry differences, with different exposure situations and doses, may contribute to varying Y:X chromosome ratios

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer.

Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35-0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51-0.89, and rs4953617; OR=1.88, 95% CI: 1.21-2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18-2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26-4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis

Studies of androgen receptor gene mutations in patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility

The androgen insensitivity syndrome (AIS) is the single most common cause of male pseudohermaphroditism, i. e., deficient masculinization which is not explained by disturbed testis development. In its most severe form it affects at least 1/20 000 newborn 46, XY males. This X-linked recessive disorder is caused by mutations in the androgen receptor (AR) gene, and has classically been divided into two subgroups according to severity; complete (CAIS) and partial androgen insensitivity syndrome (PAIS). In the complete form, the 46, XY individual presents as a phenotypically normal girl, except for absence of sexual hair. These patients have intraabdominal testes and, due to regression of Müllerian ducts, a short vagina, no uterus and lack oviducts. Partial forms of AIS present as varying degrees of undermasculinization, ranging from a predominantly female phenotype to boys with genital malformations, such as hypospadias or cryptorchidism. It has also been speculated, that subtle androgen receptor defects could cause impaired spermatogenesis without genital malformations. In the present work 13 missense mutations are described, identified in the AR gene of patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility at the other end of the spectrum. The functional properties of 10 mutations have been characterized, using the approaches of site-directed mutagenesis, transient expression in COS-1 cells, and transactivation assays using an androgen sensitive reporter gene. Hormone binding assays in transfected COS-1 cells and genital skin fibroblasts from some patients were also performed. With a few exceptions, the degrees of impairment of mutant ARs in vitro were roughly in agreement with the severity of symptoms seen in the patients. Mutation A596T was an exception. A596T was functionally normal at high concentrations of androgens in vitro, although it was found in two newborns with PAIS. In accordance with this finding, treatment of the two boys with high doses of androgens resulted in a positive response. When this study was initiated, there was no molecular evidence for involvement of the AR in infertility. However, an elongated CAG repeat in exon I of the AR was known to be associated with dysfunctional sperm production in Kennedy's disease. Therefore, the length of the CAG-repeat of 33 infertile men was determined and compared to the CAG-repeats of 294 normal men. We found no difference in repeat lengths between the two groups. On the other hand, two missense mutations, N233K and N756S, were identified in two out of ten cases of infertility, selected due to elevated levels of LH and testosterone as well as azoo- or oligozoospermia. In both men, in vitro studies showed reduced transactivational capacity as compared to wild type AR. The patient carrying the N233K mutation displayed additional symptoms not generally seen in patients with AIS; he suffered from musculoskeletal and urogenital pain. He reported a remarkable relief upon high-dose androgen treatment. We speculate, that these symptoms result from abnormal protein- protein interactions arising as a consequence of the mutation, which is located in the transactivating domain of the AR where very few mutations previously have been found. Mutations in the AR gene have not been considered to be compatible with fertility. The Q824K mutation was found in three individuals of a family who complained of gynecomastia and showed hormonal levels indicating AIS. The mutant AR showed slight functional impairment in vitro. The patients had inherited the mutation from their grandfathers through their mothers, and one of them has fathered a daughter. The E653K mutation was found in a father of two daughters, who were affected with congenital adrenal hyperplasia due to 2 1 -hydroxylase deficiency. The daughters, who were heterozygous for the mutation, showed unusually mild signs of androgen excess, but in vitro assays of the E653K mutant failed to detect any functional abnormality. In conclusion, mutations in the AR gene have been found in patients covering the whole range of clinical phenotypes of androgen insensitivity. We confirm that the syndrome can be classified into three entities; CAIS, PAIS, and minimal androgen insensitivity (MAIS), where MAIS is defined as biochemical signs of AIS, gynecomastia and / or infertility, but without genital malformations