ABSTRACT
Nitric oxide has been associated with insulin resistance and type 2 diabetes mellitus (DM). An association has been suggested between a single nucleotide polymorphism (Glu298Asp variant) of the endothelial nitric oxide synthase (eNOS) gene and increased risk of DM. However, the role of this polymorphism in favouring DM has not been investigated in hypogonadism, in which low testosterone and obesity are believed to play the major role. We aimed to evaluate whether eNOS gene single nucleotide polymorphism (Glu298Asp variant) might give a relevant contribution also to the onset of hypogonadism-associated DM. 110 men affected by late-onset hypogonadism were retrospectively reviewed. Patients were clinically and biochemically evaluated. Detection of eNOS Glu298Asp polymorphism was performed. After splitting the sample according to the three genetic variants (i.e. eNOSGG , eNOSGT , eNOSTT ), no difference was evident in age, body mass index (BMI) and total testosterone. Conversely, DM prevalence, glycaemia and glycated haemoglobin were significantly higher in eNOSTT than in eNOSGT and eNOSGG . Logistic regression analysis showed that, after adjustment for age, BMI and total testosterone, eNOSTT was positively and significantly associated with DM. Our study suggests that Glu298Asp single nucleotide polymorphism of the eNOS gene may be an independent risk factor for hypogonadism-associated type 2 DM.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Eunuchism/genetics , Nitric Oxide Synthase Type III/physiology , Polymorphism, Single Nucleotide , Age Factors , Age of Onset , Body Mass Index , Diabetes Mellitus, Type 2/etiology , Eunuchism/etiology , Humans , Male , Middle Aged , Nitric Oxide Synthase Type III/genetics , Retrospective Studies , Testosterone/bloodABSTRACT
BACKGROUND AND AIMS: Little is known about the effect of androgen receptor (AR) gene CAG repeat polymorphism in conditioning body composition changes after testosterone replacement therapy (TRT). In this study, we aimed to clarify this aspect by focussing our attention on male post-surgical hypogonadotropic hypogonadism, a condition often associated with partial or total hypopituitarism. METHODS AND RESULTS: Fourteen men affected by post-surgical hypogonadotropic hypogonadism and undergoing several replacement hormone therapies were evaluated before and after TRT. Dual-energy X-ray absorptiometry (DEXA)-derived body composition measurements, pituitary-dependent hormones and AR gene CAG repeat polymorphism were considered. While testosterone and insulin-like growth factor-1 (IGF-1) levels increased after TRT, cortisol concentration decreased. No anthropometric or body composition parameters varied significantly, except for abdominal fat decrease. The number of CAG triplets was positively and significantly correlated with this abdominal fat decrease, while the opposite occurred between the latter and Δ-testosterone. No correlation of IGF-1 or cortisol variation (Δ-) with Δ-abdominal fat was found. At multiple linear regression, after correction for Δ-testosterone, the positive association between CAG triplet number and abdominal fat change was confirmed. CONCLUSIONS: In male post-surgical hypogonadotropic hypogonadism, shorter length of AR CAG repeat tract is independently associated with a more marked decrease of abdominal fat after TRT.
Subject(s)
Abdominal Fat/physiology , Hypogonadism/drug therapy , Postoperative Complications/drug therapy , Postoperative Complications/pathology , Receptors, Androgen/genetics , Testosterone/therapeutic use , Absorptiometry, Photon , Aged , Aged, 80 and over , Body Composition , Body Weight , Hormone Replacement Therapy , Humans , Hypogonadism/pathology , Insulin-Like Growth Factor I/metabolism , Male , Polymorphism, Genetic , Receptors, Androgen/metabolism , Retrospective Studies , Waist CircumferenceABSTRACT
INTRODUCTION AND AIM: The relationship between androgen receptor (AR) CAG polymorphism and bone metabolism is highly controversial. We, therefore, aimed to evaluate the independent role of AR CAG repeat polymorphism on bone metabolism improvement induced by testosterone replacement therapy (TRT) in male post-surgical hypogonadotropic hypogonadism, a condition frequently associated with hypopituitarism and in which the effects of TRT have to be distinguished from those resulting from concomitant administration of pituitary function replacing hormones. METHODS: 12 men affected by post-surgical hypogonadotropic hypogonadism [mean duration of hypogonadism 8.3 ± 2.05 (SD) months] were retrospectively assessed before and after TRT (from 74 to 84 weeks after the beginning of therapy). The following measures were studied: parameters of bone metabolism [serum markers and bone mineral density (BMD)], pituitary dependent hormones and genetic analysis (AR CAG repeat number). RESULTS: Total testosterone, estradiol, free T4 (FT4) and insulin-like growth factor-1 (IGF-1) increased between the two phases, while follicle stimulating hormone (FSH) decreased. While serum markers did not vary significantly between the two phases, BMD improved slightly but significantly in all the studied sites. The number of CAG triplets correlated negatively and significantly with all the variations (Δ-) of BMDs. Conversely, Δ-testosterone correlated positively and significantly with all studied Δ-BMDs, while Δ-FSH, Δ-estradiol, Δ-FT4, and Δ-IGF-1 did not correlate significantly with any of the Δ-BMDs. Multiple linear regression analysis, after correction for Δ-testosterone, showed that CAG repeat length was negatively and significantly associated with ∆-BMD of all measured sites. CONCLUSIONS: Our data suggest that, in post-surgical male hypogonadotropic hypogonadism, shorter AR CAG tract is independently associated with greater TRT-induced improvement of BMD.
Subject(s)
Bone and Bones/metabolism , Hormone Replacement Therapy , Hypogonadism/drug therapy , Polymorphism, Genetic/genetics , Receptors, Androgen/genetics , Testosterone/therapeutic use , Bone Density/drug effects , Bone and Bones/drug effects , Humans , Hypogonadism/etiology , Male , Middle Aged , Pituitary Neoplasms/surgery , Postoperative Complications , Receptors, Androgen/physiology , Retrospective Studies , Testosterone/blood , Trinucleotide Repeats/geneticsABSTRACT
Androgens and a normal androgen receptor (AR) are required for normal spermatogenesis. We investigated polyglutamine (CAG) and a polyglycine (GGC) tract in Italian men with defective spermatogenesis. We studied a group of 40 infertile men with spermatogenesis failure without Y-chromosome microdeletions compared with 60 normozoospermic ones. The distributions of both polymorphisms, within the normal range of Caucasian populations, were similar among infertile men and controls. Nonetheless, we observed that the frequency comparison of each CAG allele showed a statistical difference in the allele CAG 22; GGC 17 was the more predominant allele in infertile men than in controls. Moreover, to investigate the hypothesis that semen characteristics are perturbed by androgen receptor allele variants, we tried to detect a link between triplets and sperm motility in all subjects (cases plus controls). Subjects were subdivided into three groups, based on calculated allele frequencies. A significantly decreased motility, related to a longer CAG and GGC tracts, and marked differences between the groups exist for both polymorphisms. Our data highlight a probable relationship between the allele CAG 22/GGC 17 and a defective spermatogenesis in infertile men, suggesting that these polymorphisms might have an important effect on AR function.