OBJECTIVEThis study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS).RESEARCH DESIGN AND METHODSThe efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0−6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6−12).RESULTSTRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA1c: treatment difference, −0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate.CONCLUSIONSOver a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS.

Myostatin, a member of the transforming growth factor-␤ superfamily, is a genetic determinant of skeletal muscle growth. Mice and cattle with inactivating mutations of myostatin have marked muscle hypertrophy. However, it is not known whether myostatin regulates skeletal muscle growth in adult men and whether increased myostatin expression contributes to wasting in chronic illness. We examined the hypothesis that myostatin expression correlates inversely with fat-free mass in humans and that increased expression of the myostatin gene is associated with weight loss in men with AIDS wasting syndrome. We therefore cloned the human myostatin gene and cDNA and examined the gene's expression in the skeletal muscle and serum of healthy and HIV-infected men. The myostatin gene comprises three exons and two introns, maps to chromosomal region 2q33.2, has three putative transcription initiation sites, and is transcribed as a 3.1-kb mRNA species that encodes a 375-aa precursor protein. Myostatin is expressed uniquely in the human skeletal muscle as a 26-kDa mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma. Myostatin immunoreactivity is detectable in human skeletal muscle in both type 1 and 2 fibers. The serum and intramuscular concentrations of myostatin-immunoreactive protein are increased in HIV-infected men with weight loss compared with healthy men and correlate inversely with fat-free mass index. These data support the hypothesis that myostatin is an attenuator of skeletal muscle growth in adult men and contributes to muscle wasting in HIV-infected men.

Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men.

Men treated with hemodialysis (HD) have a very poor prognosis and an elevated risk of premature cardiovascular disease (CVD). In the general population, associations between low testosterone concentrations and cardiovascular risk have been suggested. We performed a prospective observational study involving a well characterized cohort of 126 men treated with HD to examine the relationship between testosterone concentration and subsequent mortality during a mean follow-up period of 41 mo. Independent of age, serum creatinine, and sexual hormone binding globulin (SHBG), testosterone levels inversely and strongly associated with the inflammatory markers IL-6 and CRP. Patients with a clinical history of CVD had significantly lower testosterone levels. During follow up, 65 deaths occurred, 58% of which were a result of CVD. Men with testosterone values in the lowest tertile had increased all-cause and CVD mortality (crude hazard ratios [HRs] 2.03 [95% CI 1.24 to 3.31] and 3.19 [1.49 to 6.83], respectively), which persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers, but was lost after adjustment for creatinine. In summary, among men treated with HD, testosterone concentrations inversely correlate with all-cause and CVDrelated mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease.

Gender dysphoria is suggested to be a consequence of sex atypical cerebral differentiation. We tested this hypothesis in a magnetic resonance study of voxel-based morphometry and structural volumetry in 48 heterosexual men (HeM) and women (HeW) and 24 gynephillic male to female transsexuals (MtF-TR). Specific interest was paid to gray matter (GM) and white matter (WM) fraction, hemispheric asymmetry, and volumes of the hippocampus, thalamus, caudate, and putamen. Like HeM, MtF-TR displayed larger GM volumes than HeW in the cerebellum and lingual gyrus and smaller GM and WM volumes in the precentral gyrus. Both male groups had smaller hippocampal volumes than HeW. As in HeM, but not HeW, the right cerebral hemisphere and thalamus volume was in MtF-TR lager than the left. None of these measures differed between HeM and MtF-TR. MtF-TR displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus.The present data do not support the notion that brains of MtF-TR are feminized. The observed changes in MtF-TR bring attention to the networks inferred in processing of body perception.

Testosterone deficiency is a common finding among male ESRD patients, and it is independently associated with inflammation, cardiovascular co-morbidity and outcome. Future studies are needed to determine the potential adverse effects of male hypogonadism in ESRD and the possibility of improving risk profile, quality of life, and ultimately outcome with testosterone supplementation in these patients.

Although many studies indicate the interplay of genetic and environmental factors in the etiology of autism spectrum disorder (ASD), our limited understanding of the underlying mechanisms hampers the development of effective ways of detecting and preventing the disorder. Recent studies support the hypothesis that prenatal androgen exposure contributes to the development of ASD. This would suggest that maternal polycystic ovary syndrome (PCOS), a condition associated with excess androgens, would increase the risk of ASD in the offspring. We conducted a matched case–control study nested within the total population of Sweden (children aged 4–17 who were born in Sweden from 1984 to 2007). The sample consisted of 23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth. PCOS and ASD were defined from ICD codes through linkage to health-care registers. Maternal PCOS increased the odds of ASD in the offspring by 59%, after adjustment for confounders (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34–1.88). The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia (OR 2.13, 95% CI 1.46–3.10). Risk estimates did not differ between sexes. In conclusion, children of women with PCOS appear to have a higher risk of developing ASD. This finding awaits confirmation, and exploration of potentially underlying mechanisms, including the role of sex steroids in the etiology of ASD.

While there has been increasing support for the existence of cerebral sex differences, the mechanisms underlying these differences are unclear. Based on animal data, it has long been believed that sexual differentiation of the brain is primarily linked to organizational effects of fetal testosterone. This view is, however, in question as more recent data show the presence of sex differences before the onset of testosterone production. The present study focuses on the impact that sex chromosomes might have on these differences. Utilizing the inherent differences in sex and X-chromosome dosage among XXY males, XY males, and XX females, comparative voxel-based morphometry was conducted using sex hormones and sex chromosomes as covariates. Sex differences in the cerebellar and precentral gray matter volumes (GMV) were found to be related to X-chromosome dosage, whereas sex differences in the amygdala, the parahippocamus, and the occipital cortex were linked to testosterone levels. An increased number of sex chromosomes was associated with reduced GMV in the amygdala, caudate, and the temporal and insular cortices, with increased parietal GMV and reduced frontotemporal white matter volume. No selective, testosterone independent, effect of the Y-chromosome was detected. Based on these observations, it was hypothesized that programming of the motor cortex and parts of cerebellum is mediated by processes linked to X-escapee genes, which do not have Y-chromosome homologs, and that programming of certain limbic structures involves testosterone and X-chromosome escapee genes with Y-homologs.