Thyroid hormone status within the physiological range affects bone mass and density in healthy men at the age of peak bone mass

Context: The hormonal factors involved in the regulation of peak bone mass (PBM) in men have not been fully investigated. Apart from gonadal steroids and somatotropic hormones, thyroid hormones are known to affect bone maturation and homeostasis and are additional candidate determinants of adult bone mass. Objective: We aimed to investigate between-subject physiological variation in free and total thyroid hormone concentrations, TSH, and thyroid binding globulin (TBG) in relation to parameters of bone mass, geometry, and mineral density in healthy men at the age of PBM. Design and setting: We recruited 677 healthy male siblings aged 25-45 years in a cross-sectional, population-based study. Areal and volumetric bone parameters were determined using dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Total and free thyroid hormones, TBG, and TSH were determined using immunoassays. Results: Free and total thyroid hormone concentrations were inversely associated with bone mineral density (BMD) and bone mineral content (BMC) at the hip and total body (free triiodothyronine (FT(3)), total T(3) (TT(3)), and total T(4) (TT(4))) and at the spine (FT(3)). TBG was negatively associated with BMC and areal BMD at all sites. At the radius, cortical bone area was inversely associated with TT(3), TT(4), and TBG, and trabecular bone density was inversely associated with free thyroxine, TT(4), and TBG. We observed inverse associations between cortical bone area at the mid-tibia and FT(3), TT(3), TT(4), and TBG. No associations between TSH and DXA or pQCT measurements were found. Conclusion: In healthy men at the age of PBM, between-subject variation in thyroid hormone concentrations affects bone density, with higher levels of FT(3), TT(3), TT(4), and TBG being associated with less favorable bone density and content

Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome

Context/Objective: Current diagnostic criteria for polycystic ovary syndrome (PCOS) have generated distinct PCOS phenotypes, based on the different combinations of diagnostic features found in each patient. Our aim was to assess whether either each single diagnostic feature or their combinations into the PCOS phenotypes may predict insulin resistance in these women. Patients/Design: A total of 137 consecutive Caucasian women with PCOS, diagnosed by the Rotterdam criteria, underwent accurate assessment of diagnostic and metabolic features. Insulin sensitivity was measured by the glucose clamp technique. Results: Among women with PCOS, 84.7% had hyperandrogenism, 84.7% had chronic oligoanovulation, and 89% had polycystic ovaries. According to the individual combinations of these features, 69.4% of women had the classic phenotype, 15.3% had the ovulatory phenotype, and 15.3% had the normoandrogenic phenotype. Most subjects (71.4%) were insulin resistant. However, insulin resistance frequency differed among phenotypes, being 80.4%, 65.0%, and 38.1%, respectively, in the 3 subgroups (P < .001). Although none of the PCOS diagnostic features per se was associated with the impairment in insulin action, after adjustment for covariates, the classic phenotype and, to a lesser extent, the ovulatory phenotype were independently associated with insulin resistance, whereas the normoandrogenic phenotype was not. Metabolic syndrome frequency was also different among phenotypes (P = .030). Conclusions: There is a scale of metabolic risk among women with PCOS. Although no single diagnostic features of PCOS are independently associated with insulin resistance, their combinations, which define PCOS phenotypes, may allow physicians to establish which women should undergo metabolic screening. In metabolic terms, women belonging to the normoandrogenic phenotype behave as a separate group

The effects of age and obesity on postprandial dynamics of serum testosterone levels in men

Objective Guidelines recommend using fasting samples to evaluate testosterone (T) levels in men, as free and total T levels decrease postprandially. However, it is not clear whether these dynamics are affected by age or obesity. This could be relevant given the obesity epidemic, ageing population and the barrier for screening which fasting could impose. Design/Participants A total of 43 men underwent a solid mixed meal tolerance test. Serum samples were taken fasting, and at 30, 60 and 120 minutes postprandially. A commercial immunoassay was used to determine sex hormone-binding globulin (SHBG) levels, liquid chromatography coupled to tandem mass spectroscopy for total T concentrations and free T levels were calculated. Results Postprandially, both total and free T were lower at all-time points compared with fasting (all, P < .005). At 60 minutes, maximum mean decreases of 15 +/- 15% and 17 +/- 16% were seen for total and free T levels, respectively. Younger men had greater decreases in both total and free T levels compared with men older than 40 years (all, P < .05). A greater decrease at 30 and 60 minutes postprandially was observed for both total and free T levels in nonobese vs obese men (all, P < .05). Conclusions After a mixed meal, total and free T serum levels decreased whereas SHBG levels did not change. Interestingly, postprandial decreases were less pronounced in men older than 40 years and/or with obesity. Although this study indicates less pronounced decreases in certain men, fasting samples remain a prerequisite for establishing correct diagnosis of male hypogonadism

Predicting yield of photonic circuits with wafer-scale fabrication variability : invited paper

We present a workflow for variability analysis and yield prediction of photonic integrated circuits affected by fabrication variations. The technique combines synthetic wafer maps with layout-aware Monte-Carlo simulations. We demonstrate this on different layout configurations of linewidth-tolerant Mach-Zehnder interferometers

Testosterone and fathers' parenting unraveled : links with the quantity and quality of father-child interactions

Objective Individual differences in quality of father involvement in caregiving might in part be explained by fathers' testosterone (T) levels. We examined the links between fathers' (n = 32) salivary T levels, amount of time spent with their child (12-30 months of age), type of father-child interaction, and fathers' sensitivity. Methods During two home visits, video observations of father-child interactions were conducted to measure fathers' sensitivity during a challenging and harmonious interaction. Fathers' saliva was collected several times throughout the day on a working day and on the home visit days, including right before and after each father-child interaction. Results Fathers' T secretion throughout the day was lower on home visit days (i.e., days with a higher amount of time spent with their child) than on a working day. For both challenging and harmonious father-child interactions, mean T levels did not differ before and after father-child interactions. However, individual changes in fathers' T levels during the father-child interactions did predict fathers' sensitivity. Specifically, the more T increased during the challenging interaction, or decreased during the harmonious interaction, the more sensitive the father was during that interaction as well as during a subsequent interaction. Conclusions Parenting quality is most optimal when fathers' T system reacts in the expected direction given the context of the father-child interaction, i.e., a T decrease during a harmonious interaction and a T increase during a challenging interaction. Our study underscores the importance of examining the interplay between biology, behavior, and caregiving context in fathers' parenting

Sex hormone-binding globulin regulation of androgen bioactivity in vivo : validation of the free hormone hypothesis

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the in vivo physiological role of circulating SHBG remains unclear, especially since mice and rats lack circulating SHBG post-natally. To test the free hormone hypothesis in vivo, we examined total and free sex steroid concentrations and bioactivity on target organs in mice expressing a human SHBG transgene. SHBG increased total androgen and estrogen concentrations via hypothalamic-pituitary feedback regulation and prolonged ligand half-life. Despite markedly raised total sex steroid concentrations, free testosterone was unaffected while sex steroid bioactivity on male and female reproductive organs was attenuated. This occurred via a liganddependent, genotype-independent mechanism according to in vitro seminal vesicle organ cultures. These results provide compelling support for the determination of free or bioavailable sex steroid concentrations in medicine, and clarify important comparative differences between translational mouse models and human endocrinology

Metabolic inflexibility is a feature of women with polycystic ovary syndrome and is associated with both insulin resistance and hyperandrogenism

Context: Metabolic inflexibility, ie, the impaired ability of the body to switch from fat to carbohydrate oxidation under insulin-stimulated conditions, is associated with insulin resistance. This alteration in metabolic plasticity can lead to organ dysfunction and is considered a key issue among the abnormalities of the metabolic syndrome. It is still unknown whether this phenomenon occurs in women with polycystic ovary syndrome (PCOS). Objective: Our objective was to examine whether metabolic inflexibility is a feature of PCOS women and whether hyperandrogenism may contribute to this phenomenon. Design and Patients: Eighty-nine Caucasian women with PCOS were submitted to hyperinsulinemic-euglycemic clamp. Respiratory exchange ratios were evaluated at baseline and during hyperinsulinemia by indirect calorimetry to quantify substrate oxidative metabolism. Total testosterone was measured by liquid chromatography mass spectrometry and free testosterone by equilibrium dialysis. Setting: Outpatients were seen in a tertiary care academic center. Main Outcome Measure: Metabolic flexibility was assessed by the change in respiratory quotient upon insulin stimulation. Results: Sixty-five of the 89 PCOS women(73%) had increased serum free testosterone, 68 (76%) were insulin resistant, and 62 (70%) had an impaired metabolic flexibility. Comparison of hyperandrogenemic and normoandrogenemic women showed that the 2 subgroups were of similar age but differed in terms of several anthropometric and metabolic features. In particular, hyperandrogenemic women had greater body mass index (32.9 +/- 1.0 vs 24.7 +/- 0.9 kg/m(2), P < .001) and lower glucose utilization during the clamp (9.2 +/- 0.4 vs 10.9 +/- 0.7 mg/kg fat-free mass . min, P < .023) and metabolic flexibility (0.09 +/- 0.06 vs 0.12 +/- 0.01, P < .014). In univariate analysis, metabolic flexibility was associated with several anthropometric, endocrine, and metabolic features. In multivariate analysis, this feature was directly associated with baseline respiratory quotient and insulin sensitivity and inversely with free testosterone and free fatty acids concentrations under insulin suppression (R-2 = 0.634, P < .001). Conclusions: Metabolic inflexibility is a feature of PCOS women. Both insulin resistance and androgen excess might contribute to this abnormality

Sex steroids in relation to sexual and skeletal maturation in obese male adolescents

Background: Childhood obesity is associated with an accelerated skeletal maturation. However, data concerning pubertal development and sex steroid levels in obese adolescents are scarce and contrasting. Objectives: To study sex steroids in relation to sexual and skeletal maturation and to serum prostate specific antigen (PSA), as a marker of androgen activity, in obese boys from early to late adolescence. Methods: Ninety obese boys (aged 10-19 y) at the start of a residential obesity treatment program and 90 age-matched controls were studied cross-sectionally. Pubertal status was assessed according to the Tanner method. Skeletal age was determined by an x-ray of the left hand. Morning concentrations of total testosterone (TT) and estradiol (E2) were measured by liquid chromatographytandem mass spectrometry, free T (FT) was measured by equilibrium dialysis, and LH, FSH, SHBG, and PSA were measured by immunoassays. Results: Genital staging was comparable between the obese and nonobese groups, whereas skeletal bone advancement (mean, 1 y) was present in early and midadolescence in the obese males. Although both median SHBG and TT concentrations were significantly (P < .001) lower in obese subjects during mid and late puberty, median FT, LH, FSH, and PSA levels were comparable to those of controls. In contrast, serum E2 concentrations were significantly (P < .001) higher in the obese group at all pubertal stages. Conclusion: Obese boys have lower circulating SHBG and TT, but similar FT concentrations during mid and late puberty in parallel with a normal pubertal progression and serum PSA levels. Our data indicate that in obese boys, serum FT concentration is a better marker of androgen activity than TT. On the other hand, skeletal maturation and E2 were increased from the beginning of puberty, suggesting a significant contribution of hyperestrogenemia in the advancement of skeletal maturation in obese boys

The γ-secretase substrate proteome and its role in cell signaling regulation

γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.</p