Sex hormone-binding globulin at the crossroad of body composition, somatotropic axis and insulin/glucose homeostasis in young healthy men.

OBJECTIVES: Sex hormone-binding globulin (SHBG) modulates the bioavailability of sex steroids at tissue level. Genetic, hormonal and lifestyle-related factors determine the SHBG levels, and low SHBG levels are a known risk factor for the development of the metabolic syndrome, diabetes and cardiovascular diseases. We investigated to what extent different determinants contribute to the variation in SHBG levels in healthy young men. DESIGN AND PATIENTS: Healthy male siblings (n = 677) aged 25-45 year were recruited in a cross-sectional, population-based study. MEASUREMENTS: Lean and fat mass were measured using dual-energy X-ray absorptiometry (DXA), and immunoassays were used to determine the serum hormonal levels. Additional information about smoking and physical activity was obtained using questionnaires. Carriers of two SHBG polymorphisms, the Asp327Asn polymorphism and the (TAAAA)(n) repeat polymorphism, were identified. RESULTS: Weight, BMI, whole body fat mass and truncal fat mass were negatively associated with SHBG levels. Body composition characteristics did not differ between SHBG genotype groups, indicating that body composition controls SHBG levels rather than the other way around. The associations may be mediated by adipokines because leptin and adiponectin were, respectively, inversely and positively associated with SHBG levels. Insulin and glucose were negatively associated with SHBG levels, as well as IGF-1 and IGF-BP3, while no associations were found with free thyroid hormone status. CONCLUSIONS: In conclusion, we found that fat mass, insulin and IGF-1 levels are important negative determinants of SHBG levels in young healthy men. The association with fat mass could be mediated by the effects of adiponectin and/or leptin on SHBG synthesis.

The Nef-infectivity enigma: mechanisms of enhanced lentiviral infection.

The Nef protein is an essential factor for lentiviral pathogenesis in humans and other simians. Despite a multitude of functions attributed to this protein, the exact role of Nef in disease progression remains unclear. One of its most intriguing functions is the ability of Nef to enhance the infectivity of viral particles. In this review we will discuss current insights in the mechanism of this well-known, yet poorly understood Nef effect. We will elaborate on effects of Nef, on both virion biogenesis and the early stage of the cellular infection, that might be involved in infectivity enhancement. In addition, we provide an overview of different HIV-1 Nef domains important for optimal infectivity and briefly discuss some possible sources of the frequent discrepancies in the field. Hereby we aim to contribute to a better understanding of this highly conserved and therapeutically attractive Nef function.

Sex hormone-binding globulin as an independent determinant of cortical bone status in men at the age of peak bone mass.

CONTEXT: Sex steroids are important determinants of the skeletal development, growth, and maintenance after achievement of peak bone mass. A large fraction of these hormones are bound by SHBG, and previous studies have shown that SHBG could be a determinant of bone characteristics. OBJECTIVE: We investigated associations of serum SHBG levels with cortical and trabecular bone characteristics in young healthy men. DESIGN AND SETTINGS: A total of 677 healthy male siblings aged 25-45 yr were recruited in a cross-sectional, population-based study. MAIN OUTCOMES: Areal bone parameters were assessed using dual-energy x-ray absorptiometry. Cortical bone parameters at the tibia and radius and trabecular vBMD at the radius were assessed using peripheral quantitative computed tomography. Serum testosterone, estradiol, and SHBG levels were measured using immunoassays. RESULTS: Regression models including age, height, and weight showed that SHBG levels were positively associated with bone area at the hip and the whole body, but not with areal bone mineral density (BMD). Higher SHBG levels were associated with a larger cortical bone area and periosteal and endosteal circumferences at both the tibia and the radius, whereas trabecular volumetric BMD at the radius was negatively associated with SHBG levels. Associations persisted after adjustment for (free) sex steroid levels. No associations were found with cortical volumetric BMD or cortical thickness. CONCLUSION: In this population of healthy adult men at the age of peak bone mass, SHBG levels were positively associated with cortical bone size, independently from sex-steroid levels. This suggests a possible independent role of SHBG in the determination of adult bone size.

Birth weight in relation to sex steroid status and body composition in young healthy male siblings.

CONTEXT: Sex steroid concentrations have a strong genetic determination, but environmental factors and body composition play an important role. From studies in children with intrauterine growth restriction, low birth weight has been associated with altered gonadotropin concentrations. OBJECTIVE: We aim to investigate sex steroid concentrations in healthy young brothers in relation to birth weight (normal gestational age), body composition, and parental steroid concentrations. DESIGN AND SETTING: We conducted a cross-sectional, population-based sibling pair study with inclusion of parental data. PARTICIPANTS: A total of 677 men (25-45 yr old) were included in this study, with 296 independent pairs of brothers and 122 fathers. MAIN OUTCOMES: We measured testosterone, estradiol, leptin, adiponectin, IGF-I (immunoassays), and free steroid hormones (calculated) in relation to birth weight and changes in body composition (dual-energy x-ray absorptiometry). RESULTS: Birth weight was associated with serum testosterone (P = 0.0004) and SHBG (P = 0.0001), independent from weight, age, or fat mass, whereas no association with (free) estradiol, LH, or FSH was found. Paternal testosterone (P = 0.02), estradiol (P = 0.04), and SHBG (P = 0.0004) were associated with the respective sex steroid concentrations in the brothers. Weight increase (population rank) during life, was associated with lower testosterone (-15%; P < 0.001), independent from current weight and with higher free estradiol concentrations (+8%; P = 0.002), whereas weight decrease was associated with higher testosterone (+13%; P < 0.001). CONCLUSION: Birth weight and paternal steroid concentrations are associated with testosterone concentrations, independent from adult weight. These findings support the concept of in utero programming across the range of birth weight.

Early smoking is associated with peak bone mass and prevalent fractures in young, healthy men.

Smoking is associated with lower areal bone mineral density (aBMD) and higher fracture risk, although most evidence has been derived from studies in elderly subjects. This study investigates smoking habits in relation to areal and volumetric bone parameters and fracture prevalence in young, healthy males at peak bone mass. Healthy male siblings (n = 677) at the age of peak bone mass (25 to 45 years) were recruited in a cross-sectional population-based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mass was determined using dual energy X-ray absorptiometry (DXA). Sex steroids and bone markers were determined using immunoassays. Prevalent fractures and smoking habits were assessed using questionnaires. Self-reported fractures were more prevalent in the current and early smokers than in the never smokers (p < .05), with a fracture prevalence odds ratio for early smokers of 1.96 (95% confidence interval 1.18-3.24) after adjustment for age, weight, educational level, and alcohol use and exclusion of childhood fractures. Current smoking was associated with a larger endosteal circumference (beta = 0.027 +/- 0.009, p = .016) and a decreased cortical thickness (beta = -0.034 +/- 0.01, p = .020) at the tibia. In particular, early smokers (< or =16 years) had a high fracture risk and lower areal BMD, together with a lower cortical bone area at the tibia and lower trabecular and cortical bone density at the radius. An interaction between free estradiol and current smoking was observed in statistical models predicting cortical area and thickness (beta = 0.29 +/- 0.11, p = .01). In conclusion, smoking at a young age is associated with unfavorable bone geometry and density and is associated with increased fracture prevalence, providing arguments for a disturbed acquisition of peak bone mass during puberty by smoking, possibly owing to an interaction with sex steroid action.

Small effect of the androgen receptor gene GGN repeat polymorphism on serum testosterone levels in healthy men.

OBJECTIVE: The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat. DESIGN AND PATIENTS: A population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men. MEASUREMENT: Testosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique. RESULTS: The GGN repeat number was significantly associated with circulating testosterone and FT levels (P=0.017 and P=0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT. CONCLUSION: To our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable.

Fat mass is negatively associated with cortical bone size in young healthy male siblings.

CONTEXT: Body weight has been associated with bone mass and bone size through shared genetic determination and environmental influences. Whereas lean mass exerts a positive influence on bone size, the relationship between fat and bone remains unclear. OBJECTIVE: The objective of the present study was to investigate the individual influence of fat mass and lean mass on volumetric bone density and size in young healthy male siblings at age of peak bone mass. DESIGN: This was a cross-sectional, population-based sibling pair study. PARTICIPANTS: A total of 677 men (25-45 yr) were included in this study with 296 independent pairs of brothers. MAIN OUTCOME MEASURES: Areal and volumetric bone parameters were determined using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Body composition was determined by DXA. Sex steroids, leptin, and adiponectin were determined by immunoassay. RESULTS: Total and regional fat mass were found to be inversely associated with areal bone mass and bone size, independent from lean mass (radius periosteal circumference beta: -0.29 +/- 0.04; P < 0.001). Lean mass was positively associated with bone size but inversely with cortical density at both tibia and radius (P < 0.01). The negative association between total fat mass and bone size was independent from sex steroid concentrations. Leptin but not adiponectin was inversely associated with bone size, but this was no longer significant after adjustment for body fat. CONCLUSIONS: Increased fat mass is associated with smaller bone size, challenging the view of a high bone mass index as a protective factor for osteoporosis, whereas lean mass was a consistent positive determinant of bone size.

Serum estradiol is associated with volumetric BMD and modulates the impact of physical activity on bone size at the age of peak bone mass: a study in healthy male siblings.

This study investigates determinants of peak bone mass (PBM) in healthy men, focusing on effects and interactions of parameters reflecting mechanical loading and sex steroids. Healthy male siblings (n = 677; 25-45 yr) were recruited in a cross-sectional, population-based study. Physical activity score was assessed by a self-reported questionnaire. Cross-sectional muscle area (CSMA) and bone parameters of radius (4% and 66% site) and tibia (66% site) were assessed using pQCT. Peak torque of biceps and quadriceps muscles was assessed by isokinetic dynamometry. Serum testosterone (T) and estradiol (E(2)) levels were measured using immunoassays; free hormone fractions were calculated. Relations between indices of bone strength, CSMA, muscle strength, and sex steroids were studied using linear mixed-effects modeling. Physical activity, CSMA, and muscle strength were positively associated with indices of bone strength, except for volumetric BMD (vBMD). After controlling for age, weight, and height, free E(2) levels were positively associated with trabecular and cortical vBMD, negatively associated with endosteal circumference at the radius, and positively associated with cortical vBMD at the tibia. In addition, positive interactions between physical activity and serum E(2) concentrations were observed for bone size at the tibia. No associations between free T levels and pQCT bone parameters were found. In this population of healthy men at the age of PBM, parameters reflecting mechanical loading are confirmed as important determinants of bone size. E(2), but not T, levels are positively associated with vBMD and modulate the impact of physical activity on bone size at the tibia.

Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men.

OBJECTIVE: In men there is a large interindividual variation of SHBG levels and consequently of testosterone (T) and E(2) levels. Family and twin studies suggested a strong genetic contribution, besides metabolic and hormonal influences. The aim of this study was to examine the influence of a missense mutation in exon 8 (Asp327Asn) and a (TAAAA)(n)-repeat in the promoter region of the SHBG gene, on SHBG and sex steroid serum concentrations in a population of healthy men. DESIGN: SHBG and hormone levels were measured in 1485 men, contributed by three independent cohort studies and representing three different age groups (young, middle-aged and elderly men). The number of TAAAA-repeats was determined by fragment-analysis; carriers of the Asn(327)-allele were identified using restriction fragment length polymorphism analysis. RESULTS: In the different age groups, carriers of six TAAAA-repeats presented with higher SHBG (young 19%, middle-aged 20% and elderly 26%; P < 0.001) and T (young 9%, middle-aged 22% and elderly 21%; P < 0.05) levels compared to non-carriers. For free T, a modest increase was found for carriers in the middle-aged group, but not for the young and elderly group. E(2) and free E(2) did not differ between carriers and non-carriers in the different age-groups. The Asn(327)-allele was associated with higher mean SHBG (14.20%, P < 0.001) and T levels (7.33%; P = 0.01) in the middle-aged group only. CONCLUSIONS: Our findings show that and the (TAAAA)(n)-repeat and the Asp327Asn polymorphism contribute to the genetically determined interindividual variation in total serum T levels in healthy men through variation in SHBG concentrations.

Relation between fatty acid composition and clinical status or genotype in cystic fibrosis patients.

OBJECTIVE: To evaluate the relation of clinical parameters and genotype with the serum phospholipid fatty acid (FA) composition in cystic fibrosis (CF) patients. METHODS: A blood sample was taken from CF patients with stable pulmonary disease for the determination of phospholipid FA composition and vitamin E concentration who had been followed for at least 6 months at our Cystic Fibrosis Centre. Genotype, age, pancreatic function, nutritional status, caloric intake, pulmonary function and presence of Pseudomonas colonization, liver disease or diabetes mellitus were recorded. Patients were divided into two groups according to their genotype (group A: mutation class I, II, or III, group B: mutation class IV, V). RESULTS: CF patients (group A and B together) have significantly lower docosahexaenoic acid (DHA) (p < 0.007) and linoleic acid (LA) (p < 0.0001) and higher dihomogammalinolenic acid (DHGLA) (p < 0.0001), oleic acid (OA) (p < 0.0001) and Mead acid (MA) (p < 0.0001), resulting in an increased ratio of arachidonic acid (AA)/DHA (p < 0.004), MA/AA (p < 0.0001) and OA/LA (p < 0.0001). Compared to group B, group A had a lower LA (p < 0.002) and a higher DHGLA (p < 0.002), 22:4omega-6 (p < 0.03), 22:5omega-6 (p < 0.03) and 20:3omega-9 (p < 0.04). There was however no significant difference between the groups for age, pulmonary function, nutritional status and vitamin E concentration. There was no relation of serum FA composition with nutritional status, caloric intake, pancreatic function, gender, pulmonary function, Pseudomonas colonization or diabetes mellitus. In CF with liver disease the DHA was lower than in the patients of the same genotype. CONCLUSION: FA disturbances are more pronounced in the severe CF genotypes and the presence of CF-related liver disease. Future studies on supplementation should take these parameters into account.