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Design: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon‐1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all‐cause mortality in men and the influence of testosterone level on the association. Patients and Measurements: Follow‐up data to 27 January 2018 were available for men aged 40–79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). Results: One thousand nine hundred and seventy‐seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow‐up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22–23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93–1.49) and >23 CAG repeats 1.14 (0.88–1.47). In a post‐hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97–2.27) and 1.68 (1.06–2.67) versus 22–23 repeats. Conclusions: Our European‐wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation. [ABSTRACT FROM AUTHOR]

Background: Although Klinefelter syndrome (KS) is the most frequent sex‐hormone disorder, there is ongoing uncertainty about the often associated sex‐hormone deficiency, its impact on common comorbidities, and therefore about prevention and treatment. In this study, we focus on bone loss, reported to occur in over 40% of KS patients, and the impact of testosterone replacement therapy (TRT) on this comorbidity. Objectives: This single‐center retrospective cohort study in a tertiary hospital compared the effect of treatment with TRT to no TRT on evolution of bone mineral density (BMD) in KS patients. Methods: After a medical chart review, a total of 52 KS subjects were included in this study. BMD was measured by dual‐energy X‐ray absorptiometry (DXA) and expressed as T‐scores. Results: The subjects were divided into three groups, according to TRT. In the subgroup that only started TRT after baseline measurements (mean age 31 years), we observed significant gain in BMD T‐score at the lumbar spine (0.58 ± 0.60, p = 0.003; mean gain of 0.62% areal BMD per year) and total femur T‐score (0.24 ± 0.39, p = 0.041; mean gain of 0.25% areal BMD per year) after a mean follow‐up period of 7.5 years. Compared to untreated subjects, a significant difference in evolution was demonstrated at the lumbar level (+0.58 ± 0.60 vs. −0.14 ± 0.42, p = 0.007). In untreated subjects with normal testosterone levels, a loss of BMD (−0.27 ± 0.37, p = 0.029; mean loss of 0.49% areal BMD per year) at the femoral neck was measured. This decline was equal to the predicted loss seen in the general male population. Conclusion: TRT results in BMD gain in patients with KS with testosterone deficiency, mainly at the lumbar spine. However, this effect is limited (0.62% per year). Patients who were not treated with TRT because of sufficient endogenous testosterone levels, showed only the predicted age‐related bone loss during follow‐up. The need for TRT in maintaining bone health in KS should be evaluated on an individual basis according to the degree of sex steroid deficiency. [ABSTRACT FROM AUTHOR]

Background: Low testosterone levels are frequently present in men with obesity and insulin resistance. Currently available treatment options (testosterone replacement therapy or lifestyle changes) hold possible risks or are insufficient. Since low testosterone levels are closely related to obesity and type 2 diabetes, treatment modalities for these conditions could result into improvement of testosterone levels. Objectives: To summarize the available evidence on the effects of traditional and recent treatment modalities for diabetesmellitus on testosterone levels and androgendeficiency-related signs and symptoms. Materials and methods: PubMed was searched from the year 2000 till present using MESH terms: "hypogonadism," "testosterone," "testosterone deficiency," "functional hypogonadism," and the different classes of medications. Studies with observational and experimental designs on humans that evaluated the effect of antidiabetic medications on gonadotropins and testosterone were eligible for inclusion. Results: Current available data show no or only limited improvement on testosterone levels with the classic antidiabetic drugs. Studies with GLP1-receptor analogues show beneficial effects on both body weight and testosterone levels in men with low testosterone levels and obesity with or without type 2 diabetes. However, data are limited to small and heterogeneous study groups and only few studies report data about impact on and rogen-deficiency-related signs and symptoms. Discussion and conclusion: With the recent advances in the knowledge of the pathophysiological pathways in obesity, there is an enormous progress in the development of medications for obesity and type 2 diabetes. Newer incretin-based agents have a great potential for the treatment of functional hypogonadism due to obesity since they show promising weight reducing results. However, before the use of GLP1-receptor analogues can be suggested to treat functional hypogonadism, further studies are needed. [ABSTRACT FROM AUTHOR]

Introduction: The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone–binding globulin (SHBG) with incidence of dementia and Alzheimer's disease. Methods: Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables. Results: In 159,411 community‐dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P =.001, lowest vs highest quintile: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.13‐1.81), and AD (P =.017, HR = 1.80, CI = 1.21‐2.66). Lower SHBG was associated with a lower incidence of dementia (P <.001, HR = 0.66, CI = 0.51‐0.85) and AD (P =.012, HR = 0.53, CI = 0.34‐0.84). Discussion: Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older men. Additional research is needed to determine causality. [ABSTRACT FROM AUTHOR]

Background: Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell‐produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin‐like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes. Objectives: To characterize insulin‐like peptide 3 as a biomarker to assess gonadal status in aging men. Methods and materials: A large European multicenter (European Male Aging Study) cohort of community‐dwelling men was analyzed to determine how insulin‐like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters. Results and discussion: Insulin‐like peptide 3 declines cross‐sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin‐like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin‐like peptide 3 is negatively dependent on luteinizing hormone and sex hormone‐binding globulin and positively dependent on follicle‐stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin‐like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin‐like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European‐wide reference range for insulin‐like peptide 3 (95% confidence interval) adjusted for increasing age. Conclusion: Insulin‐like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin‐dependent short‐term regulation and within‐individual variation in testosterone. [ABSTRACT FROM AUTHOR]

Background: Guidelines suggest treating men with paraphilic disorder with androgen‐deprivation therapy (ADT). However, little evidence is available about the long‐term impact on bone loss and how to manage this adverse event. Objectives: The aim of this study is to assess the impact of ADT on bone mineral density (BMD) in men treated for paraphilic disorder with the androgen receptor blocker cyproterone acetate (CPA) and/or GnRH agonist triptoreline (GnRHa) and to evaluate the effect of treatment with bisphosphonates. Methods: Baseline and follow‐up dual‐energy X‐ray absorptiometry scan (DXA‐scan) data (lumbar and femoral T‐scores) were retrospectively extracted from electronic medical files of paraphilic men who received CPA and/or GnRHa. Results: A total of 53 patients with a mean age of 39.1 years (range 17.5–74.6) were included. Lumbar (−0.39 ± 0.17, Mean ± SEM, p = 0.046), femoral neck (−0.34 ± 0.09, p = 0.002) and total femur (−0.33 ± 0.12, p = 0.014) T‐scores decreased significantly in the CPA‐only group (n = 13) during a mean follow‐up of 6.0 ± 5.3 years. In the GnRHa group (n = 29), T‐scores at all sites decreased significantly over 6.6 ± 4.4 years (lumbar: −0.55 ± 0.12, p < 0.001, femoral neck: −0.53 ± 0.09, total femur: −0.44 ± 0.09, p < 0.001). In the group, who received bisphosphonates (n = 11), no significant T‐score change was observed (lumbar: −0.25 ± 0.14, p = 0.106, femoral neck −0.15 ± 0.17, p = 0.402, total femur −0.25 ± 0.14, p = 0.106) during 5.0 ± 2.8 years of follow‐up. Discussion and conclusion: Following a mean duration of 6 years of ADT, we observed a significant decline in BMD of approximately half a standard deviation in T‐score at lumbar and femoral site. Although the number of patients who received bisphosphonates was limited, this treatment seems to have a positive stabilizing effect on bone density. [ABSTRACT FROM AUTHOR]

Background: Age‐related chronic low‐grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia‐defining parameters, quality of life (QoL), and physical activity in middle‐aged and older men. Methods: Men aged 40–79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003–2005) and again after a median follow‐up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high‐sensitive C‐reactive protein (hs‐CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF‐36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole‐body dual X‐ray absorptiometry) and strength. In this subgroup, cross‐sectional associations between baseline inflammatory markers and sarcopenia‐defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking. Results: At baseline, hs‐CRP and WBC were negatively associated with PASE score (hs‐CRP: β = −7.920, P < 0.001; and WBC: β = −4.552, P < 0.001) and the physical component score of SF‐36 (hs‐CRP: β = −1.025, P < 0.001; and WBC: β = −0.364, P < 0.001). Baseline WBC levels were negatively associated with gait speed (β = −0.013; P = 0.025), quadriceps isometric 90° (β = −5.983; P = 0.035) and isokinetic 60°/s peak torque/body weight (β = −5.532; P = 0.027). The prevalence of sarcopenia at baseline was 18.1% (n = 81). Of those without sarcopenia at baseline, 64 (18.6%) satisfied criteria for sarcopenia at follow‐up. There were no significant associations between baseline inflammatory markers and either prevalent or incident sarcopenia, or change in level of sarcopenia‐defining parameters between baseline and follow‐up. Conclusions: In middle‐aged and older men, hs‐CRP and WBC were negatively associated with QoL and PASE scores, while WBC was negatively associated with gait speed and knee strength. Associations with hs‐CRP remained significant in all ages, whereas WBC levels were only associated with PASE, gait speed and knee strength in older adults (60–79 years). Baseline inflammatory markers (hs‐CRP, WBC and albumin) did not predict functional decline, decline in physical activity, decreased QoL or incident sarcopenia. [ABSTRACT FROM AUTHOR]

Objective: Serum testosterone concentrations are affected by factors unrelated to hypothalamo‐pituitary‐testicular axis pathology. We evaluated the impact of sociodemographic, lifestyle and medical factors, on serum testosterone and sex hormone–binding globulin (SHBG) in men aged 40‐69 years. Design: Cross‐sectional analysis of 208,677 community‐dwelling men from the UK Biobank. Measurements: We analysed associations of different factors with serum testosterone and SHBG (immunoassays) and calculated free testosterone (cFT), using smoothed centile plots, linear mixed models and effect size estimates. Results: Median (interquartile range) for serum testosterone was 11.6 (9.4‐14.1) nmol/L, SHBG 36.9 (27.9‐48.1) nmol/L and cFT 213 (178‐255) pmol/L. Age and BMI were inversely associated with testosterone and cFT, while SHBG was associated with age and inversely with BMI (all P <.001). Living with a partner, (South) Asian ethnicity, never or previous smoker and some medical conditions were associated with lower testosterone. Poultry or fish eater, and higher physical activity were associated with higher testosterone (all P <.001). Testosterone was lowered by ~0.5 nmol/L across ages, ~1.5 nmol/L for BMI 30 vs 25 kg/m2, ~2 nmol/L for (South) Asian ethnicity, living with partner, college/university qualifications, low red meat eater, insufficient physical activity and 0.3‐1.0 nmol/L with cardiovascular disease or diabetes. Different combinations of these factors varied serum testosterone by ~4 nmol/L, SHBG by ~30 nmol/L and cFT by ~60 pmol/L. Conclusions: The identified modifiable risk factors support lifestyle‐based interventions in men with low testosterone concentrations. Considering sociodemographic, lifestyle and medical factors facilitates more personalized interpretation of testosterone testing results with respect to existing reference ranges. [ABSTRACT FROM AUTHOR]

Mechanical stress determines bone mass and structure. It is not known whether mechanical loading affects expression of bone regulatory genes in a combined deficiency of estrogen and vitamin D. We studied the effect of mechanical loading on the messenger RNA (mRNA) expression of bone regulatory genes during vitamin D and/or estrogen deficiency. We performed a single bout in vivo axial loading with 14 N peak load, 2 Hz frequency and 360 cycles in right ulnae of nineteen weeks old female control Wistar rats with or without ovariectomy (OVX), vitamin D deficiency and the combination of OVX and vitamin D deficiency (N = 10/group). Total bone RNA was isolated 6 hours after loading, and mRNA expression was detected of Mepe, Fgf23, Dmp1, Phex, Sost, Col1a1, Cyp27b1, Vdr, and Esr1. Serum levels of 25(OH)D, 1,25(OH)2D and estradiol were also measured at this time point. The effect of loading, vitamin D and estrogen deficiency and their interaction on bone gene expression was tested using a mixed effect model analysis. Mechanical loading significantly increased the mRNA expression of Mepe, and Sost, whereas it decreased the mRNA expression of Fgf23 and Esr1. Mechanical loading showed a significant interaction with vitamin D deficiency with regard to mRNA expression of Vdr and Esr1. Mechanical loading affected gene expression of Mepe, Fgf23, Sost, and Esr1 independently of vitamin D or estrogen, indicating that mechanical loading may affect bone turnover even during vitamin D deficiency and after menopause. [ABSTRACT FROM AUTHOR]

Introduction: Functional hypogonadism increases in prevalence due to aging as well as an overall increase of obesity. Aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) could be an alternative for testosterone replacement therapy (TRT), but have not yet been established as common clinical practice. Methods: We conducted a thorough search of the literature published between 2009 and 2018. Only RCTs published in English were included. We assessed the impact of AIs and SERMs on gonadal steroids, sexual function and semen parameters, body composition and glucose homeostasis, physical function, bone mineral density (BMD), anemia, as well as potential adverse effects. Results: Twelve RCTs were included, with a total number of 645 patients. A total of 145 men were included in RCTs comparing AIs versus placebo or TRT and 476 men in RCTs with SERMs versus placebo or TRT. One RCT compared AIs versus SERMs in 24 men. Inclusion criteria were heterogenic. Most studies only included a small number of patients (range 11‐256) and follow‐up time was relatively short (6 weeks to 12 months). AIs as well as SERMs increased serum testosterone levels. Overall, there was no effect on sexual symptoms nor on semen parameters. Following aromatase inhibition, only minimal improvement of body composition and physical function was observed in some of the trials, but spinal BMD decreased. SERMs only induced a small improvement in body composition. The effect of SERMs on physical function and on BMD was not assessed. No major adverse effects occurred. Conclusion: AIs are not recommended as treatment for functional hypogonadism because of insufficient efficacy as well as a decrease in BMD. SERMs might be an alternative for TRT, but more research is needed to evaluate their effect on hypogonadal signs and symptoms, as well as on their long‐term safety profile. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding functional hypogonadism, previously referred to as 'late‐onset' hypogonadism, has increased substantially during the last 10 year. Objective: To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. Methods: Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results: The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well‐validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%‐50% represent relative contraindications for TRT. Prostate‐specific antigen and digital rectal examination of the prostate should be undertaken in men >40 years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. Conclusion: TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long‐term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision‐making. [ABSTRACT FROM AUTHOR]

Androgens via the androgen receptor (AR) are required for optimal male bone health. The target cell(s) for the effects of androgens on cortical bone remain(s) incompletely understood. In females, estrogen receptor alpha in neurons is a negative regulator of cortical and trabecular bone. Whether neuronal AR regulates bone mass in males remains unexplored. Here, we inactivated AR in neurons using a tamoxifen‐inducible CreERT2 under the control of the neuronal promoter Thy1. Tamoxifen induced a 70% to 80% reduction of AR mRNA levels in Thy1‐CreERT2‐positive brain regions cerebral cortex and brainstem as well as in the peripheral nervous tissue of male neuronal AR knockout (N‐ARKO) mice. Hypothalamic AR mRNA levels were only marginally reduced and the hypothalamic‐pituitary‐gonadal axis remained unaffected, as determined by normal levels of serum testosterone, luteinizing hormone (LH), and follicle‐stimulating hormone (FSH). In contrast to orchidectomy, deletion of neuronal AR did not alter body weight, body composition, hindlimb muscle mass, grip strength, or wheel running. MicroCT analysis of the femur revealed no changes in bone accrual during growth in N‐ARKO mice. However, 36‐ and 46‐week‐old N‐ARKO mice displayed an accelerated age‐related cortical involution, namely a more pronounced loss of cortical thickness and strength, which occurred in the setting of androgen sufficiency. Neuronal AR inactivation decreased the cancellous bone volume fraction in L5 vertebra but not in the appendicular skeleton of aging mice. MicroCT findings were corroborated in the tibia and after normalization of hormonal levels. Serum markers of bone turnover and histomorphometry parameters were comparable between genotypes, except for a 30% increase in osteoclast surface in the trabecular compartment of 36‐week‐old N‐ARKO mice. Cortical bone loss in N‐ARKO mice was associated with an upregulation of Ucp1 expression in brown adipose tissue, a widely used readout for sympathetic tone. We conclude that androgens preserve cortical integrity in aging male mice via AR in neurons. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Summary: Objective: Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone–binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). Design: Prospective observational study with a median follow‐up of 4.3 years. Patients: Three thousand three hundred sixty‐nine community‐dwelling men aged 40‐79 years from eight European centres. Measurements: Subjects were categorized according to baseline and follow‐up biochemical status into persistent eugonadal (referent group; n = 1880), incident LNSH (eugonadism to LNSH; n = 101) and incident LLSH (eugonadism to LLSH; n = 38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. Results: The cumulative incidence of LNSH and LLSH over 4.3 years was 4.9% and 1.9%, respectively. Baseline obesity predicted both LNSH and LLSH, but the former occurred more frequently in younger men. LLSH, but not LNSH, was associated with new/worsened sexual symptoms, including low desire [OR = 2.67 (1.27‐5.60)], erectile dysfunction [OR = 4.53 (2.05‐10.01)] and infrequent morning erections [OR = 3.40 (1.48‐7.84)]. Conclusions: These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT. [ABSTRACT FROM AUTHOR]

Summary: Objective: Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). Design, Patients and Measurements: We conducted a 4.3‐year prospective observational study of 3369 community‐dwelling European men aged 40‐79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. Results: Age >70 years (OR = 4.12 [2.07‐8.20]), diabetes (OR = 2.86 [1.42‐5.77]), chronic pain (OR = 2.53 [1.34‐4.77]), predegree education (OR = 1.79 [1.01‐3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24‐4.50]) predicted development of HLH. Younger age (40‐49 years, OR = 8.14 [1.35‐49.13]) and nonsmoking (OR = 5.39 [1.48‐19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85‐43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. Conclusions: Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism. [ABSTRACT FROM AUTHOR]

Relationships between 1,25-dihydroxyvitamin D (1,25(OH)2D) and skeletal outcomes are uncertain. We examined the associations of 1,25(OH)2D with bone mineral density (BMD), BMD change, and incident non-vertebral fractures in a cohort of older men and compared them with those of 25-hydroxyvitamin D (25OHD). The study population included 1000 men (aged 74.6 ± 6.2 years) in the Osteoporotic Fractures in Men (MrOS) study, of which 537 men had longitudinal dual-energy X-ray absorptiometry (DXA) data (4.5 years of follow-up). A case-cohort design and Cox proportional hazards models were used to test the association between vitamin D metabolite levels and incident nonvertebral and hip fractures. Linear regression models were used to estimate the association between vitamin D measures and baseline BMD and BMD change. Interactions between 25OHD and 1,25(OH)2D were tested for each outcome. Over an average follow-up of 5.1 years, 432 men experienced incident nonvertebral fractures, including 81 hip fractures. Higher 25OHD was associated with higher baseline BMD, slower BMD loss, and lower hip fracture risk. Conversely, men with higher 1,25(OH)2D had lower baseline BMD. 1,25(OH)2D was not associated with BMD loss or nonvertebral fracture. Compared with higher levels of calcitriol, the risk of hip fracture was higher in men with the lowest 1,25(OH)2D levels (8.70 to 51.60 pg/mL) after adjustment for baseline hip BMD (hazard ratio [HR] = 1.99, 95% confidence interval [CI] 1.19-3.33). Adjustment of 1,25(OH)2D data for 25OHD (and vice versa) had little effect on the associations observed but did attenuate the hip fracture association of both vitamin D metabolites. In older men, higher 1,25(OH)2D was associated with lower baseline BMD but was not related to the rate of bone loss or nonvertebral fracture risk. However, with BMD adjustment, a protective association for hip fracture was found with higher 1,25(OH)2D. The associations of 25OHD with skeletal outcomes were generally stronger than those for 1,25(OH)2D. These results do not support the hypothesis that measures of 1,25(OH)2D improve the ability to predict adverse skeletal outcomes when 25OHD measures are available. © 2015 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Androgens have well-established anabolic actions on skeletal muscle, although the direct effects of the androgen receptor (AR) in muscle remain unclear. We generated satellite cell-specific AR-knockout (satARKO) mice in which the AR is selectively ablated in satellite cells, the muscle precursor cells. Total-limb maximal grip strength is decreased by 7% in satARKO mice, with soleus muscles containing ~10% more type I fibers and 10% less type IIa fibers than the corresponding control littermates. The weight of the perineal levator ani muscle is markedly reduced (-52%). Thus, muscle AR is involved in fiber-type distribution and force production of the limb muscles, while it is a major determinant of the perineal muscle mass. Surprisingly,myostatin (Mstn), a strong inhibitor of skeletal muscle growth, is one of the most androgen-responsive genes (6-fold reduction in satARKO) through direct transcription activation by the AR. Consequently, muscle hypertrophy in response to androgens is augmented in Mstn-knockout mice. Our finding that androgens induce Mstn signaling to restrain their own anabolic actions has implications for the treatment of muscle wasting disorders. [ABSTRACT FROM AUTHOR]

Androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling has been mainly attributed to osteoblasts. Although osteocytes have emerged as key regulators of bone remodeling, the influence of sex steroids on these cells has been poorly studied. We aimed to investigate the role of AR signaling, specifically in osteocytes using the Cre/ LoxP system in male mice (driven by dentin matrix protein 1 [ocy-ARKOs]). Osteocyte fractions of control (AR(ex2)/Y) and ocy-ARKO (ARflox(ex2)/Y; DMP1-cre) mice isolated through sequential collagenase digestion showed increasing AR expression toward the mature osteocyte fraction of control males compared with the more immature fractions, whereas this was reduced by >80% in ocy-ARKO osteocytes. The skeletal phenotype of mutant mice was further assessed by histomorphometry and quantitative micro-computed tomography at 12 and 32 weeks of age. Ocy-ARKOs had significantly lower trabecular bone volume and number in femora and tibias at 32 weeks as well as decreased trabecular number in the L5 vertebra at 12 weeks. Biomechanical testing showed that ocy-ARKO femora were also stiffer and required a lower ultimate force to induce failure at 32 weeks. However, femoral cortical structure was not significantly different at any time point. The absence of AR in osteocyte also did not appear to affect trabecular bone formation nor its response to mechanical loading. In conclusion, selective inactivation of the AR in osteocytes of male mice accelerates age-related deterioration of skeletal integrity. These findings provide evidence for a direct role of androgens in the maintenance of trabecular bone through actions of the AR in osteocytes. © 2012 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) recognizes two types of DNA elements that are dimers of 5'-AGAACA-3'-like hexamers, either organized as inverted or direct repeats. We developed a mouse model [ (specificity affecting AR knock-in (SPARKI)] in which the AR DNA-binding domain was mutated such that it lost binding to direct repeats but not to inverted elements. The impaired fertility of the male SPARKI mice correlates with the reduced motility of the spermatozoa, a characteristic that is developed during transit through the epididymis. Comparative transcriptome analyses revealed that the expression of 39 genes is changed in SPARKI epididymis. Remarkably, the expression of the steroid 5α-reductase type II (Srd5α2) gene, which metabolizes testosterone into the more potent dihy-drotestosterone, is reduced 4-fold in SPARKI vs. wild type. The comparison of the SPARKI phenotype with that of Srd5α2-knockout mice shows, however, that the reduced Srd5α2 expression cannot explain all defects of the SPARKI epididymis. Moreover, we describe three new selective androgen response elements (AREs), which control the androgen responsiveness of the Srd5α2 gene. We conclude that the SPARKI model can be considered a knockout model for AR functioning via selective AREs and that this has a dramatic effect on sperm maturation in the epididymis. [ABSTRACT FROM AUTHOR]

Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post hoc analysis assessed the time to onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis. Data from 9355 women who were randomized in two placebo-controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.61-0.92, p = 0.0050) with significant reductions maintained at all subsequent time points. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR] = 0.74, 95% CI 0.60-0.91, p = 0.0044; year 2: OR = 0.53, 95% CI 0.42-0.66, p < 0.0001; year 3: OR = 0.61, 95% CI 0.48-0.77, p < 0.0001). This antifracture effect was persistent over 3 years, with the reductions in years 2 and 3 slightly larger than in year 1 ( p = 0.097). This analysis shows that zoledronic acid offered significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persisted for at least 3 years. © 2012 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head 'offset' data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies. © 2012 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objectives To assess the efficacy of once-yearly zoledronic acid ( ZOL) 5 mg in increasing bone mineral density ( BMD) in men with a recent hip fracture participating in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once- Yearly Recurrent Fracture Trial and to compare the efficacy with that in women from the same study. Design Randomized, placebo-controlled, double-blind trial. Setting International multicenter. Participants Five hundred and eight men and 1,619 women within 90 days of surgical repair of low-trauma hip fracture in the same study (for comparison). Intervention Once-yearly intravenous ( IV) ZOL 5 mg (n = 248) or placebo (n = 260), loading dose of vitamin D, daily calcium, and vitamin D supplements. Measurement Changes in BMD. Results Percentage change from baseline in total hip BMD at Months 12 and 24 was significantly higher with ZOL than with placebo (between-group difference, 2.0%, P = .003, and 3.8%, P = .002, respectively). Percentage change from baseline in femoral neck BMD at Month 24 was significantly higher with ZOL than with placebo (3.8%, P = .003). The BMD benefit was comparable with that observed in women in this study. New clinical fractures occurred in 36 (7.1%) participants ( ZOL, n = 16; placebo, n = 20; P = .64). The ZOL safety profile was comparable with that of placebo, with no significant differences in cardiovascular or long-term renal function and a trend toward lower mortality in ZOL-treated men. Conclusion Once-yearly IV ZOL 5 mg increases bone mass at the hip and femoral neck in men within 90 days of repair of a low-trauma hip fracture. Increases were of a similar magnitude to those observed in women in the same study. [ABSTRACT FROM AUTHOR]

To explore the associations between frailty and reproductive axis hormones (as an important regulatory system) in middle aged and older men. Cross-sectional. The European Male Aging Study. Three thousand two hundred nineteen community-dwelling European men aged 40 to 79. Interviewer-assisted questionnaires to assess physical activity, health status, and mood were administered. Testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were measured in a fasting morning blood sample. Frailty was assessed as an index (FI) according to the number (out of 43 possible) of health deficits (symptoms, signs, and functional impairments). Relationships between FI and hormone levels (as outcomes) were explored using regression models. Mean FI was 0.12 ± 0.11 (range 0-0.67) was highest in the oldest group. After adjustment for confounders, higher levels of FI were significantly associated with lower levels of total T, free T, and DHEAS and higher levels of gonadotropins and SHBG; a 1-standard deviation cross-sectional increase in FI was associated with a regression coefficient of −0.30 nmol/L (95% confidence interval (CI)=−0.53 to −0.07) decrease in total T and 0.66 U/L (95% CI=0.48-0.83) increase in LH. The associations between high FI, high gonadotropins, and well-maintained circulating T suggest that these changes are markers of aging-related disruptions of multiple physiological regulation, of which alterations in pituitary-testicular function represent a sensitive marker rather than an underlying pathogenic mechanism for frailty. [ABSTRACT FROM AUTHOR]

The article discusses a six-month randomized, controlled trial which determined the effects of whole-body vibration (WBV) training and vitamin D supplementation on isometric and dynamic muscle strength, leg muscle mass and hip bone mineral density (BMD) in institutionalized postmenopausal women. It was found that WBV training improved dynamic strength, BMD and vitamin D serum levels but did not change isometric strength and muscle mass. Compared with vitamin D supplementation, WBV was not more efficient in enhancing muscle mass, strength and BMD.

Background and aims Metabolic syndrome has been reported to have adverse effects on cognition although the results are conflicting. We investigated the association between metabolic syndrome and cognitive function in a population sample of middle-aged and older European men and whether any observed association could be explained by lifestyle or other confounding factors. Methods A total of 3369 men in the 40- to 79-year age group were recruited from population registers in eight centres for participation in the European Male Ageing Study. The subjects completed a questionnaire instrument and several cognitive function tests including the Rey-Osterrieth Complex Figure test, the Camden Topographical Recognition Memory test and the Digit Symbol Substitution Test. Metabolic syndrome data were assessed at an invited visit and metabolic syndrome was defined by the National Cholesterol Education Program's Adult Treatment Panel-III criteria. Associations between cognitive performance and metabolic syndrome were explored using linear regression. Results Complete cognitive and metabolic syndrome data from 3152 subjects were included in the analysis, of whom 1007 (32%) fulfilled criteria for metabolic syndrome. After adjustment for putative health and lifestyle confounders, no significant associations were found between any of the cognitive function scores and metabolic syndrome or between cognitive performance and high-sensitivity C-reactive protein. Analysis of the individual metabolic syndrome factors, however, revealed an inverse association between the level of glucose and cognitive performance. Conclusions Metabolic syndrome was not associated with cognitive impairment in this population. Of the individual components of the syndrome, diabetes was associated with poorer performances in memory, executive functions and processing speed, associations that warrant further investigation. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Studies of vitamin D and calcium for fracture prevention have produced inconsistent results, as a result of different vitamin D status and calcium intake at baseline, different doses and poor to adequate compliance. This study tries to define the types of patients, both at risk of osteoporosis and with established disease, who may benefit from calcium and vitamin D supplementation. The importance of adequate compliance in these individuals is also discussed. Calcium and vitamin D therapy has been recommended for older persons, either frail and institutionalized or independent, with key risk factors including decreased bone mineral density (BMD), osteoporotic fractures, increased bone remodelling as a result of secondary hyperparathyroidism and increased propensity to falls. In addition, treatment of osteoporosis with a bisphosphonate was less effective in patients with vitamin D deficiency. Calcium and vitamin D supplementation is a key component of prevention and treatment of osteoporosis unless calcium intake and vitamin D status are optimal. For primary disease prevention, supplementation should be targeted to those with dietary insufficiencies. Several serum 25-hydroxyvitamin D (25(OH)D) cut-offs have been proposed to define vitamin D insufficiency (as opposed to adequate vitamin D status), ranging from 30 to 100 nmol/l. Based on the relationship between serum 25(OH)D, BMD, bone turnover, lower extremity function and falls, we suggest that 50 nmol/l is the appropriate serum 25(OH)D threshold to define vitamin D insufficiency. Supplementation should therefore generally aim to increase 25(OH)D levels within the 50–75 nmol/l range. This level can be achieved with a dose of 800 IU/day vitamin D, the dose that was used in succesfull fracture prevention studies to date; a randomized clinical trial assessing whether higher vitamin D doses achieve a greater reduction of fracture incidence would be of considerable interest. As calcium balance is not only affected by vitamin D status but also by calcium intake, recommendations for adequate calcium intake should also be met. The findings of community-based clinical trials with vitamin D and calcium supplementation in which compliance was moderate or less have often been negative, whereas studies in institutionalized patients in whom medication administration was supervised ensuring adequate compliance demonstrated significant benefits. [ABSTRACT FROM AUTHOR]

The article discusses a study which determined the link of genetic variation in the RANKL/RANK/OPG signaling pathway with bone turnover and bone mineral density (BMD) in men. The researchers selected pairwise tag single-nucleotide polymorphisms (SNPs) in RANKL, RANK and OPG and their flanking regions. The results of the study suggest that genetic variation in the RANKL/RANK/OPG signaling pathway has an effect on bone turnover and BMD in European men.

The article discusses research done on the identification of sexual dimorphism in cortical bone size and strength using independent and time-specific actions of sex steroids and insulin-like growth factor 1. Study subjects consisted of male and female mice that were obtained in Uden, the Netherlands. The reduction of radial bone expansion in male mice using orchidectomy is also reported.

The article presents a study of the adaptive response of in vivo ulna loading in androgen receptor (AR)-estrogen receptor-alpha (ERα) knockout (KO) mice and corresponding male and female single KO and wild-type (WT) littermates through dynamic histomorphometry and immunohistochemistry. The animals were bought from the Jackson Laboratory. They concluded that AR limits the osteogenic response to loading in male mice possibly via an effect on wingless/integrated (WNT) signaling.

Objectives We determined levels of cognitive functioning in community dwelling men aged 40–79 (n = 3265) from eight European centres and investigated to what extent cognitive performance varied between centres, the association between different cognitive domains and age, educational level, co-morbidity and lifestyle factors and the respective contributions of centre and individual factors to cognitive performance. Methods Cognitive domains assessed were visuo-constructional ability and visual memory (Rey–Osterrieth Complex Figure test, ROCF), topographical memory (Camden Topographical Recognition Memory test, CTRM) and processing speed (Digit-Symbol Substitution test, DSST). Results There were significant between-centre differences in all four cognitive test scores. Using multilevel linear regression analysis (MLRA), age, education, depression, physical performance and smoking were independent predictors of cognitive function and these variables explained 10–13% of the variation in cognitive scores between centres and 17–36% of the variation in scores between individuals within centres. Conclusion Our data suggest that although a proportion of the variance in cognitive function among European men is explained by individual level differences, a significant proportion is due to contextual phenomenon. Such contextual factors need to be considered when analysing multi-centre data and European men should not be treated as homogeneous when assessing cognitive performance using existing instruments. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Life expectancy is increasing in most developed countries, in part due to improved socioeconomic conditions and in part to advances in healthcare. It is widely acknowledged that the promotion of healthy ageing by delaying, minimizing or preventing disabilities or diseases is one of the most important public health objectives in this century. In contrast to the menopausal transition in females, we know relatively little about the contribution of androgens and anabolic hormones to the quality of ageing in men. The European Male Ageing Study (EMAS) is a multicentre prospective cohort designed to examine the prevalence, incidence and geographical distribution of gender-specific and general symptoms of ageing in men, including their endocrine, genetic and psychosocial predictors. Men aged 40–79 years were recruited from eight European centres: Florence (Italy), Leuven (Belgium), Lodz (Poland), Malmö (Sweden), Manchester (UK), Santiago de Compostela (Spain), Szeged (Hungary) and Tartu (Estonia). Subjects were recruited from population registers and those who agreed to take part completed a detailed questionnaire including aspects of personal and medical history, lifestyle factors and sexual function. Objective measures of body size, cognition, vision, skeletal health and neuromuscular function were obtained. Blood and DNA specimens were collected for a range of biochemical and genetic analyses. After an average of 4 years, it is planned to resurvey the participants with similar assessments. A total of 3369 men with a mean age of 60 ± 11 years were recruited. The mean centre response rate was 43%, and highest in those aged 50–59 years. Those who participated were marginally younger than those who were invited but declined to participate (60.0 vs. 61.1 years). Participants left education slightly later than a sample of non-participants, though there were no consistent differences in levels of general health, physical activity, or smoking. EMAS will provide new population-based data concerning the main features that characterize ageing in men and its critical determinants, particularly with reference to age-related changes in hormone levels. Such information is an important prerequisite to develop effective strategies to reduce age-related disabilities and optimise health and well-being into old-age. [ABSTRACT FROM AUTHOR]

The article presents the results of research which was conducted in an effort to determine if sex variation in sex hormone genes influences heel ultrasound parameters and bone strength in middle aged and elderly men. Researchers found that there is an association between ultrasound parameters and genetic polymorphisms and that genetically determined sex hormones influence male bone health.

Osteoporosis and muscle frailty are important health problems in elderly men and may be partly related to biological androgen activity. This androgen action can be mediated directly through stimulation of the androgen receptor (AR) or indirectly through stimulation of estrogen receptor-alpha (ERα) following aromatization of androgens into estrogens. To assess the differential action of AR and ERα pathways on bone and body composition, AR-ERα double-knockout mice were generated and characterized. AR disruption decreased trabecular bone mass, whereas ERα disruption had no additional effect on the AR-dependent trabecular bone loss. In contrast, combined AR and ERα inactivation additionally reduced cortical bone and muscle mass compared with either AR or ERα disruption alone. ERα inactivation--in the presence or absence of AR--increased fat mass. We demonstrate that AR activation is solely responsible for the development and maintenance of male trabecular bone mass. Both AR and ERα activation, however, are needed to optimize the acquisition of cortical bone and muscle mass. ERα activation alone is sufficient for the regulation of fat mass. Our findings dearly define the relative importance of AR and ERα signaling on trabecular and cortical bone mass as well as body composition in male mice. [ABSTRACT FROM AUTHOR]

The article examines the impact of androgens, growth hormone and muscle on male mice during puberty. The growth hormone is considered to be a major regulator of postnatal skeletal growth. The study was administered with dihydrotestosterone or testosterone to the male during late puberty. The results shows that the administration has fully prevented trabecular bone loss. The signalling and androgens are both necessary for optimal stimulation of periosteal growth during puberty.

A correction to the article "Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk-A perspective" that was published in previous issue of the periodical is presented.

Reports news updates from the European Academy of Andrology (EAA), as of December 1999. Final program of the first European Congress of Andrology; Preliminary program of the pre-congress postgraduate course; Scientific meeting of the clinical training center of the EAA.

Discusses the international quality control program for Y-chromosomal microdeletions of the European Academy of Andrology (EAA). Implications of the deletion of the Y-chromosome into discrete genes; Problems created by the heterogeneity of the protocols employed in the analysis of the Y-chromosome in infertile males; Activities and future goals of the EAA program for Y-chromosomal microdeletions.

Objective: The aim of the current study was to investigate whether genetic variation in genes across the serotoninergic system is associated with chronic widespread pain (CWP) and the number of pain sites reported., Methods: A discovery cohort, with pain data at 3 time points, was used to investigate genetic associations with 2 phenotypes: 1) CWP (at ≥ 2 time points; n = 164) compared with pain-free controls (at 3 time points; n = 172), and 2) the maximum number of pain sites reported at any 1 of the 3 time points (range of sites 0-29; n = 989). A cohort of 2,285 men for whom a DNA sample and pain data were available (including 203 CWP cases and 929 controls) was used for validation. Pairwise tagging (r(2) > 0.8) single-nucleotide polymorphisms (SNPs) were genotyped. Logistic and zero-inflated negative binomial regression analyses were used to test for SNP associations with CWP and the number of pain sites, respectively., Results: SNPs in HTR2A were associated with both pain phenotypes in the discovery cohort, and a number of these SNP associations were replicated in the validation cohort, some of which were attenuated after adjustment for depression. There was an increased likelihood of having CWP in subjects with 1 or 2 copies of the T allele of rs12584920 (odds ratio [OR] 1.64, 95% confidence interval [95% CI] 1.01-2.60 [P = 0.03] in the discovery cohort, and OR 1.46, 95% CI 1.07-2.00 [P = 0.018] in the validation cohort). A similar association was observed between rs17289394 and the maximum number of pain sites reported in both cohorts. Results from a meta-analysis of the data from the 2 cohorts further strengthened these findings., Conclusion: The findings of this study support the role of HTR2A in the genetic predisposition to musculoskeletal pain., (Copyright © 2011 by the American College of Rheumatology.)