Androgen Deprivation Therapy/Androgen Receptor Signaling Inhibitor Treatments for Prostate Cancer: Pathophysiology and Review of Effects on Cardiovascular Disease.

Androgen deprivation therapy is the cornerstone of systemic management for prostate cancer but is associated with multiple adverse effects that must be considered during treatment. These effects occur because of the profound hypogonadism that is induced from lack of testosterone or due to the medications used in the treatment or in combination with androgen receptor signaling inhibitors. This article critically reviews the associations between androgen deprivation therapy, androgen receptor signaling inhibitors, and cardiovascular complications such as prolonged QT interval, atrial fibrillation, heart failure, atherosclerosis, coronary heart disease, venous thromboembolism, and peripheral arterial occlusive disease. These unfavorable outcomes reinforce the need for regular cardiovascular screening of patients undergoing androgen deprivation for the management of prostate cancer.

Recovery of male reproductive endocrine function after ceasing prolonged testosterone undecanoate injections.

CONTEXT: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known. OBJECTIVE: The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections. MATERIALS AND METHODS: Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later. RESULTS: In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant's own pre-treatment baseline over 12 months since the last injection. CONCLUSIONS: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

Novel splicing-site mutation in DCAF17 gene causing Woodhouse-Sakati syndrome in a large consanguineous family.

BACKGROUND: Woodhouse-Sakati syndrome is a rare autosomal recessive disease with endocrine and neuroectodermal aberrations with heterogeneous phenotypes and disease course. The most common phenotypes of the disease are progressive sensorineural hearing loss and alopecia, mild-to-moderate mental retardation and hypogonadism. The disease results from mutations in the DCAF17 gene. METHOD: Here, we reported a large consanguineous pedigree with multiple affected individuals with Woodhouse-Sakati syndrome phenotypes. Laboratory tests confirmed the endocrine perturbance in affected individuals. To find out the underlying genetic change, whole-exome sequencing was carried out. RESULT: Analysis of the exome data identified a splicing-site deletion NM_025000.3:c.1423-1_1425delGACA in DCAF17 gene. Sanger sequencing confirmed the co-segregation of the variant with the disease phenotypes in the family. CONCLUSION: The variant is predicted to cause aberrant splicing, i.e., exon skipping, resulting in the translation of a truncated functionless protein which results in appearance of typical phenotypic features and clinical laboratory findings of Woodhouse-Sakati syndrome in affected members of the family.

Effect of testosterone replacement therapy on insulin sensitivity and body composition in congenital hypogonadism: A prospective longitudinal follow-up study.

Aims: To evaluate the prevalence of metabolic syndrome (MS) and whole-body composition in patients with congenital hypogonadism and investigate the effects of replacement therapy with testosterone undecanoate on MS, insulin resistance (IR), and whole-body composition in subset of patients. Methods: In a single arm prospective longitudinal intervention study, 33 patients with congenital hypogonadism, ages 20-39 years, were recruited and their parameters of MS, whole-body composition by DXA were compared with age and BMI matched healthy controls. In 21 patients, after 9 months we prospectively studied the effect (pre-post difference) of injection testosterone undecanoate (1,000 mg) replacement on MS, IR, and whole-body compositions. Results: The prevalence of MS was similar in patients and controls (27.3% vs. 9.1%, P = 0.05). Hypogonadism patients had higher prevalence of hypertension (33% vs. 3%, P < 0.01). Patients had decrease in lean body mass (P < 0.05) as compared to controls. After testosterone replacement, there was significant decrease in waist circumference (88.6 ± 13.1 cm vs. 83.9 ± 12.9 cm, P < 0.01), truncal fat (25.9 ± 7.3% vs. 24.0 ± 6.3%, P < 0.05), fasting C-peptide (2.1 ± 0.79 ng/ml vs. 0.68 ± 0.23 ng/ml, P < 0.01), serum proinsulin [1.43 (0.32-13.4) vs. 0.5 (0.5-3.2) pmol/l, P < 0.001] and a significant increase in lean body mass (46,906 ± 8,876 gm vs. 50,083 ± 7,590 gm, P < 0.001). Homeostasis model assessment of insulin resistance (HOMA-IR) (4.6 ± 1.7 vs. 0.5 ± 0.2, P < 0.001) and homeostatic model for assessment of insulin sensitivity (HOMA%S) [21 (12-65) vs. 206 (125-714), P < 0.001] were improved significantly following testosterone replacement. Conclusion: In this study, 36 weeks of testosterone replacement resulted in significant decrease in waist circumference, IR, truncal fat, total body fat and improvement in lean body mass, and insulin sensitivity.

Timing of Pubertal Onset in Girls and Boys With Constitutional Delay.

CONTEXT: The decision whether to treat a child with delayed puberty with sex steroids is primarily based on patient, family, and provider preference. Knowing when children with constitutional delay eventually enter puberty would inform this decision. OBJECTIVE, DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: To estimate and compare rates of pubertal entry, we conducted a retrospective cohort study by reviewing medical records of children evaluated for delayed puberty at a large academic medical center between 2000 and 2015, extracting data on pubertal status for all clinical visits, then conducting time-to-event analyses. RESULTS: Of 392 girls and 683 boys with delayed puberty, constitutional delay was the most common cause, found in 32% of girls and 70% of boys. In a subcohort of 97 girls and 243 boys who were prepubertal at one or more visits, we observed a broad age range for pubertal entry, up to >16 years for girls and >17 years for boys. The probability of entering puberty within the next year for 12- to 15.5-year-old girls and 13.5- to 16.5-year-old boys with delayed puberty ranged between 38% and 74%. No differences in the rates of pubertal entry were seen between girls and boys after data harmonization. CONCLUSION: The broad range of ages at pubertal entry for children with constitutional delay challenges the concept that constitutional delay is merely an extreme of normal variation. Discussions with patients and families about management should consider the possibility that some children may need to wait years after presentation until puberty starts.

Gonadotropins for testicular descent in cryptorchid congenital hypogonadotropic hypogonadism males beyond infancy.

OBJECTIVES: To study the effect of combined gonadotropin therapy (CGT) on testicular descent ± spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients with cryptorchidism beyond infancy. METHODS: This retrospective cohort study included CHH patients with cryptorchidism [bilateral (n=5) or unilateral (n=1)] treated with CGT for testicular descent ± pubertal induction. All participants were treated with CGT [human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG)] with hMG pretreatment in three and monitored for changes in testicular volume (TV), serum total testosterone (T), serum inhibin-B, and sperm concentration. RESULTS: Complete testicular descent to the scrotal position was achieved in 5/6 patients (10/11 testes) after 4.7 ± 1.6 months of treatment. There was 44 ± 18%, 97.5% (IQR: 44-195), 10-fold (IQR: 3-19.6), and two-fold (IQR: 1.7-9.3) increase in stretched penile length, ultrasound measured TV, T level, and serum inhibin-B from baseline, respectively. In two pediatric cases, testicular descent occurred with isolated hMG therapy. At the last follow up (median: 23.5, IQR: 10.5-38.7 months), all the descended testes remained in scrotal position. In four pubertal/postpubertal age patients, continuous CGT (18-60 months) yielded T and inhibin-B levels of 16.64 ± 1.46 nmol/l and 106 ± 32.6 pg/mL, respectively. All the three patients with available semen analysis had sperm concentration of ≥5 million/mL and one of them achieved paternity. CONCLUSIONS: A trial of CGT before orchiopexy may be considered in CHH males with cryptorchidism even beyond the narrow age-window of infancy. CGT may also have beneficial effects on future spermatogenesis and fertility outcomes in these patients.

Serum concentrations of dihydrotestosterone are associated with symptoms of hypogonadism in biochemically eugonadal men.

PURPOSE: Symptoms of hypogonadism are often reported by subjects with normal serum testosterone (T) levels. We aimed to assess the association between clinical symptoms in andrological outpatients and sex steroids levels. METHODS: This is a retrospective cross-sectional cohort study in an Academic clinic and research unit. International Index of Erectile Function (IIEF, EF domain) and Aging Males Symptoms scale (AMS) questionnaires were completed by 635 and 574 men, respectively (mean age: 47.3 ± 13.9 and 47.4 ± 13.8 years, p = 0.829), free of interfering medications with complaints possibly related to hypogonadism. RESULTS: Serum total/free T as well as dihydro-T (DHT) was associated with IIEF-EF and AMS scores in the overall population using univariate analyses. Multivariate approaches revealed DHT concentrations in subjects with normal T levels (n = 416, Total T > 12 nmol/L) to be significant predictors of AMS scores. A 0.1 nmol/l serum DHT increase within the eugonadal range was associated with a 4.67% decrease in odds of having worse symptoms (p = 0.011). In men with biochemical hypogonadism (Total T < 12 nmol/L), total and free T rather than DHT were associated with AMS results. This association was not found for IIEF-EF scores. Indirect effects of age and BMI were seen for relations with hormone concentrations but not questionnaire scores. CONCLUSION: DHT can be associated with symptoms of hypogonadism in biochemically eugonadal men. Serum DHT measurement might be helpful once the diagnosis of hypogonadism has been ruled out but should not be routinely included in the primary diagnostic process.

Hypogonadism in Patients with Prader Willi Syndrome: A Narrative Review.

Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder related to the lack of a functional paternal copy of chromosome 15q11-q13. Several clinical manifestations are reported, such as short stature, cognitive and behavioral disability, temperature instability, hypotonia, hypersomnia, hyperphagia, and multiple endocrine abnormalities, including growth hormone deficiency and hypogonadism. The hypogonadism in PWS is due to central and peripheral mechanisms involving the hypothalamus-pituitary-gonadal axis. The early diagnosis and management of hypogonadism in PWS are both important for physicians in order to reach a better quality of life for these patients. The aim of this study is to summarize and investigate causes and possible therapies for hypogonadism in PWS. Additional studies are further needed to clarify the role of different genes related to hypogonadism and to establish a common and evidence-based therapy.

Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome.

The PHF6 mutation c.1024C > T; p.R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate-severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology. We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippocampus and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.

A case report of congenital idiopathic hypogonadotropic hypogonadism caused by novel mutation of GNRHR gene.

RATIONALE: This study aimed to investigate the genetic mutation characteristics of congenital idiopathic hypogonadotropic hypogonadism (IHH) through the clinical features and genetic analysis of 2 patients with IHH in 1 pedigree. PATIENT CONCERNS: A 23-year-old girl presented with primary amenorrhea, sparse pubic hair, lack of breast development, and delayed sexual development. DIAGNOSES: Combined with the clinical characteristics, auxiliary examinations, and molecular genetic analysis, the patient was diagnosed as IHH. INTERVENTIONS: Whole exome and Sanger sequencing were performed to validate the mutation in family members. OUTCOMES: A novel homozygous missense mutation c.521A > G (p.Q174R) in the GNRHR gene was identified in the 2 affected sisters. Familial segregation showed that the homozygous variant was inherited from their parents respectively and the eldest sister was the carrier without correlative symptom. LESSONS: We reported a novel GNRHR mutation in a pedigree with congenital idiopathic hypogonadotropic hypogonadism. Glutamine at amino acid position 174 was highly conserved among various species. The molecular structure of GNRHR protein showed that p.Q174R mutation brought in a new stable hydrogen bond between position 174 and 215, may impede conformational mobility of the TMD4 and TMD5. It suggests that the missense mutation c.521A > G related to congenital idiopathic hypogonadotropic hypogonadism was probably a causative factor for both sisters. Through high-throughput sequencing and experimental verification, we had basically determined the patient's pathogenic mutation and inheritance, which could better guide doctors for treatment.

Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology.

Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.

Associations between smoking, sex hormone levels and late-onset hypogonadism in men differ depending on age.

Few studies have investigated whether associations between smoking, sex hormone levels, and symptoms of late-onset hypogonadism (LOH) in men are affected by age. This multi-center, cross-sectional study involving 6,296 men aged 40-79 years was conducted between June 1, 2013 and August 31, 2016 in 6 provinces of China. Total testosterone, free testosterone, and Aging Males' Symptoms scale (AMS) scores were compared depending on smoking status and the number of cigarettes smoked. Total testosterone was higher in smokers than in non-smokers in all except the 70-79 year old subgroup. Free testosterone was higher in smokers than non-smokers for the 40-49 and 50-59 year old subgroups, but not the 60-69 and 70-79 year old subgroups. Total testosterone was positively associated with number of cigarettes consumed in smokers aged 40-49 and 50-59 years. Sexual and somatic AMS scores were higher in current and ex-smokers than in non-smokers in all age subgroups from 40 to 79 years and were negatively associated with cigarette consumption in smokers aged 40-49 years. These results indicate that, as men age, the positive association between smoking and testosterone weakens, while the positive association between smoking and LOH symptoms becomes stronger.

In Men With Obesity, T2DM Is Associated With Poor Trabecular Microarchitecture and Bone Strength and Low Bone Turnover.

INTRODUCTION: Obesity and type 2 Diabetes (T2D) are both associated with greater bone mineral density (BMD) but increased risk of fractures. The effect of the combination of both conditions on bone metabolism, microarchitecture, and strength in the obese population remains unknown. METHODS: Data from 112 obese men were collected. Bone turnover and biochemical markers were measured by enzyme-linked immunosorbent assay, body composition and BMD at all sites were assessed by dual energy X-ray absorptiometry, whereas bone microarchitecture and strength (stiffness and failure load) were measured by high-resolution peripheral computed tomography. Data were compared among metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) with and without T2D and between obese without and with T2D. RESULTS: Compared to MHO and MUHO without T2D, MUHO with T2D had significantly lower levels of osteocalcin ((7.49 ±â€…3.0 and 6.03 ±â€…2.47 vs 4.24 ±â€…2.72 ng/mL, respectively, P = 0.003) and C-terminal telopeptide of type I collagen (CTx) (0.28 ±â€…0.10 and 0.29 ±â€…0.13 vs 0.21 ±â€…0.15 ng/mL, respectively, P = 0.02). Dividing our subjects simply into those with and without T2D showed that obese men with T2D had significantly lower levels of osteocalcin (P = 0.003) and CTx (P = 0.005), greater trabecular separation at the tibia and radius (P = 0.03 and P = 0.04, respectively), and lower tibial failure load and stiffness (both P = 0.04), relative to obese men without T2D. CONCLUSION: In men, the combination of obesity and T2D is associated with reduced bone turnover and poorer trabecular bone microarchitecture and bone strength compared to those who are obese but without T2D, suggesting worse bone disease.

Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism.

PURPOSE: The pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH) is genetically complex. The aims of this study were to investigate the genetic profile and clinical manifestation of IHH in a Chinese pedigree and to discover new IHH-associated genes. METHODS: The first step was to follow up the clinical phenotype and therapeutic outcomes of the pedigree in university hospital. The second step was that mutation screening was performed in this pedigree and 100 healthy controls. The third step was to further verify the pathogenicity of the discovered rare sequencing variant (RSV) by functional experiments. Whole exome sequencing, Sanger sequencing, testicular volume (TV), semen analysis, assessment of cell migration and necroptosis were performed. RESULTS: One heterozygous RSV (p.G517E) in CHL1 was identified in two male IHH patients and their mother in the pedigree, but not in healthy controls. All the three individuals exhibited olfactory impairment. hCG/hMG treatment significantly improved TV, serum testosterone and/or semen parameters of the two male patients. Functional analysis indicated that CHL1 significantly regulated GnRH neuronal cell line (GN11 cells) migration and necroptosis, with alteration of ERK1/2 activation, calcium loading, and transcription of RIPK3 and MLKL. However, the above processes were negatively influenced by the CHL1 RSV. CONCLUSIONS: Our study reports the genetic relevance of CHL1 in IHH, and characterizes the phenotypic and therapeutic profiles in patients carrying the CHL1 RSV. CHL1 may act as a new IHH-associated gene, and should be taken into consideration in future investigations for this field.

The effect of long-term hypogonadism on body composition and morphometry of aged male Wistar rats.

Clinical studies show that hypogonadism in the aging male is associated with obesity and osteoporosis. Experimental studies are mostly conducted on relatively young adult animals and the induced hypogonadism lasts for a relatively short time. The present study aimed to describe the effect of long-term hypogonadism beginning in puberty on body composition, morphometry, and bone mineral density in aged male rats. Morphometric measurements and dual-energy X-ray absorptiometry were conducted at the age of 30 months on control and gonadectomized males. Long-term hypogonadism did not affect body weight, but led to a higher fat mass (by 26 %), lower lean mass (by 44 %), shorter body length (by 9 %), and anogenital distance (by 26 %), as well as to lower tail circumference (by 15 %) in comparison to control males. Lower bone mineral density (by 13 %) and bone mineral content (by 15 %) were observed in gonadectomized males. Results showing sarcopenic obesity and osteoporosis in this model of long-term hypogonadism might mimic the situation in aging males better than the widely used short-term hypogonadism induced in young animals. The morphometric analysis could potentially be a useful tool to study normal weight obesity without the need for specific equipment.

Health status is related to testosterone, estrone and body fat: moving to functional hypogonadism in adult men with HIV.

OBJECTIVE: Hypogonadism is common in HIV-infected men. The relationship between health status, sex steroids and body composition is poorly known in HIV. The aim was to investigate the association between health status (comorbidities/frailty), body composition, and gonadal function in young-to-middle-aged HIV-infected men. DESIGN: Prospective, cross-sectional, observational study. METHODS: HIV-infected men aged <50 years and ongoing Highly Active Antiretroviral Therapy were enrolled. Serum total testosterone (TT), estradiol (E2), estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, LH and FSH by immunoassay. Free testosterone (cFT) was calculated by Vermeulen equation. Body composition was assessed by dual-energy X-ray absorptiometry and abdominal CT scan. Multimorbidity (MM) and frailty were defined as ≥3 comorbidities and by a 37-item index, respectively. RESULTS: A total of 316 HIV-infected men aged 45.3 ± 5.3 years were enrolled. Body fat parameters were inversely related to cFT and TT, and directly related to E1 and E2/testosterone (TS) ratio. Patients with MM had lower cFT (P < 0.0001) and TT (P = 0.036), and higher E1 (P < 0.0001) and E2/TS ratio (P = 0.002). Frailty was inversely related to cFT (R2 = 0.057, P < 0.0001) and TT (R2 = 0.013, P = 0.043), and directly related to E1 (R2 = 0.171, P < 0.0001), E2 (R2 = 0.041, P = 0.004) and E2/TS ratio (R2 = 0.104, P < 0.0001). CONCLUSIONS: Lower TT and cFT, higher E1, E2/TS ratio and visceral fat were independently associated to poor health status and frailty, being possible hallmarks of unhealthy conditions in adult HIV-infected men. Overall, MM, frailty and body fat mass are strictly associated to each other and to sex steroids, concurring together to functional male hypogonadism in HIV.

Functional Characteristics of Novel FGFR1 Mutations in Patients with Isolated Gonadotropin-Releasing Hormone Deficiency.

BACKGROUND: Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) has a wide phenotypic spectrum including Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). FGFR1 mutations have been identified in 3-10% of patients with KS or nIHH. This study was performed to investigate clinical phenotypes and functional characteristics of FGFR1 mutations in patients with IGD. METHODS: This study included 8 patients (from 7 families) with FGFR1 mutations identified by targeted gene panel sequencing or whole exome sequencing (WES). The impact of the identified mutations on FGFR1 function was assessed using in vitro studies. RESULTS: Seven heterozygous mutations in FGFR1 were identified in 8 patients from 7 independent families. The patients exhibited a wide spectrum of pubertal development, including anosmia in a prepubertal boy (n=1), delayed puberty (n=2), nIHH (n=3), and KS (n=2). Four of the mutations were classified as likely pathogenic, and the other three were variants of uncertain significance. FGF8-FGFR1 signaling activities for the novel FGFR1 variants (p.Y339H, p.S681I, and p.N185Kfs*16) were reduced by in vitro functional assay, indicating loss-of-function mutations. CONCLUSIONS: This study identified seven rare sequence variants in FGFR1 in patients with KS and nIHH. Probands with an FGFR1 mutations displayed a wide phenotypic spectrum ranging from KS to anosmia. A prepubertal male with anosmia should be followed up to assess pubertal development because they can manifest hypogonadotropic hypogonadism after puberty. These results expand the phenotypic spectrum of FGFR1 mutations and suggest a broader biologic role of FGFR1 in reproduction.

Testosterone Replacement Therapy Added to Intensive Lifestyle Intervention in Older Men With Obesity and Hypogonadism.

BACKGROUND: Obesity and hypogonadism additively contribute to frailty in older men; however, appropriate treatment remains controversial. OBJECTIVE: Determine whether testosterone replacement augments the effect of lifestyle therapy on physical function in older men with obesity and hypogonadism. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: VA Medical Center. PARTICIPANTS: 83 older (age ≥65 years) men with obesity (body mass index ≥30 kg/m2) and persistently low am testosterone (<10.4 nmol/L) associated with frailty. INTERVENTIONS: Participants were randomized to lifestyle therapy (weight management and exercise training) plus either testosterone (LT+Test) or placebo (LT+Pbo) for 6 months. OUTCOME MEASURES: Primary outcome was change in Physical Performance Test (PPT) score. Secondary outcomes included other frailty measures, body composition, hip bone mineral density (BMD), physical functions, hematocrit, prostate specific antigen (PSA), and sex hormones. RESULTS: PPT score increased similarly in LT+Test and LT+Pbo group (17% vs. 16%; P = 0.58). VO2peak increased more in LT+Test than LT+Pbo (23% vs. 16%; P = 0.03). Despite similar -9% weight loss, lean body mass and thigh muscle volume decreased less in LT+Test than LT+Pbo (-2% vs. -3%; P = 0.01 and -2% vs -4%; P = 0.04). Hip BMD was preserved in LT+Test compared with LT+Pbo (0.5% vs -1.1%; P = 0.003). Strength increased similarly in LT+Test and LT+Pbo (23% vs 22%; P = 0.94). Hematocrit but not PSA increased more in LT+Test than LT+Pbo (5% vs 1%; P < 0.001). Testosterone levels increased more in LT+Test than LT+Pbo (167% vs 27%; P < 0.001). CONCLUSION: In older, obese hypogonadal men, adding testosterone for 6 months to lifestyle therapy does not further improve overall physical function. However, our findings suggest that testosterone may attenuate the weight loss-induced reduction in muscle mass and hip BMD and may further improve aerobic capacity.

Prevalence of late-onset hypogonadism among middle-aged and elderly males in China: results from a national survey.

This study aimed to propose an operational definition of late-onset hypogonadism (LOH) that incorporates both clinical symptoms and serum testosterone measurements to evaluate the prevalence of LOH in aging males in China. A population-based sample of 6296 men aged 40 years-79 years old was enrolled from six representative provinces in China. Serum total testosterone (TT), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were measured and free testosterone (cFT) was calculated. The Aging Males' Symptoms (AMS) scale was used to evaluate the LOH symptoms. Finally, 5078 men were included in this analysis. The TT levels did not decrease with age (P = 0.59), and had no relationship with AMS symptoms (P = 0.87 for AMS total score, P = 0.74 for ≥ 3 sexual symptoms). The cFT levels decreased significantly with age (P < 0.01) and showed a negative association with the presence of ≥ 3 sexual symptoms (P = 0.03). The overall estimated prevalence of LOH was 7.8% (395/5078) if a cFT level <210 pmol l-1 combined with the presence of ≥ 3 sexual symptoms was used as the criterion of LOH. Among them, 26.1% (103/395) and 73.9% (292/395) had primary and secondary hypogonadism, respectively. After adjustment for confounding factors, primary and secondary hypogonadism was positively related to age and comorbidities. Body mass index was an independent risk factor for secondary hypogonadism. The results suggest that the AMS total score is not an appropriate indicator for decreased testosterone, and that the cFT level is more reliable than TT for LOH diagnosis. Secondary hypogonadism is the most common form of LOH.