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Introduction: Testosterone deficiency is a clinical disorder due to either failure of the testes to produce testosterone or failure of the hypothalamus or pituitary to produce sufficient gonadotropins. Previous formulations of oral testosterone therapy, particularly methyltestosterone, have been associated with adverse liver effects. Many different routes of testosterone delivery have been developed, each with their own administrative benefits and challenges. Newer formulations of oral testosterone undecanoate (TU) provide a convenient administration option, although their use has been limited by hepatotoxicity concerns based on older methyltestosterone data, and prescribing physicians may still be concerned about adverse liver effects., Objectives: In this review, we discuss the history of oral testosterone development, clarify the mechanism of action of oral TU, and describe the relevant liver safety findings., Methods: Relevant literature was allocated to present a review on the history of oral TU development and the mechanism of action of oral TU. We pooled data from individual studies of oral TU products to present a safety summary., Results: Overall, safety results from studies of the newer formulations of oral TU showed that increased liver function test values are not generally associated with oral TU formulations and that no clinically significant liver toxicities were noted in clinical trials of oral TU., Conclusion: Continued research into the safety of oral TU will contribute to a better understanding of the potential risks in patients receiving this therapy, an outcome that highlights the importance of providing patient education and reassurance regarding oral TU safety., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine.)

Objective: Assessment of the efficacy and safety/tolerability of the aromatase inhibitor leflutrozole to normalise testosterone in Obesity-associated Hypogonadotropic Hypogonadism (OHH)., Design: Placebo-controlled, double-blind, RCT, in 70 sites in Europe/USA., Methods: Patient inclusion criteria: men with BMI of 30-50 kg/m2, morning total testosterone (TT) < 10.41 nmol/L, and two androgen deficiency symptoms (at least one of sexual dysfunction). Patients randomised to weekly leflutrozole (0.1/0.3/1.0 mg) or placebo for 24 weeks. Primary endpoint: normalisation of TT levels in ≥75% of patients after 24 weeks. Secondary endpoints (included): time to TT normalisation and change in LH/FSH. Safety was assessed through adverse events and laboratory monitoring., Results and Conclusions: Of 2103 screened, 271 were randomised, 81 discontinued. Demographic characteristics were similar across groups. Mean BMI was 38.1 kg/m2 and TT 7.97 nmol/L. The primary endpoint was achieved in all leflutrozole-treated groups by 24 weeks with a dose-tiered response; mean TT 15.89; 17.78; 20.35 nmol/L, for leflutrozole 0.1 mg, 0.3 mg, and 1.0 mg groups respectively, vs 8.04 nmol/L for placebo. LH/FSH significantly increased in leflutrozole vs placebo groups. No improvements in body composition or sexual dysfunction were observed. Semen volume/total motile sperm count improved with leflutrozole vs placebo. Treatment-emergent adverse events, more common in leflutrozole-treated groups included, raised haematocrit, hypertension, increased PSA, and headache. Some reduction in lumbar bone density was observed with leflutrozole (mean -1.24%, -1.30%, -2.09%) and 0.66% for 0.1 mg, 0.3 mg, 1.0 mg, and placebo, respectively, without change at the hip. This RCT of leflutrozole in OHH demonstrated normalisation of TT in obese men. FSH/LH and semen parameter changes support that leflutrozole may preserve/improve testicular function., Clinical Trial Registration Number: NCT02730169., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase., Objective: To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men., Design, Setting, and Participants: The UK Biobank prospective cohort study of community-dwelling men aged 40-69 years old, followed for 11 years., Main Outcome Measures: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa., Results: In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06-1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09-1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63-0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59-0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72-0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results., Conclusions: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Hypogonadism is a well-established consequence of opioid use. It has been reported in both men and women, although more widely studied in men., Evidence Acquisition: PubMed was searched for articles in English until December 2019 for opioids and hypogonadism. Bibliography of retrieved articles was searched for relevant articles., Evidence Synthesis: The prevalence of opioid-induced hypogonadism (OIH) varies between studies but was reported to be 69% in a recent systematic review. There is large heterogeneity in the studies, with different factors shown to have stronger association with hypogonadism such as specific types of opioids, higher doses, and longer durations of use. The consequences of OIH include sexual dysfunction, depression, decreased quality of life, and low bone density. There is paucity of randomized controlled trials assessing the efficacy of testosterone replacement therapy (TRT) for OIH in men, and even less studies on treating OIH in women. TRT studies in men reported varying outcomes with some studies favoring and others showing no clear benefit of TRT on different measures., Conclusions: Despite the high prevalence of OIH, it remains underrecognized and undertreated with multiple endocrine and metabolic consequences. A reasonable approach in patients using opioids includes informing them of this complication and its potential consequences, screening for signs and symptoms of hypogonadism then sex hormone levels if prolonged opioid use > 3 months, and treating patients diagnosed with hypogonadism, if and when clinically indicated, with sex hormones if chronic opioids are planned to be continued for ≥ 6 months., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Based on the 2018 American College of Cardiology/American Heart Association cholesterol guidelines, the number of individuals eligible for statin therapy to reduce atherosclerotic cardiovascular disease risk has greatly expanded. Statins inhibit cholesterol biosynthesis, which can impair gonadal steroidogenesis. We evaluated the effect of statins on endogenous sex hormones in a large epidemiological study., Methods: A total of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants underwent the baseline examination. Of these, 6171 had measurements of serum sex hormones available: dehydroepiandrosterone (DHEA), SHBG, estradiol, and total and bioavailable testosterone. Multivariable linear regression models were used to assess the relationship of statin use with each sex hormone., Results: A total of 345 women (17.4%) and 464 men (14.7%) were statin users (mean age, 67 years; 41% white, 29% black, 11% Chinese, and 19% Hispanic). Among the users vs nonusers of statins, the mean SHBG was 3.54 nmol/L (P < 0.01) lower in women and 3.37 nmol/L (P < 0.001) lower in men; the mean DHEA was 1.06 nmol/L (P < 0.05) lower in women and 0.70 nmol/L (P < 0.01) lower in men, after adjustment for potential confounders. With further propensity score adjustment, the mean DHEA and SHBG levels were 0.67 nmol/L (P < 0.05) and 3.49 nmol/L (P < 0.001) lower, respectively, for statin users vs nonusers. No statistically significant association was noted between estradiol, total testosterone, and bioavailable testosterone and statin use., Conclusion: Statin users have lower levels of SHBG and DHEA. This is especially relevant owing to the increasing use of statin therapy., (Copyright © 2019 Endocrine Society.)

Background: The Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF) is a patient-reported outcome measurement designed to evaluate the symptoms of hypogonadism. The HIS-Q-SF is an abbreviated version including17 items from the original 28-item HIS-Q., Aim: To conduct item analyses and reduction, evaluate the psychometric properties of the HIS-Q-SF, and provide guidance on score interpretation., Methods: A 12-week observational longitudinal study of hypogonadal men was conducted as part of the original HIS-Q psychometric evaluation. Participants completed the original HIS-Q every 2 weeks. Blood samples were collected to evaluate testosterone levels. Participants completed the Aging Male's Symptoms Scale, the International Index of Erectile Function, the Short Form-12, and the PROMIS Sexual Activity, Satisfaction with Sex Life, Sleep Disturbance, and Applied Cognition Scales (baseline and weeks 6 and 12). Clinicians completed the Clinical Global Impression of Severity and Change scales and a clinical form., Main Outcome Measures: Item performance was evaluated using descriptive statistics and Rasch analyses. Reliability (internal consistency and test-retest), validity (concurrent and know groups), and responsiveness were assessed., Results: One hundred seventy-seven men participated (mean age = 54.1 years, range = 23-83). Similar to the full HIS-Q, the final abbreviated HIS-Q-SF instrument includes five domains (sexual, energy, sleep, cognition, and mood) with two sexual subdomains (libido and sexual function). For key domains, test-retest reliability was very good, and construct validity was good for all domains. Known-groups validity was demonstrated for all domain scores, subdomain scores, and total score based on the Clinical Global Impression-Severity. All domains and subdomains were responsive to change based on patient-rated anchor questions., Clinical Implications: The HIS-Q-SF could be a useful tool in clinical practice, epidemiologic studies, and other academic research settings., Strengths and Limitations: Careful consideration was given to the selection of the final HIS-Q-SF items based on quantitative data and clinical expert feedback. Overall, the reduced set of items demonstrated strong psychometric properties. Testosterone levels for the participating men were not as low as anticipated, which could have limited the ability to examine the relations between the HIS-Q-SF and testosterone levels. Further, the analyses used data collected through administration of the full HIS-Q, and future studies should administer the standalone HIS-Q-SF to replicate the psychometric analyses reported in the present study., Conclusion: Similar to the original HIS-Q, the HIS-Q-SF has evidence supporting reliability, validity, and responsiveness. The short form includes a smaller set of items that might be more suitable for use in clinical practice or academic research settings. Gelhorn HL, Roberts LJ, Khandelwal N, et al. Psychometric Evaluation of the Hypogonadism Impact of Symptoms Questionnaire Short Form (HIS-Q-SF). J Sex Med 2017;14:1046-1058., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The extent to which inflammation, immune activation/immunosenescence, and hormonal abnormalities are driven by human immunodeficiency virus (HIV) or frailty is not clear., Methods: HIV-infected frail men (n = 155) were matched to nonfrail, HIV-infected (n = 141) and HIV-uninfected (n = 150) men by age, calendar year, and antiretroviral therapy use (HIV-infected men only). Frailty was defined by ≥3 frailty-related phenotype criteria (weight loss, exhaustion, low activity, slowness) at ≥2 visits, or at 1 visit with ≥1 criteria at ≥2 visits. The following measurements were obtained: interleukin 6, high-sensitivity C-reactive protein, soluble receptors for tumor necrosis factor α 1 and 2, the percentages of CD4+CD28-, CD8+CD28-, CD4+CD38+HLA-DR+, and CD8+CD38+HLA-DR+ T cells, dehydroepiandrosterone sulfate, free testosterone, homeostatic model assessment of insulin resistance, and insulin-like growth factor 1. Log-linear regressions were adjusted for a priori selected covariates to determine differences by frailty and HIV status., Results: In multivariate analyses adjusted for covariates, frailty was associated among HIV-infected men with higher interleukin 6 and high-sensitivity C-reactive protein and lower free testosterone and dehydroepiandrosterone levels. In contrast, HIV infection but not frailty was associated with significantly greater immune senescence (percentage of CD4+CD28- or CD8+CD28- T cells) and immune activation (percentages of CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ T cells)., Conclusions: Frailty among HIV-infected men was associated with increased inflammation and lower hormone levels, independent of comorbid conditions. Interventions targeting these pathways should be evaluated to determine the impact on prevention or reversal of frailty among HIV-infected men., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Introduction: Hypogonadism in men is often associated with poor libido, erectile dysfunction, irritability, fatigue, and psychological and relationship problems. Many of these symptoms can be best assessed through patient report. The 28-item Hypogonadism Impact of Symptoms Questionnaire (HIS-Q) was developed to evaluate hypogonadism symptoms in men with low testosterone in the context of clinical trials., Aim: To develop a briefer version of the HIS-Q that could be practical for use in treatment settings., Methods: Participants with low testosterone levels and symptoms consistent with hypogonadism were recruited through clinical sites. Focus groups and interviews were conducted to elicit symptom concepts and identify those that were most relevant to patients, including changes as a consequence of treatment., Main Outcome Measures: Systematic analysis of the qualitative data and expert clinician input were used to develop the HIS-Q short form (HIS-Q-SF). One-on-one cognitive interviews were conducted to confirm the content validity of the HIS-Q-SF., Results: Thirty-five men participated in this qualitative research. Concept elicitation was conducted through focus group discussions (n = 18) and telephone interviews (n = 2); then, the draft HIS-Q-SF was evaluated through cognitive interviews (n = 15). The mean age of total sample was 53.2 ± 6.8 years, and the mean serum total testosterone level was 184.9 ± 55.2 ng/dL. Results suggest that the HIS-Q-SF has demonstrated content validity, including the content coverage, comprehensibility, and the appropriateness of the response options and recall period. The final version of the HIS-Q-SF includes 17 items and is aligned with the original longer version of the instrument., Conclusion: The HIS-Q-SF is a comprehensive measurement of hypogonadism symptom severity in men. Content coverage and content validity were confirmed. The instrument will be evaluated further to establish the psychometric characteristics and to assess the utility of the measurement in clinical treatment settings., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The Hypogonadism Impact of Symptoms Questionnaire (HIS-Q) is a patient-reported outcome measurement designed to comprehensively evaluate the symptoms of hypogonadism and to detect changes in these symptoms in response to treatment., Aim: To conduct item analysis and reduction, evaluate the psychometric properties of the HIS-Q, and provide guidance on interpreting the instrument score., Methods: A 12-week observational, longitudinal study of hypogonadal men was conducted. Participants completed the HIS-Q every 2 weeks. Blood samples were collected to evaluate testosterone levels. Participants also completed the Aging Male's Symptoms Scale, the International Index of Erectile Function, the Short Form-12 Health Survey, and the Patient-Reported Outcomes Measurement Information System Sexual Activity, Satisfaction with Sex Life, Sleep Disturbance, and Applied Cognition Scales (at baseline and weeks 6 and 12). Clinicians completed the Clinical Global Impression of Severity and Change measurements and a clinical form., Main Outcome Measures: Individual item performance was evaluated using descriptive statistics and Rasch analyses. Reliability (internal consistency and test-retest), validity (concurrent and know groups), and responsiveness were assessed., Results: In total, 177 men participated in the study (mean age = 54.1 years, range = 23-83). The original 53-item draft HIS-Q was reduced to 28 items; the final instrument included five domains (sexual, energy, sleep, cognition, and mood) with two sexual subdomains (libido and sexual function). For all domains, test-retest reliability was acceptable (intraclass correlation coefficients > 0.70), construct validity was good (|r > 0.30| for all comparisons). Known-groups validity was demonstrated for all HIS-Q domain scores, subdomain scores, and the total score as measured by the Clinical Global Impression of Severity, and total testosterone level at baseline (P < .05 for all comparisons). All domains and subdomains were responsive to change based on patient-rated anchor questions (P < .05 for all comparisons)., Conclusion: The final 28-item HIS-Q is reliable, valid, and responsive. The HIS-Q is suitable for inclusion in future clinical trials to help characterize the effects of testosterone replacement therapy., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Androgen excess may be adrenal and/or ovarian in origin; we hypothesized that a subgroup of patients with polycystic ovarian syndrome (PCOS) may have some degree of abnormal adrenocortical function., Objective: The objective of the study was to evaluate the pituitary adrenal axis with an oral low- and high-dose dexamethasone-suppression test (Liddle's test) in women with PCOS., Design: This was a case-control study., Setting: The study was conducted at the National Institutes of Health Clinical Center., Participants: A total of 38 women with PCOS and 20 healthy volunteers (HV) aged 16-29 years participated in the study., Main Outcome Measures: Urinary free cortisol (UFC) and 17-hydroxysteroids (17OHS) before and after low- and high-dose dexamethasone and assessment of adrenal volume by computed tomography scan were measured., Results: Twenty-four-hour urinary 17OHS and UFC were measured during day 1 to day 6 of the Liddle's test. Baseline UFC levels were not different between PCOS and HVs; on the day after the completion of high-dose dexamethasone administration (d 6), UFC was higher in the PCOS group (2.0 ± 0.7 μg/m(2)·d) than the HV group (1.5 ± 0.5) (P = .038). On day 5, 17OHS and UFC were negatively correlated with adrenal volumes (left side, rp = -0.47, P = .009, and rp = -0.61, P < .001, respectively). PCOS patients above the 75th percentile for UFC and/or 17OHS after high-dose dexamethasone (n = 15) had a significantly smaller total adrenal volume (6.9 ± 1.9 cm(3) vs 9.2 ± 1.8 cm(3), P = .003) when compared with the remaining PCOS patients (n = 22), but they did not have worse insulin resistance or hyperandrogenism., Conclusions: In a subset of young women with PCOS, we detected a pattern of glucocorticoid secretion that mimicked that of patients with micronodular adrenocortical hyperplasia: they had smaller adrenal volumes and higher steroid hormone secretion after dexamethasone compared with the group of PCOS with appropriate response to dexamethasone.

Context: Epidemiologic studies suggest that endogenous testosterone (T) levels in males may be implicated in cardiovascular disease (CVD), however further clarification is needed., Objective: We assessed the cross-sectional relationship between endogenous plasma T and mean carotid intima media thickness (cIMT), and the longitudinal relationship with incident clinical CVD events, cardiac mortality, and all-cause mortality using male participants in the Atherosclerosis Risk in Communities (ARIC) study., Design: This study involved a subset of men from visit 4 of the ARIC study., Setting: The study was conducted in a community based cohort., Participants: Males who provided a morning blood sample excluding those taking androgen therapy, with prevalent coronary heart disease (CHD), stroke, or heart failure (HF) (n = 1558)., Intervention: None., Main Outcome Measures: Plasma T by liquid chromatography mass spectrometry and carotid IMT using high resolution B-mode ultrasound were obtained at visit 4. Incident CHD, HF, cardiac mortality, and all-cause mortality were identified by surveillance through 2010 (median 12.8 years)., Results: Lower T was significantly associated with higher body mass index, greater waist circumference, diabetes, hypertension, lower HDL, and never smoking (P = 0.01). T was not associated with mean cIMT in unadjusted or adjusted analyses. Following multivariable adjustment, there was no association of quartile (Q) of T with incident CHD [hazard ratio (HR) = 0.87 (95% CI = 0.60-1.26) for Q1; 0.97 (95% CI = 0.69-1.38) for Q2; 0.97 (95% CI = 0.69-1.36) for Q3 compared to reference of Q4] or for incident HF [HR = 0.77 (95% CI = 0.46-1.29) for Q1; 0.72 (95% CI = 0.43-1.21) for Q2; 0.87 (95% CI = 0.53-1.42) for Q3 compared to reference of Q4]. Similarly there was no association of Q of T with mortality or cardiac-associated mortality., Conclusions: Low male plasma T is cross-sectionally associated with key CVD risk factors, but after adjustment there was no association with mean cIMT, incident cardiac events, or mortality. Our results are reassuring that neither high nor low T levels directly predict atherosclerosis, but are a marker for other cardiovascular risk factors.

Introduction: Little is known about the effect of body mass index (BMI) on the efficacy and safety of testosterone therapy in hypogonadal men. A prior noncomparative trial demonstrated that testosterone 2% gel restored testosterone levels in hypogonadal men and was generally well tolerated., Aim: This post hoc analysis evaluated the influence of BMI on the pharmacokinetics of testosterone therapy in men with low testosterone., Methods: Men (N = 149) aged 18-75 applied testosterone 2% gel to the front and inner thigh once daily for 90 days. Starting dose was 40 mg/day, which could be adjusted at days 14, 35, and 60. Patients were split into categories depending on baseline BMI: Tertile 1 (≤ 29.1 kg/m(2)), Tertile 2 (29.2-32.4 kg/m(2)), and Tertile 3 (>32.4 kg/m(2))., Main Outcome Measures: Efficacy end points were average serum total testosterone concentrations over 24 hours and maximum serum testosterone concentrations at day 90. Adverse events were recorded., Results: The efficacy analysis included 129 men with low testosterone (mean age 52.9, 54.0, and 54.2 years for Tertiles 1, 2, and 3, respectively) defined as serum testosterone <250-300 ng/dL. Baseline testosterone levels were comparable across BMI tertiles. After 90 days of treatment with testosterone 2% gel (≥ 40 mg/day), 79.1%, 79.5%, and 73.8% of patients in Tertiles 1, 2, and 3, respectively, achieved serum testosterone concentrations in the physiologic range (i.e., ≥ 300 to ≤ 1,140 ng/dL). The mean average daily dose at day 90 was higher in participants in Tertiles 3 vs. 2 (P = 0.039) and Tertiles 3 vs. 1 (P = 0.010). The gel was generally well tolerated, with skin reactions the most commonly reported adverse event (16.1%; n = 24)., Conclusions: In this study, daily application of testosterone 2% gel was effective at returning serum testosterone to physiologic levels in men with low testosterone and high BMI, although required dose was affected by BMI., (© 2013 International Society for Sexual Medicine.)

The association of sex hormone levels with mortality over a median of 16 years of follow-up was evaluated in a prospective cohort study. The study included 1,114 US men who participated in phase 1 (1988-1991) of the Third National Health and Nutrition Examination Survey Mortality Study and had no history of cardiovascular disease or cancer at baseline. Multivariable adjusted hazard ratios for all-cause mortality associated with a decrease in hormone concentration equal to the difference between the 90th and 10th percentiles of the sex hormone distributions were estimated by using proportional hazards regression. The hazard ratios associated with low free testosterone and low bioavailable testosterone levels were 1.43 (95% confidence interval (CI): 1.09, 1.87) and 1.52 (95% CI: 1.15, 2.02), respectively, for follow-up between baseline and year 9; they were 0.94 (95% CI: 0.51, 1.72) and 0.98 (95% CI: 0.56, 1.72), respectively, for follow-up between year 9 and year 18. Men with low free and bioavailable testosterone levels may have a higher risk of mortality within 9 years of hormone measurement. Future studies should be conducted to fully characterize the association of low free and bioavailable testosterone concentrations and mortality in men and to describe the mechanism underlying the association.

Context: In postmenopausal women, endogenous bioavailable testosterone (T) and estradiol (E2) have been positively associated, and SHBG has been negatively associated, with incident type 2 diabetes (T2DM). Previous studies have not explored possible factors explaining these relationships., Objective: Our objective was to examine the association of endogenous sex hormones with incident T2DM in postmenopausal women and possible explanatory factors., Design, Setting, and Participants: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective study that included 1612 postmenopausal women aged 45-84 yr, followed between the years 2000-2006, who were not taking hormone replacement therapy, had no prevalent cardiovascular disease or diabetes, and had complete ascertainment of sex hormones., Main Outcome Measures: T2DM was defined based on fasting glucose and/or treatment for diabetes., Results: There were 116 incident cases of diabetes during follow-up. Across higher quartiles of bioavailable T and E2 and lower quartiles of SHBG, we found significantly greater hazards of developing incident T2DM (all P for trend

Context: Recent clinical trials of im testosterone in eugonadal men suggest positive effects on verbal memory, but other studies find no effect., Objective: Our objective was to determine whether supraphysiological testosterone influences verbal memory and brain function during a verbal memory task in healthy eugonadal older men., Patients, Design, and Setting: Fifteen cognitively normal men, aged 66-86 yr, participated in a randomized, double-blind, placebo-controlled crossover trial involving 9 months of participation per participant at a hospital-based research facility., Intervention: We used testosterone enanthate (200 mg im every other week for 90 d) crossed over with placebo (sesame oil vehicle im) with a 90-d washout between treatments., Main Outcome Measures: Performance was assessed on a standardized verbal memory test, and brain activity (relative glucose metabolic rates) in medial temporal and frontal regions was measured with positron emission tomography during a verbal memory task., Results: Treatment increased total testosterone by 241%. Behavioral results showed a significant decrease in short-delay verbal memory with treatment (P < 0.05, effect size = 0.59 sd) and a nonsignificant decrease on a composite verbal memory measure (P = 0.09, effect size = 0.48 sd). Positron emission tomography scans revealed decreased relative activity in ventromedial temporal cortex (i.e. right amygdala/entorhinal cortex) and increased relative activity in bilateral prefrontal cortex with treatment., Conclusions: Decreased verbal memory and altered relative activity in medial temporal and prefrontal regions suggest possible detrimental effects of supraphysiological testosterone supplementation in elderly men. The results do not rule out potential benefits with other regimens, cognitive tests, or populations.

Context: Higher testosterone in black compared with white men has been postulated to explain their higher prostate cancer incidence. Previous studies comparing hormone levels by race might have been limited by size, restricted age variation, or lack of representation of the general population., Objective: Our objective was to compare serum testosterone, estradiol, and SHBG concentrations among non-Hispanic black, non-Hispanic white, and Mexican-American men., Participants, Design, and Setting: A total of 1413 men aged 20+ yr and who attended the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988-1991 were included in this cross-sectional study., Measurement: Serum hormone concentrations were measured by electrochemiluminescence immunoassays., Results: After applying sampling weights and adjusting for age, percent body fat, alcohol, smoking, and activity, testosterone concentrations were not different between non-Hispanic blacks (n = 363; geometric mean, 5.29 ng/ml) and non-Hispanic whites (n = 674; 5.11 ng/ml; P > 0.05) but were higher in Mexican-Americans (n = 376; 5.48 ng/ml; P < 0.05). Non-Hispanic blacks (40.80 pg/ml) had a higher estradiol concentration than non-Hispanic whites (35.46 pg/ml; P < 0.01) and Mexican-Americans (34.11 pg/ml; P < 0.01). Non-Hispanic blacks (36.49 nmol/liter) had a higher SHBG concentration than non-Hispanic whites (34.91 nmol/liter; P < 0.05) and Mexican-Americans (35.04 nmol/liter; P < 0.05)., Conclusions: Contrary to the postulated racial difference, testosterone concentrations did not differ notably between black and white men. However, blacks had higher estradiol levels. Mexican-Americans had higher testosterone than whites but similar estradiol and SHBG concentrations. Given these findings, it may be equally if not more important to investigate estradiol as testosterone in relation to diseases with racial disparity.

Context: In postmenopausal women, endogenous estradiol (E2) and free testosterone (T) have been positively associated with glucose intolerance and type 2 diabetes. Most studies have not examined these associations in a large group of postmenopausal women., Objective: The objective was to examine the association between endogenous sex hormones and glucose tolerance in postmenopausal women., Design, Setting, and Participants: This was a cross-sectional study of 1973 postmenopausal women ages 45-84 yr, not taking hormone replacement therapy, in the Multi-Ethnic Study of Atherosclerosis baseline examination., Main Outcome Measures: Impaired fasting glucose (IFG) and diabetes were defined based on fasting blood sugar and/or treatment for diabetes. In women with normal glucose tolerance, insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR)., Results: Increasing quartiles of bioavailable T and E2 and decreasing quartiles of SHBG were associated with significantly increased odds of IFG and diabetes (all P for trend<0.001). Except for the association of bioavailable T with diabetes, the other associations persisted after multivariable adjustment. Although higher dehydroepiandrostenedione (DHEA) was associated with greater odds of IFG (P for trend=0.02), it was not associated with diabetes. Of 1100 women with normal glucose tolerance, E2 and DHEA were positively associated, and SHBG was inversely associated with HOMA-IR (all P<0.001) after multivariable adjustment. Bioavailable T was associated with HOMA-IR (P<0.001), but not fasting glucose., Conclusion: Of postmenopausal women, endogenous bioavailable T, E2, and DHEA were positively associated and SHBG was negatively associated with insulin resistance.

Context: Recently, the field of androgen therapy in postmenopausal women has received much attention and press. Although the ovary ceases to produce follicles and estrogen at menopause, it continues to produce androgens. Hence, many oophorectomized women complain of sexual dysfunction (despite adequate estrogenization). Previous studies of nontransdermal testosterone replacement have shown an improvement in libido and sexual frequency, although at the cost of supraphysiological testosterone levels. Transdermal testosterone patch (Intrinsa) was developed to deliver a physiological amount of testosterone. In 2004, the Food and Drug Administration voted not to approve Intrinsa until long-term safety data are available., Evidence Acquisition: Recent trials of Intrinsa in postmenopausal women were included. A MEDLINE search was conducted for articles published over the last 40 yr based on the key words androgen therapy/replacement and postmenopausal women. Relevant placebo-controlled trials of nontransdermal androgen therapy in postmenopausal women were also reviewed., Evidence Synthesis: Early results from industry-funded trials show that transdermal testosterone therapy results in only moderate (although statistically significant) improvement in libido in surgically menopausal women (on estrogen). However, the published data are of short duration (24 wk). Hence, long-term safety in these women remains unclear., Conclusion: We recommend a short-term trial (not to exceed 24 wk) of transdermal testosterone therapy (once approved) in surgically menopausal (estrogenized) women with distressful sexual dysfunction. Until the patch gets approval, a short trial of oral methyltestosterone in deserving estrogenized women may be justified.

Objective: To determine the prevalence of, risk factors for, and clinical manifestations of low androgen levels in older men who have or who are at risk of acquiring human immunodeficiency virus (HIV) infection, we performed a cross-sectional analysis of an observational cohort of men aged > or =49 years old., Methods: A standardized interview (regarding demographic characteristics, behaviors, and medical history) was performed, and body mass index, HIV serologic data, CD4+ cell count, the presence of hepatitis C virus (HCV) markers, and serum testosterone and human sex-binding hormone levels were determined. Factors associated with androgen levels were assessed using logistic regression models., Results: Among 502 men (age, 49-81 years) who were not taking androgens, 54% had total testosterone levels of <300 ng/dL. Low androgen levels were associated with injection drug use, HCV infection, high body mass index, and use of psychotropic medications (P<.05); black race was associated with higher androgen levels. Only among men who reported having sex with men was low testosterone level associated with HIV infection (adjusted odds ratio [OR(adj)] for total testosterone level of <300 ng/dL, 5.1; 95% confidence interval [CI], 1.2-22.4), but among all HIV-seropositive men, HIV load of >10,000 copies/mL was associated with a testosterone level of <200 ng/dL (OR(adj), 2.1; 95% CI, 1.1-4.3; P=.03). On univariate analysis, low androgen levels were associated with decreased interest in sex, depressive symptoms, loss of concentration/memory, difficulty sleeping, osteopenia, and poorer subjective health (P<.05)., Conclusions: Most older men at risk for HIV infection have low androgen levels. Injection drug use, high body mass index, HCV infection, and use of psychotropic medications are associated with low androgen levels, and low androgen levels are associated with symptoms of hypogonadism.

Previous studies have revealed that exogenous estrogen has a beneficial effect on the lipid profile; however, studies examining the relation between endogenous hormones and lipid profiles in postmenopausal women have yielded conflicting results. We sought to characterize the cross-sectional relationship between endogenous hormones and lipid parameters in postmenopausal women with significant (cases, n = 156) and minimal (controls, n = 172) carotid atherosclerosis not taking hormone therapy in the Atherosclerosis Risk in Communities Study. Endogenous hormone status was assessed by measuring levels of estrone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and SHBG. Free testosterone was estimated using the free androgen index (total testosterone/SHBG). Lipid parameters assessed included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. We found that SHBG was significantly associated with a more favorable lipid profile, including lower total and LDL cholesterol and triglycerides and higher HDL cholesterol among controls. This association was less prominent among cases where SHBG was only associated with higher triglycerides and lower HDL cholesterol. The free androgen index was associated with a more atherogenic lipid profile, including increased LDL cholesterol among controls and increased total and LDL cholesterol and triglycerides among cases. These relations were independent of demographic and metabolic factors and health behaviors. In contrast to controls, estrone was associated with higher total cholesterol and triglycerides among cases in multivariate analyses. Our data suggest that endogenous sex hormones may play a role in regulating lipid metabolism in postmenopausal women.

In 1990-1992, the authors investigated the association of total and free testosterone with the metabolic syndrome in postmenopausal US women not taking hormone replacement therapy (n=362) in a prevalent case-control study of carotid atherosclerosis. Free testosterone was estimated by using the free androgen index (FAI) (total testosterone/sex hormone-binding globulin ratio). The metabolic syndrome was defined as the presence of three or more of the following criteria: waist circumference > or =35 inches (88.9 cm), triglycerides > or =150 mg/dl, high density lipoprotein cholesterol <40 mg/dl, blood pressure >130/80 mmHg, fasting insulin > or =100 pmol/liter, or impaired glucose homeostasis (fasting glucose > or =110 mg/dl or diagnosed diabetes mellitus). FAI, but not total testosterone, was strongly associated with the metabolic syndrome. Compared with women in the lowest FAI quartile, those in the highest quartile had a fivefold greater odds of having the metabolic syndrome (odds ratio=5.38, 95% confidence interval: 2.70, 10.7) after adjustment for age, race, and carotid atherosclerosis status. In multivariate analyses, the three-component metabolic syndrome combinations that contained both hyperinsulinemia and hyperglycemia were most strongly associated with increased FAI (absolute increase=0.41-0.54 compared with that for women who did not have these combinations; all p's < 0.001). Higher FAI was associated with the hyperinsulinemia and hyperglycemia components of the metabolic syndrome. The role of androgens in glucose homeostasis in postmenopausal women requires further study.

A new mucoadhesive testosterone buccal system (Striant), 30 mg testosterone (T), was applied twice daily in 82 hypogonadal men for 3 months. Serum T, free T, and 5alpha-dihydrotestosterone were measured during this period. T pharmacokinetics were determined from the data obtained during a 24-h sampling at wk 12. Physiological mean serum T concentrations were steady and consistently maintained. The mean percentage of time over a 24-h period that total serum T concentrations were above the lower limit of adult male range was 80.1%. During treatment, mean serum 5alpha-dihydrotestosterone, free T, and estradiol concentrations paralleled serum T. T pharmacokinetics were not significantly affected by body mass index, age, food or beverage, gum abnormalities, or medications known to cause dry mouth. Gum-related adverse events occurred in 16.3% of subjects. Except for three subjects, the gum adverse effects occurred early during treatment, did not cause interruption of treatment, and resolved rapidly and completely. The T buccal system is a novel T formulation that offers a safe, effective, and convenient alternative to existing formulations for physiological T replacement therapy in hypogonadal men.

Transdermal testosterone (T) delivery represents an effective alternative to injectable androgens. We studied 163 hypogonadal men who applied 5, 7.5, or 10 g AndroGel (T gel) 1% CIII per day for up to 42 months. Efficacy data were presented in 123 subjects considered evaluable. Continuous AndroGel treatment normalized mean serum T and free T levels. Mean serum 5alpha-dihydrotestosterone concentrations and 5alpha-dihydrotestosterone/T ratio slightly increased, mean serum estradiol/T ratio doubled, and mean serum FSH and LH levels were suppressed by T replacement. Sexual function and mood parameters improved rapidly and were maintained throughout T treatment. Lean body mass increased (P = 0.0001) and fat mass decreased (P = 0.0001), and these changes were maintained with treatment but were not accompanied by significant increases in muscle strength. Increases in serum bone markers suggestive of increased bone formation were followed by gradual and progressive increases in bone mineral density more in the spine (P = 0.0001) than the hip (P = 0.0004). Mild local skin irritation occurred in 12 subjects, resulting in discontinuation in only one subject. Except for the anticipated increase in hematocrit and hemoglobin, there were no clinically significant changes in blood counts or biochemistry. In three subjects with elevated serum prostate-specific antigen, prostate biopsies showed cancer. We conclude that continued application of AndroGel resulted in beneficial effects similar to those with injectables and other transdermal preparations. This study was neither placebo controlled nor powered to determine the effects of T treatment on prostate cancer risk. Thus, monitoring for prostatic disease and assessment for erythrocytosis are strongly advised to reduce the risk of adverse events with T treatment of hypogonadal men.

We undertook anthropometric assessments of 530 HIV-seropositive and 314 HIV-seronegative men in the Multicenter AIDS Cohort Study at a regular visit that occurred between 1 April and 30 September 1999. We found anthropomorphic differences that were independent of age: the 384 seropositive men receiving HAART had diminished body size and higher frequency and severity of body habitus abnormalities, particularly lipoatrophy, compared with the 314 seronegative men.

Reduced bone mineral density (BMD) and abnormalities in fat redistribution, glucose homeostasis, and lipid metabolism are prevalent among HIV-infected patients on highly active antiretroviral therapy (HAART). The relationship between the metabolic and skeletal complications of HIV is unclear. Fifty-one HIV patients on HAART (aged 30-54 yr, 86% male) and 21 HIV-negative control subjects (aged 31-51 yr, 82% male) were examined with oral glucose tolerance testing, a fasting lipid profile, and dual x-ray absorptiometry, and markers of bone formation (serum osteocalcin) and resorption (urinary deoxypyridinoline). HIV-infected subjects had a higher prevalence of either osteopenia or osteoporosis (World Health Organization criteria) at the spine, hip, or forearm, compared with HIV-negative controls (63% vs. 32%, P = 0.02) and evidence of increased bone resorption (urine deoxypyridinoline, 14.7 +/- 6.5 vs. 10.9 +/- 2.5 nmol/mmol creatinine, P = 0.012). Among the HIV-infected patients, those with reduced bone mineral density (n = 32) were similar to the group with normal BMD (n = 19) in the use of protease inhibitors, duration of HAART therapy, or other demographic variables. Plasma glucose 2 h after a glucose load (odds ratio 1.02 per 1 mg/dl increase, 95% confidence interval 1.01-1.05, P = 0.009) and central adiposity (trunk fat/total fat) (odds ratio 1.09 per 1% ratio increase, 95% confidence interval 1.00-1.18, P = 0.012) were associated with reduced BMD. These associations remained significant in a multivariate model including age and body mass index. Bone resorption was associated with female gender (P < 0.001) and non-high-density lipoprotein cholesterol (P = 0.034) in a multivariate linear regression model controlling for age, body mass index, protease inhibitor use, duration of HAART, and extremity fat. Reduced BMD is prevalent in HIV-infected patients on HAART and is related to central adiposity and postload hyperglycemia. Bone resorption is independently associated with female gender and dyslipidemia. HIV-infected patients with metabolic abnormalities may represent a population that would benefit from bone density screening.

Cross-sex hormone treatment is an important component in medical treatment of transsexual people. Endocrinologists are often faced with designing treatment recommendations. Although guidelines from organizations, such as the Harry Benjamin International Gender Dysphoria Association, have been helpful, management remains complex and experience guided. We discuss the range of treatment used by transsexual people, the rationale behind these, and the expectation from such treatment. Recommendations from seven clinical research centers treating transsexual people are discussed. In addition, self-reported hormonal regimens from 25 male-to-female transsexual people and five female-to-male transsexual people are reported. Finally, the potential adverse effects of cross-sex hormone treatment of transsexual people are reviewed. In light of the complexity of managing treatment goals and adverse effects, the active involvement of a medical doctor experienced in cross-sex hormonal therapy is vital to ensure the safety of transsexual people.

Endocrine and metabolic abnormalities are common in human immunodeficiency virus (HIV) disease and have been attributed to both the disease and its treatment. Other risk factors and behaviors may also be important. Approximately 28% of new HIV infections occur in users of injection drugs, such as opiates. We focus on the effects of opiates on multiple endocrine systems and their potential to contribute to the metabolic and endocrine problems in HIV. Opiate use has been associated with hypogonadism, adrenal dysfunction, reduced bone mineral density, and growth-hormone abnormalities. In addition, some studies have suggested abnormalities in glucose and lipid metabolism among opiate users. Although much of the evidence should be viewed as preliminary, these potential abnormalities should be kept in mind when treating opiate-dependent patients infected with HIV.

The authors examined the impact of potent antiretroviral therapy (ART) on the diagnosis of wasting syndrome in the Multicenter AIDS Cohort Study. Study time was divided into the periods 1988-1990, 1991-1993, 1994-1995, and 1996-1999 to correspond to different treatment eras. The proportion of acquired immunodeficiency syndrome diagnoses in which wasting was present increased from 5% in 1988-1990 to 7.1% in 1991-1993, 7.7% in 1994-1995, and 18.9% in 1996-1999. The incidence of wasting per 1,000 person-years increased from 7.5 in 1988-1990 to 14.4 in 1991-1993 and 22.1 in 1994-1995; it decreased to 13.4 in 1996-1999. Fewer patients with wasting had low hemoglobin and hematocrit levels and reported oral thrush in 1996-1999 than in any other period. Analysis of change in body mass index (weight (kg)/height (m)(2)) after wasting showed a faster return to prewasting levels in 1994-1995 and 1996-1999 than in earlier periods. Case-control analysis showed that wasting prior to 1996 was weakly associated with fatigue (p = 0.10), low hemoglobin (p = 0.11), and CD4-positive T-lymphocyte count (p = 0.04). During 1996-1999, wasting was weakly associated with diarrhea (p = 0.05) and potent ART (p = 0.097). Predictors of wasting have changed with potent ART. Further research is needed to determine whether lipodystrophy may be misdiagnosed as wasting syndrome.

Menopause is associated with decreased lean body mass and increased fat due to aging and declining hormone secretion. Estrogens or estrogen-progestins have been used to alleviate vasomotor symptoms. However, estrogen-androgen (E/A) therapy is also used for vasomotor symptom relief and has been shown to increase lean body mass while decreasing fat mass. The objective of this 16-wk, double-blind, randomized, parallel group clinical trial was to compare esterified estrogen plus methyltestosterone (1.25 mg estrogen + 2.5 mg methyltestosterone/d; E/A group) vs. esterified estrogen alone (1.25 mg/d; E group) on body composition. Forty postmenopausal women (mean age, 57 yr) participated. Compared with estrogen treatment alone, women in the E/A group increased their total lean body mass and reduced their percentage fat for all body parts (P < 0.05). After E/A treatment, there were statistically significant increases in lean body mass by 1.232 kg [0.181 +/- 0.004, 0.81 +/- 0.057, and 0.24 +/- 0.009 kg in the upper body (P = 0.021), trunk (P = 0.001), and lower body (P = 0.047), respectively]. In the E group, the increase was 0.31 +/- 0.004, 0.021 +/- 0.03, and 0.056 +/- 0.05 kg in the upper body, trunk, and lower body, respectively. In the E/A group, body fat was reduced by 0.90 kg (P = 0.18 for the trunk only), and percentage body fat declined by 7.4% (P < or = 0.05 for all body parts). Lower body strength increased by 23.1 kg (51 lb) in the E/A group vs. only 11 kg (24.25 lb) in the E group (P = 0.002 between groups). A statistically significant increase in weight (2.7 +/- 5.1 vs. 0.1 +/- 4.6 lb; P < 0.05) was observed in the E/A group compared with the E group. When subjects were given self-reporting questionnaires, more improvement was noted in sexual functioning and quality of life in the E/A group when compared with patients receiving E alone. There were no noteworthy side effects. In conclusion, E/A replacement therapy can improve body composition, lower-body muscle strength, quality of life, and sexual functioning in postmenopausal women.