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The relationship between testosterone and related hormones and cardiovascular and mortality outcomes is debated. The authors of this study obtained individual patient–level data from 9 cohort studies and aggregate data from 11 studies in total. These data enabled them to describe the associations of testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol with all-cause mortality, cardiovascular death, and incident cardiovascular events while accounting for other cardiac risk factors. Background: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. Purpose: To clarify associations of sex hormones with these outcomes. Data Sources: Systematic literature review to July 2019, with bridge searches to March 2024. Study Selection: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. Data Extraction: Independent variables were testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. Data Synthesis: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. Limitations: Observational study design, heterogeneity among studies, and imputation of missing data. Conclusion: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668) [ABSTRACT FROM AUTHOR]

To describe patterns of testosterone concentrations among men across a range of sociodemographic, lifestyle, and health characteristics, the authors systematically searched and obtained individual participant and aggregate data from eligible cohort studies. This study reports the findings from a 2-stage random-effects meta-analysis of 9 studies with individual patient data and 2 studies with aggregate data. Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. Purpose: To clarify factors associated with variations in sex hormone concentrations. Data Sources: Systematic literature searches (to July 2019). Study Selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. Data Extraction: Individual participant data (IPD) (9 studies; n  = 21 074) and aggregate data (2 studies; n  = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. Data Synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, −0.27 nmol/L [−7.8 ng/dL] [CI, −0.71 to 0.18 nmol/L {−20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (−1.55 nmol/L [−44.7 ng/dL] [CI, −2.05 to −1.06 nmol/L {−59.1 to −30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, −2.42 nmol/L [−69.7 ng/dL] [CI, −2.70 to −2.13 nmol/L {−77.8 to −61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, −0.57 nmol/L [−16.4 ng/dL] [CI, −0.89 to −0.26 nmol/L {−25.6 to −7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (−0.51 nmol/L [−14.7 ng/dL] [CI, −0.90 to −0.13 nmol/L {−25.9 to −3.7 ng/dL}]); were former smokers (−0.34 nmol/L [−9.8 ng/dL] [CI, −0.55 to −0.12 nmol/L {−15.9 to −3.5 ng/dL}]); or had hypertension (−0.53 nmol/L [−15.3 ng/dL] [CI, −0.82 to −0.24 nmol/L {−23.6 to −6.9 ng/dL}]), cardiovascular disease (−0.35 nmol/L [−10.1 ng/dL] [CI, −0.55 to −0.15 nmol/L {−15.9 to −4.3 ng/dL}]), cancer (−1.39 nmol/L [−40.1 ng/dL] [CI, −1.79 to −0.99 nmol/L {−51.6 to −28.5 ng/dL}]), or diabetes (−1.43 nmol/L [−41.2 ng/dL] [CI, −1.65 to −1.22 nmol/L {−47.6 to −35.2 ng/dL}]). Sex hormone–binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668) [ABSTRACT FROM AUTHOR]

Background: By modulating the levels of sex steroid hormones and sex hormone-binding globulin (SHBG), caffeine could be a factor in the development of several conditions in men, including prostate cancer. The aim of this study was to evaluate if caffeine consumption is associated with concentrations of sex steroid hormones and SHBG in men.Methods: 1,410 men aged 20 + years who attended the morning examination session of the Third National Health and Nutrition Examination Survey (1988-1991) were included in the analysis. Coffee and soft drink consumption was assessed using a food frequency questionnaire. Daily caffeine intake was estimated by multiplying caffeine content per cup times the daily frequency of coffee, tea, or soft drink consumption. Serum levels of hormones and SHBG were measured by immunoassay. Associations of frequency of beverage consumption or estimated caffeine intake with hormone levels were examined using multivariable linear regression.Results: Coffee consumption was positively associated with SHBG concentration (p = 0.045) taking lifestyle factors into account, but mutually adjusting for testosterone and estradiol attenuated the association; no association with SHBG was observed for soft drink consumption or caffeine intake. No associations between caffeinated beverage consumption and androgen or estrogen concentrations were observed.Conclusion: Men who drink coffee more frequently may have higher circulating SHBG concentration, but there were no consistent associations for soft drinks or caffeine intake. [ABSTRACT FROM AUTHOR]

Objectives Whether endogenous sex hormones play a role in cardiovascular disease ( CVD) risk in men is unclear. Few studies have examined associations of sex hormones with atherosclerosis measured by coronary artery calcium score ( CACS) and carotid intima-media thickness ( cIMT). We evaluated the association of testosterone (T) and other sex hormones with CACS and cIMT. Methods Using the large multi-ethnic cohort of 3164 men without known CVD in the Multi-Ethnic Study of Atherosclerosis ( MESA), cross-sectional associations of tertiles of endogenous sex hormones with CACS and cIMT were analysed. Results In regard to CAC, there was a significant negative trend (P-trend = 0·02) for CACS>0 over tertiles of free T ( FT) with RRs (95% CI) for the lowest to highest tertiles. There was also a marginally significant positive trend (P-trend = 0·06) for CACS>0 over tertiles of sex hormone-binding globulin ( SHBG) with RRs for the lowest to highest tertiles. There were no significant associations with CACS >0 for tertiles of TT (Total T), bioavailable T ( BT), oestradiol (E2) and dehydroepiandrosterone ( DHEA). There was significantly higher log CACS after adjustment for CVD risk factors for lower TT levels, compared to higher levels, using 9·54 and 10·4 nmol/l as cut-off points. In regard to cIMT, there was a significant positive trend ( P = 0·003) in mean cIMT over the tertiles of BT, but not for TT, FT, E2, DHEA and SHBG. There was significantly lower cIMT after adjustment for CVD risk factors for lower TT levels compared to higher levels. Conclusion In a population of male subjects with no known CVD, lower FT is associated with higher RR of CACS>0 and lower TT is associated with higher log CACS. Lower BT and TT are associated with lower cIMT. While these findings support the positive correlation between low T and coronary atherosclerosis, the opposite findings on cIMT warrant further evaluation. [ABSTRACT FROM AUTHOR]

Objective: To determine whether frailty is associated with circulating total and free testosterone, total and free estradiol, and sex hormone-binding globulin (SHBG) in older men. Methods: With NHANES III data of 461 men aged 60 years and older, we used logistic regression to analyze the associations between serum concentrations of sex steroid hormones, SHBG and frailty. Participants meeting any three or more of the five frailty criteria were classified as 'frail', all others were considered as non-frail. Results: 2.5% of men were frail. Men with SHBG ≥66 nmol/L had three times the odds of frailty (OR = 2.97; 95% CI 1.28-6.86) compared to men with SHBG <66 nmol/L. Men with free testosterone levels below 243 pmol/L had an increased odds of frailty (OR = 3.92; 95% CI 1.29-11.89). None of these associations was statistically significant after additionally adjusting for body mass index, smoking and history of cardiovascular diseases (CVD). Total testosterone, and total and free estradiol serum levels were not statistically significantly associated with frailty. Conclusions: In this US nationally representative study of older men, low free testosterone and high SHBG serum levels were associated with a significantly increased odds of frailty after adjustment for age and race/ethnicity. These associations may, however, be explained by confounding due to obesity, smoking, and the higher prevalence of CVD in frail men or by low hormones or high SHBG mediating the association between obesity, smoking, CVD and frailty. [ABSTRACT FROM AUTHOR]

Summary Background Physiologic processes during ageing leading to multi-morbidity and diseases that increase risk of premature death may be influenced by ageing-associated changes in endogenous hormone production. Objective To evaluate the decline in sex steroid hormone levels across age and estimate the number of US men 40+ years old who may have low hormone levels. Design We measured serum testosterone, oestradiol and sex hormone binding globulin by immunoassay in 1351 men 20+ years old in Third National Health and Nutrition Examination Survey. We estimated free hormones by mass action. Results Free testosterone declined most rapidly with age (a 2% decline in geometric mean concentration occurred after ageing 1·3 years), followed by total testosterone (2·4 years), free oestradiol (4·1 years) and total oestradiol (8·1 years). These hormone changes with age translated into 25·0% and 30·2% of men 70+ years old having low total (which we defined as <10·4 n [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Abstract: A reduced concentration of serum testosterone resulting in male hypogonadism is a well described endocrine abnormality associated with classical signs and symptoms. This manuscript presents one such patient. However, low serum testosterone is being recognized more commonly associated with aging and chronic disease. It is in this situation in which the signs and symptoms of male hypogonadism can be subtle and non-specific. This manuscript reviews examples of such situations and highlights our need to have a reliable and accurate measure of serum testosterone. Both clinicians and researchers need better assays to better understand basic mechanisms, diagnose, treat, and monitor men with testosterone deficiency. [Copyright &y& Elsevier]

Abstract: The traditional lipid profile differs by sex hormone levels. However, associations of sex hormones with lipoprotein subfractions, which may more accurately represent metabolic pathways to atherosclerosis, are not well studied. We quantified the cross-sectional associations of endogenous sex hormones with lipoprotein subfractions in 3143 men and 2038 postmenopausal women who were not on hormone replacement therapy, aged 45 to 84 years, in the Multi-Ethnic Study of Atherosclerosis baseline examination. Particle sizes and numbers of very low-density (VLDL), low-density (LDL), and high-density (HDL) lipoproteins were measured by nuclear magnetic resonance. In both men and women, after multivariable adjustment, higher sex hormone binding globulin (SHBG) levels are associated with smaller, fewer VLDL; larger, fewer LDL; and larger, more numerous HDL particles, whereas higher endogenous estradiol levels are associated with smaller VLDL and smaller, more numerous HDL and LDL particles (all P < .05). Testosterone (adjusted for SHBG) is associated with smaller VLDL particles in men but not women (sex difference P = .040). Higher dehydroepiandrosterone levels are associated with more numerous, smaller VLDL particles only in women (sex difference P = .030, .004, respectively). In conclusion, we found sex differences in the association of endogenous androgens with lipoprotein particle sizes and numbers. Higher endogenous estradiol, but lower SHBG, is associated with a more atherogenic lipoprotein particle profile. These findings highlight the potential to improve the lipoprotein profile with sex hormones, but emphasize the intricacies of the interactions. [Copyright &y& Elsevier]

Drug use and HIV infection may affect sex hormone levels in women. One hundred and ninety-six women with and without a history of illicit drug use (50 HIV-negative and 148 HIV-infected), with regular menses, who never used antiretrovirals, were evaluated. Luteinizing hormone levels were significantly higher in women with a CD4 cell count p p = 0.03) and higher levels of prolactin ( p = 0.002); mean estradiol levels were 43% lower in women who used intravenous drugs ( p [ABSTRACT FROM AUTHOR]

This study examined the impact of sex hormones on functional cerebral hemispheric lateralization and cognition in a group of male-to-female transsexuals receiving cross-sex hormone therapy compared to eugonadal men with a male gender identity. Cerebral lateralization was measured with a handedness questionnaire and a visual-split-field paradigm and cognitive tests sensitive to sex hormone exposure (identical pictures, 3-D mental rotation, building memory) were also administered. Endocrine measures on the day of participation for transsexual and control subjects included total testosterone, free testosterone, estradiol, gonadotropins, and sex hormone binding globulin concentrations. Compared to controls, male-to-female transsexuals had elevated estradiol and sex hormone binding globulin concentrations and suppressed testosterone concentrations. Transsexual subjects showed a trend toward less exclusive right-handedness than controls. No group differences were observed on the visual-split-field or cognitive tasks. No direct associations were observed between endocrine measures and the laterality measures and cognitive performance. Previous observations of female-typical patterns in cerebral lateralization and cognitive performance in male-to-female transsexuals were not found in the current study. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To assess associations of sex hormones with impaired fasting glucose (IFG) and type 2 diabetes in men. RESEARCH DESIGN AND METHODS -- A total of 3,156 African American, Non-Hispanic white, Hispanic, and Chinese-American men aged 45-84 years who participated in the baseline visit of the Multi-Ethnic Study of Atherosclerosis (MESA) were included. Odds ratios and 95% CIs for type 2 diabetes and IFG compared with normal fasting glucose for quartiles of hormones were estimated. RESULTS-- After adjusting for age, ethnicity, BMI, and waist circumference, IFG and diabetes were associated inversely with total testosterone and sex hormone-binding globulin (SHBG) and positively with estradiol (E2). Dehydroepiandrosterone was positively associated with IFG but not with diabetes. Associations did not differ across ethnic groups. CONCLUSIONS -- Regardless of obesity, total testosterone and SHBG were associated inversely and E2 was associated positively with IFG and diabetes in men. Further research is warranted to better understand the underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

Testosterone (T) is the principal male sex hormone. As men age, T levels typically fall. Symptoms of low T include decreased libido, vasomotor instability, and decreased bone mineral density. Other symptoms may include depression, fatigue, erectile dysfunction, and reduced muscle strength/mass. Epidemiology studies show that low levels of T are associated with more atherosclerosis, coronary artery disease, and cardiovascular events. However, treating hypogonadism in the aging male has resulted in discrepant results in regard to its effect on cardiovascular events. Emerging studies suggest that T may have a future role in treating heart failure, angina, and myocardial ischemia. A large, prospective, long-term study of T replacement, with a primary endpoint of a composite of adverse cardiovascular events including myocardial infarction, stroke, and/or cardiovascular death, is needed. The Food and Drug Administration recently put additional restrictions on T replacement therapy labeling and called for additional studies to determine its cardiac safety. [ABSTRACT FROM AUTHOR]

Abstract: We examined cross-sectional associations between sex hormones and carotid artery intimal-medial thickness (cIMT) and coronary artery calcium in women in the Multi-Ethnic Study of Atherosclerosis. Serum testosterone, estradiol, sex hormone binding globulin (SHBG), and dehydroepiandrosterone levels were measured in 1947 postmenopausal women aged 45–84 years (30% White, 14% Chinese-American, 31% Black, and 25% Hispanic) and not on hormone therapy. Using multiple linear regression we evaluated associations between log(sex hormone) levels and log(cIMT) adjusted for age, ethnicity, body mass index (BMI) and cardiac risk factors. Associations between sex hormone levels and the presence and extent of coronary calcium were evaluated. Total and bioavailable testosterone were positively associated with common cIMT independent of age, BMI, hypertension, smoking, HDL-cholesterol, LDL-cholesterol and insulin sensitivity (p =0.009 and p =0.002, respectively). SHBG was negatively associated with common cIMT (p =0.001) but further adjustment for BMI, cardiovascular risk factors, and LDL- and HDL-cholesterol removed significance. Estradiol and dehydroepiandrosterone were not associated with common cIMT. Sex hormones were not associated with presence of coronary calcium. Among women with measurable coronary calcium, higher SHBG (p =0.012) and lower bioavailable testosterone (p =0.007) were associated with greater coronary calcium score. No heterogeneity by ethnicity was found. In postmenopausal women, testosterone is independently associated with greater common cIMT. SHBG is negatively associated and this may be mediated by LDL- and HDL-cholesterol. In contrast, SHBG and testosterone were associated with extent of coronary calcium but in the opposite direction compared to carotid intimal-medial thickness. These differences warrant further evaluation. [Copyright &y& Elsevier]

Abstract: Background: Hypogonadism is common with opiate-like drug use and may contribute to cognitive abnormalities. With the increasing epidemic of HIV and substance use (SU) worldwide, it is important to understand the impact of these conditions on cognition, which may affect quality of life and possibly decrease adherence to treatment. We hypothesized that men with SU, by virtue of hypogonadism secondary to HIV and/or SU, may demonstrate impaired cognition. Methods: We recruited men aged 18–50 from a population of low income, inner-city individuals. Details of HIV and SU status, serum blood levels of total testosterone (TT), free testosterone (FT) and estradiol (E2) were assessed. All subjects were administered ten neuropsychological tests. Results: Our sample consisted of 68 men (mean age: 43.2 years (SD 5.8), African Americans: 86.6%). The recruited population was primarily from low socioeconomic status and unemployed. The mean level of TT was 553.9ng/dL (SD 262.0), the mean level of FT was 69.5pg/mL (SD 34.8), mean E2 was 3.2pg/mL (SD 4.4). We found that 30.9% were hypogonadal and it was associated with higher SU. We observed some relationships between sex hormones and cognitive domains, however, after adjustment for age, drug use category, education, depression, HIV, there was no statistically significant correlation between cognitive performance and sex hormone levels. Conclusions: In this cross-sectional study of men with a high prevalence of SU and hypogonadism, endogenous levels of TT, FT or E2 were not related to cognitive performance. Other factors need to be identified which may contribute to poor cognitive function in the setting of SU. [Copyright &y& Elsevier]