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Objective: We examined associations between intensive lifestyle intervention (ILS) and changes in testosterone and associations with mood among middle-aged men., Design: Secondary analysis of men (n=886) participating in the Diabetes Prevention Program which randomized glucose-intolerant, overweight men to ILS, metformin, or placebo between 1996 and 1999., Main Outcome Measures: Changes in testosterone between baseline and 1-year follow-up asnd associations of these changes with mood measures (Beck Depression Inventory [BDI-II], Beck Anxiety Inventory [BAI])., Results: Median baseline testosterone was 10.98nmol/l and 44% (n=385) had testosterone<10.41nmol/l or 300ng/dl. Testosterone increases were greater among men randomized to ILS vs. metformin vs. placebo (1.15nmol/l vs. -0.12nmol/l vs. -0.27nmol/l, p<0.001). The association between changes in testosterone and mood differed by study arm (p<0.001 for interaction); there were no significant associations between changes in testosterone and mood changes among men in the ILS or placebo arms. Among men in the metformin arm, increases in testosterone were significantly associated with decreases in BDI-II (improved depressive symptoms) (β-coefficient -0.2336, p=0.0002) indicating a 0.23 decrease in BDI-II for every 1nmol/l increase in testosterone and decreases in BAI (improved anxiety symptoms) (β-coefficient -0.2147, p=0.0014). Similar patterns were observed for bioavailable testosterone., Conclusions: Among overweight middle-aged men with glucose-intolerance, ILS increased endogenous testosterone slightly but without significant improvements in mood. Metformin did not increase testosterone, but among metformin users, testosterone increases were associated with improvements in mood. Thus, interventions that increase endogenous testosterone may not also improve mood., (Copyright © 2016. Published by Elsevier Ltd.)

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., (© 2015 John Wiley & Sons Ltd.)

Context: Sex hormones may differ by race/ethnicity in postmenopausal women. Whether racial/ethnic differences also exist among those who are overweight and glucose intolerant is not clear., Objectives: The objective of the study was to compare sex hormones by race/ethnicity [non-Hispanic white (NHW), Hispanic, African-American (AA)] in overweight, glucose-intolerant, postmenopausal women., Design: This was a secondary analysis of a randomized controlled trial., Participants: Participants included postmenopausal glucose-intolerant women participating in the Diabetes Prevention Program., Interventions: Interventions included intensive lifestyle modification (consisting of diet and physical activity) or metformin 850 mg twice a day vs. placebo., Main Outcome Measures: Baseline levels and 1-yr intervention-related changes in SHBG, total and bioavailable estradiol (E2), total and bioavailable testosterone, and dehydroepiandrosterone were measured., Results: At baseline, among women not using estrogen (n = 370), NHW had higher total and bioavailable E2 and testosterone levels than Hispanics independent of age, type of menopause, waist circumference, alcohol intake, and current smoking. NHW also had higher levels of bioavailable E2 and lower levels of SHBG than AA. At baseline, among estrogen users (n = 310), NHW had higher total and bioavailable E2 than Hispanics and higher levels of SHBG than AA after adjustment. At 1 yr, among women not using estrogen, NHW had larger declines in total E2 and bioavailable E2 levels than AA after adjustment for the above covariates, changes in waist circumference, and randomization arm. At 1 yr, among estrogen users, sex hormone changes did not differ by race/ethnicity., Conclusions: Among postmenopausal women, there were significant race/ethnicity differences in baseline sex hormones and changes in sex hormones.

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

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. Odd sratios 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.

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.

Objective: Low levels of androgens in men may play a role in the development of diabetes; however, few studies have examined the association between androgen concentration and diabetes in men in the general population. The objective of this study is to test the hypothesis that low normal levels of total, free, and bioavailable testosterone are associated with prevalent diabetes in men., Research Design and Methods: The study sample included 1,413 adult men aged > or =20 years who participated in the morning session of the first phase of the Third National Health and Nutrition Examination Survey, a cross-sectional survey of the civilian, noninstitutionalized population of the U.S. Bioavailable and free testosterone levels were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations., Results: In multivariable models adjusted for age, race/ethnicity, and adiposity, men in the first tertile (lowest) of free testosterone level were four times more likely to have prevalent diabetes compared with men in the third tertile (odds ratio 4.12 [95% CI 1.25-13.55]). Similarly, men in the first tertile of bioavailable testosterone also were approximately four times as likely to have prevalent diabetes compared with men in the third tertile (3.93 [1.39-11.13]). These associations persisted even after excluding men with clinically abnormal testosterone concentrations defined as total testosterone <3.25 ng/ml or free testosterone <0.07 ng/ml. No clear association was observed for total testosterone after multivariable adjustment (P for trend across tertiles = 0.27)., Conclusions: Low free and bioavailable testosterone concentrations in the normal range were associated with diabetes, independent of adiposity. These data suggest that low androgen levels may be a risk factor for diabetes in men.

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.

Studies examining the relation between endogenous postmenopausal hormone levels and cardiovascular disease have yielded conflicting results. After excluding women with a history of hormone replacement therapy (HRT) use, the authors conducted a US case-control study in 1987-1992 comparing endogenous postmenopausal hormone levels in women with and without significant carotid atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) cohort. Atherosclerosis was assessed by using B-mode ultrasound to measure carotid artery intimal-medial thickness (IMT). Cases (n = 182) were postmenopausal women with average IMT measurements greater-than-or-equal the 95th percentile. Controls (n = 182) were frequency matched to cases on age and ARIC center and had IMT measurements < the 75th percentile. After adjustment for cardiovascular risk factors, no association was found between the odds of atherosclerosis and increasing quartiles of estrone, dehydroepiandrosterone sulfate, or androstenedione. Compared with participants in the lowest quartile of sex hormone-binding globulin (SHBG), those in the highest quartile had a significantly lower odds of atherosclerosis (odds ratio = 0.48, 95% confidence interval: 0.24, 0.97). Similarly, participants in the highest quartile of total testosterone had a lower odds of atherosclerosis (odds ratio = 0.38, 95% confidence interval: 0.20, 0.74). The authors found higher total testosterone and SHBG to be inversely related to carotid atherosclerosis, suggesting their potential importance in reducing atherosclerotic risk in postmenopausal women not using HRT.

Many studies have investigated the role of estrogen during menopause; however, less attention has been paid to the role of androgen. Given the possible opposite effects of estrogen and androgen on cardiovascular disease risk, it is suggested that relative androgen excess may better predict the increased risk of cardiovascular disease in women over the age of 50 years than estrogen levels alone. Three phases of hormonal milieu changes are hypothesized as a better way to identify the hormone-cardiovascular disease risk association. A first phase, prepause, occurs before estrogen levels decline (approximately 2 years before menopause). A second phase, interpause, occurs from the end of prepause until approximately age 55. A third phase, postpause, occurs after interpause. The duration of the interpause phase, characterized by relative androgen excess, may be an independent risk factor of cardiovascular disease. This hypothesis could provide a basis for further clinical and epidemiologic research, and it could have important implications for establishing the initiation and duration of estrogen replacement therapy use as a means to prevent cardiovascular disease. [ABSTRACT FROM PUBLISHER]