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Background: Despite sex differences in T2D, few studies have examined the role of sex hormones. We sought to assess the impact of weight loss, the cornerstone of T2D management, on sex hormone levels., Methods: This was an ancillary study to the Look AHEAD (Action for Health In Diabetes) Study (n=850 postmenopausal females, n=890 males, with T2D and BMI ≥25 kg/m2). We measured total testosterone (T), estradiol (E2) and sex hormone binding globulin (SHBG) and calculated bioavailable T (bioT). We examined the effect of the intensive lifestyle intervention (ILI) on hormone changes, whether changes were mediated by waist circumference and sex differences in treatment effect., Results: The baseline mean age was 60 years with a higher proportion of Black females (21%) vs. males (9%) and higher mean BMI in females vs. males (36.3 vs. 34.8 kg/m2). At year 1 in females, ILI decreased E2 by 15% and bioT by 13% and increased SHBG by 21%. At year 1 in males, ILI did not change E2 levels, but increased T by 14% and increased SHBG by 18%. The effect was attenuated over 4 years, there were statistically significant sex differences in treatment effect and change in waist circumference due to ILI at year 1 was a significant mediator of sex hormone changes., Conclusion: Weight loss in T2D resulted in sex hormone changes, which varied by sex and were mediated by changes in WC. Changes in sex hormone due to weight loss in T2D should be considered in the context of an individual's health risks, including cardiovascular, bone health, menopausal symptoms and cognition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Introduction: There are known disparities in diabetes complications by race and ethnicity. Although diabetes subgroups may contribute to differential risk, little is known about how subgroups vary by race/ethnicity., Methods: Data were pooled from 1293 (46% female) participants of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) and the Multi-Ethnic Study of Atherosclerosis (MESA) who had diabetes (determined by diabetes medication use, fasting glucose, and glycated hemoglobin [HbA1c]), including 217 South Asian, 240 non-Hispanic white, 125 Chinese, 387 African American, and 324 Hispanic patients. We applied k-means clustering using data for age at diabetes diagnosis, body mass index, HbA1c, and homeostatic model assessment measures of insulin resistance and beta cell function. We assessed whether diabetes subgroups were associated with race/ethnicity, concurrent cardiovascular disease risk factors, and incident diabetes complications., Results: Five diabetes subgroups were characterized by older age at diabetes onset (43%), severe hyperglycemia (26%), severe obesity (20%), younger age at onset (1%), and requiring insulin medication use (9%). The most common subgroup assignment was older onset for all race/ethnicities with the exception of South Asians where the severe hyperglycemia subgroup was most likely. Risk for renal complications and subclinical coronary disease differed by diabetes subgroup and, separately, race/ethnicity., Conclusions: Racial/ethnic differences were present across diabetes subgroups, and diabetes subgroups differed in risk for complications. Strategies to eliminate racial/ethnic disparities in complications may need to consider approaches targeted to diabetes subgroup., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes., Objective: To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF)., Design: Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years., Setting: General community., Participants: 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively., Exposure: Plasma sex hormone levels were measured at visit 4 (1996-1998)., Main Outcome Measures: Incident HF events were identified through hospital discharge codes and death certificates., Results: The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant., Conclusion: In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Previous studies have suggested less cardioprotective benefit of aspirin in adults with diabetes, raising concerns about "aspirin resistance" and potentially reduced effectiveness for prevention of cardiovascular disease (CVD)., Objective: To examine differences in platelet response to aspirin by diabetes status., Design, Setting, Participants: We examined platelet response before and after aspirin (81 mg/day for 14 days) in 2113 adults (175 with diabetes, 1,938 without diabetes), in the Genetic Study of Aspirin Responsiveness cohort, who had family history of early-onset CVD., Main Outcome Measures: In vivo platelet activation (urinary thromboxane B2), in vitro platelet aggregation to agonists (arachidonic acid, adenosine diphosphate, collagen), and platelet function analyzer-100 closure time., Results: Although adults with diabetes had higher in vivo platelet activation before aspirin, the reduction in in vivo platelet activation after aspirin was similar in those with vs without diabetes. Likewise, the reduction in multiple in vitro platelet measures was similar after aspirin by diabetes status. In regression analyses adjusted for age, sex, race, BMI, smoking, platelet counts, and fibrinogen levels, in vivo platelet activation remained higher in adults with vs without diabetes after aspirin (P = 0.04), but this difference was attenuated after additional adjustment for preaspirin levels (P = 0.10). No differences by diabetes status were noted for any of the in vitro platelet measures after aspirin in fully adjusted models that also accounted for preaspirin levels., Conclusions: In vitro platelet response to aspirin does not differ by diabetes status, suggesting no intrinsic differences in platelet response to aspirin. Instead, factors extrinsic to platelet function should be investigated to give further insights into aspirin use for primary prevention in diabetes.

Context: Sex hormones may influence sex differences in cardiovascular disease (CVD). N-terminal pro-B-type natriuretic peptide (NT-proBNP), a predictor of CVD, is higher in women than men, which may relate to sex hormones., Objective: To evaluate whether total testosterone (T), bioavailable T, free T, estradiol, dehydroepiandrosterone (DHEA), and SHBG are associated with NT-proBNP., Design: Cohort study., Participants: Cross-sectional sample included 2371 postmenopausal women and 2688 men free of CVD, of which 2041 women and 2348 men were included longitudinally., Main Outcome Measures: NT-proBNP at baseline (2000 to 2002) and one or more repeat NT-proBNPs (through 2012). Analyses adjusted for CVD risk factors., Results: Women had higher NT-proBNP than men (median 79.9 vs 38.5 pg/mL). Cross-sectionally, higher bioavailable T, free T, DHEA, and lower SHBG levels were independently associated with lower NT-proBNP among both women and men (all P < 0.05). Higher total T in women and estradiol in men were also associated with lower NT-proBNP (both P < 0.05). Longitudinally, in women, higher total T, bioavailable T, free T, DHEA, and lower estradiol and SHBG were associated with greater 10-year increase in NT-proBNP (all P < 0.05). In men, higher free T and estradiol were associated with greater NT-proBNP increase (both P < 0.05)., Conclusions: A more androgenic sex hormone pattern was inversely associated with NT-proBNP cross-sectionally and may contribute to sex differences in NT-proBNP. Longitudinally, a more androgenic sex hormone pattern was associated with greater increase in NT-proBNP in women, which may reflect a mechanism for CVD risk after menopause.

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability., Objective: To investigate the genetic regulation of serum E2 and E1 in men., Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts., Main Outcome Measures: Genetic determinants of serum E2 and E1 levels., Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance., Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.

Context: Although the health risks of obesity compared to normal weight have been well studied, the cumulative risk associated with chronic obesity remains unknown. Specifically, debate continues about the importance of recommending weight loss for those with metabolically healthy obesity., Objective: We hypothesized that relatively greater severity and longer duration of obesity are associated with greater incident metabolic syndrome. Design, Setting, Participants, and Measures: Using repeated measures logistic regression with random effects, we investigated the association of time-varying obesity severity and duration with incident metabolic syndrome in 2,748 Multi-Ethnic Study of Atherosclerosis participants with obesity (body mass index ≥30 kg/m 2 ) at any visit. Obesity duration was defined as the cumulative number of visits with measured obesity and obesity severity by the World Health Organization levels I-III based on body mass index. Metabolic syndrome was defined using Adult Treatment Panel III criteria modified to exclude waist circumference., Results: Higher obesity severity (level II odds ratio [OR], 1.32 [95% confidence interval, 1.09-1.60]; level III OR, 1.63 [1.25-2.14] vs level I) and duration (by number of visits: two visits OR, 4.43 [3.54-5.53]; three visits OR, 5.29 [4.21-6.63]; four visits OR, 5.73 [4.52-7.27]; five visits OR, 6.15 [4.19-9.03] vs one visit duration of obesity) were both associated with a higher odds of incident metabolic syndrome., Conclusion: Both duration and severity of obesity are positively associated with incident metabolic syndrome, suggesting that metabolically healthy obesity is a transient state in the pathway to cardiometabolic disease. Weight loss should be recommended to all individuals with obesity, including those who are currently defined as metabolically healthy.

Context: Sex hormones may influence adipose tissue deposition, possibly contributing to sex disparities in cardiovascular disease risk., Objective: We hypothesized that associations of sex hormone levels with visceral and subcutaneous fat differ by sex., Design, Setting, and Participants: Participants were from the Multi-Ethnic Study of Atherosclerosis with sex hormone levels at baseline and visceral and subcutaneous fat measurements from computed tomography at visit 2 or 3 (n = 1835)., Main Outcome Measures: Multivariable linear regression was used to investigate the relationships between sex hormones and adiposity. Testing for interaction by sex, race/ethnicity, and age was conducted., Results: In adjusted models, there was a modest significant positive association between estradiol and visceral fat in both sexes (percent difference in visceral fat for 1% difference in hormone [95% confidence interval] in women, 5.44 [1.82, 9.09]; and in men, 8.22 [0.61, 16.18]). Higher bioavailable T was significantly associated with higher visceral and subcutaneous fat in women and with the reverse in men (women, 14.38 [10.23, 18.69]; men, -7.69 [-13.06, -1.00]). Higher dehydroepiandrosterone was associated with higher visceral fat in women (7.57 [1.71, 13.88]), but not in men (-2.47 [-8.88, 4.29]). Higher SHBG was associated with significantly lower levels of adiposity in both sexes (women, -24.42 [-28.11, -20.55]; men, -27.39 [-32.97, -21.34]). There was no significant interaction by race/ethnicity or age., Conclusion: Sex hormones are significantly associated with adiposity, and the associations of androgens differ qualitatively by sex. This heterogeneity may help explain the complexity of the contribution of sex hormones to sex differences in cardiovascular disease.

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: 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.