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1.  Interrelation Between Sex Hormones and Plasma Sex Hormone-Binding Globulin and Hemoglobin A1c in Healthy Postmenopausal Women 
Abstract
Background
Androgenicity, as measured by low sex hormone-binding globulin (SHBG) and elevations in testosterone and free androgen index (FAI), is associated with adverse cardiovascular (CV) outcomes, possibly due to effects on insulin resistance and glycemia.
Methods
Glycosylated hemoglobin (HbA1c) concentration, SHBG, and sex hormones were available in 200 non-diabetic postmenopausal women who were not using hormone therapy (HT) in the Women's Health Study. Of these, 98 were cardiovascular disease (CVD) cases; the remainders were matched controls. To achieve normality, continuous values were log transformed and geometric means were calculated. Associations between sex hormones and HbA1c were examined using general linear models (GLM), partial correlations, and multiple linear regression analyses.
Results
Lower SHBG levels and higher FAI and HbA1c values were found among the CVD cases, and all analyses were adjusted for this factor. In GLM, higher values of HbA1c were observed in the highest quartiles of FAI and the lowest quartiles of SHBG. However, the correlation between SHBG and HbA1c across quartiles was eliminated after adjusting for body mass index (BMI). In partial correlations, HbA1c values were inversely associated with SHBG (r = −0.19, P = 0.008) and positively associated with FAI (r = 0.19, P = 0.01), even after adjusting for age, CVD case–control status, and BMI. In multivariate models, a significant inverse association between SHBG and HbA1c persisted, as well as a significant positive association between FAI and HbA1c.
Conclusions
Androgenicity, as measured by low SHBG and high FAI, is associated with glycemia, and thereby may contribute to CVD risk in postmenopausal women.
doi:10.1089/met.2008.0081
PMCID: PMC2880893  PMID: 19344226
2.  Interrelation between Sex Hormones and Plasma Sex Hormone–Binding Globulin and Hemoglobin A1c in healthy postmenopausal women 
Background
Androgenicity, as measured by low sex hormone-binding globulin (SHBG) and elevations in testosterone and free androgen index (FAI), is associated with adverse cardiovascular (CV) outcomes, possibly due to effects on insulin resistance and glycemia.
Methods
Glycosylated hemoglobin (HbA1c) concentration, total testosterone, estradiol, SHBG, FAI, free estrogen index (FEI), and HbA1c were available in 200 nondiabetic postmenopausal women who were not using hormone therapy (HT) in the Women's Health Study. Of these, 98 were CVD cardiovascular disease (CVD) cases, while the remainders were matched controls. To achieve normality, continuous values were log transformed and geometric means were calculated. Associations between sex hormones and HbA1c were examined using general linear models (GLM), partial correlations and multiple linear regression analyses.
Results
Lower SHBG levels and higher FAI and HbA1c values were found among women who were CVD cardiovascular disease (CVD) cases compared to controls, and all analyses were adjusted for this factor. In GLM, higher values of HbA1c were observed in the highest quartiles of FAI and the lowest quartiles of SHBG. However, the correlation between SHBG and HbA1c across quartiles was eliminated after adjusting for body mass index (BMI). In partial correlations, HbA1c values were inversely associated with SHBG (r=-0.19, p=0.008) and positively associated with FAI (r=0.19, p=0.01), even after adjusting for age, CVD case-control status and BMI. In multivariable linear models, a significant inverse association between SHBG and HbA1c persisted, as well as, a significant positive association between FAI and HbA1c.
Conclusions
Androgenicity, as measured by low SHBG and high FAI, is associated with glycemia, and thereby may contribute to CVD risk in post-menopausal women.
doi:10.1089/met.2008.0081
PMCID: PMC2880893  PMID: 19344226
sex hormones; hemoglobin A1c; postmenopausal women
3.  Genetic Determinants of Serum Testosterone Concentrations in Men 
PLoS Genetics  2011;7(10):e1002313.
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
Author Summary
Testosterone is the most important testicular androgen in men. Low serum testosterone concentrations are associated with cardiovascular morbidity, metabolic syndrome, type 2 diabetes mellitus, atherosclerosis, osteoporosis, sarcopenia, and increased mortality risk. Thus, there is growing evidence that serum testosterone is a valuable biomarker of men's overall health status. Studies in male twins indicate that there is a strong heritability of serum testosterone. Here we perform a large-scale genome-wide association study to examine the effects of common genetic variants on serum testosterone concentrations. By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (SHBG) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.
doi:10.1371/journal.pgen.1002313
PMCID: PMC3188559  PMID: 21998597
4.  Associations of Estrogen and Testosterone With Insulin Resistance in Pre- and Postmenopausal Women With and Without Hormone Therapy 
Background
Estrogen deficiency due to natural menopause or surgical menopause has been suggested to have an adverse effect on insulin resistance. Testosterone and sex hormone–binding globulin (SHBG) as well as estrogen are also associated with insulin resistance in women. However, to date, the associations of estradiol, testosterone and SHBG with insulin resistance according to estrogen level have not been clarified.
Objectives
We examined the associations of estradiol, testosterone and SHBG with insulin resistance in pre- and in postmenopausal women and postmenopausal women who had received hormone therapy to clarify whether the associations differ depending on the estrogen status.
Patients and Methods
Twenty premenopausal women and thirty-two postmenopausal women were enrolled in this study. Fifteen postmenopausal women received oral conjugated equine estrogen (CEE) (0.625 mg) everyday for 12 months. Serum levels of estradiol, testosterone, SHBG and insulin and plasma levels of glucose were measured.
Results
Serum estradiol levels tended to have a negative correlation with homeostasis model assessment of insulin resistance (HOMA-IR) in premenopausal women but not in postmenopausal women. On the other hand, free testosterone levels tended to have a positive correlation with HOMA-IR in postmenopausal women but not in premenopausal women. Serum SHBG levels showed significant negative correlations with HOMA-IR in both pre- and postmenopausal women. SHBG level was significantly increased, free testosterone level was significantly decreased and HOMA-IR was significantly decreased at 12 months after CEE administration. However, there were no significant correlations of changes between estradiol, SHBG or free testosterone and HOMA-IR.
Conclusions
The associations of sex steroid hormones with insulin resistance are different depending on the estrogen status.
doi:10.5812/ijem.5333
PMCID: PMC3693666  PMID: 23825975
Estradiol; Testosterone; Sex Hormone-Binding Globulin; HOMA-IR
5.  Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study 
Background
Sex hormone-binding globulin (SHBG) levels and sex hormones have been implicated in the pathogenesis of type 2 diabetes and cardiovascular diseases. As fatty liver has been suggested to be a major determinant of SHBG levels, we examined whether the associations of SHBG and testosterone with diabetes were independent of fatty liver.
Methods
We conducted a case–control study that included 300 diabetes cases (215 men and 85 women) and 300 matched controls from the Saku cohort study. Diabetes was defined by either fasting plasma glucose levels ≥126 mg/dL, 2-h post-load glucose levels ≥200 mg/dL after a 75 g oral glucose tolerance test, or diabetes diagnosed by physicians. We fitted conditional logistic regression models to examine the associations between SHBG and total testosterone levels with diabetes by sex. To evaluate the impact of fatty liver, we used the fatty liver index (FLI), a validated measure derived from serum triglyceride levels, body mass index (BMI), waist circumference, and γ-glutamyltransferase levels.
Results
After adjusting for age, family history of diabetes, smoking, physical activity, BMI, and FLI, SHBG levels were inversely associated with diabetes among women (odds ratio [OR] comparing the highest with the lowest quartiles, 0.13 [95% confidence interval {CI}, 0.02–0.96]), but not among men. Similar patterns were observed in a subgroup analysis restricted to postmenopausal women"(OR, 0.12 [95% CI, 0.01–1.17]). In contrast, testosterone levels were inversely associated with diabetes among men (OR, 0.45 [95% CI, 0.23–0.89]), but not among women.
Conclusions
Our findings suggest that SHBG in women and testosterone in men may be inversely associated with diabetes.
doi:10.1186/1475-2840-11-130
PMCID: PMC3537568  PMID: 23066943
Sex hormone; Sex hormone-binding globulin; Sex difference; Fatty liver disease
6.  Sex Hormones Levels and Subclinical Atherosclerosis in Postmenopausal Women: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;204(1):255-261.
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 1,947 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.
doi:10.1016/j.atherosclerosis.2008.08.037
PMCID: PMC2729280  PMID: 18849030
Gonadal steroid hormones; atherosclerosis; postmenopausal women; carotid intimal-medial thickness; coronary calcium
7.  Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study 
Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (≥65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone (P < 0.001), IL-6 (P < 0.001), CRP (P < 0.001), and HOMA (P < 0.001) and lower levels of SHBG (P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS (P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21–0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.
doi:10.1152/ajpendo.00339.2006
PMCID: PMC2645662  PMID: 16968811
sex hormone-binding globulin; hormonal dysregulation; insulin-like growth factor I; androgens
8.  Association of Sex Hormones and SHBG with Depressive Symptoms in Post-menopausal Women: the Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.y.)  2012;19(8):877-885.
Objective
Sex hormones are thought to play an important role in the pathophysiology of depressive disorders in women. This study assessed the associations of total testosterone (T), bioavailable T, estradiol (E2), dehydroepiandrosterone (DHEA) and sex hormone binding globulin (SHBG) with depressive symptoms stratified on postmenopausal stage to determine whether associations were strongest for early postmenopausal women.
Methods
Women (N=1824) free of depressive symptoms at baseline (2000–2002) in the Multi-Ethnic Study of Atherosclerosis were categorized into tertiles of years postmenopause: T1, 0–10 years; T2, 11–20 years; and T3, 21–58 years. Multivariable-adjusted relative risks (RR) and 95% confidence intervals were computed for the incidence of depressive symptoms, as defined by a score of 16 or higher on the Center for Epidemiologic Studies Depression scale at examination 3 (2004–2005).
Results
In analysis including all sex hormones, the RRs for incident depressive symptoms associated with 1 unit higher log(total T) was 0.57 (p=0.13), log(E2) was 0.78 (p=0.04), log(SHBG) was 1.84 (p=0.003) and log(DHEA) was 1.45 (p=0.08) in T1. Without adjustment for SHBG, the RR for log(bioavailable T) was 0.16 (p=0.04). However, in T2 and T3, there were no meaningful associations of hormone or SHBG levels with incident depressive symptoms. When stratified by HT use, results were consistent for HT users but attenuated for HT non-users.
Conclusions
In women early postmenopause, sex hormones were associated with incident depressive symptoms.
doi:10.1097/gme.0b013e3182432de6
PMCID: PMC3376685  PMID: 22415566
sex hormones; CES-D; depression; testosterone; estradiol; SHBG
9.  Premenopausal serum androgens and breast cancer risk: a nested case-control study 
Introduction
Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited.
Methods
A case-control study nested within the New York University Women's Health Study was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls were included. Matching variables included age and date, phase, and day of menstrual cycle at blood donation. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) were measured using direct immunoassays. Free testosterone was calculated.
Results
Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. In models adjusted for known risk factors of breast cancer, the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9 to 2.3), 1.2 (95% CI, 0.7 to 1.9), 1.4 (95% CI, 0.9 to 2.3) and 1.8 (95% CI, 1.1 to 2.9; Ptrend = 0.04), and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7 to 1.8), 1.5 (95% CI, 0.9 to 2.3), 1.5 (95% CI, 0.9 to 2.3), and 1.8 (95% CI, 1.1 to 2.8, Ptrend = 0.01). A marginally significant positive association was observed with androstenedione (P = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients for samples collected from 0.8 to 5.3 years apart (median 2 years) in 138 cases and 268 controls were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls).
Conclusions
Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (that is, a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results. The impact of including testosterone or free testosterone in breast cancer risk prediction models for women between the ages of 40 and 50 years should be assessed. Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer.
doi:10.1186/bcr3117
PMCID: PMC3496150  PMID: 22339988
10.  Low Sex-Hormone Binding Globulin is Associated with the Metabolic Syndrome in Postmenopausal Women 
Metabolism: clinical and experimental  2006;55(11):1473-1480.
Although an association between the metabolic syndrome and hyperandrogenism has been suggested in women with polycystic ovarian syndrome, few studies have investigated this relationship in postmenopausal women. We measured estradiol, testosterone, and sex hormone binding globulin (SHBG) and calculated the free androgen index (FAI) in 212 postmenopausal women not using hormone therapy in the Women's Health Study. A modified ATP III definition of the metabolic syndrome (3 or more of the following: abdominal obesity, hypertriglyceridemia, low HDL, elevated blood pressure, and abnormal glucose metabolism) was used. Women with the metabolic syndrome had higher mean levels of estradiol, testosterone, and FAI values, and lower SHBG levels. Higher FAI and lower SHBG were associated with all components of the metabolic syndrome. After adjustment for BMI and other factors, women in the highest tertile of FAI had an OR of 12.6 (95% CI: 3.8, 41.6) for the metabolic syndrome, while those in the lowest SHBG tertile had an OR of 7.3 (95% CI: 2.7, 19.8). When stratified by BMI, the associations with high FAI and low SHBG remained significant even in women with BMI < 26.7 kg/m2. An androgenic hormone profile is associated with both the individual components of the metabolic syndrome and clustering of metabolic abnormalities in postmenopausal women.
doi:10.1016/j.metabol.2006.06.017
PMCID: PMC1633722  PMID: 17046549
estradiol; gonadal steroid hormones; metabolic syndrome X; sex hormone binding globulin; testosterone
11.  ENDOGENOUS SEX HORMONES, BLOOD PRESSURE CHANGE, AND RISK OF HYPERTENSION IN POSTMENOPAUSAL WOMEN: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Atherosclerosis  2012;224(1):228-234.
Objective
Sex steroid hormones have been postulated to involve in blood pressure (BP) regulation. We examine the association of endogenous sex hormone levels with longitudinal change of BP and risk of developing hypertension in initially normotensive postmenopausal women.
Methods
We conducted prospective analysis among 619 postmenopausal women free of hypertension at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Change of BP and development of incident hypertension were assessed during a mean of 4.8 years follow-up.
Results
After adjusting for age, race/ethnicity, and lifestyle factors, baseline serum estradiol (E2), total and bioavailable testosterone (T), dehydroepiandrosterone (DHEA) were each positively and sex- hormone binding globulin (SHBG) was inversely associated with risk of hypertension. Additional adjustment for body mass index eliminated the associations for E2 and T but only attenuated the associations for DHEA and SHBG. The corresponding multivariable hazard ratios (95% CIs) in the highest quartile were 1.28 (0.83–1.97) for E2, 1.38 (0.89–2.14) for total T, 1.42 (0.90–2.23) for bioavailable T, 1.54 (1.02–2.31) for DHEA, and 0.48 (0.30–0.76) for SHBG. Adjustment for fasting glucose, insulin, and C-reactive protein further attenuated the association for DHEA but not SHBG. Associations of sex hormones with longitudinal BP change were similar.
Conclusion
In postmenopausal women, higher endogenous E2, T, and DHEA and lower SHBG were associated with higher incidence of hypertension and greater longitudinal rise in BP. The associations for E2, T, and DHEA were mostly explained by adiposity, while the association for SHBG was independent of measures of adiposity, insulin resistance, and systemic inflammation.
doi:10.1016/j.atherosclerosis.2012.07.005
PMCID: PMC3428144  PMID: 22862963
sex steroid hormones; hypertension; blood pressure; postmenopausal women; prospective study; epidemiology
12.  Sex Hormones, Sex Hormone Binding Globulin, and Abdominal Aortic Calcification in Women and Men in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2008;200(2):432-438.
Background
Conflicting findings exist regarding the associations of sex hormones with subclinical atherosclerosis.
Methods
This is a substudy from MESA of 881 postmenopausal women and 978 men who had both abdominal aortic calcification (AAC) quantified by computed tomography and sex hormone levels assessed [Testosterone (T), estradiol (E2), dehydroepiandrosterone (DHEA), and sex hormone binding globulin (SHBG)]. We examined the association of sex hormones with presence and extent of AAC.
Results
For women, SHBG was inversely associated with both AAC presence [OR=0.62, 95% CI 0.42 to 0.91 for 1 unit greater log(SHBG) level] and extent [0.29 lower log(AAC) for 1 unit greater log(SHBG) level, β= −0.29 (95% CI −0.57 to −0.006)] adjusting for age, race, hypertension, smoking, diabetes, BMI, physical activity, and other sex hormones. After further adjustment for total and HDL-cholesterol, SHBG was not associated with ACC presence or extent. In men, there was no association between SHBG and AAC. In both men and women, neither T, E2, nor DHEA was associated with AAC presence or extent.
Conclusion
After adjustment for non-lipid cardiovascular risk factors, SHBG levels are inversely associated with both the presence and severity of AAC in women but not in men, which may be accounted for by HDL.
doi:10.1016/j.atherosclerosis.2007.12.032
PMCID: PMC2607033  PMID: 18262187
sex hormone binding globulin; abdominal aortic calcification; sex hormones; subclinical atherosclerosis
13.  Sex hormone changes during weight loss and maintenance in overweight and obese postmenopausal African-American and non-African-American women 
Breast Cancer Research : BCR  2012;14(5):R141.
Introduction
Changes in sex hormones with weight loss might have implications for breast cancer prevention but have not been examined extensively, particularly in African-American (AA) women.
Methods
We conducted a prospective study of 278 overweight/obese postmenopausal women (38% AA) not taking hormone therapy within the Weight Loss Maintenance Trial. All participants lost at least 4 kg after a 6-month weight-loss phase and attempted to maintain weight loss during the subsequent 12 months. We evaluated the percentage changes in estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate and sex hormone-binding globulin (SHBG) using generalized estimating equations.
Results
In all study phases, AA women had higher levels of estrogen and testosterone concentrations, independent of adiposity. On average, participants lost 7.7 kg during the weight-loss phase, and concentrations of estrone (-5.7%, P = 0.006), estradiol (-9.9%, P <0.001), free estradiol (-13.4%, P <0.0001), and free testosterone (-9.9%, P <0.0001) decreased, while the SHBG concentration (16.2%, P <0.001) increased. Weight change did not significantly affect total testosterone or other androgen concentrations. Compared with non-AA women, AA women experienced less change in estrogens per kilogram of weight change (that is, per 1 kg weight loss: estrone, -0.6% vs. -1.2%, P-interaction = 0.10; estradiol, -1.1% vs. -1.9%, P-interaction = 0.04; SHBG, 0.9% vs. 1.6%, P-interaction = 0.006; free estradiol, -1.4% vs. -2.1%, P-interaction = 0.01).
Conclusion
To the best of our knowledge this is the first study to examine and compare the effects of intentional weight loss and maintenance on a panel of sex hormones in AA women and non-AA women. Although speculative, these data suggest hormonal differences may contribute to different racial patterns of breast cancer incidence and mortality and encourage further investigations to understand the long-term effects of weight loss on sex hormones in obese postmenopausal women.
Trial Registration
ClinicalTrials.gov: NCT00054925
doi:10.1186/bcr3346
PMCID: PMC3635052  PMID: 23113944
14.  Influence of Sex and Hormone Status on Circulating Natriuretic Peptides 
Objectives
To assess the relationship between sex hormones and natriuretic peptide levels in community-based adults
Background
Women have higher circulating natriuretic peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion.
Methods
We measured plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone binding globulin (SHBG) in 4,056 men and women (mean age 40±9 years) from the Framingham Heart Study Third Generation cohort. Sex/hormone status was grouped as: 1) men, 2) postmenopausal women not receiving hormone replacement therapy, 3) premenopausal women not receiving hormonal contraceptives, 4) postmenopausal women receiving hormone replacement therapy and 5) premenopausal women receiving hormonal contraceptives.
Results
Circulating NT-proBNP was associated with sex/hormone status (overall P<0.0001). Men had lower NT-proBNP than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP than women who were not receiving hormone therapy (all P<0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, FT decreased and SHBG increased in tandem with increasing NT-proBNP. In sex-specific analyses, NT-proBNP decreased across increasing quartiles of free testosterone in men (P for trend<0.01) and in women (P for trend<0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations.
Conclusions
These findings suggest that lower circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.
doi:10.1016/j.jacc.2011.03.042
PMCID: PMC3170816  PMID: 21798425
natriuretic peptides; sex; hormones
15.  Comparison of postmenopausal endogenous sex hormones among Japanese, Japanese Brazilians, and non-Japanese Brazilians 
BMC Medicine  2011;9:16.
Background
Differences in sex hormone levels among populations might contribute to the variation in breast cancer incidence across countries. Previous studies have shown higher breast cancer incidence and mortality among Japanese Brazilians than among Japanese. To clarify the difference in hormone levels among populations, we compared postmenopausal endogenous sex hormone levels among Japanese living in Japan, Japanese Brazilians living in the state of São Paulo, and non-Japanese Brazilians living in the state of São Paulo.
Methods
A cross-sectional study was conducted using a control group of case-control studies in Nagano, Japan, and São Paulo, Brazil. Participants were postmenopausal women older than 55 years of age who provided blood samples. We measured estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex hormone-binding globulin (SHBG) by immunoradiometric assay. A total of 363 women were included for the present analyses, comprising 185 Japanese, 44 Japanese Brazilians and 134 non-Japanese Brazilians.
Results
Japanese Brazilians had significantly higher levels of estradiol, bioavailable estradiol, estrone, testosterone and free testosterone levels, and lower SHBG levels, than Japanese. Japanese Brazilians also had significantly higher levels of bioavailable estradiol, estrone and DHEAS and lower levels of SHBG and androstenedione than non-Japanese Brazilians. Levels of estradiol, testosterone and free testosterone, however, did not differ between Japanese Brazilians and non-Japanese Brazilians. These differences were observed even after adjustment for known breast cancer risk factors. We also found an increase in estrogen and androgen levels with increasing body mass index, but no association for most of the other known risk factors.
Conclusions
We found higher levels of estrogens and androgens in Japanese Brazilians than in Japanese and levels similar to or higher than in non-Japanese Brazilians. Our findings may help explain the increase in the incidence and mortality rate of breast cancer among Japanese Brazilians.
doi:10.1186/1741-7015-9-16
PMCID: PMC3050759  PMID: 21324183
16.  The Relationship between Endogenous Androgens and Body Fat Distribution in Early and Late Postmenopausal Women 
PLoS ONE  2013;8(3):e58448.
Objectives
To investigate the relationship between endogenous androgens and body fat distribution in early and late postmenopausal women.
Materials and Methods
We enrolled postmenopausal women consisting of an early group (≤5 years since menopause, n = 105) and a late group (≥10 years since menopause, n = 107). Each group was subdivided into normal weight (BMI <24 kg/m2) group, overweight and obese (BMI ≥24 kg/m2) group. Fasting total testosterone (T), dehydroepiandrosterone-sulfate (DHEA-S) and sex hormone-binding globulin (SHBG) levels were measured. Body fat distribution was evaluated by dual-energy X-ray absorptiometry (DEXA).
Results
Late postmenopausal women had a higher proportion of body fat than early postmenopausal women. The body fat of the overweight and obese women had a greater tendency to accumulate in the abdomen compared with the normal weight women both in early and late postmenopausal groups. The overweight and obese women had a higher free testosterone (FT) than the normal weight women in early postmenopausal women (P<0.05). In late postmenopausal women, the overweight and obese women had higher DHEA-S levels than normal weight women (P<0.05). No direct relationship was observed between the T levels and body fat distribution both in early and late postmenopausal groups (P>0.05).The FT in early postmenopausal women and the DHEA-S levels in late postmenopausal women correlated positively with the trunk/leg fat ratio (T/L) and the proportion of android fat whereas correlated negatively with the proportion of gynoid fat in the partial correlation and multiple linear regression analyses (all P<0.05).
Conclusions
Serum T levels do not correlate directly with body fat distribution, the FT in early postmenopausal women and DHEA-S levels in late postmenopausal women correlate positively with abdominal fat accumulation.
doi:10.1371/journal.pone.0058448
PMCID: PMC3587576  PMID: 23484029
17.  Endogenous Hormones and Coronary Heart Disease in Postmenopausal Women 
Atherosclerosis  2011;216(2):414-419.
The association between serum levels of endogenous estrogens in postmenopausal women and the subsequent risk of coronary heart disease (CHD) was examined in a prospective case-control study nested within the New York University Women's Health Study (NYUWHS). The NYUWHS is a prospective cohort study of 14,274 healthy women enrolled between 1985 and 1991. A total of 99 women who were postmenopausal and free of cardiovascular disease at enrollment and who experienced CHD, defined as non-fatal myocardial infarction (MI), fatal CHD, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG), were matched 1:2 by baseline age, blood sampling date, and postmenopausal status to controls who remained free of CHD as of the date of diagnosis of the matching case. Biochemical analyses for total estradiol, estrone, percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), and SHBG were performed on pre-diagnostic stored serum samples. Participants had not used any hormone medications in the 6 months prior to blood collection. In the model adjusting only for matching factors, the risk of CHD in the top tertile of calculated bioavailable estradiol was elevated compared with the bottom tertile (OR=2.10; 95% CI = 1.13-3.90, p for trend = 0.03), and the risk in the top tertile of SHBG was reduced (OR = 0.50, 95% CI = 0.28-0.92, p for trend < 0.01). However, these associations disappeared after adjusting for baseline hypertension status, body mass index, and serum cholesterol levels. These findings suggest that circulating estradiol and SHBG are not associated with CHD risk in postmenopausal women beyond what can be explained by the variation in hypertension status, BMI, and cholesterol.
doi:10.1016/j.atherosclerosis.2011.01.053
PMCID: PMC3663480  PMID: 21367421
18.  No relationship between circulating levels of sex steroids and mammographic breast density: the Prospect-EPIC cohort 
Background
High breast density is associated with increased breast cancer risk. Epidemiologic studies have shown an increase in breast cancer risk in postmenopausal women with high levels of sex steroids. Hence, sex steroids may increase postmenopausal breast cancer risk via an increase of breast density. The objective of the present study was to study the relation between circulating oestrogens and androgens as well as sex hormone binding globulin (SHBG) in relation to breast density.
Methods
We conducted a cross-sectional study among 775 postmenopausal women, using baseline data of a random sample of the Prospect-EPIC study. Prospect-EPIC is one of two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition, and women were recruited via a breast cancer screening programme. At enrolment a nonfasting blood sample was taken and a mammogram was made. Oestrone, oestradiol, dehydroepiandrosterone sulfate, androstenedione, testosterone and SHBG levels were measured, using double-antibody radioimmunoassays. Concentrations of free oestradiol and free testosterone were calculated from the measured oestradiol, testosterone and SHBG levels Mammographic dense and nondense areas were measured using a semiquantitative computerized method and the percentage breast density was calculated. Mean breast measures for quintiles of hormone or SHBG levels were estimated using linear regression analyses.
Results
Both oestrogens and testosterone were inversely related with percent breast density, but these relationships disappeared after adjustment for BMI. None of the sex steroids or SHBG was associated with the absolute measure of breast density, the dense area.
Conclusion
The results of our study do not support the hypothesis that sex steroids increase postmenopausal breast cancer risk via an increase in breast density.
doi:10.1186/bcr1758
PMCID: PMC2206729  PMID: 17692133
19.  Levels of sex steroid and CVD measures in premenopausal and hormone-treated women at mid-life: implications for the “timing hypothesis” 
Archives of internal medicine  2008;168(19):2146-2153.
Background
The “timing hypothesis”, in addressing findings from the Women’s Health Initiative trial, suggests that hormone therapy (HT) use should be initiated within six years of the menopause transition to extend a favorable estrogenic environment after menopause.
Methods
We compared sex steroid and cardiovascular profiles at visit 05 in a community-based, longitudinal study of the menopause transition (Study of Women’s Health Across the Nation). Women, aged 47–57 years, were in one of four groups: premenopausal, using conjugated equine estrogen (CEE) with or without progestin, or postmenopausal (<5 years). Cardiovascular assays included low density lipoprotein cholesterol (LDL-c), oxidized LDL-c, high density lipoprotein cholesterol (HDL-c), triglycerides, apolipoproteins A-1 and B, F2a-isoprostanes, C-reactive protein (CRP), and lipoprotein(a)-1. Sex steroid assays were for estradiol (E2), estrogen receptor ligand load (ERLL), 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), total testosterone, and sex hormone-binding globulin (SHBG).
Results
HT users had 50% higher SHBG levels (p<0.0001 for both groups), which limits sex steroids binding to their receptors, and higher excreted estrone metabolites (more than 60%, p<0.0001 for both groups) than pre- or postmenopausal women. These were, in turn, associated with higher F2a-isoprostanes, an oxidative stress measure, compared to premenopausal women. HT users had a more favorable HDL-c/LDL-c ratio than pre- or postmenopausal women (p<0.01), but higher triglyceride levels (p<0.01).
Conclusions
Though HT users had some more favorable lipid profiles than pre- and postmenopausal women, there was evidence of adverse HT effects even in women free of atherosclerosis evaluated within the approximate 6-year time period proposed with the “timing hypothesis”.
doi:10.1001/archinte.168.19.2146
PMCID: PMC2727614  PMID: 18955645
hormone therapy; conjugated equine estrogens (CEE); estrogen; cardiovascular disease; lipids; sex hormone binding globulin
20.  Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies 
British Journal of Cancer  2011;105(5):709-722.
Background:
Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.
Methods:
Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.
Results:
Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.
Conclusion:
Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.
doi:10.1038/bjc.2011.254
PMCID: PMC3188939  PMID: 21772329
breast cancer; hormones; oestrogens; androgens; sex hormone-binding globulin
21.  Sensitive and specific markers for insulin resistance, hyperandrogenemia, and inappropriate gonadotrophin secretion in women with polycystic ovary syndrome: a case-control study from Bahrain 
Background
In women with polycystic ovary syndrome (PCOS), despite a high prevalence of insulin resistance, hyperandrogenemia, and disturbances in the secretion of gonadotrophin, the principal causes of biochemical abnormalities and the best endocrine markers for PCOS have not been fully identified.
Subjects and methods
Serum levels of insulin, glucose, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, estrogen, sex hormone-binding capacity (SHBG), and other related indices such as homeostasis model assessment, insulin glucose ratios, LH/FSH ratios, and the free androgen index (FAI) were determined and compared in women with PCOS (n = 50) and women without PCOS (n = 50).
Results
In multivariate logistic regression analyses, among all insulin resistance indices, only hyperinsulinemia (odds ratio [OR] = 2.6; confidence interval [CI]: 1.3–5.2; P = 0.008) was significantly and independently associated with PCOS when adjusted for body mass index (BMI), hyperandrogenemia, and LH/FSH ratios. The LH/FSH ratio (OR = 5.4; CI: 1.2–23.0, P = 0.03) was the only marker among those indices for inappropriate gonadotrophin secretion that significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. Among those indices for hyperandrogenemia, FAI (OR = 1.1; CI: 1.0–2.7; P = 0.02) and SHBG (OR = 1.2; CI: 1.2–3.4; P = 0.03) were significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. In addition, receiver operating characteristic analysis showed that the best predictive markers for PCOS were insulin (area under the curve [AUC] = 0.944; CI: 0.887–0.989), FAI (AUC = 0.932; CI: 0.895–0.993), SHBG (AUC = 0.924; CI: 0.87–0.978), and LH/FSH ratios (AUC = 0.906; CI: 0.821–0.965).
Conclusion
For insulin and LH/FSH ratios, FAI, and SHBG seemed the best predictors and markers for insulin resistance, inappropriate gonadotrophin secretion, and hyperandrogenemia, respectively, with high sensitivity and specificity for identifying Bahraini women with and without PCOS.
doi:10.2147/IJWH.S30661
PMCID: PMC3363136  PMID: 22654525
polycystic ovary syndrome; insulin resistance; gonadotrophin; hyperandrogenemia; diagnostic markers
22.  Physical Activity and Sex Hormone Levels in Estradiol- and Placebo-Treated Postmenopausal Women 
Menopause (New York, N.Y.)  2011;18(10):1079-1086.
Objective
Postmenopausal changes in the hormonal milieu in women with or without hormone therapy (HT) are hypothesized to be the pathway for a number of menopause-associated modifications in physiology and disease risk. Physical activity may modify these changes in women’s hormone profiles. The crucial yet complex relationship between physical activity and physiologic and pharmacologic sex hormone levels in postmenopausal women has not been investigated sufficiently.
Methods
Using structured recall, physical activity was assessed longitudinally over two years in 194 postmenopausal women (90 randomized to daily 1 mg 17β-estradiol and 104 to placebo) in the Estrogen in the Prevention of Atherosclerosis Trial. Levels of physical activity were correlated to serum sex hormone and serum hormone-binding globulin (SHBG) levels in each treatment group.
Results
In placebo-treated women, total energy expenditure was positively associated with sex hormone-binding globulin (SHBG) (p<0.001) and inversely associated with testosterones (total, bioavailable, free) and androstenedione (p<0.001 for all), as well as with estradiol (p=0.02). In estradiol-treated women, estradiol levels were inversely associated with total energy expenditure (p=0.002) and weekly hours spent in moderate or more vigorous physical activity (p=0.001).
Conclusion
Physical activity is associated with lower serum levels of estradiol in both HT-treated and untreated women. In placebo-treated women only, physical activity is associated with reduced androgen levels and elevated SHBG levels.
doi:10.1097/gme.0b013e318215f7bd
PMCID: PMC3183237  PMID: 21646925
Physical activity; sex hormones; estradiol; menopause
23.  A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation 
Coviello, Andrea D. | Haring, Robin | Wellons, Melissa | Vaidya, Dhananjay | Lehtimäki, Terho | Keildson, Sarah | Lunetta, Kathryn L. | He, Chunyan | Fornage, Myriam | Lagou, Vasiliki | Mangino, Massimo | Onland-Moret, N. Charlotte | Chen, Brian | Eriksson, Joel | Garcia, Melissa | Liu, Yong Mei | Koster, Annemarie | Lohman, Kurt | Lyytikäinen, Leo-Pekka | Petersen, Ann-Kristin | Prescott, Jennifer | Stolk, Lisette | Vandenput, Liesbeth | Wood, Andrew R. | Zhuang, Wei Vivian | Ruokonen, Aimo | Hartikainen, Anna-Liisa | Pouta, Anneli | Bandinelli, Stefania | Biffar, Reiner | Brabant, Georg | Cox, David G. | Chen, Yuhui | Cummings, Steven | Ferrucci, Luigi | Gunter, Marc J. | Hankinson, Susan E. | Martikainen, Hannu | Hofman, Albert | Homuth, Georg | Illig, Thomas | Jansson, John-Olov | Johnson, Andrew D. | Karasik, David | Karlsson, Magnus | Kettunen, Johannes | Kiel, Douglas P. | Kraft, Peter | Liu, Jingmin | Ljunggren, Östen | Lorentzon, Mattias | Maggio, Marcello | Markus, Marcello R. P. | Mellström, Dan | Miljkovic, Iva | Mirel, Daniel | Nelson, Sarah | Morin Papunen, Laure | Peeters, Petra H. M. | Prokopenko, Inga | Raffel, Leslie | Reincke, Martin | Reiner, Alex P. | Rexrode, Kathryn | Rivadeneira, Fernando | Schwartz, Stephen M. | Siscovick, David | Soranzo, Nicole | Stöckl, Doris | Tworoger, Shelley | Uitterlinden, André G. | van Gils, Carla H. | Vasan, Ramachandran S. | Wichmann, H.-Erich | Zhai, Guangju | Bhasin, Shalender | Bidlingmaier, Martin | Chanock, Stephen J. | De Vivo, Immaculata | Harris, Tamara B. | Hunter, David J. | Kähönen, Mika | Liu, Simin | Ouyang, Pamela | Spector, Tim D. | van der Schouw, Yvonne T. | Viikari, Jorma | Wallaschofski, Henri | McCarthy, Mark I. | Frayling, Timothy M. | Murray, Anna | Franks, Steve | Järvelin, Marjo-Riitta | de Jong, Frank H. | Raitakari, Olli | Teumer, Alexander | Ohlsson, Claes | Murabito, Joanne M. | Perry, John R. B.
PLoS Genetics  2012;8(7):e1002805.
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Author Summary
Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabetes and to hormone-sensitive cancers such as breast and prostate cancer. SHBG concentrations are approximately 50% heritable in family studies, suggesting SHBG concentrations are under significant genetic control; yet, little is known about the specific genes that influence SHBG. We conducted a large study of the association of SHBG concentrations with markers in the human genome in ∼22,000 white men and women to determine which loci influence SHBG concentrations. Genes near the identified genomic markers in addition to the SHBG protein coding gene included PRMT6, GCKR, ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes represent a wide range of biologic pathways that may relate to SHBG function and sex steroid hormone biology, including liver function, lipid metabolism, carbohydrate metabolism and type 2 diabetes, and the development and progression of sex steroid hormone-responsive cancers.
doi:10.1371/journal.pgen.1002805
PMCID: PMC3400553  PMID: 22829776
24.  Mortality in Pharmacologically Treated Older Adults with Diabetes: The Cardiovascular Health Study, 1989–2001 
PLoS Medicine  2006;3(10):e400.
Background
Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age.
Methods and Findings
From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5%), and 194 with DM treated with insulin (3.3%). Participants were followed (1989–2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95% confidence interval [CI], 1.10 to 1.62) and 2.04 (95% CI, 1.62 to 2.57); CVD mortality, 1.99 (95% CI, 1.54 to 2.57) and 2.16 (95% CI, 1.54 to 3.03); CHD mortality, 2.47 (95% CI, 1.89 to 3.24) and 2.75 (95% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95% CI, 0.70 to 2.59) and 6.55 (95% CI, 4.18 to 10.26), respectively. The interaction of age (65–74 y versus ≥75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin.
Conclusions
DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.
The negative impact on mortality of diabetes persists into old age. Elderly people with diabetes might be twice as likely to die from CVD as people without diabetes. More aggressive treatment of CVD risk factors in older patients should be considered.
Editors' Summary
Background.
Diabetes is a growing global health problem. By 2030, 300 million people worldwide may have this chronic, incurable disorder, double the current number. People with diabetes have dangerously high amounts of sugar in their blood. Blood-sugar levels are normally controlled by insulin, a hormone made by the pancreas that tells cells to absorb sugar from the blood. This control fails in people with diabetes, either because they make no insulin (type 1 diabetes) or because their cells are insensitive to insulin (type 2 diabetes). Type 1 diabetes is controlled with insulin injections; type 2 diabetes is controlled with diet, exercise, and pills that reduce blood-sugar levels. Long-term complications of diabetes include kidney failure, blindness, and nerve damage. Individuals with diabetes also have an increased risk of developing cardiovascular disease (CVD)—heart problems, strokes, and poor circulation—because of damage to their blood vessels.
Why Was This Study Done?
Epidemiological studies (investigations of disease patterns, causes, and control in populations) have indicated that diabetes increases the risk of death (mortality) from CVD in young and middle-aged people, but it is not known whether this is also true for old people. It is also not known what effect long-term treatment for diabetes has on mortality or whether the risk of death from CVD is decreasing in diabetic people as it is in the general US population. This information would help physicians provide health care and lifestyle advice to people with diabetes. In this study, the researchers have investigated mortality patterns in elderly diabetic people by looking at data collected between 1989 and 2001 by the US Cardiovascular Health Study, an observational study of nearly 6,000 people aged over 65 years (in this type of study participants are observed without imposing any specific changes to their lifestyle, behavior, medical care, or treatments).
What Did the Researchers Do and Find?
Participants were screened at the start of the Cardiovascular Health Study for CVD and diabetes (defined as drug-treated disease), for established CVD risk factors such as high blood pressure and smoking, for recently recognized CVD risk factors (for example, subclinical CVD), and for psychosocial factors associated with diabetes that might influence mortality, such as frailty and depression. At this time, about 5% of the participants were taking oral hypoglycemic agents for diabetes and about 3% were taking insulin. During the 11-year study, 40% of the participants died. After adjusting for CVD risk factors and psychosocial factors, the researchers calculated that people treated with oral hypoglycemic agents were 1.3 times as likely to die from all causes and people treated with insulin were twice as likely to die as people without diabetes. The risk of death from CVD was about twice as high in both groups of diabetic participants as in non-diabetic participants; the risk of death from coronary heart disease was increased about 2.5-fold. These adjusted relative risks are very similar to those found in previous studies. The researchers also report that participants treated with insulin were six times more likely to die from infectious diseases or renal failure than nondiabetic participants, and women treated with insulin had a particularly high mortality risk.
What Do These Findings Mean?
These findings indicate that the negative impact on mortality of diabetes persists into old age and that death from CVD is currently declining in both older diabetic people and nondiabetic people. In addition, they show that diabetic people treated with insulin are at a greater risk of dying relative to people without diabetes and those taking oral hypoglycemic agents. This might reflect the type of diabetes that these people had, but this was not investigated. How long participants had had diabetes was also not considered, nor how many people developed diabetes during the study. These and other limitations might mean that the reported excess mortality due to diabetes is an underestimate. Nevertheless, the estimate that elderly people with diabetes are twice as likely to die from CVD as people without diabetes is important. Many elderly people die anyway because of CVD, so this increased risk represents many more deaths than the similar increased risk in younger diabetic populations. Yet, elderly people often receive less-intensive management of CVD risk factors than younger people. The results of this study suggest that rectifying this situation could prolong the lives of many elderly people with diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030400.
MedlinePlus encyclopedia has pages on diabetes, heart disease, stroke and poor circulation
The US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on diabetes
Information for patients on prevention, diagnosis, and management of diabetes is available from the America Diabetes Association
Patient information is available from the American Heart Association on all aspects of heart disease, including its association with diabetes
Wikipedia pages on diabetes and cardiovascular disease (note that Wikipedia is a free online encyclopedia that anyone can edit)
Further information is available about the Cardiovascular Health Study
doi:10.1371/journal.pmed.0030400
PMCID: PMC1609124  PMID: 17048978
25.  Statin Therapy Is Associated With Lower Total but Not Bioavailable or Free Testosterone in Men With Type 2 Diabetes 
Diabetes Care  2008;32(4):541-546.
OBJECTIVE
There is a high prevalence of hypogonadism in men with type 2 diabetes. This will lead to an increase in assessments of hypogonadism. Statins could potentially decrease testosterone levels by reducing the availability of cholesterol for androgen synthesis. We compared testosterone levels and hypogonadal symptoms with statin use in a cross-sectional study of 355 men with type 2 diabetes.
RESEARCH DESIGN AND METHODS
Total testosterone, sex hormone–binding globulin (SHBG), and estradiol were measured by an enzyme-linked immunosorbent assay. Bioavailable testosterone was measured by the modified ammonium sulfate precipitation method. Free testosterone was calculated using Vermeulen's formula. Symptoms of hypogonadism were assessed using the Androgen Deficiency in the Aging Male questionnaire.
RESULTS
Statins were associated with lower total testosterone (11.9 vs. 13.4 nmol/l, P = 0.006) and a trend toward lower SHBG (29.4 vs. 35.3 nmol/l, P = 0.034) compared with no treatment. Bioavailable testosterone, free testosterone, estradiol, and hypogonadal symptoms were not affected. Subanalysis showed that atorvastatin was associated with reduced total testosterone (11.4 vs. 13.4 nmol/l, P = 0.006) and a trend toward reduced SHBG (27.6 vs. 35.3 nmol/l, P = 0.022) compared with no treatment, and there was an apparent dose-response effect with the lowest levels of total testosterone seen in men treated with ≥20 mg atorvastatin (9.6 nmol/l, P = 0.017). Simvastatin use was not associated with significant reductions in testosterone or SHBG levels.
CONCLUSIONS
Assessing androgen status using total testosterone in men with type 2 diabetes treated with statins, particularly atorvastatin, may potentially lead to diagnostic error. Levels of bioavailable testosterone or free testosterone are recommended for the assessment of hypogonadism in this group if total testosterone levels are borderline.
doi:10.2337/dc08-1183
PMCID: PMC2660443  PMID: 19114614

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