Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study

OBJECTIVE: The objective was to examine prospectively the association between low testosterone and sex hormone-binding globulin (SHBG) levels and the subsequent development of type 2 diabetes in men. RESEARCH DESIGN AND METHODS: Analyses were conducted on the cohort of the Massachusetts Male Aging Study, a population-based random sample of men aged 40-70. Of the 1,709 men enrolled in 1987-1989 (T1), 1,156 were followed up 7-10 years later (T2). Testosterone and SHBG levels at T1 were used to predict new cases of diabetes between T1 and T2. RESULTS: After controlling for potential confounders, diabetes at follow-up was predicted jointly and independently by lower baseline levels of free testosterone and SHBG. The odds ratio for future diabetes was 1.58 for a decrease of 1SD in free testosterone (4 ng/dl) and 1.89 for a 1SD decrease in SHBG (16 nmol/l), both significant at P < 0.02. CONCLUSIONS: Our prospective findings are consistent with previous, mainly cross-sectional reports, suggesting that low levels of testosterone and SHBG play some role in the development of insulin resistance and subsequent type 2 diabetes.     

Serum gamma-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men

OBJECTIVE: To investigate the association between serum gamma-glutamyltransferase (GGT) and risk of metabolic syndrome and type 2 diabetes in Japanese male office workers. RESEARCH DESIGN AND METHODS: This study included 2,957 metabolic syndrome-free men and 3,260 nondiabetic men aged 35-59 years who did not have medication for hepatitis, alanine aminotransferase (ALT) levels higher than three times the upper limit of the reference range, or a history of cardiovascular disease at study entry. Subjects were reexamined at periodic annual health examinations over a 7-year period. We used a modified National Cholesterol Education Program definition of metabolic syndrome with BMI instead of waist circumference and the revised criteria of the American Diabetes Association for type 2 diabetes. RESULTS: With adjustment for age, family history of diabetes, BMI, alcohol intake, cigarette smoking, regular physical activity (fasting plasma glucose for the risk of type 2 diabetes), and white blood cell (WBC) count, the risk of metabolic syndrome and type 2 diabetes increased in correlation with the levels of serum GGT, ALT, aspartate aminotransferase (AST), and alkaline phosphatase. Additional adjustment for all of the other liver enzymes attenuated these associations, but serum GGT remained a significant risk factor for the risk of both metabolic syndrome and type 2 diabetes (P for trend <0.001 for both). Top one-fifth versus bottom one-fifth relative risks of metabolic syndrome and type 2 diabetes were 2.23 (95% CI 1.51-3.30) and 2.44 (1.34-4.46), respectively. CONCLUSIONS: These results indicate that serum GGT may be an important predictor for developing metabolic syndrome and type 2 diabetes in middle-aged Japanese men.     

Sex hormone-binding globulin levels in middle-aged premenopausal women. Associations with visceral obesity and metabolic profile.

OBJECTIVE: Low sex hormone-binding globulin (SHBG) levels in women are associated not only with hyperinsulinemia, increased risk for cardiovascular disease, and type 2 diabetes but also with excess body fatness and abdominal obesity. We tested the hypothesis that an elevated total or intra-abdominal adipose tissue accumulation mediates the relationship between low SHBG levels and an altered metabolic profile. RESEARCH DESIGN AND METHODS: We measured body composition (dual-energy X-ray absorptiometry [DEXA]) and body fat distribution (computed tomography) in 52 middle-aged (46.7 +/- 0.4, mean +/- SEM) premenopausal women. Insulin and glucose responses to a 75-g oral glucose load and plasma lipid-lipoprotein levels were also measured. RESULTS: Low plasma SHBG concentrations were associated with increased total body fat mass (r = -0.41, P < 0.005) and subcutaneous abdominal (r = -0.39, P < 0.005) and intra-abdominal (r = -0.37, P < 0.008) adipose tissue area. Low SHBG was also associated with a greater insulin response to oral glucose (r = -0.40, P < 0.005), higher triglyceride levels (r = -0.29, P < 0.05), higher cholesterol/HDL cholesterol ratio (r = -0.51, P < 0.005), but lower HDL cholesterol concentrations (r = 0.65, P < 0.005). When matched for intra-abdominal fat or total fat mass, subjects with either low or high SHBG showed no difference in the insulin response to an oral glucose challenge. Statistical adjustment for differences in intra-abdominal adipose tissue accumulation or total body fat mass also eliminated the associations between SHBG levels and metabolic variables, with the exception of the association between SHBG and HDL cholesterol levels (r = 0.52, P < 0.005). CONCLUSIONS: Our results suggest that the previously reported relationship between low SHBG levels and increased metabolic disease risk in women is mediated, to a large extent, by concomitant variation in body fatness and intra-abdominal adipose tissue accumulation.     

Evaluation of a sex hormone-binding globulin automated chemiluminescent assay

Abstract

Background. Sex hormone-binding globulin (SHBG) is the main transport protein of sex steroids. This study evaluated the analytical performance of the recently developed Access SHBG assay (Beckman Coulter) and compared it with other commercial methods for the determination of serum SHBG. Clinical validation was also performed. Methods. Analytical performance including within-run and between-run imprecision was assessed for Access SHBG assay on the automated Beckman UniCel DxI800 analyzer. Linearity was assessed using five dilutions of the serum samples. For methods comparison, SHBG levels were determined also with Immulite 2000 analyzer (Siemens Healthcare) using clinical serum samples (n = 104). For clinical validation 135 specimens from healthy subjects, pregnant women, hypothyroid and hyperthyroid patients were analyzed. Results. Total coefficients of variation were < 5.5%. Linearity test showed > 90% recovery for all samples and for all dilution rates. Comparison analysis (Bland-Altman difference analysis and Passing-Bablock regression) showed an acceptable agreement between selected methods. SHBG values measured by Access SHBG assay in different groups of subjects were in agreement with other clinical evidence. Conclusions. Automated Access SHBG assay appears to be a reliable and easy to perform assay, as necessary for application in routine diagnostics.     

Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: the framingham heart study

OBJECTIVE

The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We determined whether testosterone or sex hormone–binding globulin (SHBG) is independently associated with the risk of metabolic syndrome.

RESEARCH DESIGN AND METHODS

Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography–tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria.

RESULTS

Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components.

CONCLUSIONS

SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men.Epidemiological studies have reported that low total testosterone levels are associated with an increased risk of metabolic syndrome in men (1–8). Circulating testosterone levels also have been associated with individual components of metabolic syndrome, such as insulin resistance (9,10), visceral adiposity (10), hypertension (11), and dyslipidemia. These epidemiological observations have led to speculation that testosterone deficiency contributes to the pathophysiology of metabolic syndrome and that diagnostic evaluation for androgen deficiency and testosterone therapy might be indicated in men with metabolic syndrome (12,13).Circulating testosterone is partly bound to sex hormone–binding globulin (SHBG) with high affinity, and testosterone levels are strongly related to SHBG concentrations. SHBG levels also have been associated with the risk of metabolic syndrome in men (1–4,8). However, we do not know whether the observed association between total testosterone and metabolic syndrome reflects an independent influence of testosterone on the risk of metabolic syndrome or primarily an association of SHBG with this disorder. The relationship of free testosterone and metabolic syndrome has been inconsistent or weak (1–8), suggesting that SHBG may be the primary determinant of the apparent relationship between total testosterone and metabolic syndrome.This issue has therapeutic implications; if low testosterone levels are causally related to metabolic syndrome, then testosterone therapy of men with low testosterone levels might be expected to prevent or ameliorate metabolic syndrome, as has been suggested (12–14). If SHBG is the primary determinant of this apparent relationship between total testosterone and metabolic syndrome, as we hypothesize, then efforts should be directed at remediable factors, such as obesity and insulin resistance that regulate SHBG as well as the risk of metabolic syndrome.Here, we investigated the relationship between total and free testosterone as well as SHBG with metabolic syndrome cross-sectionally in community-dwelling men in the Framingham Heart Study (FHS) and confirmed these associations in a validation sample. We also longitudinally evaluated the association of these hormones with incident metabolic syndrome. Previous studies measured testosterone levels using immunoassays (1–7) that lack accuracy in the low range (15). We measured total testosterone by liquid chromatography–tandem mass spectrometry (LC-MS/MS), the method with the highest accuracy and specificity (15). We adjusted the analyses for factors that independently affect metabolic syndrome and testosterone levels, such as age, BMI, smoking, and insulin sensitivity index (homeostasis model assessment of insulin resistance [HOMA-IR]). We also determined whether testosterone levels were associated with metabolic syndrome after adjusting for SHBG. We hypothesized that the apparent relationship between total testosterone and metabolic syndrome is driven mostly by the association of SHBG with metabolic syndrome.     

性激素结合球蛋白测定的方法学评价及相关性研究

目的对性激素结合球蛋白(SHBG)商品试剂盒进行方法学评价,以确定其分析性能是否符合临床实验室应用的要求;建立SHBG的实验室参考范围,并分析其与睾酮、雌二醇的相关性。方法依据美国临床实验室标准化协会颁布的EP5-A、EP6-P文件,分别对SHBG试剂盒进行批内和日间精密度、线性评价;评价分析方法的最低检测限。通过健康人建立实验室SHBG的参考范围,分析睾酮或雌二醇水平与SHBG的相关性。结果不同SHBG浓度批内精密度变异系数(CV)分别为2.50%和2.16%,日间精密度CV分别为4.33%和2.63%;线性范围为0.80～183.60nmol/L时测定结果为线性;其他指标符合性能评价要求。男、女性SHBG呈正态分布,60岁以下男性SHBG参考范围确定为8.76～61.44nmol/L,60岁以上男性SHBG参考范围确定为20.41～97.43nmol/L;女性SHBG参考范围确定为10.26～129.94nmol/L。总睾酮或总雌二醇与SHBG无相关性。结论 Roche公司生产的SHBG试剂盒在精密度、线性范围等方面的性能满足实验室要求。总睾酮或总雌二醇与SHBG无相关性。     

Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study)

OBJECTIVE

This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS).

RESEARCH DESIGN AND METHODS

The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0−6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6−12).

RESULTS

TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA_1c: treatment difference, −0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate.

CONCLUSIONS

Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS.Low serum testosterone is common in men with type 2 diabetes and/or metabolic syndrome (MetS) and numerous studies have reported an association between testosterone deficiency and visceral obesity, insulin resistance (IR) and dyslipidemia (1–4). In men with type 2 diabetes, low testosterone is associated with a high prevalence of symptomatic hypogonadism (3), frequently due to hypogonadotrophic hypogonadism (5).Small studies have demonstrated that testosterone replacement therapy (TRT) in hypogonadal men with and without type 2 diabetes is associated with reductions in IR, waist circumference, cholesterol, glycated hemoglobin (HbA_1c), and fasting plasma glucose (FPG) concentrations (6–9). Conversely, withdrawal of TRT in hypogonadal men leads to decreased insulin sensitivity (10). Furthermore, androgen suppression therapy for prostate cancer can result in alterations of individual cardiovascular risk factors and increases the occurrence of incident diabetes, myocardial infarction and sudden cardiac death (11,12). Epidemiologic studies have reported that low testosterone in men is associated with increased all-cause and cardiovascular mortality (13).The TIMES2 (Testosterone replacement In hypogonadal men with either MEtabolic Syndrome or type 2 diabetes) study investigated the effects of transdermal TRT on IR, selected cardiovascular risk factors, and symptoms in hypogonadal men with MetS and/or type 2 diabetes. The safety and tolerability of a novel, metered-dose, transdermal 2% testosterone gel were also examined.     

Self-rated health and risk factors for metabolic syndrome among middle-aged men

OBJECTIVES: To examine lifestyle and clinical risk factors for metabolic syndrome (MBO) and compare their significance between levels of self-rated health among middle-aged men. DESIGN: A cross-sectional baseline study. SAMPLE: 273 men, aged 40, living in Helsinki, Finland. METHODS: Postal questionnaires and health examinations by public health nurses were used in data collection. Statistical differences between groups of self-rated health and risk factors were analyzed by chi-square tests. RESULTS: Of all the respondents, 55% rated their health as good and 45% as average. Two thirds were overweight or obese, and 35% had waist-hip ratio more than 100 cm. Approximately 43% had diastolic blood pressure greater than 90 mmHg. Over half of the men smoked daily, and 28% used alcohol excessively. CONCLUSIONS: The men in this sample were found to be at high risk of developing MBO. The results underscore the importance of understanding the contradiction that exists between subjective and objective health ratings. Public health nurses are in a key position to educate men on how to use simple measurements to objectively assess their risk factors and, thus, potentially reduce their risk of developing diabetes, heart attack, or stroke.     

中老年男性血清睾酮与代谢综合征的关系

目的 探讨中老年男性代谢综合征(MS)患者血清睾酮下降的原因.方法 选取45～ 83岁的中老年男性56例为研究对象,分别测量其血压、身高、体质量,计算体质量指数(BMI),检测空腹状态下生化指标[血糖(FBG)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)]、空腹胰岛素(FIN)及血清睾酮,并用稳态公式(HOMA)计算胰岛素抵抗指数(HOMA-IR).根据CDS建议的MS诊断标准,将研究对象分为MS组及非MS组,分析睾酮浓度与各指标的关系.结果 中老年男性MS组血清睾酮浓度明显低于非MS组[(9.97±3.87)nmol/L与(13.73±3.93)nmol/L,t=3.337,P＜0.01],多因素回归分析显示,血清睾酮浓度与年龄、腰围、HOMA-IR呈负相关(回归系数分别为-0.214、-0.329、-0.317,标准回归系数分别为-0.730、-0.597、-0.313,t值分别为-5.833、-4.681、-2.686,P均＜0.01).结论 中老年男性MS患者血清睾酮浓度下降,血清睾酮浓度与年龄、腰围、胰岛素抵抗密切相关.     

2型糖尿病患者绝经后血清性激素结合球蛋白与下肢血管病变的相关性

目的探讨血清性激素结合球蛋白水平(SHBG)与绝经后2型糖尿病(T2DM)患者下肢血管病变的相关性。方法选取150例绝经后T2DM患者,根据双下肢高分辨彩色多普勒检查分为单纯T2DM(A组)50例,合并轻度下肢动脉粥样硬化(B组)45例,合并重度下肢动脉粥样硬化(C组)55例;并选取同期来本院体检的45例绝经后健康者为对照(NC)组,对各组患者进行临床资料收集及常规生化指标检测,采用电化学发光法检测各组空腹血清SHBG及睾酮(T)、雌二醇(E2),促卵泡刺激素(FSH),黄体生成素(LH)水平,并分析SHBG与其他指标的关系。结果4组血清SHBG水平依次为:NC组[(60.4±8.8)μg/L]A组[(44.1±6.1)μg/L]B组[(33.6±4.9)μg/L]C组[(25.83±3.4)μg/L];T2DM组中,血清SHBG水平与HbA1c、TG、T、LDL-C、HOMA-IR负相关(r值分别为-0.605、-0.164、-0.351、-0.247、-0.649,P0.05);回归分析结果显示,校正混杂因素后,血清SHBG水平仍与糖尿病下肢血管病变相关(OR=1.674,P=0.001,95%CI:1.124~2.146)。结论低水平的SHBG是绝经后2型糖尿病患者下肢血管病变的危险因素之一。     

Association of follicle-stimulating hormone and sex hormone binding globulin with the metabolic syndrome in postmenopausal women

ObjectivesWe compared the association of follicle-stimulating hormone (FSH) and sex hormone binding globulin (SHBG) with metabolic syndrome (MetS).Design and methodsWe examined 320 postmenopausal women (148 with MetS and 172 without MetS).ResultsFSH was more strongly associated with MetS probability in the logistic regression model compared to SHBG. Receiver operating characteristic (ROC) curves comparison showed greater areas under the curve for FSH than SHBG concentrations.ConclusionsFSH exhibited a stronger coherence to MetS than SHBG in postmenopausal women.     

Estimation of serum sex hormone-binding globulin by five direct and two indirect methods

Serum sex hormone-binding globulin (SHBG) has been estimated over the range 2-190 nM by six commercially available methods. The Farmos immunoradiometric assay (IRMA) and the Pharmacia-LKB DELFIA fluoroimmunoassay, which use the same monoclonal antiserum, produced statistically identical but widely spread results. The Techland polyclonal radioimmunoassay produced similar results but was considerably less sensitive, and agreement with the other two direct methods was poor at low concentrations. These three direct methods gave slightly higher results than those obtained with the two indirect methods: the BioMerieux concanavalin-A-binding method and, especially, the Serono ammonium sulphate precipitation method. The Diagnostic Products monoclonal IRMA gave results that were up to double the values obtained with the other five methods and is considered unsatisfactory. Monoclonal antibodies are now available for the direct estimation of SHBG, although an amino acid sequence has not yet been published for this protein, and there is still some controversy about the size of its structural units.