Judith S. Brand

Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies

BACKGROUNDnAccumulating evidence suggests a sex-dependent role of circulating testosterone in the metabolic syndrome (MetS).nnnMETHODSnWe conducted a meta-analysis of observational studies (PubMed and EMBASE-1 May 2010) relating MetS to determinants of testosterone status [total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG)].nnnRESULTSnA total of 52 studies were identified, comprising 22u2009043 men and 7839 women and presenting relative risk (RR) estimates or hormone levels for subjects with and without MetS. Endogenous TT and FT levels were lower in men with MetS [TT mean differenceu2009=u2009-2.64u2009nmol/l, 95% confidence interval (CI) -2.95 to -2.32; FT standardized mean differenceu2009=u2009-0.26u2009pmol/l, 95% CI -0.39 to -0.13] and higher in women with MetS (TT mean differenceu2009=u20090.14u2009nmol/l, 95% CI 0.07-0.20; FT standardized mean differenceu2009=u20090.52u2009pmol/l, 95% CI 0.33-0.71) compared with those without. Similarly, men with higher TT levels had a lower MetS risk (RR estimateu2009=u20090.38, 95% CI 0.28-0.50) whereas higher TT levels increased the risk of MetS in women (RR estimateu2009=u20091.68, 95% CI 1.15-2.45). In both sexes, higher SHBG levels were associated with a reduced risk (men: RR estimateu2009=u20090.29, 95% CI 0.21-0.41; women: RR estimateu2009=u20090.30, 95% CI 0.21-0.42).nnnCONCLUSIONnThis meta-analysis supports the presence of a sex-dependent association between testosterone and MetS: TT and FT levels are lower in men with MetS, whereas they are higher in women with MetS. There are no indications for a sex-specific association between SHBG and MetS. In both men and women, MetS is associated with lower SHBG levels.

Testosterone, Sex Hormone-Binding Globulin and the Metabolic Syndrome in Men : An Individual Participant Data Meta-Analysis of Observational Studies

Background Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. Objectives We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. Data sources Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. Study Eligibility Criteria Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. Methods We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. Results Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. Conclusions Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

Age at Menarche and Type 2 Diabetes Risk The EPIC-InterAct study

OBJECTIVE Younger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by adiposity. RESEARCH DESIGN AND METHODS The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI. RESULTS Mean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m2 lower adult BMI. Women in the earliest menarche quintile (8–11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio [HR], 1.70; 95% CI, 1.49–1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18–1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes. CONCLUSIONS Women with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk.

Age at Menopause, Reproductive Life Span, and Type 2 Diabetes Risk: Results from the EPIC-InterAct study

OBJECTIVE Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk. RESEARCH DESIGN AND METHODS Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied. RESULTS Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04–1.69), 1.09 (0.90–1.31), 0.97 (0.86–1.10), and 0.85 (0.70–1.03) for women with menopause at ages <40, 40–44, 45–49, and ≥55 years, respectively, relative to those with menopause at age 50–54 years. The HR per SD younger age at menopause was 1.08 (1.02–1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 [1.01–1.12]). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all > 0.05). CONCLUSIONS Early menopause is associated with a greater risk of type 2 diabetes.

Testosterone, SHBG and cardiovascular health in postmenopausal women

Cardiovascular disease (CVD) affects men and women differently with women having a lower incidence and later onset of disease. Research has recently refocused interest on the cardiovascular role of androgens. The purpose of this review is to summarize the evidence available on the association between testosterone and cardiovascular health in postmenopausal women. Published studies relating testosterone and sex hormone-binding globulin (SHBG) to CVD and its risk factors were reviewed. Studies included in this review suggest that increased androgenicity, characterized by high testosterone and low SHBG levels, is associated with an adverse CVD risk factor profile in postmenopausal women. However, evidence for an association with cardiovascular events is lacking and it is uncertain whether the observed associations with endogenous testosterone have clinical implications regarding the use of postmenopausal testosterone therapy. Large-scale, longitudinal studies relating testosterone and SHBG levels to cardiovascular risk factors and endpoints are needed to determine the temporal relationship between androgenicity and cardiovascular risk and to ascertain the long-term efficacy and safety of testosterone therapy in postmenopausal women.

Cigarette Smoking and Endogenous Sex Hormones in Postmenopausal Women

CONTEXTnSex hormones play a key role in womens health, but little is known about lifestyle factors that influence their levels.nnnOBJECTIVEnThe objective of the study was to investigate the relationship between cigarette smoking habits and endogenous sex hormone levels in postmenopausal women.nnnDESIGN AND PARTICIPANTSnThis was a cross-sectional study among 2030 postmenopausal women aged 55-81 yr from the Norfolk population of the European Prospective Investigation into Cancer. All women were at least 1 yr postmenopausal and not currently using hormone replacement therapy. General linear models were used to examine the relationship between smoking habits and sex hormone levels.nnnRESULTSnAmong current smokers, the daily number of cigarettes smoked was associated with increased levels of testosterone (19-37%), free testosterone (19-34%), 17-hydroxprogesterone (17-22%), androstenedione (2-23%), SHBG (6-10%), and estradiol (-2 to 15%). Stratified analysis for body mass index revealed an interaction such that the association with SHBG was restricted to lean women, whereas a smoking-related increase in free estradiol was found only in overweight women. No clear dose-response relationship was observed for estrone, although its levels were highest in heavy smokers. Current smoking habit was associated with a larger difference in sex hormone levels than lifetime cigarette exposure as measured by pack-years. Among former smokers, sex hormones were at levels of never smokers within 1-2 yr of smoking cessation.nnnCONCLUSIONSnCigarette smoking is associated with higher circulating levels of androgens, estrogens, 17-hydroxprogesterone, and SHBG in postmenopausal women. The almost immediate lower levels with smoking cessation may indicate that hormone related disease risks could potentially be modified by changing smoking habits.

Domains contributing to disability in activities of daily living.

OBJECTIVEnThe WHO International Classification of Functioning, Disability, and Health (ICF)-model describes disability in activities of daily living (ADL) as a multifactorial concept. According to this model, ADL disability is influenced by health conditions, body function and structures, environmental and personal factors, and participation. Current research on ADL disability often focuses on one domain and the contribution of multiple domains is not taken into account. The aim was to investigate which domains contribute to ADL disability.nnnDESIGNnCross-sectional study.nnnSETTINGnGeneral community.nnnPARTICIPANTSnA total of 537 middle-aged and older persons.nnnMEASUREMENTSnHealth conditions included number of chronic diseases. Body function comprised Mini-Mental State Examination (MMSE), processing speed, memory, grip strength, physical performance score (PPS), physical activity, sensory problems, body mass index (BMI), intra-abdominal fat, and cholesterol/HDL ratio. Body structure included atherosclerosis and bone mineral density. Environmental factors comprised the degree of urbanization. Personal factors included age, sex, education, smoking, self-management abilities, quality of life, anxiety/panic disorders, and depressive symptoms. Associations between candidate predictors and ADL disability, measured on the Katz ADL-scale, were examined by multivariable adjusted logistic regression analysis. Nagelkerke R(2)-statistic was calculated to investigate the contribution of each domain to ADL disability.nnnRESULTSnNumber of chronic diseases (domain health condition), MMSE, PPS, physical activity, BMI, intra-abdominal fat (domain body function), atherosclerosis (domain body structure) and sex, education, smoking, quality of life, and depressive symptoms (domain personal factors) were significant predictors of ADL disability. Fifty-seven percent of the variance in ADL disability was explained by the model. For each domain, the explained variance materially decreased after its exclusion, except for environmental factors.nnnCONCLUSIONnThe present study shows that multiple domains (ie, health condition, body function, body structure, and personal factors) contribute to current ADL disability.

Associations of endogenous testosterone and SHBG with glycated haemoglobin in middle-aged and older men.

Objectiveu2002 Low circulating levels of testosterone and sex‐hormone‐binding globulin (SHBG) are associated with increased cardiovascular risk in men. This association may be partially mediated through changes in glucose metabolism, but relatively few data are available on the relationship between sex hormones and markers of long‐term glycaemia. We assessed the associations of endogenous testosterone and SHBG with glycated haemoglobin (HbA1c) in men.

Physical functioning is related to both an impaired physical ability and ADL disability: A ten year follow-up study in middle-aged and older persons

OBJECTIVEnIdentification of measures of physical function that mediate or link impaired physical ability with disability in activities of daily living (ADL) is necessary to facilitate the development of interventions to prevent or delay the onset of ADL disability. We examined whether measures of physical function at baseline are determinants of the Short Physical Performance Battery, as measure of physical ability, and disability, at ten years follow-up.nnnSTUDY DESIGNnProspective cohort study in 625 middle-aged and older persons.nnnMAIN OUTCOME MEASURESnPhysical ability was measured by Guralniks Short Physical Performance Battery (impaired physical ability: score <6) and ADL ability by the KATZ questionnaire (ADL disability: score ≥ 1). Physical function was measured by lung function (in men only), handgrip strength, leg strength, and physical activity. The associations between physical function and the dichotomized impaired physical ability and disability-score were estimated using Poisson regression.nnnRESULTSnBetter lung function and higher leg strength were associated with a lower risk of having impaired physical ability, RR=0.98, 95% CI [0.96; 0.99] per 10 L/min and RR=0.97, 95% CI [0.94; 0.99] per 10Nm, respectively. Higher handgrip strength, leg strength and level of physical activity were associated with a lower risk of having ADL disability, RR=0.72, 95% CI [0.57; 0.92] per 10 kg, RR=0.95, 95% CI [0.92; 0.98] per 10Nm, RR=0.98, 95% CI [0.96; 0.99] per point-score, respectively. Additional adjustment for baseline ADL disability did not materially changed the point-estimates (except for handgrip strength).nnnCONCLUSIONnOverall, leg extensor strength was associated with both an impaired physical ability and ADL disability. Other measures of physical functioning were either related to an impaired physical ability or ADL disability. ADL disability may be an intermediate factor for hand grip strength in the causal chain from impaired physical ability to ADL disability at follow-up. The results of this study show that leg strength might be a relevant parameter to consider for future intervention studies.

Diabetes and onset of natural menopause: results from the European Prospective Investigation into Cancer and Nutrition

STUDY QUESTIONnDo women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes?nnnSUMMARY ANSWERnAlthough there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause.nnnWHAT IS KNOWN ALREADYnToday, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health.nnnSTUDY DESIGN, SIZE, DURATIONnWe investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnDeterminant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale.nnnMAIN RESULTS AND THE ROLE OF CHANCEnOverall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM.nnnLIMITATIONS, REASONS FOR CAUTIONnStrengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes.nnnWIDER IMPLICATIONS OF THE FINDINGSnBased on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association.nnnSTUDY FUNDING/COMPETING INTERESTSnThe coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de lEducation Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.