IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.

CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

IGF-1-based screening reveals a low prevalence of acromegaly in patients with obstructive sleep apnea.

PURPOSE: Recent epidemiologic studies suggest a high prevalence of acromegaly. The prevalence of obstructive sleep apnea syndrome (OSAS) in acromegaly patients ranges from 47 to 70%. A recent study identified 2 patients with acromegaly among 567 OSAS patients. However, it remains unclear whether screening for acromegaly among OSAS patients is necessary. The aim was to screen for acromegaly among OSAS patients by measuring IGF-1 levels and performing confirmatory tests if necessary. METHODS: We performed a prospective cross-sectional diagnostic study on the prevalence of acromegaly in patients with OSAS. A total of 507 patients with a confirmed diagnosis of OSAS (357 male, 150 female) were screened. RESULTS: Seven male and three female patients (1.97% of total) were positively screened for elevated IGF-1 levels. Nine out of ten patients suppressed growth hormone levels during OGTT excluding acromegaly, whereas one individual was identified to have acromegaly according to established criteria (1/507, prevalence 0.2%). Analysis of the data showed no correlation between elevated IGF-1 values and the severity of OSAS or BMI. CONCLUSIONS: Our data demonstrate a low prevalence of acromegaly in patients with OSAS. Until data from population-based studies is available we suggest restricting screening for acromegaly in OSAS to those patients who have additional clinical features of acromegaly.

Low Prevalence of Isolated Growth Hormone Deficiency in Patients After Brain Injury: Results From a Phase II Pilot Study.

Growth hormone deficiency (GHD) results in an impaired health-related quality of life (HrQoL) and cognitive impairment in the attention and memory domain. GHD is assumed to be a frequent finding after brain injury due to traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH) or ischemic stroke. Hence, we set out to investigate the effects of growth hormone (GH) replacement therapy in patients with isolated GHD after brain injury on HrQoL, cognition, and abdominal fat composition. In total, 1,408 patients with TBI, SAH or ischemic stroke were screened for inclusion. Of those, 54 patients (age 18-65 years) were eligible, and 51 could be tested for GHD with GHRH-L-arginine. In 6 patients (12%), GHD was detected. All patients with isolated GHD (n = 4 [8%], male, mean age ± SD: 49.0 ± 9.8 years) received GH replacement therapy for 6 months at a daily dose of 0.2-0.5 mg recombinant GH depending on age. Results were compared with an untreated control group of patients without hormonal insufficiencies after brain injury (n = 6, male, mean age ± SD: 49.5 ± 13.6 years). HrQoL as well as mood and sleep quality assessed by self-rating questionnaires (Beck Depression Index, Pittsburgh Sleep Quality Index) did not differ between baseline and 6 months within each group or between the two groups. Similarly, cognitive performance as assessed by standardized memory and attention tests did not show significant differences within or between groups. Body mass index was higher in the control vs. the GH replacement group at baseline (p = 0.038), yet not different at 6 months and within groups. Visceral-fat-by-total-fat-ratio measurements obtained from magnetic resonance imaging in 2 patients and 5 control subjects exhibited no consistent pattern. In conclusion, this single center study revealed a prevalence of GHD of about 12% (8% with isolated GHD) in brain injury patients which was lower compared with most of the previously reported cohorts. As a consequence, the sample size was insufficient to conclude on a benefit or no benefit of GH replacement in patients with isolated GHD after brain injury. A higher number of patients will be necessary to draw conclusions in future studies. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01397500.

Body Image Perception in Acromegaly Is Not Associated with Objective Acromegalic Changes but Depends on Depressive Symptoms.

OBJECTIVE: Diagnosis of acromegaly is delayed up to 10 years after disease onset despite obvious external/objective changes such as bone and soft tissue deformities. We hypothesized that a lack of subjective perception of the disease state, possibly mediated by psychiatric or cognitive alterations, might contribute to the delayed initiation of a diagnostic workup. DESIGN: Cross-sectional study. METHODS: We investigated perceived body image by standardized questionnaires (FKB-20: Fragebogen zum Körperbild; FBeK: Fragebogen zur Beurteilung des eigenen Körpers) in 81 acromegalic patients and contrasted them to (a) a clinical control group of 60 patients with nonfunctioning pituitary adenomas (NFPA) who lack severe facial and physical alterations and (b) healthy controls. We further evaluated body image in relation to objective acromegalic changes as judged by medical experts and psychiatric pathology, e.g. depression and cognitive impairment. RESULTS: Patients with acromegaly did not lack subjective perception of the disease state; they showed more negative body image, less vitality, more insecurity/paresthesia and more accentuation of the body compared to normal controls. NFPA patients differed from acromegalic patients only in the 'vital body dynamics' scale of the FKB-20, although they hardly exhibit any physical/bodily changes. Depression correlated with worse body image. No associations were found between body image and objective acromegalic changes as judged by medical experts, cognitive decline or treatment status. CONCLUSIONS: Negative body image in acromegalic patients is unrelated to their objective appearance and similar to those of NFPA patients without major bodily changes. Depression, but not cognitive decline or treatment status, contributes to negative body image.

Proposal of a clinical response score and predictors of clinical response to 2 years of GH replacement therapy in adult GH deficiency.

OBJECTIVE: There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response. DESIGN: This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database). METHODS: We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses. RESULTS: In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815). CONCLUSIONS: A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT.

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.

Thyroid-stimulating hormone, white matter hyperintensities, and functional outcome in acute ischemic stroke patients.

BACKGROUND: Thyroid-stimulating hormone (TSH) concentrations are frequently altered in acute ischemic stroke patients. It is becoming increasingly apparent that various hormones in the hypothalamus-pituitary-thyroid axis may be associated with functional stroke outcome. We have previously shown that white matter hyperintensities (WMH) of presumed vascular origin are strong indicators of functional outcome. It is unclear whether an association exists between WMH and TSH. We therefore sought to determine whether TSH levels, measured in acute ischemic stroke patients, are associated with WMH and functional outcome. METHODS: We analyzed all first ischemic stroke patients who participated in the Berlin 'Cream & Sugar' Study (NCT 01378468) and completed a 1-year follow-up assessment from January 2009 to March 2013. Patients were stratified into 3 groups: (1) low TSH (0.1-0.44 µU/ml); (2) normal TSH (0.44-2.5 µU/ml), and (3) high TSH (2.5-20 µU/ml). WMH were assessed using the Fazekas and Wahlund visual rating scales. Functional outcome was assessed using the modified Rankin Scale and was performed via telephone at 1 year by a certified rater. RESULTS: 183 patients were included [median age 66, interquartile range (IQR) 54-75; 33% females; median National Institute of Health Stroke Scale 3, IQR 1-4, range 0-24]. Venous samples were collected a median of 4 days (IQR 3-5) following initial symptom onset between 8 and 9 a.m. following a 10-hour fast. Patients with normal TSH levels (n = 132; 72%) had significantly higher rates of prestroke diabetes than patients with high TSH levels (normal TSH 17%; high TSH 1%; p = 0.03). Additionally, patients with normal TSH levels tended to have higher estimated glomerular filtration rates than patients with high and low TSH concentrations (normal TSH median estimated glomerular filtration rates: 83 ml/min/1.73 m(2); high TSH median estimated glomerular filtration rates: 76 ml/min/1.73 m(2); low TSH median: 78 ml/min/1.73 m(2); p = 0.068). Logistical regression analysis force-adjusted for age (quartiles), NIHSS (quartiles), prestroke diabetes status, and stroke subtype revealed significant associations between WMH and TSH [Wahlund scores: odds ratio 2.547, 95% confidence interval (CI) 1.159-5.598, p = 0.020; Fazekas scores: odds ratio 2.530, 95% CI 1.115-5.741, p = 0.003]. Functional outcome was not significantly associated with TSH levels in univariate or multivariate models. CONCLUSION: TSH levels are independently associated with WMH in acute ischemic stroke patients. Based on our findings, we cannot recommend assessing TSH to estimate the 1-year functional outcome following ischemic stroke.

Correlates of adverse outcomes in abdominally obese individuals: findings from the five-year followup of the population-based study of health in Pomerania.

BACKGROUND: Abdominal obesity is a major risk factor of cardiovascular disease (CVD), type 2 diabetes (T2DM), and premature death. However, it has not been resolved which factors predispose for the development of these adverse obesity-related outcomes in otherwise healthy individuals with abdominal obesity. METHODS: We studied 1,506 abdominal obese individuals (waist-to-height ratio (WHtR) ≥ 0.5) free of CVD or T2DM from the population-based Study of Health in Pomerania and assessed the incidence of CVD or T2DM after a five-year followup. Logistic regression models were adjusted for major cardiovascular risk factors and liver, kidney diseases, and sociodemographic status. RESULTS: During follow-up time, we observed 114 and 136 new T2DM and CVD cases, respectively. Regression models identified age, waist circumference, serum glucose, and liver disease as predictors of T2DM. Regarding CVD, only age, unemployment, and a divorced or widowed marital status were significantly associated with incident CVD. In this subgroup of obese individuals blood pressure, serum glucose, or lipids did not influence incidence of T2DM or CVD. CONCLUSION: We identified various factors associated with an increased risk of incident T2DM and CVD among abdominally obese individuals. These findings may improve the detection of high-risk individuals and help to advance prevention strategies in abdominal obesity.

Clinical review: Outcome of bilateral adrenalectomy in Cushing's syndrome: a systematic review.

BACKGROUND: The outcome of bilateral adrenalectomy (BADx) in patients with Cushing's syndrome (CS) is not well characterized. METHODS: A literature search was performed with the search terms "bilateral adrenalectomy" or "total adrenalectomy" and "Cushing's" or "Cushing." Immediate and long-term outcomes after BADx in CS were analyzed using descriptive statistics (median [range]). RESULTS: From 549 screened publications, 37 studies met inclusion criteria (1320 patients, 82% having Cushing's disease [CD], 13% having ectopic CS, and 5% having primary adrenal hyperplasia). Surgical morbidity and mortality of BADx (23 studies, 739 patients) were 18% (6-31) and 3% (0-15), respectively. In patients with CD, surgical mortality was below 1%. Although residual cortisol secretion due to accessory adrenal tissue or adrenal remnants was found in 3-34% (5 studies, 236 patients), less than 2% had a relapse of CS. Symptoms of hypercortisolism (eg, hypertension, obesity, or depression) improved in the majority of the patients after BADx (7 studies, 195 patients). The number of adrenal crises per 100 patient-years was 9.3 (6 studies, 203 patients). Nelson's syndrome occurred in 21% (0-47) of the patients (24 studies, 768 patients). Mortality (23 studies, 690 patients) was 17% (0-88) at a follow-up of 41 months (14-294). Remarkably, 46% of the patients died in the first year after surgery. The median ages at death were 62 years (CD) and 53 years (ectopic CS). CONCLUSION: BADx is relatively safe and provides adequate success. Excess mortality within the first year after surgery suggests that intensive clinical care for patients after BADx is warranted.

The influence of gender on the injury severity, course and outcome of traumatic brain injury.

OBJECTIVE: To examine the independent association of gender with injury severity, clinical course, pituitary dysfunction and outcome after traumatic brain injury (TBI). DESIGN: Prospective cohort, analysis of a data sub-set collected as part of the nation-wide database 'The Structured Data Assessment of Hypopituitarism after TBI and SAH'. METHODS AND PROCEDURES: Four hundred and twenty-seven patients following TBI were observed from acute care through neurological rehabilitation. Outcome was measured by Glasgow Outcome Scale (GOS), employment status and living situation post-injury. As a secondary outcome measure anterior pituitary function was assessed. RESULTS: There were no differences in injury severity between men and women. Age had a significant effect on the GCS score (p = 0.0295), but gender did not (p = 0.4105). The outcome was equivalent between men and women once corrected for age. Logistic regression revealed that gender had no effect (p = 0.8008), but age (p = 0.0021) and initial injury severity (p = 0.0010) had an effect on the GOS. After correcting for pre-injury living situation and employment only initial injury severity (p = 0.0005) influenced GOS. Pituitary insufficiency was not affected by sex or age. CONCLUSION: Gender does not seem to influence the course and outcome of TBI. Outcome parameters were affected foremost by initial injury severity and by age, but not by sex.

Improved prediction of all-cause mortality by a combination of serum total testosterone and insulin-like growth factor I in adult men.

OBJECTIVE: Lower levels of anabolic hormones in older age are well documented. Several studies suggested that low insulin-like growth factor I (IGF-I) or testosterone levels were related to increased mortality. The aim of the present study was to investigate the combined influence of low IGF-I and low testosterone on all-cause mortality in men. METHODS AND RESULTS: From two German prospective cohort studies, the DETECT study and SHIP, 3942 men were available for analyses. During 21,838 person-years of follow-up, 8.4% (n=330) of men died. Cox model analyses with age as timescale and adjusted for potential confounders revealed that men with levels below the 10th percentile of at least one hormone [hazard ratio (HR) 1.38 (95% confidence-interval (CI) 1.06-1.78), p=0.02] and two hormones [HR 2.88 (95% CI 1.32-6.29), p<0.01] showed a higher risk of all-cause mortality compared to men with non-low hormones. The associations became non-significant by using the 20th percentile as cut-off showing that the specificity increased with lower cut-offs for decreased hormone levels. The inclusion of both IGF-I and total testosterone in a mortality prediction model with common risk factors resulted in a significant integrated discrimination improvement of 0.5% (95% CI 0.3-0.7%, p=0.03). CONCLUSIONS: Our results prove that multiple anabolic deficiencies have a higher impact on mortality than a single anabolic deficiency and suggest that assessment of more than one anabolic hormone as a biomarker improve the prediction of all-cause mortality.

Structured assessment of hypopituitarism after traumatic brain injury and aneurysmal subarachnoid hemorrhage in 1242 patients: the German interdisciplinary database.

Clinical studies have demonstrated that traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) are frequent causes of long-term disturbances of hypothalamo-pituitary function. This study aimed to assess the prevalence and associated factors of post-traumatic hypopituitarism in a large national registry of patients with TBI and SAH. Data were collected from 14 centers in Germany and Austria treating patients for TBI or SAH and performing endocrine assessments. Data were collected using a structured, internet-based study sheet, obtaining information on clinical, radiological, and hormonal parameters. A total of 1242 patients (825 TBI, age 43.5±19.7 years; 417 SAH, age 49.7±11.8 years) were included. We studied the prevalence of hypopituitarism reported based on different definitions of laboratory values and stimulation tests. Stimulation tests for the corticotropic and somatotropic axes were performed in 26% and 22% of the patients, respectively. The prevalence of hypopituitarism in the chronic phase (at least 5 months after the event) by laboratory values, physician diagnoses, and stimulation tests, was 35%, 36%, and 70%, respectively. Hypopituitarism was less common in the acute phase. According to the frequency of endocrine dysfunction, pituitary hormone secretion was impaired in the following sequence: ACTH, LH/FSH, GH, and TSH. TBI patients with abnormal stimulation tests had suffered from more severe TBI than patients with normal stimulation tests. In conclusion, our data confirm that hypopituitarism is a common complication of TBI and SAH. It is possible that patients with a higher likelihood of hypopituitarism were selected for endocrine stimulation tests.

The association of serum prolactin concentration with inflammatory biomarkers - cross-sectional findings from the population-based Study of Health in Pomerania.

OBJECTIVE: Prolactin (PRL) is involved in immune regulation and may contribute to an atherogenic phenotype. Previous results on the association of PRL with inflammatory biomarkers have been conflicting and limited by small patient studies. Therefore, we used data from a large population-based sample to assess the cross-sectional associations between serum PRL concentration and high-sensitivity C-reactive protein (hsCRP), fibrinogen, interleukin-6 (IL-6), and white blood cell (WBC) count. DESIGN AND POPULATION: From the population-based Study of Health in Pomerania (SHIP), a total of 3744 subjects were available for the present analyses. METHODS AND MEASUREMENTS: PRL and inflammatory biomarkers were measured. Linear and logistic regression models adjusted for age, sex, body-mass-index, total cholesterol and glucose were analysed. RESULTS: Multivariable linear regression models revealed a positive association of PRL with WBC. Multivariable logistic regression analyses showed a significant association of PRL with increased IL-6 in non-smokers [highest vs lowest quintile: odds ratio 1·69 (95% confidence interval 1·10-2·58), P = 0·02] and smokers [OR 2·06 (95%-CI 1·10-3·89), P = 0·02]. Similar results were found for WBC in non-smokers [highest vs lowest quintile: OR 2·09 (95%-CI 1·21-3·61), P = 0·01)] but not in smokers. Linear and logistic regression analyses revealed no significant associations of PRL with hsCRP or fibrinogen. CONCLUSIONS: Serum PRL concentrations are associated with inflammatory biomarkers including IL-6 and WBC, but not hsCRP or fibrinogen. The suggested role of PRL in inflammation needs further investigation in future prospective studies.

A novel approach to the detection of acromegaly: accuracy of diagnosis by automatic face classification.

CONTEXT: The delay between onset of first symptoms and diagnosis of the acromegaly is 6-10 yr. Acromegaly causes typical changes of the face that might be recognized by face classification software. OBJECTIVE: The objective of the study was to assess classification accuracy of acromegaly by face-classification software. DESIGN: This was a diagnostic study. SETTING: The study was conducted in specialized care. PARTICIPANTS: Participants in the study included 57 patients with acromegaly (29 women, 28 men) and 60 sex- and age-matched controls. INTERVENTIONS: We took frontal and side photographs of the faces and grouped patients into subjects with mild, moderate, and severe facial features of acromegaly by overall impression. We then analyzed all pictures using computerized similarity analysis based on Gabor jets and geometry functions. We used the leave-one-out cross-validation method to classify subjects by the software. Additionally, all subjects were classified by visual impression by three acromegaly experts and three general internists. MAIN OUTCOME MEASURE: Classification accuracy by software, experts, and internists was measured. FINDINGS: The software correctly classified 71.9% of patients and 91.5% of controls. Classification accuracy for patients by visual analysis was 63.2 and 42.1% by experts and general internists, respectively. Classification accuracy for controls was 80.8 and 87.0% by experts and internists, respectively. The highest differences in accuracy between software and experts and internists were present for patients with mild acromegaly. CONCLUSIONS: Acromegaly can be detected by computer software using photographs of the face. Classification accuracy by software is higher than by medical experts or general internists, particularly in patients with mild features of acromegaly. This is a promising tool to help detecting acromegaly.

Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients.

OBJECTIVE: Although associations between testosterone and cardiovascular (CV) morbidity in women have been proposed, no large prospective study has evaluated potential associations between testosterone and mortality in women. The objective was to determine whether baseline testosterone levels in women are associated with future overall or CV morbidity and mortality. DESIGN: Prospective cohort study with a 4.5-year follow-up period. METHODS: From a representative sample of German primary care practices, 2914 female patients between 18 and 75 years were analyzed for the main outcome measures: CV risk factors, CV diseases, and all-cause mortality. RESULTS: At baseline, the study population was aged 57.96±14.37 years with a mean body mass index of 26.71±5.17 kg/m(2). No predictive value of total testosterone for incident CV risk factors or CV diseases was observed in logistic regressions. Patients with total testosterone levels in the lowest quintile Q1, however, had a higher risk to die of any cause or to develop a CV event within the follow-up period compared to patients in the collapsed quintiles Q2-Q5 in crude and adjusted Cox regression models (all-cause mortality: Q2-Q5 versus Q1: crude hazard ratios (HR) 0.49, 95% confidence interval (CI) 0.33-0.74; adjusted HR 0.62, 95% CI 0.42-0.939; CV events: Q2-Q5 versus Q1: crude HR 0.54, 95% CI 0.38-0.77; adjusted HR 0.68, 95% CI 0.48-0.97). Kaplan-Meier curves revealed similar data. CONCLUSIONS: Low baseline testosterone in women is associated with increased all-cause mortality and incident CV events independent of traditional risk factors.

The predictive value of different measures of obesity for incident cardiovascular events and mortality.

CONTEXT: To date, it is unclear which measure of obesity is the most appropriate for risk stratification. OBJECTIVE: The aim of the study was to compare the associations of various measures of obesity with incident cardiovascular events and mortality. DESIGN AND SETTING: We analyzed two German cohort studies, the DETECT study and SHIP, including primary care and general population. PARTICIPANTS: A total of 6355 (mean follow-up, 3.3 yr) and 4297 (mean follow-up, 8.5 yr) individuals participated in DETECT and SHIP, respectively. INTERVENTIONS: We measured body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) and assessed cardiovascular and all-cause mortality and the composite endpoint of incident stroke, myocardial infarction, or cardiovascular death. RESULTS: In both studies, we found a positive association of the composite endpoint with WHtR but not with BMI. There was no heterogeneity among studies. The relative risks in the highest versus the lowest sex- and age-specific quartile of WHtR, WC, WHR, and BMI after adjustment for multiple confounders were as follows in the pooled data: cardiovascular mortality, 2.75 (95% confidence interval, 1.31-5.77), 1.74 (0.84-3.6), 1.71 (0.91-3.22), and 0.74 (0.35-1.57), respectively; all-cause mortality, 1.86 (1.25-2.76), 1.62 (1.22-2.38), 1.36 (0.93-1.69), and 0.77 (0.53-1.13), respectively; and composite endpoint, 2.16 (1.39-3.35), 1.59 (1.04-2.44), 1.49 (1.07-2.07), and 0.57 (0.37-0.89), respectively. Separate analyses of sex and age groups yielded comparable results. Receiver operating characteristics analysis yielded the highest areas under the curve for WHtR for predicting these endpoints. CONCLUSIONS: WHtR represents the best predictor of cardiovascular risk and mortality, followed by WC and WHR. Our results discourage the use of the BMI.