Search

BackgroundTestosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of genetically determined testosterone on complex diseases in both sexes.MethodsLeveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality.ResultsWe show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes.ConclusionsOverall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences.Plain language summaryHormones, such as testosterone, travel around the body communicating between the different parts. Testosterone is present at higher levels in men, but also present in women. Variable testosterone levels explain some differences in human traits and disease prevalence. Here, we study how adult testosterone levels relate to health and disease. Genetic, i.e. inherited, differences in testosterone levels contribute to many traits specific to men or women, such as women's reproductive health, hormonal cancers, and hair growth typical in males. However, testosterone levels do not appear as a major cause of most traits studied, including psychiatric diseases and metabolic health. Normal variation in baseline testosterone levels thus seems to have a relatively minor impact on health and disease.Leinonen et al. investigate correlations between testosterone levels and disease using genetic and health registry data from the UK Biobank and FinnGen. There is a lack of evidence for normal variation in testosterone levels having a causal contribution to most non-sex-specific traits.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further similar to 15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

This Review provides insight into sexual dimorphism in adipose tissue distribution and substrate metabolism in adipose tissue, skeletal muscle and liver, as well as the underlying mechanisms. The effects of these sex differences on cardiometabolic health are outlined and the potential for developing sex-specific prevention and treatment strategies is discussed.Obesity is associated with many adverse health effects, such as an increased cardiometabolic risk. Despite higher adiposity for a given BMI, premenopausal women are at lower risk of cardiometabolic disease than men of the same age. This cardiometabolic advantage in women seems to disappear after the menopause or when type 2 diabetes mellitus develops. Sexual dimorphism in substrate supply and utilization, deposition of excess lipids and mobilization of stored lipids in various key metabolic organs (such as adipose tissue, skeletal muscle and the liver) are associated with differences in tissue-specific insulin sensitivity and cardiometabolic risk profiles between men and women. Moreover, lifestyle-related factors and epigenetic and genetic mechanisms seem to affect metabolic complications and disease risk in a sex-specific manner. This Review provides insight into sexual dimorphism in adipose tissue distribution, adipose tissue, skeletal muscle and liver substrate metabolism and tissue-specific insulin sensitivity in humans, as well as the underlying mechanisms, and addresses the effect of these sex differences on cardiometabolic health. Additionally, this Review highlights the implications of sexual dimorphism in the pathophysiology of obesity-related cardiometabolic risk for the development of sex-specific prevention and treatment strategies.

Context The role of androgen excess as a contributing factor to abnormal glucose metabolism (AGM) and insulin resistance in women remains controversial. Objective To investigate whether hyperandrogenemia (HA) estimated by serum testosterone (T) level and free androgen index (FAI) at ages 31 and 46 years is associated with insulin resistance, insulin secretion and AGM by age 46. Design Prospective study including 5889 females followed at ages 31 and 46 years. Setting General community. Participants Women with HA were compared with normoandrogenic women at ages 31 and 46 years. Intervention None. Main outcome measurements AGM, including prediabetes and type 2 diabetes mellitus, homeostatic model assessments of insulin resistance (HOMA-IR) and of pancreatic β-cell function (HOMA-B). Results At age 31 years, HA women displayed increased HOMA-IR (P = 0.002), HOMA-B (P = 0.007), and higher fasting insulin (P = 0.03) than normoandrogenic women after adjusting for body mass index (BMI). At age 46 years, there was a nonsignificant trend toward higher fasting glucose (P = 0.07) and glycated hemoglobin A1 (P = 0.07) levels in HA women. Women in the highest T quartile (odds ratio [OR] = 1.80; 95%CI, 1.15-2.82) at age 31 years and in the 2 highest FAI quartiles at ages 31 (Q4: OR = 3.76; 95% CI, 2.24-6.32) and 46 (Q4: OR = 2.79; 95% CI, 1.74-4.46) years had increased risk for AGM, independently of BMI, when compared with women in Q1. SHBG was inversely associated with AGM (at age 31 years: Q4: OR = 0.37; 95% CI, 0.23-0.60, at age 46 years: Q4: OR = 0.28; 95% CI, 0.17-0.44). Conclusion Hyperandrogenemia and low SHBG in early and middle age associates with AGM independently of BMI.

The increased global prevalence of obesity over the last 40-years has driven a rise in prevalence of obesity-related co-morbidities, including polycystic ovary syndrome (PCOS). On a background of genetic susceptibility, PCOS often becomes clinically manifest following weight gain, commonly during adolescence. A common endocrinopathy affecting between 6%-10% of reproductive-age women, PCOS presents with the cardinal features of hyperandrogenism, reproductive and metabolic dysfunction. PCOS associates with insulin resistance, independently of (but amplified by) obesity. Insulin resistance in PCOS is characterized by abnormal post-receptor signalling within the phosphatidylinositol-kinase (PI3-K) pathway. Multiple factors (including most notably, weight gain) contribute towards the severity of insulin resistance in PCOS. Compensatory hyperinsulinaemia ensues, resulting in over-stimulation of the (intact) post-receptor mitogen-activated protein kinase (MAP-K) insulin pathway, with consequent implications for steroidogenesis and ovarian function. In this concise review, we explore the effects of weight gain and obesity on the pathogenesis of PCOS from the perspective of its three cardinal features of hyperandrogenism, reproductive and metabolic dysfunction, with a focus on the central mediating role of the insulin pathway. We also consider key lifestyle strategies for the effective management of obese and overweight women with PCOS.

Context Premature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS). Objective To study features of PCOS in young adult women with a history of PA. Methods Thirty PA and 42 control females were followed from prepuberty to young adulthood (median age 18.1 years). The main outcome measures were ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism. Results We found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone–binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/L, P Conclusion PA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens.

Background: The relationship between insulin resistance (IR) and prognostic factors in breast cancer (BC) in premenopausal (pre-M) and postmenopausal (post-M) women is still controversial. We evaluated the potential association between hemoglobin A1c (HbA1c), fasting blood glucose (FBG), fasting insulin levels (FILs), the homeostasis model assessment index (HOMA), and the prognostic factors of BC in nondiabetic patients with pre-M and post-M breast tumors. Methods: We compared 80 nondiabetic patients with pre-M and post-M breast tumors to 60 women with normal mammography as a control. Results: Age, body mass index (BMI), FBG, and HbA1c did not differ between the groups. FIL (P < 0.001) and HOMA-IR (P < 0.001) of the BC group were significantly higher than in the control group. FIL (P < 0.001) and HOMA-IR (P < 0.001) of the BC group were significantly higher than in the control group, for both pre- and post-M patients. FIL and HOMA-IR values were found to be significantly higher in the patients with stage IV BC than in other stages of BC. FIL and HOMA-IR are highly specific and sensitive parameters in their ability to diagnose BC. Conclusions: FIL and HOMA-IR are associated with BC risk in nondiabetic patients with pre-M and post-M breast tumors. When BC risk was evaluated according to the stage of menopause, no difference was observed; only the disease stage was significant. FIL and IR may function as potential biomarkers and therapeutic targets for human cancers. J Endocrinol Metab. 2021;11(2):42-48 doi: https://doi.org/10.14740/jem729

Objective It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term. Design The ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm ( Methods We measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L). Results Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (−2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject’s birth weight s.d. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70). Conclusions Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.

This Review provides insight into sexual dimorphism in adipose tissue distribution and substrate metabolism in adipose tissue, skeletal muscle and liver, as well as the underlying mechanisms. The effects of these sex differences on cardiometabolic health are outlined and the potential for developing sex-specific prevention and treatment strategies is discussed.Obesity is associated with many adverse health effects, such as an increased cardiometabolic risk. Despite higher adiposity for a given BMI, premenopausal women are at lower risk of cardiometabolic disease than men of the same age. This cardiometabolic advantage in women seems to disappear after the menopause or when type 2 diabetes mellitus develops. Sexual dimorphism in substrate supply and utilization, deposition of excess lipids and mobilization of stored lipids in various key metabolic organs (such as adipose tissue, skeletal muscle and the liver) are associated with differences in tissue-specific insulin sensitivity and cardiometabolic risk profiles between men and women. Moreover, lifestyle-related factors and epigenetic and genetic mechanisms seem to affect metabolic complications and disease risk in a sex-specific manner. This Review provides insight into sexual dimorphism in adipose tissue distribution, adipose tissue, skeletal muscle and liver substrate metabolism and tissue-specific insulin sensitivity in humans, as well as the underlying mechanisms, and addresses the effect of these sex differences on cardiometabolic health. Additionally, this Review highlights the implications of sexual dimorphism in the pathophysiology of obesity-related cardiometabolic risk for the development of sex-specific prevention and treatment strategies.

Caffeine has been found to exert various biological effects including, antiangiogenic, antiproliferative, antimetastatic activity, increased fat oxidation and mobilization of glycogen in muscle, increased lipolysis, and reduction of body fat. The aim of this review is to analyze the endocrine effects of coffee consumption. A systematic literature search was conducted on PubMed and Web of Science databases seeking articles published until May 2019, dealing with coffee consumption and diabetes, osteoporosis, thyroid gland, adrenal, and gonads. The results of the most epidemiologic studies reported that coffee consumption has positive effects on combating type 2 diabetes risk, has no significant effects on bone mineral density levels but fracture risk was shown to be higher in the high coffee consumer group. Coffee intake has no significant effect on thyroid cancer, increases sex hormone binding globulin levels, has no effect on fertility but higher consumption was related to spontaneous abortion. Studies pertaining to coffee consumption and endocrine effects have contrary results. More randomized clinical studies with a long term follow up period are required.

Contains fulltext : 220949.pdf (Publisher’s version ) (Open Access) The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

Men with obesity often present with low testosterone (T) and sex hormone-binding globulin (SHBG) levels. Several mechanisms for this have been proposed, but as SHBG is secreted by hepatocytes and sex steroids undergo hepatic metabolization, this study investigates whether severity and histological components of nonalcoholic fatty liver disease (NAFLD) are associated with sex steroid levels in obese men. This cross-sectional study included 80 obese men (age: 46 ± 11 years; body mass index: 42.2 ± 5.5 kg m−2). Serum levels of total T and estradiol (E2) were measured using liquid chromatography coupled with tandem mass spectroscopy (LC/MS-MS) and SHBG and gonadotropins by immunoassay. Liver biopsies were evaluated using Steatosis, Activity, and Fibrosis scoring. Participants with steatohepatitis had similar median (1st quartile–3rd quartile) total T levels (7.6 [5.0–11.0] nmol l−1 vs 8.2 [7.2–10.9] nmol l−1; P = 0.147), lower calculated free T (cFT) levels (148.9 [122.9–188.8] pmol l−1 vs 199.5 [157.3–237.6] pmol l−1; P = 0.006), and higher free E2/T ratios (10.0 [6.4–13.9] x10-3 vs 7.1 [5.7–10.7] x10-3; P = 0.026) compared to men with only nonalcoholic fatty liver. Among the histological components of NAFLD, only steatosis was independently associated with total T (rs = −0.331, P = 0.003) and cFT levels (rs = −0.255, P = 0.025). Obese men with steatohepatitis have even lower cFT levels compared to those without, an association mainly driven by grade of steatosis. Whether this reflects a subgroup of men with a more severe obesity-related phenotype or results from direct relations between hepatic steatosis and sex steroid metabolism needs further investigation.

OBJECTIVES: Older age and Major depressive disorder (MDD) are both risk factors for the development of cardiovascular diseases. Testosterone has been associated with MDD and Metabolic Syndrome (MetS) in men, though associations in women are less clear. Therefore, we investigated whether testosterone is associated with MetS and whether this association is different for depressed and non-depressed older men and women.METHODS: In this prospective cohort study, 478 participants (349 patients with MDD and 129 controls) aged between 60 and 93 years from the Netherlands Study of Depression in Older Persons (NESDO) were included. Total testosterone (TT) and sex-hormone binding globulin (SHBG) levels were measured using a second generation radioimmune assay. Free testosterone (FT) was calculated based on TT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria.RESULTS: A higher risk for MetS was found in men with low FT and TT (Odds Ratio [OR]: 0.67, 95% confidence interval [95%CI]: 0.47-0.95 and OR: 0.51, 95%CI: 0.34-0.75), and in women with high FT (OR: 1.41, 95%CI: 1.08-1.82). Strong associations in the same direction were found with adiposity, glucose and plasma lipid MetS components at baseline, but not with changes in these components at two-year follow-up. The associations did not significantly differ between MDD patients and controls.CONCLUSIONS: Independently of having MDD, low testosterone levels in men, and in contrast, high testosterone levels in women were significantly associated with MetS and its components.

Context Elevated IL-1 receptor antagonist (IL-1Ra) concentrations are associated with obesity, insulin resistance, and cardiovascular disease (CVD) risk in adults. Objective To determine if serum IL-1Ra and high-sensitivity C-reactive protein (hs-CRP) levels are associated with markers of reduced insulin sensitivity (IS) and serum lipids in 12-year-old children. Design and Participants Of 191 children (n = 109 girls), 78 were categorized as having had birth weight and length appropriate for gestational age (AGA), 69 were small for gestational age, and 44 were AGA and from preeclamptic pregnancies. Serum markers of low-grade inflammation, IS, and lipids were measured. Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated. Results Mean serum IL-1Ra levels did not differ between the sexes or among the gestational categories. Children in the highest IL-1Ra tertile had lower QUICKI, IGF-binding protein-1, SHBG, and high-density lipoprotein cholesterol values; and higher body mass index (BMI), waist circumference to height ratio (WHtR), and serum insulin, hs-CRP, leptin, and triglyceride concentrations than those in the lowest IL-1Ra tertile. Logistic regression analysis showed higher serum hs-CRP and leptin levels, and WHtR were associated with high serum IL-1Ra levels. IL-1Ra concentration could be used to discriminate the children with lowest IS (area under the curve, 0.68; P < 0.001); hs-CRP level could not. Conclusion Children with the highest IL-1Ra levels had lower IS, higher hs-CRP levels and BMI, and a less favorable lipid profile than those with the lowest IL-1Ra levels, suggesting that high IL-1Ra concentrations may be associated with increased CVD risk in 12-year-old children., Preteens with highest IL-1Ra levels had lower IS and high-density lipoprotein cholesterol levels, and higher BMI and hs-CRP and triglyceride levels than those with lower IL-1Ra. IL-1Ra, but not hs-CRP, could be used to predict low IS.

International audience; Objective: To update the "Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2008. Participants: The participants include an Endocrine Society-appointed task force of seven medical experts and a methodologist. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: Group meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. Conclusion: Wesuggest testing for elevated androgen levels in allwomenwith an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest starting with pharmacological therapy and adding direct hair removal methods (electrolysis, photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral combined estrogen-progestin contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For most women who choose hair removal therapy, we suggest laser/photoepilation.

The overall impact of proteomics on clinical research and its translation has lagged behind expectations. One recognized caveat is the limited size (subject numbers) of (pre-)clinical studies performed at the discovery stage, the findings of which fail to be replicated in larger verification/validation trials. Compromised study designs and insufficient statistical power are consequences of the to-date still limited capacity of mass spectrometry (MS)-based workflows to handle large numbers of samples in a realistic time frame, while delivering comprehensive proteome coverages. We developed a highly automated proteomic biomarker discovery workflow. Herein, we have applied this approach to analyze 1'000 plasma samples from the multi-centered human dietary intervention study "DiOGenes". Study design, sample randomization, tracking, and logistics were the foundations of our large-scale study. We checked the quality of the MS data and provided descriptive statistics. The dataset was interrogated for proteins with most stable expression levels in that set of plasma samples. We evaluated standard clinical variables that typically impact forthcoming results and assessed body mass index-associated and gender-specific proteins at 2 time points. We demonstrate that analyzing a large number of human plasma samples for biomarker discovery with MS using isobaric tagging is feasible, providing robust and consistent biological results.

Many biomarkers are associated with type 2 diabetes (T2D) risk in epidemiological observations. The aim of this study was to identify and summarize current evidence for causal effects of biomarkers on T2D. A systematic literature search in PubMed and EMBASE (until April 2015) was done to identify Mendelian randomization studies that examined potential causal effects of biomarkers on T2D. To replicate the findings of identified studies, data from two large-scale, genome-wide association studies (GWAS) were used: DIAbetes Genetics Replication And Meta-analysis (DIAGRAMv3) for T2D and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for glycaemic traits. GWAS summary statistics were extracted for the same genetic variants (or proxy variants), which were used in the original Mendelian randomization studies. Of the 21 biomarkers (from 28 studies), ten have been reported to be causally associated with T2D in Mendelian randomization. Most biomarkers were investigated in a single cohort study or population. Of the ten biomarkers that were identified, nominally significant associations with T2D or glycaemic traits were reached for those genetic variants related to bilirubin, pro-B-type natriuretic peptide, delta-6 desaturase and dimethylglycine based on the summary data from DIAGRAMv3 or MAGIC. Several Mendelian randomization studies investigated the nature of associations of biomarkers with T2D. However, there were only a few biomarkers that may have causal effects on T2D. Further research is needed to broadly evaluate the causal effects of multiple biomarkers on T2D and glycaemic traits using data from large-scale cohorts or GWAS including many different genetic variants.

Hepatic steatosis is an underlying feature of nonalcoholic fatty liver disease (NAFLD), which is the most common form of liver disease and is present in up to similar to 70% of individuals who are overweight. NAFLD is also associated with hypertriglyceridaemia and low levels of HDL, glucose intolerance, insulin resistance and type 2 diabetes mellitus. Hepatic steatosis is a strong predictor of the development of insulin resistance and often precedes the onset of other known mediators of insulin resistance. This sequence of events suggests that hepatic steatosis has a causal role in the development of insulin resistance in other tissues, such as skeletal muscle. Hepatokines are proteins that are secreted by hepatocytes, and many hepatokines have been linked to the induction of metabolic dysfunction, including fetuin A, fetuin B, retinol-binding protein 4 (RBP4) and selenoprotein P. In this Review, we describe the factors that influence the development of hepatic steatosis, provide evidence of strong links between hepatic steatosis and insulin resistance in non-hepatic tissues, and discuss recent advances in our understanding of how steatosis alters hepatokine secretion to influence metabolic phenotypes through inter-organ communication.

Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed.

Background: Childhood obesity is associated with an accelerated skeletal maturation. However, data concerning pubertal development and sex steroid levels in obese adolescents are scarce and contrasting. Objectives: To study sex steroids in relation to sexual and skeletal maturation and to serum prostate specific antigen (PSA), as a marker of androgen activity, in obese boys from early to late adolescence. Methods: Ninety obese boys (aged 10-19 y) at the start of a residential obesity treatment program and 90 age-matched controls were studied cross-sectionally. Pubertal status was assessed according to the Tanner method. Skeletal age was determined by an x-ray of the left hand. Morning concentrations of total testosterone (TT) and estradiol (E2) were measured by liquid chromatographytandem mass spectrometry, free T (FT) was measured by equilibrium dialysis, and LH, FSH, SHBG, and PSA were measured by immunoassays. Results: Genital staging was comparable between the obese and nonobese groups, whereas skeletal bone advancement (mean, 1 y) was present in early and midadolescence in the obese males. Although both median SHBG and TT concentrations were significantly (P < .001) lower in obese subjects during mid and late puberty, median FT, LH, FSH, and PSA levels were comparable to those of controls. In contrast, serum E2 concentrations were significantly (P < .001) higher in the obese group at all pubertal stages. Conclusion: Obese boys have lower circulating SHBG and TT, but similar FT concentrations during mid and late puberty in parallel with a normal pubertal progression and serum PSA levels. Our data indicate that in obese boys, serum FT concentration is a better marker of androgen activity than TT. On the other hand, skeletal maturation and E2 were increased from the beginning of puberty, suggesting a significant contribution of hyperestrogenemia in the advancement of skeletal maturation in obese boys.

Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis. ispartof: Asian Journal of Andrology vol:16 issue:2 pages:213-222 ispartof: location:China status: published

Oestrogen receptors are overexpressed in around 70% of all breast cancers, and are a target for endocrine therapy. These receptors can be visualised on PET with use of 16 alpha-[F-18]-fluoro-17 beta-oestradiol (F-18-FES) as a tracer. Compared with biopsy, which enables assessment of individual sites, whole-body F-18-FES-PET enables quantification of oestrogen-receptor expression in all metastases. In several studies, measurement of tumour protein expression in oestrogen receptors by F-18-FES-PET, concurrent with biopsy, detected oestrogen-receptor-positive tumour lesions with a sensitivity of 84% and specificity of 98%. Roughly 45% of patients with metastatic breast cancer have discordant oestrogen-receptor expression across lesions (ie, F-18-FES-positive and F-18-FES-negative metastases). Low tumour F-18-FES uptake in metastases can predict failure of hormonal therapy in patients with oestrogen-receptor-positive primary tumours. Finally, F-18-FES-PET has shown that oestrogen-receptor binding capacity changes after intervention with hormonal drugs, but findings need to be confirmed. Factors other than oestrogen-receptor expression, including menopausal status and concomitant therapies, that can affect tumour F-18-FES uptake must be taken into account.

Oestrogen receptors are overexpressed in around 70% of all breast cancers, and are a target for endocrine therapy. These receptors can be visualised on PET with use of 16 alpha-[F-18]-fluoro-17 beta-oestradiol (F-18-FES) as a tracer. Compared with biopsy, which enables assessment of individual sites, whole-body F-18-FES-PET enables quantification of oestrogen-receptor expression in all metastases. In several studies, measurement of tumour protein expression in oestrogen receptors by F-18-FES-PET, concurrent with biopsy, detected oestrogen-receptor-positive tumour lesions with a sensitivity of 84% and specificity of 98%. Roughly 45% of patients with metastatic breast cancer have discordant oestrogen-receptor expression across lesions (ie, F-18-FES-positive and F-18-FES-negative metastases). Low tumour F-18-FES uptake in metastases can predict failure of hormonal therapy in patients with oestrogen-receptor-positive primary tumours. Finally, F-18-FES-PET has shown that oestrogen-receptor binding capacity changes after intervention with hormonal drugs, but findings need to be confirmed. Factors other than oestrogen-receptor expression, including menopausal status and concomitant therapies, that can affect tumour F-18-FES uptake must be taken into account.

A generic high-throughput bioaffinity liquid chromatography-mass spectrometry (BioMS) approach was developed and applied for the screening and identification of known and unknown recombinant human sex hormone-binding globulin (rhSHBG)-binding designer steroids in dietary supplements. For screening, a semi-automated competitive inhibition binding assay was combined with fast ultrahigh-performance-LC-electrospray ionization-triple-quadrupole-MS (UPLC-QqQ-MS). 17β-Testosterone-D3 was used as the stable isotope label of which the binding to rhSHBG-coated paramagnetic microbeads was inhibited by any other binding (designer) steroid. The assay was performed in a 96-well plate and combined with the fast LC-MS, 96 measurements could be performed within 4 h. The concentration-dependent inhibition of the label by steroids in buffer and dietary supplements was demonstrated. Following an adjusted bioaffinity isolation procedure, suspect extracts were injected into a chip-UPLC(NanoTile)-Q-time-of-flight-MS system for full-scan accurate mass identification. Next to known steroids, 1-testosterone was identified in three of the supplements studied and the designer steroid tetrahydrogestrinone was identified in a spiked supplement. The generic steroid-binding assay can be used for high-throughput screening of androgens, estrogens, and gestagens in dietary supplements to fight doping. When combined with chip-UPLC-MS, it is a powerful tool for early warning of unknown emerging rhSHBG bioactive designer steroids in dietary supplements.

Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating, and defecating at a metabolic rate of only 25% of the summer activity rate. Nonetheless, they emerge healthy and alert in spring. We quantified the biochemical adaptations for hibernation by comparing the proteome, metabolome, and hematological features of blood from hibernating and active free-ranging subadult brown bears with a focus on conservation of health and energy. We found that total plasma protein concentration increased during hibernation, even though the concentrations of most individual plasma proteins decreased, as did the white blood cell types. Strikingly, antimicrobial defense proteins increased in concentration. Central functions in hibernation involving the coagulation response and protease inhibition, as well as lipid transport and metabolism, were upheld by increased levels of very few key or broad specificity proteins. The changes in coagulation factor levels matched the changes in activity measurements. A dramatic 45-fold increase in sex hormone-binding globulin levels during hibernation draws, for the first time, attention to its significant but unknown role in maintaining hibernation physiology. We propose that energy for the costly protein synthesis is reduced by three mechanisms as follows: (i) dehydration, which increases protein concentration without de novo synthesis; (ii) reduced protein degradation rates due to a 6 degrees C reduction in body temperature and decreased protease activity; and (iii) a marked redistribution of energy resources only increasing de novo synthesis of a few key proteins. The comprehensive global data identified novel biochemical strategies for bear adaptations to the extreme condition of hibernation and have implications for our understanding of physiology in general. Funding Agencies|Lundbech Foundation [R126-2012-12408]; Aalborg University

The intake of the n-3 fatty acids alpha-linolenic acid (ALA), acid (EPA) and docosahexaenoic acid (DHA) has been related to testosterone levels in epidemiological analyses. The aim of this study was to assess whether the n-3 fatty acids affects testosterone levels in post-myocardial infarction (MI) patients, who are at risk of testosterone deficiency. In a double-blind, placebo-controlled trial of low-dose supplementation of n-3 fatty acids, we included 1850 male post-MI patients aged 60–80 years who participated in the Alpha Omega Trial. Patients were randomly allocated to margarines that provided 400 mg/day of EPA–DHA (n = 453), 2 mg/day of ALA (n = 467), EPA–DHA plus ALA (n = 458), or placebo (n = 472). Serum testosterone levels were assessed at baseline and after 41 months using whole day blood samples obtained at the subjects’ home or at the hospital. Subjects were on average age of 68.4 (SD 5.3) years old and had baseline mean serum total testosterone of 14.8 (SD 5.6) nmol/L. The four randomized groups did not differ for baseline characteristics. ALA, EPA–DHA, and EPA–DHA plus ALA supplementation did not affect serum total testosterone compared to placebo. Moreover, n-3 fatty acid supplementation did not affect the risk of incident testosterone deficiency (n = 76 with total testosterone

Testosterone is an important hormone for both bone gain and maintenance in men. Hypogonadal men have accelerated bone turnover and increased fracture risk. In these men, administration of testosterone inhibits bone resorption and maintains bone mass. Testosterone, however, is converted into estradiol via aromatization in many tissues including male bone. The importance of estrogen receptor alpha activation as well of aromatization of androgens into estrogens was highlighted by a number of cases of men suffering from an inactivating mutation in the estrogen receptor alpha or in the aromatase enzyme. All these men typically had low bone mass, high bone turnover and open epiphyses. In line with these findings, cohort studies have confirmed that estradiol contributes to the maintenance of bone mass after reaching peak bone mass, with an association between estradiol and fractures in elderly men. Recent studies in knock-out mice have increased our understanding of the role of androgens and estrogens in different bone compartments. Estrogen receptor activation, but not androgen receptor activation, is involved in the regulation of male longitudinal appendicular skeletal growth in mice. Both the androgen and the estrogen receptor can independently mediate the cancellous bone-sparing effects of sex steroids in male mice. Selective KO studies of the androgen receptor in osteoblasts in male mice suggest that the osteoblast in the target cell for androgen receptor mediated maintenance of trabecular bone volume and coordination of bone matrix synthesis and mineralization. Taken together, both human and animal studies suggest that testosterone has a dual mode of action on different bone surfaces with involvement of both the androgen and estrogen receptor. ispartof: Journal of Osteoporosis vol:2011 pages:240328- ispartof: location:United States status: published

Context Serum testosterone levels decline significantly with aging. Testosterone supplementation to older men might beneficially affect the aging processes.Objective To investigate the effect of testosterone supplementation on functional mobility, cognitive function, bone mineral density, body composition, plasma lipids, quality of life, and safety parameters in older men with low normal testosterone levels.Design, Setting, and Participants Double-blind, randomized, placebo-controlled trial of 237 healthy men between the ages of 60 and 80 years with a testosterone level lower than 13.7 nmol/L conducted from January 2004 to April 2005 at a university medical center in the Netherlands.Intervention Participants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for 6 months.Main Outcome Measures Functional mobility (Stanford Health Assessment questionnaire, timed get up and go test, isometric handgrip strength, isometric leg extensor strength), cognitive function (8 different cognitive instruments), bone mineral density of the hip and lumbar spine (dual-energy x-ray absorptiometry scanning), body composition (total body dual-energy x-ray absorptiometry and abdominal ultrasound of fat mass), metabolic risk factors (fasting plasma lipids, glucose, and insulin), quality of life (Short-Form Health 36 Survey and the Questions on Life Satisfaction Modules), and safety parameters (serum prostate-specific antigen level, ultrasonographic prostate volume, International Prostate Symptom score, serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, hemoglobin, and hematocrit).Results A total of 207 men completed the study. During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P=.07). Quality-of -life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected.Conclusion Testosterone supplementation during 6 months to older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects.Trial Registration isrctn.org Identifier: ISRCTN23688581.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of the four major enterolignan precursors [secoisolariciresinol, matairesinol, lariciresinol, and pinoresinol] in foods. The method consists of alkaline methanolic extraction, followed by enzymatic hydrolysis using Helix pomatia (H. pomatia) beta-glucuronidase/sulfatase. H. pomatia was selected from several enzymes based on its ability to hydrolyze isolated lignan glucosides. After ether extraction samples were analyzed and quantified against secoisolariciresinol-d8 and matairesinol-d6. The method was optimized using model products: broccoli, bread, flaxseed, and tea. The yield of methanolic extraction increased up to 81%, when it was combined with alkaline hydrolysis. Detection limits were 4-10 microg/(100 g dry weight) for solid foods and 0.2-0.4 microg/(100 mL) for beverages. Within- and between-run coefficients of variation were 6-21 and 6-33%, respectively. Recovery of lignans added to model products was satisfactory (73-123%), except for matairesinol added to bread (51-55%).

BackgroundMetabolic syndrome (MetS) is a complex disorder characterized by coexistence of several cardiometabolic (CM) factors, i.e. hyperlipidemia, obesity, high blood pressure and insulin resistance. The presence of MetS is strongly associated with increased risk of cardiovascular disease (CVD). The syndrome was originally defined as an adult disorder, but MetS has become increasingly recognized in children and adolescents.MethodsGenetic variants influence biological components common to the CM factors that comprise MetS. We investigated single locus associations between six single nucleotide polymorphisms (SNPs), previously shown to modulate lipid or sex hormone binding globulin (SHBG) levels, with MetS in a Turkish pediatric cohort (37 cases, 323 controls).ResultsLogistic regression analysis revealed a significant association between rs1799941, located in SHBG, and MetS (OR = 3.09, p-value = 0.006). The association with MetS remained after sequential adjustment for each CM factor included in the syndrome definition, indicating that the identified association is not being driven by any single trait. A relationship between rs1799941 and SHBG levels, was also discovered, but it was dependent on MetS status. In control subjects, the A allele of rs1799941 associated with a significant increase in SHBG levels (p = 0.012), while in cases there was no association between rs1799941 and SHBG levels (p = 0.963).ConclusionsThe significant association between rs1799941 and MetS in children is not contingent on any single CM trait. Additionally, the presence of MetS may abrogate effect of rs1799941 polymorphism on SHBG levels in children.

How does insulin action change during pregnancy in women with polycystic ovary syndrome (PCOS) who develop gestational diabetes (GDM) compared with women with PCOS who do not?Women with PCOS who develop GDM already show disturbed insulin action early in pregnancy.Pregnant women with PCOS are at increased risk of developing GDM compared with women without PCOS.This study represents a post hoc analysis of a subgroup of pregnant women with PCOS participating in a multicentre prospective cohort study. A total of 72 women were included.Women with PCOS and a wish to conceive were included before conception and followed during pregnancy. Insulin, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), sex hormone-binding globulin (SHBG) and testosterone were analysed at three different time points in women who developed GDM and women who did not.Seventy-two pregnant women with PCOS were included of which 22 (31%) women developed GDM. Both insulin levels and HOMA-IR were significantly higher at each sampling point in women with PCOS who developed GDM. SHBG levels were significantly lower before conception and in the second trimester compared with women who did not develop GDM. Testosterone concentrations were significantly lower before conception in women who developed GDM. After adjusting for BMI, waist circumference and waist/hip ratio, the differences in insulin, HOMA-IR, SHBG and testosterone levels remained largely the same.Selection bias cannot be excluded since only women from one centre with a complete blood sampling set were included in this study.The knowledge that women with PCOS who develop GDM already have a disturbed insulin action early in pregnancy is likely to be useful in considering the pathophysiology processes underlying this disorder in this specific group of women.This study was funded by the Child Health research programme of the University Medical Centre Utrecht. M.A.d.W., A.J.G., S.M.V.-V., A.F. and M.P.H.K. have no conflicts of interest to disclose. M.J.C.E. has received grant support from the following companies (in alphabetic order): Illumina and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Ferring, Ova-Science, PregLem SA, Roche and Watson Laboratories. The authors declare complete independence from funders.Clinicaltrials.gov, number NCT00821379.

Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed.

BACKGROUND Most previous studies concerning the relationship between IGF-I and age used assays measuring total IGF-I, Although free IGF-I is considered of greater biological relevance, little is known about its relationship with sex steroids levels in elderly healthy subjects,MEASUREMENTS In a cross-sectional study of 218 healthy people (103 men, 115 women) aged 55-80 years we measured serum total and free IGF-I, IGFBP-1 and IGFBP3 levers and sex steroids. Free androgen index and free oestradiol index were used as an indicator for free oestradiol and free testosterone levels, respectively.RESULTS Free IGF-I revels did not decline with age in the whole study population. Free IGF-I levels even increased in individuals above 70 years of age in comparison to those aged between 55 and 70 years (mean +/- SE 0.106 +/- 0.007 nmol/l vs, 0.086 +/- 0.004 nmol/l, P = 0.009). Total IGF-I and IGFBP-3 decreased with age (r = -0.20, P = 0.005 and r = -0.24, P = 0.001, respectively). Total IGF-I levels were positively related with free oestrogen index in both sexes. Free IGF-I did not relate to free oestrogen or androgen index. In women only, free IGF-I was related positively with DHEAS while IGFBP-1 was inversely correlated with DHEAS.CONCLUSIONS Free IGF-I levels do not decrease with age and are even higher in individuals above 70 years. There was no relationship between free IGF-I and free androgen or oestrogen index in either gender. We hypothesize that higher free IGF-I levels in older persons may be the consequence of selective survival in the cohort: subjects with high free IGF-I levels may live longer. The absence of a relationship between free IGF-I levels and free androgen and oestrogen indices suggests that there is no direct interaction between the biological activity of circulating IGF-I levels and sex hormone production in a healthy ageing population.

Cardiovascular risk factors and atherosclerosis precursors were examined in 365 Turkish children and adolescents. Study participants were recruited at five different state schools. We tested single and multi-locus effects of six polymorphisms from five candidate genes, chosen based on prior known association with lipid levels in adults, for association with low (10(th) percentile) high density lipoprotein cholesterol (HDL-C) and high (90(th) percentile) triglycerides (TG), and the related continuous outcomes. We observed an association between CETP variant rs708272 and low HDL-C (allelic p=0.020, genotypic p=0.046), which was supported by an independent analysis, PRAT (PRAT control p=0.027). Sex-stratified logistic regression analysis showed that the B2 allele of rs708272 decreased odds of being in the lower tenth percentile of HDL-C measurements (OR=0.36, p=0.02) in girls; this direction of effect was also seen in boys but was not significant (OR=0.64, p=0.21). Logistic regression analysis also revealed that the T allele of rs6257 (SHBG) decreased odds of being in the top tenth percentile of TG measurements in boys (OR=0.43, p=0.03). Analysis of lipid levels as a continuous trait revealed a significant association between rs708272 (CETP) and LDL-C levels in males (p=0.02) with the B2B2 genotype group having the lowest mean LDL-C; the same direction of effect was also seen in females (p=0.05). An effect was also seen between rs708272 and HDL-C levels in girls (p=0.01), with the B2B2 genotype having the highest mean HDL-C levels. Multi-locus analysis, using quantitative multifactor dimensionality reduction (qMDR) identified the previously mentioned CETP variant as the best single locus model, and overall model, for predicting HDL-C levels in children. This study provides evidence for association between CETP and low HDL-C phenotype in children, but the results appear to be weaker in children than previous results in adults and may also be subject to gender effects.

Objective: To investigate the relation between noninsulin-dependent diabetes mellitus and bone mineral density at the lumbar spine and hip.Design: Population-based study with a cross-sectional survey,Setting: A district of Rotterdam, the Netherlands.Participants: 5931 residents (2481 men, 3450 women) of the district aged 55 years or more.Measurements: Participants were classified as having non-insulin-dependent diabetes mellitus if they were receiving antidiabetic medication or if they had a serum glucose level of 11.1 mmol/L or more after a nonfasting oral glucose tolerance test. Bone mineral density, measured at the lumbar spine and proximal femur using dual-energy x-ray absorptiometry and the frequency of nonvertebral fractures during the preceding 5 years were compared between persons with and without non-insulin-dependent diabetes mellitus.Results: 243 men and 335 women had non-insulin-dependent diabetes mellitus. Both men and women with this condition had substantially higher mean bone mineral density values at all four sites measured than those with normal glucose tolerance. The increase could not be explained by age; obesity; use of estrogens, thiazides, or loop diuretics; impairment in abilities of daily living; smoking; or osteoarthritis. Women with non-insulin-dependent diabetes mellitus reported having had fewer fractures in the 5 preceding years than women without this condition (adjusted odds ratio, 0.63; 95% CI, 0.44 to 0.90). The frequency of fractures in men was similar for those with and without noninsulin-dependent diabetes mellitus (adjusted odds ratio, 0.96; CI, 0.60 to 1.52).Conclusions: Men and women with non-insulin-dependent diabetes mellitus have increased bone mineral density. Non-insulin-dependent diabetes mellitus in women is associated with a lower frequency of nonvertebral fractures.

BACKGROUND: The metabolic syndrome (MS) might increase the risk of cardiovascular disease in testicular cancer (TC) survivors. We investigated its prevalence, development, vascular implications, and the role of gonadal function.METHODS: TC survivors treated with chemotherapy and follow-up ≥3 years (N = 370, study I) were retrospectively evaluated for the development of cardiovascular risk factors. A subgroup followed 3-20 years (N = 173, study II) was compared with controls (N = 1085) for MS prevalence and evaluated for vascular function.RESULTS: In TC survivors (study I), 24% developed overweight, 24% hypercholesterolemia, and 30% hypertension, after median follow-up of 1.7, 0.9, and 5.1 years, respectively. At the median follow-up of 5 years (study II), 25% of survivors have the MS {odds ratio (OR) 2.2, [95% confidence interval (CI) 1.5-3.3] compared with controls}. Survivors with MS have features of inflammation and prothrombotic state, increased carotid artery intima-media thickness. Survivors with testosterone levels CONCLUSIONS: The current data suggest that the MS occurs at earlier age in TC survivors treated with chemotherapy compared with controls and is accompanied by early signs of atherosclerosis. As low testosterone may have a causal role, it is a target for interventions.

BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Document Type : Book Chapter; International audience; Obesity is a recognized breast cancer risk factor in postmenopausal women. A recent hypothesis suggests a major role for adipose tissue in carcinogenesis. During many years, the adipose tissue was only considered as a fat storage of energy. This tissue is now described as an endocrine organ secreting a large range of molecules called adipokines. Among these adipokines, adiponectin may play a major role in breast cancer. Plasma adiponectin levels were found to be decreased in cases of breast cancer and in obese patients. Adiponectin may act directly on breast cancer cells by inhibiting proliferation and angiogenesis or by stimulating apoptosis. Increasing adiponectin levels may be of major importance in the prevention and/or the treatment of breast cancer. This therapeutic approach may be of particular significance for obese patients. The beneficial effects of adiponectin and its possible therapeutic applications will be discussed in this review.

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, 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.

Context Serum testosterone levels decline significantly with aging. Testosterone supplementation to older men might beneficially affect the aging processes. ObjectiveTo investigate the effect of testosterone supplementation on functional mobility, cognitive function, bone mineral density, body composition, plasma lipids, quality of life, and safety parameters in older men with low normal testosterone levels.Design, Setting, and ParticipantsDouble-blind, randomized, placebo-controlled trial of 237 healthy men between the ages of 60 and 80 years with a testosterone level lower than 13.7 nmol/L conducted from January 2004 to April 2005 at a university medical center in the Netherlands.InterventionParticipants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for 6 months.Main Outcome Measures Functional mobility (Stanford Health Assessment Questionnaire, timed get up and go test, isometric handgrip strength, isometric leg extensor strength), cognitive function (8 different cognitive instruments), bone mineral density of the hip and lumbar spine (dual-energy x-ray absorptiometry scanning), body composition (total body dual-energy x-ray absorptiometry and abdominal ultrasound of fat mass), metabolic risk factors (fasting plasma lipids, glucose, and insulin), quality of life (Short-Form Health 36 Survey and the Questions on Life Satisfaction Modules), and safety parameters (serum prostate-specific antigen level, ultrasonographic prostate volume, International Prostate Symptom score, serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, hemoglobin, and hematocrit). Results A total of 207 men completed the study. During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P = .07). Quality-of-life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected. ConclusionTestosterone supplementation during 6 months to older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects.Trial Registration isrctn.org Identifier: ISRCTN23688581

BACKGROUND Most previous studies concerning the relationship between IGF-I and age used assays measuring total IGF-I, Although free IGF-I is considered of greater biological relevance, little is known about its relationship with sex steroids levels in elderly healthy subjects, MEASUREMENTS In a cross-sectional study of 218 healthy people (103 men, 115 women) aged 55-80 years we measured serum total and free IGF-I, IGFBP-1 and IGFBP3 levers and sex steroids. Free androgen index and free oestradiol index were used as an indicator for free oestradiol and free testosterone levels, respectively. RESULTS Free IGF-I revels did not decline with age in the whole study population. Free IGF-I levels even increased in individuals above 70 years of age in comparison to those aged between 55 and 70 years (mean +/- SE 0.106 +/- 0.007 nmol/l vs, 0.086 +/- 0.004 nmol/l, P = 0.009). Total IGF-I and IGFBP-3 decreased with age (r = -0.20, P = 0.005 and r = -0.24, P = 0.001, respectively). Total IGF-I levels were positively related with free oestrogen index in both sexes. Free IGF-I did not relate to free oestrogen or androgen index. In women only, free IGF-I was related positively with DHEAS while IGFBP-1 was inversely correlated with DHEAS. CONCLUSIONS Free IGF-I levels do not decrease with age and are even higher in individuals above 70 years. There was no relationship between free IGF-I and free androgen or oestrogen index in either gender. We hypothesize that higher free IGF-I levels in older persons may be the consequence of selective survival in the cohort: subjects with high free IGF-I levels may live longer. The absence of a relationship between free IGF-I levels and free androgen and oestrogen indices suggests that there is no direct interaction between the biological activity of circulating IGF-I levels and sex hormone production in a healthy ageing population.

Objective: To investigate the relation between noninsulin-dependent diabetes mellitus and bone mineral density at the lumbar spine and hip. Design: Population-based study with a cross-sectional survey, Setting: A district of Rotterdam, the Netherlands. Participants: 5931 residents (2481 men, 3450 women) of the district aged 55 years or more. Measurements: Participants were classified as having non-insulin-dependent diabetes mellitus if they were receiving antidiabetic medication or if they had a serum glucose level of 11.1 mmol/L or more after a nonfasting oral glucose tolerance test. Bone mineral density, measured at the lumbar spine and proximal femur using dual-energy x-ray absorptiometry and the frequency of nonvertebral fractures during the preceding 5 years were compared between persons with and without non-insulin-dependent diabetes mellitus. Results: 243 men and 335 women had non-insulin-dependent diabetes mellitus. Both men and women with this condition had substantially higher mean bone mineral density values at all four sites measured than those with normal glucose tolerance. The increase could not be explained by age; obesity; use of estrogens, thiazides, or loop diuretics; impairment in abilities of daily living; smoking; or osteoarthritis. Women with non-insulin-dependent diabetes mellitus reported having had fewer fractures in the 5 preceding years than women without this condition (adjusted odds ratio, 0.63; 95% CI, 0.44 to 0.90). The frequency of fractures in men was similar for those with and without noninsulin-dependent diabetes mellitus (adjusted odds ratio, 0.96; CI, 0.60 to 1.52). Conclusions: Men and women with non-insulin-dependent diabetes mellitus have increased bone mineral density. Non-insulin-dependent diabetes mellitus in women is associated with a lower frequency of nonvertebral fractures.