The heritability of circulating testosterone, oestradiol, oestrone and sex hormone binding globulin concentrations in men: the Framingham Heart Study.

OBJECTIVE: Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. DESIGN: Cross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005. PARTICIPANTS: A total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. MEASUREMENTS: Levels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. RESULTS: Age-adjusted heritability estimates were 0·19, 0·40, 0·40, 0·30 and 0·41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (ρG ) indicated substantial genetic association between TT and cFT (ρG = 0·68), between TT and SHBG (pG = 0·87), between E1 and E2 (ρG = 0·46) and between TT and E2 (ρG = 0·48). CONCLUSION: Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.

Circulating testosterone and SHBG concentrations are heritable in women: the Framingham Heart Study.

CONTEXT: Many factors influence the concentration of circulating testosterone and its primary binding protein, SHBG. However, little is known about the genetic contribution to their circulating concentrations in women, and their heritability in women is not well established. OBJECTIVE: Our objective was to estimate the heritability of circulating total testosterone (TT), free testosterone (FT), and SHBG in women in families from the Framingham Heart Study. METHODS: Women in the Framingham Heart Study who were not pregnant, had not undergone bilateral oophorectomy, and were not using exogenous hormones were eligible for this investigation. TT was measured using liquid chromatography tandem mass spectrometry and SHBG using an immunofluorometric assay (Delfia-Wallac), and FT was calculated. Heritability estimates were calculated using variance-components methods in Sequential Oligogenic Linkage Analysis Routines (SOLAR) and were adjusted for age, age(2), body mass index (BMI), BMI(2), diabetes, smoking, and menopausal status. Bivariate analyses were done to assess genetic correlation between TT, FT, and SHBG. RESULTS: A total of 2685 women were studied including 868 sister pairs and 688 mother-daughter pairs. Multivariable adjusted heritability estimates were 0.26 ± 0.05 for FT, 0.26 ± 0.05 for TT, and 0.56 ± 0.05 for SHBG (P < 1.0 × 10(-7) for all). TT was genetically correlated with SHBG [genetic correlation coefficient (ρG) = 0.31 ± 0.10] and FT (ρG = 0.54 ± 0.09), whereas SHBG was inversely correlated with FT (ρG = -0.60 ± 0.08). CONCLUSION: Circulating TT, FT, and SHBG concentrations in women are significantly heritable, underscoring the importance of further work to identify the specific genes that contribute significantly to variation in sex steroid concentrations in women. The strong shared genetic component among pairs of TT, FT, and SHBG concentrations suggests potential pleiotropic effects for some of the underlying genes.

Lipomatosis-associated inflammation and excess collagen may contribute to lower relative resting energy expenditure in women with adiposis dolorosa.

BACKGROUND: Adiposis dolorosa (AD) is a syndrome of obese and non-obese individuals whose hallmark is lipomatosis: unencapsulated painful fatty masses in subcutaneous fat. Lipomatosis may contain excess collagen and multi-nucleated giant (MNG) cells. Case reports suggest metabolic defects in AD. OBJECTIVES: (1) To determine whether women with AD have altered relative resting energy expenditure (REE per total body mass) compared with controls; and (2) to quantitate lipomatosis-associated collagen, MNGs and tissue and blood cytokines that may influence REE. METHODS: A total of 10 women with AD were compared with age, body mass index, fat and weight-matched control women. Adipose tissue was obtained from five women with AD and five controls and evaluated for collagen and macrophages/MNGs. Fat mass and fat-free mass were identified by dual X-ray absorptiometry. REE was by determined indirect calorimetry and related to mass. Adipokines and cytokines were evaluated in blood and tissue. RESULTS: Relative REE (REE per total body mass) was lower in women with AD compared with controls (P=0.007). Only lipomatosis (group) and total body mass were significant predictors of REE in forward stepwise regression (P<0.0001). Adipose interleukin (IL)-6 levels were elevated (P=0.03) and connective tissue was increased fourfold in lipomatosis compared with control tissue (P <0.0001). There was no difference in adipose tissue macrophages between groups; 30% of women with AD had MNG cells. Anti-inflammatory IL-13 levels were elevated (P=0.03), and cytokines important in the recruitment of monocytes, Fraktalkine (P=0.04) and macrophage inflammatory protein-1beta (P=0.009), were significantly lower in the blood of women with AD compared with controls. CONCLUSIONS: The lower relative REE in women with AD compared with controls was associated with increased connective (non-metabolic) tissue in the lipomatosis, and inflammation, although underlying metabolic defects may be important as well. Understanding the pathophysiology and metabolism of lipomatosis in AD may contribute to a better understanding of metabolism in non-lipomatosis obesity.