The Heritability of Sex Steroid Concentrations in Men
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 sex steroid concentrations exhibit tremendous inter- and intra-individual variation in population-based studies of men. Although numerous comorbid and behavioural factors have been associated with sex steroid concentrations in adults, it is thought that some proportion of this variation may be determined by genetic inheritance. To establish the degree to which genetic factors regulate male reproductive function in adulthood, it is important to estimate how much variation in sex steroid concentrations is attributable to genetic variation, as distinct from environmental causes.
Existing data, derived primarily from classical twin and family studies, have estimated the heritability of testosterone in adult men to be between approximately 0·2 and 0·7, while indicating that the proportion of variation in sex steroid levels under genetic control may vary tremendously across the male life course, presumably as the relative import of environmental influences waxes and wanes with age. There are fewer population-based estimates of the heritability of oestradiol and oestrone concentrations – important for the maintenance of bone mass and suppression of fracture risk in men – and few existing investigations have produced estimates of the genetic correlation between testosterone and oestradiol.
Because testosterone and – to a lesser extent – oestradiol are bound to sex hormone binding globulin (SHBG) in circulation, SHBG concentrations influence the bioavailability of these hormones. Inter-individual variation in SHBG levels is partially under genetic control, and polymorphisms of the SHBG gene may have influence on its binding to testosterone as well as downstream biomedical outcomes. Population-based estimates of the genetic correlation between circulating testosterone and SHBG are therefore of great interest.
To provide estimates of the heritability of and genetic correlation between sex steroids in men from extended families, we analysed data from the 3367 men who are members of the second- and third-generation cohorts enrolled in the Framingham Heart Study (FHS). These men have had state-of-the-art measurement of total testosterone (TT) and calculated free testosterone (cFT), oestrone (E1) and oestradiol (E2) and SHBG, from which heritability estimates for each of the sex steroids were obtained. Estimates of genetic correlation between testosterone fractions, TT and SHBG, oestrone and oestradiol, and between TT and E2 were also generated.
Abstract and Introduction
Abstract
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.
Introduction
Circulating sex steroid concentrations exhibit tremendous inter- and intra-individual variation in population-based studies of men. Although numerous comorbid and behavioural factors have been associated with sex steroid concentrations in adults, it is thought that some proportion of this variation may be determined by genetic inheritance. To establish the degree to which genetic factors regulate male reproductive function in adulthood, it is important to estimate how much variation in sex steroid concentrations is attributable to genetic variation, as distinct from environmental causes.
Existing data, derived primarily from classical twin and family studies, have estimated the heritability of testosterone in adult men to be between approximately 0·2 and 0·7, while indicating that the proportion of variation in sex steroid levels under genetic control may vary tremendously across the male life course, presumably as the relative import of environmental influences waxes and wanes with age. There are fewer population-based estimates of the heritability of oestradiol and oestrone concentrations – important for the maintenance of bone mass and suppression of fracture risk in men – and few existing investigations have produced estimates of the genetic correlation between testosterone and oestradiol.
Because testosterone and – to a lesser extent – oestradiol are bound to sex hormone binding globulin (SHBG) in circulation, SHBG concentrations influence the bioavailability of these hormones. Inter-individual variation in SHBG levels is partially under genetic control, and polymorphisms of the SHBG gene may have influence on its binding to testosterone as well as downstream biomedical outcomes. Population-based estimates of the genetic correlation between circulating testosterone and SHBG are therefore of great interest.
To provide estimates of the heritability of and genetic correlation between sex steroids in men from extended families, we analysed data from the 3367 men who are members of the second- and third-generation cohorts enrolled in the Framingham Heart Study (FHS). These men have had state-of-the-art measurement of total testosterone (TT) and calculated free testosterone (cFT), oestrone (E1) and oestradiol (E2) and SHBG, from which heritability estimates for each of the sex steroids were obtained. Estimates of genetic correlation between testosterone fractions, TT and SHBG, oestrone and oestradiol, and between TT and E2 were also generated.
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