Dataset Information

Genetic determinants of serum testosterone concentrations in men.

ABSTRACT: 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 <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p?=?1.2×10(-41) and rs6258, p?=?2.3×10(-22)). Subjects with ? 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p?=?5.6×10(-16)). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

SUBMITTER: Ohlsson C

PROVIDER: S-EPMC3188559 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Genetic determinants of serum testosterone concentrations in men.

Ohlsson Claes C Wallaschofski Henri H Lunetta Kathryn L KL Stolk Lisette L Perry John R B JR Koster Annemarie A Petersen Ann-Kristin AK Eriksson Joel J Lehtimäki Terho T Huhtaniemi Ilpo T IT Hammond Geoffrey L GL Maggio Marcello M Coviello Andrea D AD Ferrucci Luigi L Heier Margit M Hofman Albert A Holliday Kate L KL Jansson John-Olov JO Kähönen Mika M Karasik David D Karlsson Magnus K MK Kiel Douglas P DP Liu Yongmei Y Ljunggren Osten O Lorentzon Mattias M Lyytikäinen Leo-Pekka LP Meitinger Thomas T Mellström Dan D Melzer David D Miljkovic Iva I Nauck Matthias M Nilsson Maria M Penninx Brenda B Pye Stephen R SR Vasan Ramachandran S RS Reincke Martin M Rivadeneira Fernando F Tajar Abdelouahid A Teumer Alexander A Uitterlinden André G AG Ulloor Jagadish J Viikari Jorma J Völker Uwe U Völzke Henry H Wichmann H Erich HE Wu Tsung-Sheng TS Zhuang Wei Vivian WV Ziv Elad E Wu Frederick C W FC Raitakari Olli O Eriksson Anna A Bidlingmaier Martin M Harris Tamara B TB Murray Anna A de Jong Frank H FH Murabito Joanne M JM Bhasin Shalender S Vandenput Liesbeth L Haring Robin R

PLoS genetics 20111006 10

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 testosteron ...[more]

PMID: 21998597

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Project description:Marijuana has been reported to have several effects on the male reproductive system. Marijuana has previously been linked to reduced adult testosterone, however, a study in Denmark reported increased testosterone concentrations among marijuana users. This study was performed to estimate the effect of marijuana use on testosterone in U.S. males. Data on serum testosterone, marijuana use, and covariates for 1577 men from the 2011-2012 U.S. National Health and Nutrition Examination Survey (NHANES) were analyzed. Information on marijuana use was collected by a self-administered computer-assisted questionnaire. Serum testosterone was determined using isotope dilution liquid chromatography tandem mass spectrometry. The effects of marijuana use on serum testosterone concentrations were examined by frequency, duration, and recency of use. Adjusted means and 95% confidence intervals (CI) of serum testosterone across levels of marijuana use were estimated using multiple linear regression weighted by the survey weights. The majority (66.2%) of the weighted study population reported ever using marijuana with 26.6% reporting current marijuana use. There was no difference in serum testosterone between ever users (adjusted mean = 3.69 ng/mL, 95% CI: 3.46, 3.93) and never users (adjusted mean = 3.70 ng/mL, 95% CI: 3.45, 3.98) upon multivariable analysis. However, serum testosterone was inversely associated with time since last regular use of marijuana (p-value for trend = 0.02). When restricted to men aged 18-29 years, this relationship strengthened (p-value for trend <0.01), and serum testosterone was also inversely associated with time since last use (p-value for trend <0.01), indicating that recency of use, and not duration or frequency, had the strongest relationship with testosterone levels. Serum testosterone concentrations were higher in men with more recent marijuana use. Studies are needed to determine the extent to which circulating testosterone concentrations mediate the relationship of marijuana use with male reproductive outcomes.

Project description:Abstract BACKGROUND: In men, obesity is often associated with low testosterone (T) levels, but information is limited as to how body weight affects the pharmacokinetic profile or dosing of testosterone therapy (TTh) in men with T deficiency. Historically, men with body mass index (BMI) >32.4 kg/m2 required higher doses of T 2% gel to achieve physiological T levels than men with BMI ≤29.1 or 29.2–32.4 kg/m2.(1) In a phase 3 trial (N=150) of subcutaneous (SC) testosterone enanthate (TE) administered weekly, concentration-guided dosing raised T levels to within physiological range in 92.7% of patients.(2) Here, we report a post hoc analysis evaluating the association between body weight and serum T levels attained with SC TE. Methods: SC TE was evaluated in an open-label, single-arm, dose-blinded, 52-week phase 3 trial (NCT02159469). Patients self-administered 75 mg SC TE weekly during the titration phase; blinded dose-adjustments in 25 mg increments occurred at pre-defined time points beyond the sixth dose. The primary endpoint of this study was the percentage of patients achieving an average serum T concentration (Cavg0-168h) of 300 to 1,100 ng/dL at week 12. For this post hoc analysis, a linear regression model with weight and dose as independent variables was used to assess differences in mean minimum T concentration (Cmin) and Cavg0-168h at week 12. Results: For this analysis, 137 patients were included. Doses were 50 mg (n=25), 75 mg (n=93), and 100 mg (n=19). The mean weight was 84.4 kg, 102.2 kg, and 112.0 kg for the 50 mg, 75 mg, and 100 mg dose groups, respectively (range, 49.9–146.5 kg). The dose-normalized T Cmin was 9.2 ng/dL, 5.7 ng/dL, and 4.3 ng/dL per 1 mg of SC TE for the 50 mg, 75 mg, and 100 mg groups, respectively. The dose-normalized T Cavg0-168h was 12.0 ng/dL, 7.2 ng/dL, and 5.7 ng/dL per 1 mg of SC TE. In an overall linear regression model, 48.2% (P<0.0001) and 55.0% (P<0.0001) of the total variance in Cmin and Cavg0-168h, respectively, can be predicted from the independent weight and dose variables. Conclusion: Our results show an inverse relationship between body weight and T exposure. Men with higher mean body weights required higher doses of SC TE to achieve physiologic T levels compared with men with lower mean body weights. The available doses provide effective options to reach target exposures. These findings highlight the impact of weight and dose selection on SC TE exposure. References: (1) Dobs et al., J Sex Med 2014;11:857–864; (2) Kaminetsky et al., J Urol. 2019;201:587–94.

Dataset Information

Genetic determinants of serum testosterone concentrations in men.

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Genetic determinants of serum testosterone concentrations in men.

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