Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses

Abstract

Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.

Purpose: To clarify factors associated with variations in sex hormone concentrations.

Data sources: Systematic literature searches (to July 2019).

Study selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.

Data extraction: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.

Data synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.

Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.

Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.

Primary funding source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Figure 1.

Summary curves and forest plots for the associations of sociodemographic factors with testosterone, SHBG, and LH concentrations after controlling for all other sociodemographic predictors in Model 1 (refer Appendix Table A1). MD = mean difference; vertical dashed line on summary curves identifies the reference level (ref.) for the predictor of interest; dotted lines show 95% prediction intervals; forest plots show the MD from the reference level of the categorical predictor (refer Supplementary Tables S2, S3). MD=mean difference, CI=confidence interval, T=testosterone, SHBG=sex hormone-binding globulin, LH=luteinising hormone, BMI=body mass index, Pred. interval=prediction interval. ARIC=Atherosclerosis Risk in Communities Study, BHS=Busselton Health Study, CHS=Cardiovascular Health Study, EMAS=European Male Ageing Study, FHS=Framingham Heart Study, HIMS=Health In Men Study, MAILES=Men Androgen Inflammation Lifestyle Environment and Stress study, MrOS USA=Osteoporotic Fractures in Men USA study, SHIP=Study of Health in Pomerania SHIP.

Figure 2.

Summary curves and forest plots for the associations of prevalent health conditions with testosterone concentration after controlling for all sociodemographic and lifestyle predictors (refer Appendix Table A1). MD = mean difference; vertical dashed line on summary curves identifies the reference level (ref.) for the predictor of interest; dotted lines show 95% prediction intervals; forest plots show the MD from the reference level of the categorical predictor (refer Supplementary Tables S2, S3). MD=mean difference, T=testosterone, BP=blood pressure, HDL=high density lipoprotein, LDL=low density lipoprotein, CVD=cardiovascular disease, COPD=chronic obstructive pulmonary disease, CI=confidence interval, Pred. interval=prediction interval. ARIC=Atherosclerosis Risk in Communities Study, BHS=Busselton Health Study, CHS=Cardiovascular Health Study, EMAS=European Male Ageing Study, FHS=Framingham Heart Study, HIMS=Health In Men Study, MAILES=Men Androgen Inflammation Lifestyle Environment and Stress study, MrOS USA=Osteoporotic Fractures in Men USA study, SHIP=Study of Health in Pomerania SHIP.

Figure 3.

Sensitivity of summary estimates (IPD only: for Models 1, 2, 7 and 10) to the inclusion of aggregate level data (IPD + AD) provided by two additional studies. Summary estimates show the mean difference from the reference level of the categorical predictor. * = summary estimates presented as change for 1 standard deviation increase around the Ref. value (Supplementary Table S5). BMI=body mass index.