Hypothalamic-Pituitary-Testicular Axis Disruptions in Older Men Are Differentially Linked to Age and Modifiable Risk Factors: The European Male Aging Study

Abstract Context: The cause of declining testosterone (T) in aging men and their relationships with risk factors are unclear. Objective: The objective of the study was to investigate the relationships between lifestyle and health with reproductive hormones in aging men. Design: This was a baseline cross-sectional survey on 3200 community-dwelling men aged 40–79 yr from a prospective cohort study in eight European countries. Results: Four predictors were associated with distinct modes of altered function: 1) age: lower free T (FT; −3.12 pmol/liter·yr, P < 0.001) with raised LH, suggesting impaired testicular function; 2) obesity: lower total T (TT; −2.32 nmol/liter) and FT (−17.60 pmol/liter) for body mass index (BMI; ≥ 25 to < 30 kg/m2) and lower TT (−5.09 nmol/liter) and FT (−53.72 pmol/liter) for BMI 30 kg/m2 or greater (P < 0.001–0.01, referent: BMI < 25 kg/m2) with unchanged/decreased LH, indicating hypothalamus/pituitary dysfunction; 3) comorbidity: lower TT (−0.80 nmol/liter, P < 0.01) with unchanged LH in younger men but higher LH in older men; and 4) smoking: higher SHBG (5.96 nmol/liter, P < 0.001) and LH (0.77 U/liter, P < 0.01) with increased TT (1.31 nmol/liter, P < 0.001) but not FT, compatible with a resetting of T-LH-negative feedback due to elevated SHBG. Conclusions: Complex multiple alterations in the hypothalamic-pituitary-testicular axis function exist in aging men against a background of progressive age-related testicular impairment. These changes are differentially linked to specific risk factors. Some risk factors operate independently of but others interact with age, in contributing to the T decline. These potentially modifiable risk factors suggest possible preventative measures to maintain T during aging in men.