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

Department of Endocrinology (F.C.W.W.), Manchester Royal Infirmary, University of Manchester, Manchester M13 9WL, United Kingdom; ARC Epidemiology Unit (A.T., S.R.P., A.J.S., J.D.F., T.W.O.), The University of Manchester, Manchester M13 9PT, United Kingdom; Department of Obstetrics, Gynaecology, and Andrology (G.B.), Albert Svent-Gyorgy Medical University, Szeged 6725, Hungary; Department of Medicine (F.C.), Santiago de Compostela University, 15705 Santiago de Compostela, Spain; Andrology Unit (G.F.), Department of Clinical Physiopathology, University of Florence, 50121 Florence, Italy; Scanian Andrology Centre (A.G.), Department of Urology, Malmö University Hospital, University of Lund, SE20502 Lund, Sweden; Department of Reproductive Biology (I.T.H.), Imperial College London, Hammersmith Campus, London SW7 2AZ, United Kingdom; Department of Andrology and Reproductive Endocrinology (K.K.), Medical University of Lodz, 90-419 Lodz, Poland; Andrology Unit (M.P.), United Laboratories of Tartu University Clinics, 50406 Tartu, Estonia; and Department of Andrology and Endocrinology (S.B., D.V.), Catholic University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Professor Frederick C. W. Wu, Department of Endocrinology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom. E-mail: frederick.wu{at}manchester.ac.uk.

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.

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