T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 363;2 nejm

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.

Objective: Health and lifestyle factors are associated with variations in serum testosterone levels in ageing men. However, it remains unclear how age-related changes in testosterone may be attenuated by lifestyle modifications. The objective was to investigate the longitudinal relationships between changes in health and lifestyle factors with changes in hormones of the reproductive endocrine axis in ageing men. Design: A longitudinal survey of 2736 community-dwelling men aged 40-79 years at baseline recruited from eight centres across Europe. Follow-up assessment occurred mean (GS.D.) 4.4G0.3 years later. Results: Paired testosterone results were available for 2395 men. Mean (GS.D.) annualised hormone changes were as follows: testosterone K0.1G0.95 nmol/l; free testosterone (FT) K3.83 G16.8 pmol/l; sex hormone-binding globulin (SHBG) 0.56G2.5 nmol/l and LH 0.08G0.57 U/l. Weight loss was associated with a proportional increase, and weight gain a proportional decrease, in testosterone and SHBG. FT showed a curvilinear relationship to weight change; only those who gained or lost R15% of weight showed a significant change (in the same direction as testosterone). Smoking cessation was associated with a greater decline in testosterone than being a non-smoker, which was unrelated to weight change. Changes in number of comorbid conditions or physical activity were not associated with significant alterations in hypothalamic-pituitary-testicular (HPT) axis function. Conclusions: Body weight and lifestyle factors influence HPT axis function in ageing. Weight loss was associated with a rise, and weight gain a fall, in testosterone, FT and SHBG. Weight management appears to be important in maintaining circulating testosterone in ageing men, and obesity-associated changes in HPT axis hormones are reversible following weight reduction.

Sarcopenia is associated with low BMD(a) and osteoporosis in middle-aged and elderly men. Further studies are necessary to assess whether maintaining muscle mass contributes to prevent osteoporosis.

Life expectancy is increasing in most developed countries, in part due to improved socioeconomic conditions and in part to advances in healthcare. It is widely acknowledged that the promotion of healthy ageing by delaying, minimizing or preventing disabilities or diseases is one of the most important public health objectives in this century. In contrast to the menopausal transition in females, we know relatively little about the contribution of androgens and anabolic hormones to the quality of ageing in men. The European Male Ageing Study (EMAS) is a multicentre prospective cohort designed to examine the prevalence, incidence and geographical distribution of gender-specific and general symptoms of ageing in men, including their endocrine, genetic and psychosocial predictors. Men aged 40-79 years were recruited from eight European centres: Florence (Italy), Leuven (Belgium), Lodz (Poland), Malmö (Sweden), Manchester (UK), Santiago de Compostela (Spain), Szeged (Hungary) and Tartu (Estonia). Subjects were recruited from population registers and those who agreed to take part completed a detailed questionnaire including aspects of personal and medical history, lifestyle factors and sexual function. Objective measures of body size, cognition, vision, skeletal health and neuromuscular function were obtained. Blood and DNA specimens were collected for a range of biochemical and genetic analyses. After an average of 4 years, it is planned to resurvey the participants with similar assessments. A total of 3369 men with a mean age of 60 +/- 11 years were recruited. The mean centre response rate was 43%, and highest in those aged 50-59 years. Those who participated were marginally younger than those who were invited but declined to participate (60.0 vs. 61.1 years). Participants left education slightly later than a sample of non-participants, though there were no consistent differences in levels of general health, physical activity, or smoking. EMAS will provide new population-based data concerning the main features that characterize ageing in men and its critical determinants, particularly with reference to age-related changes in hormone levels. Such information is an important prerequisite to develop effective strategies to reduce age-related disabilities and optimise health and well-being into old-age.

LOH is associated with multiple end-organ deficits compatible with androgen deficiency. These data support the existence of a syndrome of LOH in only a minority of aging men, especially those with T below 8 nmol/liter.

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.

Objective: Interrelationships between hormones of the hypothalamic-pituitary-testicular (HPT) axis, hypogonadism, vitamin D and seasonality remain poorly defined. We investigated whether HPT axis hormones and hypogonadism are associated with serum levels of 25-hydroxyvitamin D (25(OH)D) in men. Design and methods: Cross-sectional survey of 3369 community-dwelling men aged 40-79 years in eight European centres. Testosterone (T), oestradiol (E 2 ) and dihydrotestosterone were measured by gas chromatography-mass spectrometry; LH, FSH, sex hormone binding globulin (SHBG), 25(OH)D and parathyroid hormone by immunoassay. Free T was calculated from total T, SHBG and albumin. Gonadal status was categorised as eugonadal (normal T/LH), secondary (low T, low/normal LH), primary (low T, elevated LH) and compensated (normal T, elevated LH) hypogonadism. Associations of HPT axis hormones with 25(OH)D were examined using linear regression and hypogonadism with vitamin D using multinomial logistic regression. Results: In univariate analyses, free T levels were lower (PZ0.02) and E 2 and LH levels were higher (P!0.05) in men with vitamin D deficiency (25(OH)D !50 nmol/l). 25(OH)D was positively associated with total and free T and negatively with E 2 and LH in age-and centre-adjusted linear regressions. After adjusting for health and lifestyle factors, no significant associations were observed between 25(OH)D and individual hormones of the HPT axis. However, vitamin D deficiency was significantly associated with compensated (relative risk ratio (RRR)Z1.52, PZ0.03) and secondary hypogonadism (RRRZ1.16, PZ0.05). Seasonal variation was only observed for 25(OH)D (P!0.001). Conclusions: Secondary and compensated hypogonadism were associated with vitamin D deficiency and the clinical significance of this relationship warrants further investigation.