The classical role played by vitamin D and parathyroid hormone (PTH) in maintaining bone health and controlling calcium metabolism is well documented Whether synthesised in the skin or derived from dietary sources, vitamin D is first hydroxylated in the liver to produce 25-hydroxyvitamin D (25(OH)D), which is in turn further hydroxylated (primarily in the kidneys) to yield the active molecule, 1,25(OH)2D. Serum levels of 25(OH)D, the major circulating form of the vitamin, are typically measured to determine an individual's vitamin D status. An increasing body of observational data has linked low serum levels of vitamin D to a variety of chronic diseases related to ageing, including diabetes and cardiovascular disease. However, the nature of these associations is poorly defined and our understanding of the pathophysiological role(s) of vitamin D other than in calcium homeostasis remains rudimentary. Age-related declines in testosterone (T) and other anabolic hormones have been well documented in men from the age of 40 years onwards (6, 7, 8), with low T levels suggested to be a risk factor for diabetes and cardiovascular disease. However, the degree to which these changes in hypothalamic–pituitary–testicular (HPT) axis function directly or indirectly influence age-related declines in physical (frailty), cardiovascular (atherosclerosis, erectile dysfunction) and psychological health (cognitive function) remains contentious. Recently, Wehr et al. observed a positive, cross-sectional association between T and 25(OH)D together with a concordant pattern of seasonal variation for both hormones. The authors hypothesise that serum vitamin D levels may impact directly on gonadal functioning, with biological plausibility stemming from the presence of vitamin D receptor (VDR) in the testis, hypothalamus and pituitary gland. Previous work in our group has shown that multilevel functional alterations in the HPT axis are linked to distinct risk factors, such as obesity and comorbidity that interact with age to contribute to declining T levels. Since serum concentrations of vitamin D have also been linked to a number of other adverse health and lifestyle factors, it is important to investigate in more detail how 25(OH)D and also seasonality are associated with hormones of the HPT axis in men. Using baseline data from the European Male Ageing Study (EMAS), we aimed to determine whether 25(OH)D levels were associated with the key hormonal components of the HPT axis, to evaluate the influence of season on vitamin D and individual HPT axis hormone levels, and to investigate whether biochemical hypogonadism, based on combined T/LH levels, was associated with low vitamin D status.
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.
In univariate analyses, free T levels were lower (P=0.02) 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)=1.52, P=0.03) and secondary hypogonadism (RRR=1.16, P=0.05). Seasonal variation was only observed for 25(OH)D (P<0.001).
Secondary and compensated hypogonadism were associated with vitamin D deficiency and the clinical significance of this relationship warrants further investigation."