An investigation into the link between vitamin D status, erectile dysfunction and cardiovascular risk factors in ageing men in New Zealand : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Palmerston North, New Zealand

Abstract

Background Cardiovascular disease (CVD) is the leading cause of death worldwide, particularly amongst ageing males. Prevention and/or early identification and effective intervention are essential in the fight against CVD. Erectile dysfunction (ED) is a prevalent and multi-factorial condition that is now accepted to be an early marker of subclinical CVD: the common denominator is endothelial dysfunction. Both the enzymatic capability for bioactivation of vitamin D and the vitamin D receptor (VDR) are expressed in endothelial cells and vitamin D may play a role in endothelial function. Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) concentrations ˂50 nmol/L) is a worldwide pandemic and serum 25(OH)D levels ˂75 nmol/L may result in metabolic and vascular deterioration leading to endothelial dysfunction, ED and CVD. Assessment of erectile function can be used to identify otherwise asymptomatic men at high risk of developing clinical CVD, at a time when effective intervention may prevent, delay or reverse its progression. Vitamin D status may be associated with ED and CVD risk and could help improve erectile function and vascular health. Objectives The aim of this research was to investigate the postulated link between vitamin D status, ED, and CVD risk factors. The objectives were (1) to assess the prevalence of ED (using the 5-item International Index of Erectile Function (IIEF-5)) and its associated sociodemographic, lifestyle, and medical correlates in New Zealand (NZ) men aged 40-70 years; (2) to investigate the relationship between vitamin D status (serum 25(OH)D concentration), ED and other CVD risk factors in men aged 40-70 years living in the Manawatu region of NZ; and (3) to examine the impact of common VDR gene (VDR) polymorphisms on this relationship. Method Two thousand men aged 40-70 years were randomly selected from the NZ Electoral Roll and sent an anonymous postal survey designed to assess the prevalence of ED and its sociodemographic, lifestyle, and medical risk factors. Six hundred men aged 40-70 years living in the Manawatu region were randomly selected from the NZ Electoral Roll and invited to participate in an observational study designed to provide a comprehensive health profile of self-reported healthy men and investigate the relationship between vitamin D status, ED, and a range of CVD risk factors. Eligible participants (n=100) completed a comprehensive health assessment including a medical history, anthropometric and cardiovascular assessment, fasting blood sample, computer-based questionnaire, a submaximal fitness test and a handgrip iv strength test. Blood samples were assessed for four common VDR polymorphisms (rs11568820 (Cdx2), rs10735810 (FokI), rs1544410 (BsmI) and rs731236 (TaqI)) using polymerase chain reaction-high resolution amplicon melt (PCR-HRM) analysis. Results The survey showed 38.4% of respondents presented with ED (IIEF-5 ≤21). Older age, non-European ethnicity and current smoking were significant independent predictors of an increased risk of ED, while a high household income and regular vigorous physical activity (PA) were deemed protective. The observational study showed 30 men presented with ED and a further 37 men had <75 nmol/L 25(OH)D. There was a weak positive correlation between IIEF-5 scores and 25(OH)D levels (rs=0.238, p=0.017). Men with <75 nmol/L had lower IIEF-5 scores compared to men with ≥75 nmol/L 25(OH)D (22(7) vs. 24(3), p=0.001). Men with ED had lower 25(OH)D levels compared to men without ED (74.5(34) vs. 84.5(24), p=0.062). Every 1 nmol/L of 25(OH)D predicted a 2% decrease in the age-adjusted risk of ED (age-adjusted OR=0.98 [0.96-1.00], p=0.046). The PCR-HRM analysis showed that the Cdx2, FokI and BsmI polymorphisms were all significantly associated with an adverse cardiovascular risk profile. The Cdx2 G allele was associated with lower IIEF-5 scores compared to the A allele (23(4) vs. 24(2), p=0.008) and the GA and GG genotypes were predictors of an increased age-adjusted risk of ED (age-adjusted OR=18.78 [1.98-178.60], p=0.011 and 8.53 [1.00-72.73], p=0.050 respectively). However, Cdx2 was not found to modify the age-adjusted association between 25(OH)D levels and ED (multi-adjusted OR=0.97 [0.95-1.00], p=0.032). Conclusions These results suggest that over a third of NZ men aged 40-70 years suffer from ED and it is associated with sociodemographic, lifestyle and medical factors simliar to CVD. Low serum 25(OH)D is associated with the presence and severity of ED in a self-reported healthy population. Common VDR polymorphisms are also associated with ED; however, they do not modify the association between serum 25(OH)D and ED. A randomised placebo-controlled human intervention trial is warranted to investigate whether improving vitamin D status in men with vitamin D deficiency and ED ameliorates symptoms and reduces the risk of CVD