The gene SRD A encodes

The gene SRD5A2 encodes the 5-α-reductase enzyme, which converts testosterone into dihydrotestosterone. Although dihydrotestosterone levels are considerably lower than testosterone, dihydrotestosterone has a five-fold stronger binding capacity to the androgen receptor and, thereby, a considerably more potent androgenic effect. In vitro the variant Murine for SNP rs523349 is associated with decreased activity of the 5-α-reductase enzyme, thus leading to lower levels of dihydrotestosterone [21]. Compared to testosterone, the effect of dihydrotestosterone on metabolic risk factors is less well understood. In a population-based study of Yeap et al., several associations with metabolic risk factors were equal between dihydrotestosterone and testosterone, but additional distinct associations with diabetes and fasting glucose indicated an additive role of dihydrotestosterone [29]. Recently, Aschim et al. reported on several polymorphisms that modify the effect of different treatments on endocrine status [20]. They found that patients heterozygous for SNP rs9282858 in SRD5A2 had lower testosterone levels after radiotherapy compared with patients who were treated with surgery only. Because of the low numbers of patients heterozygous for this SNP rs9282858, which results in increased functionality of 5-α-reductase in in vitro studies, we could not properly analyze this in our study. SNPs in SRD5A2, in particular rs523349, have been studied extensively to determine polymorphisms that are associated with prostate cancer risk and biochemical recurrence after prostate cancer. Although individual studies have yielded conflicting results, meta-analyses point to a lack of association between rs523349 and prostate cancer risk [30]. In the urinary steroid profile analysis, we observed no differences in E/A ratio between wild type and variant genotype for rs523349. One would expect lower levels of androsterone and a relatively high E/A ratio in case of lower functionality of 5-α-reductase. E/A ratio in the normal population shows a wide variation; for men aged 17–50 years, the reference value is 0.4–1.8 [31]. Differences in functionality of 5-α-reductase are probably too subtle and not detectable by comparing the ratio of these metabolites. By using direct determination of dihydrotestosterone levels, we would have been able to get a more accurate estimate of 5-α-reductase activity. However, accurate determination of plasma dihydrotestosterone remains a technical challenge, although recently progress has been made [32], [33]. We also observed differences in vascular parameters: IMT and albumin excretion were higher in patients who were homozygous or heterozygous variant for SNP rs523349. This could indicate that patients with a variant genotype are prone to subclinical vascular damage, although the vascular changes could also be secondary to adverse metabolic changes. The vascular effects of testosterone and dihydrotestosterone are not yet fully understood. Testosterone was found to be a negative predictor of arterial stiffness and the carotid IMT, but the specific effect of dihydrotestosterone is largely unknown [15]. In conclusion, we found an association between SNP rs523349 in SRD5A2 and the metabolic syndrome, which is an important late effect of platinum-based chemotherapy. Patients homozygous or heterozygous variant for SNP rs523349 have an odds ratio of 2.56 for the metabolic syndrome after treatment for metastatic testicular cancer compared to wild-type patients. In patients with lower testosterone levels and a variant genotype for SNP rs523349, the prevalence of the metabolic syndrome is even higher. Validation of these findings is necessary, and when confirmed, these data may help to identify patients who are particularly prone to develop cardiovascular disease as a late effect of chemotherapy for testicular cancer. These patients may benefit from early intervention strategies, i.e. a physical exercise programme or testosterone supplementation. Further exploration of the role of androgens and genetic susceptibility in testicular cancer survivors is needed to facilitate these early interventions.