rs G allele was previously associated with
rs523349 G allele was previously associated with a decrease in the conversion rate of testosterone to DHT (Beesley et al., 2007). This SRDA52 variant may have a trend towards higher testosterone availability, which according to the US Food and Drug Administration is described as a teratogen of category ‘X’ (reference ID: 3752414–FDA). This effect could be related to the known role of DHT around 12 weeks in fetal males, perhaps one of the keys in fetal development in the second trimester (Reyes et al., 1973). Decreased testosterone levels during fetal development, however, do not represent a known cause of compromised male or female fetal viability. Experiments administering testosterone to pregnant rats showed no effect on fetal viability, although a certain dismorphologic sign in the female fetus was observed (Wolf et al., 2002). To date, we have failed to find in the literature any correlation between low alpha 5-reductase activity and fetal development. Only one study shows that the administration of finasteride (an alpha 5-reductase inhibitor) in Macaca mulatta, apparently do not involve a decrease in fetal viability either in male or female fetuses (Prahalada et al., 1997). By contrast, our results showed a significant increase in female late miscarriage as a possible consequence of the decreased activity of DHT or the increased levels of testosterone. We suggest that the functional polymorphism in SRDA52 may exert an effect in association with other factors. In relation to this we found some indirect evidence regarding CYP19A1 and ESR1, based on their HWE disequilibrium and a detectable although non-statistically-significant overrepresentation among cases of the RTA-408 showing less oestrogen production (CYP19A1) and less oestrogenic activity (ESR1). However, due to the limitation of the population size studied we decided to be conservative and to exclude those SNPs from downstream analysis. Taking together all available data, we postulate that the final effect is due to a decrease in the oestrogenic action. Approximately 60% of the placental oestrogens come from the fetal DHEA. Oestrogens are essential for fetal adrenal gland development, the majority of which takes place during the second trimester. Although we have only obtained significant data on SRD5A2 polymorphism, which can increase the T/DHT ratio by higher testosterone levels, a decreased activity of CYP19A1 and a lower ESR1 response would lead to a diminished oestrogenic activity. This might be a plausible explanation of the observed results. Alpha 5-reductase Val89Leu mutation, or an unknown variant in complete linkage disequilibrium with it, is associated with late miscarriage.
Our data highlighted some questions that will require additional studies. For instance, is there a critical hormonal imbalance to the fetal viability? We wonder whether it is possible that the changes in the risk associated with gene variant distributions during the second trimester may be influencing hormonal disruptions affecting fetal development. Following the same idea, it would be necessary to explore whether physiological changes in the pregnant woman may be affecting the hormonal condition of the developing fetus during the second trimester (Pineda et al., 2010).
In conclusion, our results show an association between the functional polymorphism Val89Leu of the SRD5A gene, which is related to an imbalance of testosterone/dihydrotestosterone, and higher risk of miscarriage, mainly in the second trimester of pregnancy.
Acknowledgements The authors thank Traducciones HumanBioMed for help with English language editing. The present study was supported by the Ministry of Health (Spain) project number SAF 2008.
Alpha-blockers (AB) and inhibitors of 5-alpha-reductase (5-ARI) are the most commonly used pharmacological groups in the medical treatment of benign prostatic hyperplasia (BPH). On many occasions, when we prescribe these medications we forget to advise patients on the interactions of these agents with food and alcohol.