br Conclusion There have been multiple clinical trials and

Conclusion There have been multiple clinical trials and pre-clinical studies that have tested the utility of 5ARIs in treating prostate disease, as summarized in Fig. 1. Inhibiting androgen action through the use of finasteride and dutasteride has been established as a valuable resource for physicians. These two inhibitors have already been proven safe and effective for treatment of LUTS and inhibiting BPH disease progression; both finasteride and dutasteride have also shown promise in preventing prostate cancer in men at risk for developing the disease. The year 2010 should be exciting, since results from three dutasteride trials will be reported. As more information becomes available regarding the mechanism(s) of action of 5ARIs at the molecular level and how a patient's genetic profile can predict drug-response, it Wortmannin synthesis is anticipated that the efficacy of 5ARIs in treating prostate disease will be enhanced.
Introduction Spontaneous pregnancy loss (miscarriage, i.e. fetal death before 22 weeks of gestation) is the most frequent adverse outcome of pregnancy (Norsker et al., 2012). According to estimates, up to 20% of pregnancies end in miscarriage during the first trimester (Zinaman et al., 1996). Miscarriages have been associated with multiple causes but, in clinical practice, they have not been identified in half of cases. While infections, chemical toxicity, endocrine disorders, maternal diseases and other factors have been considered a negative impact for embryonic development, it is clear that genetic factors play an important role in miscarriage (Garcia-Enguidanos et al., 2002; Pandey et al., 2005; Rynekrova et al., 2012). In particular, it is known that chromosomal abnormalities are the most frequent cause of miscarriage during the first trimester (50–60%); in the second trimester of pregnancy this falls to 5–15% (Simpson, 2007). In recent years there have been great efforts to investigate the role of common genetic variants in the predisposition to undergo miscarriage, such as polymorphisms of the immune system, variations in the Factor V gene, or in the MTHFR gene (Rynekrova et al., 2012). However, although sex hormones are involved in all stages of reproduction and fetal development, polymorphisms in genes involved in metabolic pathways have not been extensively studied. Thus, the relationship between fetal genetic variants and idiopathic miscarriage remains unclear (Pandey et al., 2005). There are several genetic polymorphisms directly involved with sex hormone homeostasis and whose individual contribution and interaction can cause variations in hormone balance, affecting both development and fetal viability (). Oestrogens are important for reproductive success, because they influence endometrial development as well as placental function, maturation and perfusion (Albrecht et al., 2000; Guibourdenche et al., 2009). Different polymorphisms mapping oestrogen receptor 1 gene (ESR1) have been evaluated in female patients with recurrent miscarriage, but the role of these variants in the fetus has not yet been clarified (Alessio et al., 2008; Pan et al., 2014). Recent studies have proposed the association between PvuII (rs2234693) and XbaI (rs9340799) polymorphisms in ESR1 and miscarriage in women with pregnancy loss and fetal tissues (Anousha et al., 2013; Pineda et al., 2010), respectively. This suggests that reduced oestrogen activity due to the variations in ESR1 of the fetal genome could affect fetal and placental development and stability during pregnancy. In addition, associations between polymorphisms within CYP19A1 and miscarriage have also been reported (Cupisti et al., 2009). This enzyme is found in the endoplasmic reticulum of the cell and catalyses the final steps in the biosynthesis of oestrogens. Gene polymorphisms at CYP19A1 functionally affect the aromatase activity during oestradiol conversion. This is the case with the rs4646 C-allele and rs10046 T-allele, which favour oestradiol conversion, thereby increasing oestradiol levels (Haiman et al., 2007). On the other hand, rs2236722 C-allele has been associated with a lower enzymatic activity affecting testosterone clearance to oestradiol (Nativelle-Serpentini et al., 2002).