Study on the mechanism that SNPs related to sex hormone metabolism regulate the imbalance of sex hormones and lead to BPH in rats

Background: Benign prostatic hyperplasia (BPH) is a common disease in middle-aged and elderly men, and its etiology is not completely clear. the dihydrotestosterone (DHT) theory is the main mechanism to promote BPH. Our previous study to find the increase of estrogen and the decrease of androgen to estrogen ratio were high-risk factors for BPH. Because aromatase inhibitors (such as anastrozole) can inhibit the conversion of androgens to estrogens, they help maintain the balance of androgens and estrogens. Due to the limitations of the effects produced by the sole use of 5α-reductase inhibitors (such as finasteride), and given that the role of estrogen in BPH has received increasing attention, at the same time, the clinical practice advocates the use of combined therapy to treat BPH. Furthermore, our previous research has shown that the single nucleotide polymorphisms (SNP) of genes related to sex hormone metabolism are correlated with BPH. Thus, it is speculated that the genetic polymorphisms may be involved in the pathogenesis of BPH by regulating the multi-level imbalance of sex hormones. Therefore, we designed this experiment with the aim of further exploring the pathogenesis of BPH and evaluating the efficacy of the combination of finasteride and anastrozole in treating BPH in rats. Materials and Methods: A total of 264 male Sprague–Dawley rats were randomly divided into a testosterone-induced BPH group and a naturally aging BPH control group. The two groups were further divided into anastrozole (A), finasteride (F), A combined with F intervention subgroup, and placebo (P) subgroup, respectively. Namely: BPH-A, BPH-F, BPH-A+F, BPH-P and Control-A, Control-F, Control-A+F, Control-P, a total of 8 subgroups, the number of each subgroup was 33. Starting from the 8th week of age, experimental intervention was carried out. 4 weeks after the intervention, and every 8 weeks after that, 3 rats were randomly selected for the experiment from each of the above 8 subgroups. According to the chronological order, 11-time points were recorded in the above 8 subgroups. The following indicators were measured and compared: prostate-related indicators including prostate weight (PW), prostate index (PI), and prostate volume (PV); sex hormone indicators including testosterone (T), including free testosterone (fT) and total testosterone (tT), dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), and estradiol (E2), and the T/E ratio; the specific prostate antigen (PSA); the biochemical analyses including fasting blood glucose (FBG), triglycerides (TG), HDL-C, and total cholesterol (TC); and the SNPs. Results: As the age of the rats increased, PW, PV, PI, E2, DHT, PSA, TG, TC, LDL-C, and FBG all showed an increasing trend, and tT, fT, T/E, and SHBG all showed an increasing and then decreasing trend, but HDL-C showed a downward trend. Compared with the placebo treatment (BPH-P and Control-P), the combination of finasteride and anastrozole (BPH-A+F and Control-A+F) had a more significant effect in reducing PW, PV, and PI, and in increasing tT, fT, T/E, and SHBG, as well as in inhibiting increase E2, DHT, PSA, TG, TC, LDL-C, and FBG, and in preventing reduction HDL-C than the use of either drug alone. Moreover, when comparing among the groups, the differences were statistically significant (all P < 0.001). In terms of SNPs, for the genotypes of rs105294130 (GG), rs105453793 (CC), rs105712404 (TT), rs105128248 (AA), rs198630901 (CC and TT) in the CYP17A1 gene, as well as for the genotypes of rs198337055 (AA), rs106952843 (AA), and rs197770329 (CC) in the CYP19A1 gene, there was a significant correlation with BPH (all P < 0.001). Conclusions: Finasteride combined with anastrozole can prevent and treat BPH in rats; The multi-factorial pathogenic factors of sex hormone imbalance (T↓, E2↑, T/E↓, DHT↑) can play a decisive role in the pathogenesis of BPH; The SNPs of genes related to sex hormone metabolism can have had a significant impact on the onset of BPH.