Androgenic to Estrogenic Switch in the Prostate Gland of Overweight Patients
Zongwei Wang, PhD1, Libing Hu, MD1; Shulin Wu, MD1; Shahin Tabetabaei, MD1; Chin-Lee Wu, MD1; Aria F. Olumi, MD2
1Massachusetts General Hospital, Boston, MA; 2Beth Israel Deaconess Medical Center, Boston, MA
Background: The steroid 5-α reductase type 2 (SRD5A2) is critical for prostatic development and growth. Strategies to block SRD5A2 using 5-alpha reductase inhibitors (5ARI) remain a mainstay in the treatment of benign prostatic hyperplasia (BPH). However, one-third of men are resistant to 5ARI therapies. We previously showed that body mass index (BMI) correlates with increased SRD5A2 gene promoter methylation and decreased protein expression in men with symptomatic BPH. We have demonstrated that there is an "androgenic to estrogenic switch" when SRD5A2 is absent in the prostate gland. Here we wished to identify whether BMI is associated with the androgenic to estrogenic switch in human prostate tissue. METHODS: Prostate specimens were collected from 35 patients who underwent transurethral resection of the prostate for symptomatic BPH at Massachusetts General Hospital. Medical records were reviewed to retrospectively collect clinical and pathological data. Patients were categorized by BMI as lean (less than 25 kg/m2), and overweight (25 kg/m2 or greater). Use and duration of alpha-blockers and/or 5ARIs was assessed. Methylation of SRD5A2 promoter was assessed using Methylated CpG Island Recovery Assay (MIRA). Prostatic levels of testosterone, dihydrotestosterone and estradiol were measured by HPLC-MS. RESULTS: We found that BMI was significantly correlated with methylation of SRD5A2 gene promoter (p<0.05) and absence of SRD5A2 protein expression. Higher BMI was associated with higher prostatic estradiol levels (p<0.05). IIEF-5 score, International Index of Erectile Function Questionnaire score, was negatively associated with BMI (p<0.05). Treatment with 5ARIs dramatically increased the level of prostate testosterone levels and testosterone/estradiol ratio in the prostate specimens (p<0.01, p=0.01, respectively), and decreased the level of dihydrotestosterone (p<0.05). CONCLUSIONS: Our study demonstrates for the first time that there is an androgenic to estrogenic switch in the prostate glands of overweight patients. Associated with body weight, somatic epigenetic silencing of SRD5A2 changes the prostatic hormonal milieu, and may modulate prostatic homeostasis and growth. Targeting the estrogenic signaling may serve as an effective treatment strategy in subset of patients with increased BMI.
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