Clinical studies found that there was a small group of BPH patients ≤50 years old with severe LUTS that needed TURP to relieve LUTS. However, the causes of these clinical symptomatic BPH in men ≤50 years old remain unclear. Therefore, this study was designed to reveal the characteristic of these early progression BPH patients, and the mechanism was also investigated.
Prostate tissues were obtained from 3 groups of BPH patients: 1. age ≤50 years old who underwent TURP (Early-onset BPH) vs. 2. age-matched patients with bladder cancer who underwent cystoprostatectomy (age-matched control) vs. 3. age ≥70 years old who underwent TURP for symptomatic BPH (Elderly BPH). The difference of histopathology between the three groups were examined by HE staining, Masson staining, and IHC for α-SMA, collagen I, CYP19 and GPER. MTT, Q-PCR and western blot were performed to examine the cell growth and fibrosis genes with the E2 or G1 treatment in WPMY-1 cells and prostate primary stromal cells (Prsc).
The results showed that the Early-onset BPH group had larger prostate volume than the age-matched control group, but much smaller than the Elderly BPH group (Table 1). The main characteristic of histopathology in early-onset BPH tissues appeared to be increased stromal components and increased prostatic stromal fibrosis (Fig.1). IHC staining found these early-onset BPH tissues have higher expression of CYP19 and GPER in the prostate (Fig.1). Importantly, E2 could promote the proliferation and fibrosis of prostatic stromal cells via activating GPER in WPMY-1 cells and Prsc (Fig.2 and 3). Mechanism dissection revealed that E2 could function via GPER to modulate the EGFR/ERK to increase the prostatic stromal cells growth (Fig.2 and 3) and E2/GPER could induce the expression of HIF-1α which may promote the prostatic stromal fibrosis (Fig.4).
Together, results from human specimens and in vitro cell lines’ data concluded that the increased stromal components in prostate and prostatic fibrosis may play key roles for the development of the early-onset BPH that lead to the severe LUTS at a younger age than other men. Targeting this newly identified CYP19/Estrogen/GPER signaling may help us to develop a new therapy to better treat BPH patients at early age.