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Best Abstracts: Altering the CYP19/oestrogen/GPER signalling pathway in younger patients with BPH

By Dr. Yang Yang (Beijing, CN)

Dr. Yang Yang is one of the authors of the abstract “Increased stromal components and prostatic fibrosis via altering the CYP19/Estrogen/GPER signalling in the early progression of BPH tissues of men ≤ 50 years old”, which won the third prize in the EAU20 Best Abstract Awards Non-Oncology. This article reflects its highlights.

Benign prostatic hyperplasia (BPH) is thought to occur mostly in men older than 50 years. With the increase of age, elderly men will gradually develop lower urinary tract symptoms due to BPH, and eventually develop clinically advanced BPH that requires medication and surgical intervention. Generally, this process takes about 10-20 years.

However, researchers from China, Dr. Yang and Dr. Jin, found that a small number of BPH patients show rapid clinical progression of BPH under the age of 50 and need medication or even surgical intervention.

Therefore, Dr. Yang and Dr. Jin believe that revealing the causes of early onset in these BPH patients will help to better understand the pathophysiology of BPH occurrence and development. Moreover, it can provide drug targets for individualised treatment of BPH patients.

Specific study
In this study, researchers enrolled the prostate specimens from three groups of patients: BPH patients ≤ 50 years old (defined as Early progressed BPH patients), ≥ 70 years old (defined as Elderly BPH patients) with end-stage clinical progression that need surgery treatment, and bladder cancer patients ≤ 50 years old who underwent cystoprostatectomy (Age-matched control group). They first attempted to explore the pathological characteristics of patients with early progressed BPH by comparing the pathological differences in prostate tissues among these three groups of patients. They found that the main histopathological characteristics of BPH tissues with early progressed BPH appear to be increased stromal components with higher ratios of stromal fibrosis, which was accompanied with higher myofibroblast accumulation and collagen deposition.

Difference in prostate stroma
The question is: what causes the difference in prostate stroma? Further analysis of the specimens showed that aromatase (CYP19) was highly expressed in the early progressed BPH tissues compared to the other two groups, whereas SRD5A2 and androgen receptor were weakly expressed. The results suggested that there is a switch from androgens to oestrogens in the BPH tissues with accelerated progression. Interestingly, they noticed that the early progressed BPH group had higher BMI, which is associated with high expression and activity of aromatase as well as increased circulating oestrogen levels. To clarify which type of oestrogen receptors (ERs) is involved in the oestrogen-promoted stromal cells proliferation and prostatic fibrosis of early progressed BPH patients, researchers examined the expression of three types of ERs: ERα, ERβ, and G protein-coupled oestrogen receptor (GPER) in the prostate specimens. They found that only GPER expression in early progressed BPH group was higher than in the other two BPH groups.

GPER key factor?
In vitro data also revealed that oestrogen may not function through ERα or ERβ. However, the GPER could promote prostatic stromal cells’ proliferation and fibrosis, which indicates that GPER may be a key factor for the increased stromal components and fibrosis process of prostate in accelerated clinical progressive BPH patients. By further dissecting the mechanism of prostatic fibrosis regulation by oestrogen/GPER, the authors found that oestrogen could upregulate the protein level of HIF-1α through protecting its protein stability in prostatic stromal cells, which may consequently result in the fibrosis of prostatic stromal cells.

In addition, oestrogen/GPER can also activate EGFR/ERK signalling to promote the proliferation of prostatic stromal cells. Therefore, mechanism dissection suggested the CYP19/oestrogen/GPER signalling pathway may be involved in the regulation of stromal cell proliferation and prostatic fibrosis that may accelerate the clinical progression of BPH patients.

Increased stromal components
The overall results of this study provide the description of prostatic histopathological characteristics of early progressed BPH patients. Dr. Yang and his team pointed out that the increased stromal components and prostatic fibrosis with higher myofibroblast accumulation and collagen deposition may be the key factors for the early clinical progression of BPH/LUTS. The CYP19/oestrogen/GPER pathway modulates the EGFR/ERK and HIF-1α signalling, all of which have key roles on the proliferation and fibrogenesis of prostatic stromal cells in patients with accelerated clinical progression of BPH.

“Prostatic fibrosis should be considered one of the pathobiological processes associated with accelerated clinical progression of BPH.”

Personalised medicine
It has been reported that still more than 30% of patients suffer from BPH progression after the administration of 5ARIs and α-adrenergic blockers, which are the mainstays of current medical therapy to prevent BPH progression. Therefore, the goals of BPH therapy are not only to alleviate bothersome LUTS but also to delay the clinical progression of BPH to optimize personalised management of BPH patients beyond the limitations of current medications. This study from Dr. Yang and Dr. Jin suggests that prostatic fibrosis should be considered one of the pathobiological processes associated with accelerated clinical progression of BPH, other than prostatic enlargement and smooth muscle contraction. The development of prostatic fibrosis enriches the pathophysiological mechanism of BPH/LUTS.

Moreover, the findings reported here may provide personalised medicine with therapeutic targets for stromal hyperplasia with prostatic fibrosis. In the future, antifibrotic treatment by targeting the CYP19/oestrogen/GPER signalling pathway combined with current drugs may be efficacious in delaying the progression of BPH patients with prostatic fibrosis.

Sign up now for EAU20 Virtual to attend Dr. Yang’s presentation on Saturday 18 July!