Estrogen regulation in the prostate underlies racial disparity in men with benign prostatic hyperplasia

Abstract

Lower urinary tract symptoms (LUTS), associated with benign prostatic hyperplasia (BPH), are an aging-related disease, with more than 210 million cases worldwide. Estrogen exposure and estrogen regulation have been implicated in a variety of disease processes, with estrogen receptor (ER)-α pathways associated with disease progression and ERβ pathways considered to be disease-protective through enhanced apoptosis and reduced cellular proliferation. Preclinical models of LUTS/BPH have shown that ERα activation contributes to disease initiation and progression. Self-identified African American (AA) men have a high incidence of LUTS/BPH, with increased incidence of non-surgical treatment failure, larger prostates at time of surgery, and surgery occurring at a younger age compared with self-identified European American (EA) men. While circulating estrogen levels are higher in AA individuals, regulation of ERs, particularly ERβ, in normal and LUTS/BPH human prostate has not been well characterized. In this study, we examined differences in ER expression between peripheral zone (PZ) and transition zone (TZ) prostate tissues using multiplex, multispectral imaging. Additionally, we assessed changes in ERs and steroid metabolism genes involved in ERβ signaling between normal and LUTS/BPH prostate samples. Our study revealed underlying differences in steroid metabolism gene expression between normal AA and EA prostates, which were further altered with LUTS/BPH. Importantly, the contribution of ERα to LUTS/BPH was more pronounced in EA prostate samples, whereas AA prostate samples exhibited an overall increase in the expression of both ER and estrogen metabolism-related genes. Although estrogens have also been implicated in collagen deposition in the prostate of LUTS/BPH patients, we did not observe significant differences in collagen deposition between AA and EA samples. These results suggest that racial differences in steroid hormone signaling pathways within the benign prostate represent a promising area for the development of precision-based therapies to reduce LUTS in aging men. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: BPH; ERβ signaling; LUTS; estrogen signaling; multiplex IHC; normal prostate; racial disparity.

Figure 1

Estrogen signaling pathway within the prostate. ERα activation occurs upon binding of high‐affinity ligand 17β‐estradiol. ERβ activation occurs upon binding of high‐affinity ligand 3β‐diol. AKR1C1 and CYP7B1 are integral in the metabolism of 3β‐diol from DHT. COX2 inhibits ERβ activation through the production of reactive oxygen species. Androgens are depicted in blue; estrogens are depicted in red.

Figure 2

Tissue and cellular segmentation of multiplex IHC prostate tissue. (A) Representative brightfield image of the normal transition zone (TZ) shows both glandular and stromal tissue. (B) Representative image of prostate from a benign prostatic hyperplasia (BPH) patient shows classification of glandular nodules surrounding internodule (IN) tissue. * indicates prostate nodules. (C) Representative image of BPH tissue identifying a nodule next to normal adjacent tissue. (D) Deconvolution of each fluorophore using InForm allows for the visualization of individual proteins within each tissue.

Figure 3

Estrogen signaling pathway in normal tissue differs within different zones of the prostate. (A) Stromal expression of ERα is unchanged within the transition zone (TZ), normal adjacent prostate (NAP), and internodules (IN). The expression of ERα is significantly lower than that for prostate originating from the peripheral zone (PZ). There were no significant differences in stromal ERβ, AKR1C1, CYP7B1, and COX2. (B) Epithelial expression of ERα, ERβ, and E‐cadherin is unchanged within the TZ, NAP, and IN. ERα and E‐cadherin were significantly increased in the PZ, while ERβ was significantly decreased. There were no significant differences in epithelial AKR1C1, CYP7B1, and COX2. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001; n.s., not significant.

Figure 4

Estrogen signaling pathway is different in NPT between EA and AA men. (A) Stromal ERα, ERβ, AKR1C1, and CYP7B1 are significantly increased in African American (AA) men compared with European American (EA) men. Stromal COX2 is significantly decreased in AA men. (B) Epithelial ERβ, AKR1C1, and CYP7B1 are significantly increased in AA men compared with EA men. Epithelial COX2 is significantly decreased in AA men compared with EA men. ERα and E‐cadherin are unchanged between races. *p < 0.05, **p < 0.01, ****p < 0.0001.

Figure 5

Contribution of the estrogen signaling pathway to BPH is different between races. (A) Stromal ERα is significantly increased in European American (EA) men with benign prostatic hyperplasia (BPH) compared with normal prostatic tissue (NPT). There is no significant difference in ERα expression in African American (AA) men. (B) Stromal ERβ was unchanged between NPT and BPH in EA and AA men. However, ERβ was significantly higher in AA men than in EA men in both NPT and BPH. (C) Stromal AKR1C1 was not different between NPT and BPH. AKR1C1 was significantly higher in AA NPT than in EA NPT. (D) Stromal CYP7B1 was significantly increased in BPH compared with NPT in EA men. There was no significant difference between NPT and BPH in AA men. However, AA men had significantly higher expression of stromal CYP7B1 compared with EA men. (E) Stromal COX2 was unchanged between BPH and NPT in both EA and AA men. (F) Epithelial ERα was significantly increased in BPH compared with NPT in EA men. There was no difference in AA men. (G) Epithelial ERβ showed no difference with disease in either EA or AA men. However, ERβ was significantly increased in AA NPT compared with EA NPT. (H) Epithelial AKR1C1 showed no significant difference with disease in either EA or AA men. AKR1C1 was significantly higher in AA NPT than in EA NPT. (I) Epithelial CYP7B1 was unchanged between NPT and BPH in both EA and AA men. However, AA men had significantly higher expression of epithelial CYP7B1 compared with EA men. (J) No significant difference was observed between COX2 expression between BPH and NPT in either EA or AA men. *p < 0.05, ***p < 0.001, ****p < 0.0001.

Figure 6

PSR staining assesses total collagen deposition and collagen fiber thickness. (A–D) Representative images of normal prostatic tissue (NPT) from European American (EA) men (A), benign prostatic hyperplasia (BPH) from EA men (B), NPT from African American (AA) men (C), and BPH from AA men (D), with brightfield (left) and birefringence (right). (E) Quantification of birefringent images shows a significant decrease of fibrosis within the BPH nodule but no difference in collagen thickness distribution. Collagen bundle thickness under circular polarized light ranged from green (thinnest) to yellow to orange to red (thickest). *p < 0.05.