Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5‐alpha reductase inhibitor treated human benign prostate hyperplasia patients

Abstract

Background The development of benign prostatic hyperplasia (BPH) and medication‐refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. Methods Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. Results BPH patients on 5‐α‐reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5‐α‐reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate‐specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha‐adrenergic receptor antagonists (α‐blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. Conclusions After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI‐induced pathway increased tissue levels of GC not seen in patients on α‐blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI‐induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5‐alpha reductase inhibitor resistance

“…11 We reported that BPH patients, who underwent surgical intervention to relieve LUTS due to failure of a 5ARI or an α-blocker plus 5ARI, had high transition zone (TZ) tissue levels of testosterone (T), low levels of tissue dihydrotestosterone (DHT), and diminished activation of the androgen receptor (AR). 12 These findings confirmed that a 5ARI continues to block androgenesis in men who fail medical therapy suggesting that the mechanism of growth is independent of AR activation. However, 5ARI treatment raised prostatic tissue levels of glucocorticoids (GC), whereas BPH patients on α-blocker or no drug showed low levels of glucocorticoids.…”

“…Since patients on a 5ARI showed elevated levels of glucocorticoids (GS) and decreased levels of dihydrotestosterone (DHT), 12 we compared the 5ARI (n = 6) and α-blocker plus 5ARI (n = 7) patients to a combined group of patients on no medical therapy (none: n = 7)…”

“…This is consistent with our report that 5ARI lowered DHT in BPH patients who fail medical therapy. 12…”

“…11 These data suggest that 5ARIs increase GC levels, which can serve as a master regulator of prostatic growth in the absence of androgens. 12 In summary, different approaches to select the number DEG by using human prostatic tissue (BPH377, BPH3377, and 5ARI363) and benign prostatic organoid culture experiments (GC359) repeatedly identified similar networks of genes. This approach of reduction analysis to limit the DEGs to central networks identified pathways showing significant linkage to transcription and chromatin remodeling that could control early development and morphogenesis pathways.…”

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

“…Compared with controls, androgen-depleted animals have lower bacterial counts and inflammation, reducing the risk of BPH development. 417,418 Recent research also suggests that BPH may be an immuneinflammatory disease. Approximately 90% of prostate immune cells are T lymphocytes, which promote the release of cytokines and growth factors.…”