Abstract
Epidemiologic studies revealed a context between lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and metabolic syndrome. However, molecular mechanisms underlying this relationship are largely unknown. Prostate enlargement and increased prostate smooth muscle tone are important factors in the pathophysiology of LUTS suggestive of BPH. In the present study, we studied effects of the metabolic hormone ghrelin on prostate enlargement in rats with experimentally induced BPH, growth of cultured stromal cells from human prostate (WPMY-1), and smooth muscle contraction of human prostate tissues. Ghrelin (20 nmol/kg daily, p.o., 2 weeks) increased prostate size in rats with testosterone-induced BPH. Microarray identified 114 ghrelin-upregulated genes (2-fold or more) in these prostates, with possible roles in growth, smooth muscle contraction, or metabolism. 12 genes were selected for further analyses. In human prostate tissues, mRNA levels of 11 of them correlated positively with ghrelin receptor (GHSR) expression, but only two with the degree of BPH. Accordingly, no correlation was evident between GHSR expression level and BPH in human prostate tissues. In WPMY-1 cells, the GHRS agonist MK0677 upregulated 11 of the selected genes. MK0677 induced proliferation of WPMY-1 cells, shown by EdU assay, colony formation, proliferation markers, flow cytometry, and viability. In myographic measurements, GHSR agonists enhanced contractions of human prostate strips. Together, ghrelin may aggravate prostate enlargement, stromal cell growth, and prostate smooth muscle contraction in BPH. Ghrelin may deteriorate urethral obstruction independently from BPH, qualifying the ghrelin system as an attractive new target to be tested for LUTS treatment in BPH.
Highlights
Benign prostatic hyperplasia (BPH) is commonly associated with lower urinary tract symptoms (LUTS), resulting from urethral obstruction due to prostate enlargement and increased prostate smooth muscle tone [1]
Our findings demonstrate that Growth hormone secretagogue receptor TURP (GHSR) activation promotes prostate growth and prostate smooth muscle contraction in BPH, being imparted by genomic and nongenomic GHSR effects
Ghrelin may aggravate prostate enlargement, prostate smooth muscle tone, and urethral obstruction in patients with BPH. This may take place independent from the degree of BPH, so that ghrelin may deteriorate hyperplastic growth and bladder outlet obstruction in addition to BPH, e.g., in patients with BPH and metabolic syndrome. This may represent a mechanism explaining the association of metabolic syndrome with BPH and/or LUTS, which was previously evidenced by epidemiologic studies
Summary
Benign prostatic hyperplasia (BPH) is commonly associated with lower urinary tract symptoms (LUTS), resulting from urethral obstruction due to prostate enlargement and increased prostate smooth muscle tone [1]. Treatment becomes often inevitable and is aimed (1) at improving symptoms and (2) at preventing BPH progression and complications [2]. Widespread options for medical treatment of LUTS suggestive of BPH are α1-adrenoceptor antagonists and phosphodiesterase-5 inhibitors, which may improve symptoms by inhibition of prostate smooth muscle contraction, and 5α-reductase inhibitors to reduce prostate growth [2]. Combination therapies are commonly applied to address prostate size and symptoms at once [2]. The risk of symptomatic progression can be reduced at most by 35-40% by monotherapy and by 66% by combination therapies [3]
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