Preclinical therapy of benign prostatic hyperplasia with neuropeptide hormone antagonists

Abstract

Benign prostatic hyperplasia (BPH) is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells. BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes. Current medical therapies mostly consist of inhibitors of 5α-reductase or α₁-adrenergic blockers; their efficacy is often insufficient. Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH. At first, antagonists of luteinizing hormone-releasing hormone (LHRH) have been introduced to the therapy aimed to reduce serum testosterone levels. However, they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects. Since then, several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH. In contrast, antagonists of growth hormone-releasing hormone (GHRH) and gastrin-releasing peptide (GRP) have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH. They act at least in part, by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate, and by inhibition of autocrine insulin-like growth factors-I/II and epidermal growth factor production. GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone. This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH, GHRH and GRP in BPH, as well as suggesting a potential role for somatostatin analogs in experimental therapies.

Keywords: Benign prostatic hyperplasia; Luteinizing hormone-releasing hormone; Growth hormone-releasing hormone; Gastrin-releasing peptide; Somatostatin; Targeted therapy

Core tip: A new, effective treatment for benign prostatic hyperplasia (BPH) is critically needed. Present side effects of therapy include impotence, decreased libido, abnormal ejaculation, dizziness, weakness, blurred vision and insomnia. Preclinical data suggest that antagonists of neuropeptides growth hormone-releasing hormone, luteinizing hormone-releasing hormone and gastrin-releasing peptide are effective in shrinking prostates in part by suppressing growth factors and inflammatory cytokines. Their effect is exerted through a decrease in levels of circulating hormones and also on a direct action on their respective prostatic receptors. These analogs seem to have the same clinical effects as the currently available BPH medical therapies but possess greater efficacy and have fewer or no side effects.