Hormonal Imbalance in BPH Results in Disrupted Cell Death Pathways

Hormonal Imbalance in BPH Results in Disrupted Cell Death Pathways

Benign prostatic hyperplasia (BPH) has been widely linked to disturbances in apoptotic (cell death) pathways. In a recent review, Italian researchers described the apoptotic pathways that are modified in patients with BPH and the mechanisms of action used in current BPH therapies.

The review titled “Apoptotic Pathways Linked to Endocrine System as Potential Therapeutic Targets for Benign Prostatic Hyperplasia,” was published in the International Journal of Molecular Sciences.

BPH is a chronic condition that causes an increase in prostate volume, a decrease in maximum urinary flow rate, and the development of acute urinary retention. It is a common disease in older men than can result in bothersome lower urinary tract symptoms (LUTS) in association with sexual dysfunctions.

Although the specific mechanisms that lead to the smooth muscle cell and epithelial cell proliferation observed in BPH are not fully known, recent studies have suggested that chronic inflammation, deregulation of circulating hormonal levels, and abnormal tissue remodeling are common features of BHP patients that may be involved in the process.

The development and growth of the prostate is controlled by normal levels of androgens and estrogens which makes BPH often associated with a hormonal imbalance that results in the disregulation of the balance between cell growth and cell death. In fact, testosterone can increase prostate proliferation and prostate volume as well as inhibit the apoptotic pathways in the prostate cells. Similarly, the types of estrogens and estrogen receptors (ER) may influence the proliferative and apoptotic pathways in the prostate.

Bcl-2 and Bax are though to be the most important genes involved in apoptosis. While cells overexpressing Bcl-2 often undergo carcinogenesis usually associated with suppression of apoptosis, those with high levels of Bax undergo apoptosis.

Several proteins are known to modulate the ratio of Bax to Bcl-2 in BPH including TGFβ, Dkk3, and inhibitors of apoptosis proteins (IAPs) some of which might be confirmed as diagnostic markers in BPH patients.

Most patients with BPH are managed with drugs that control the increase of prostatic size and reduce the tone of smooth muscle cells. The best options in terms of effectiveness are the drugs that reduce the smooth muscle cell tone, such as α1-blockers (Uroxatral, Cardura, Flomax, and Hytrin). The observations that those drugs interfere with the apoptotic pathways suggest that targeting apoptosis pathways may be a potential approach for long-term BPH therapies.

Other conventional treatments for symptomatic BPH include 5α-reductase inhibitors (5-ARIs), the combination of α1-blockers (α1-ARAs) with 5-ARIs, or phytotherapy alternatives.

Propecia (finasteride), a selective 5-ARIs that blocks testosterone has been shown to reduce prostate size by induction of apoptosis and reducing microvessel density. Some phytotherapic compounds were also found to modulate apoptosis and inhibit 5-ARIs in the prostate cells.

NX-1207 and PRX-302 are two novel drugs currently under clinical development that were shown to activate apoptosis and show beneficial effects in BPH patients.

According to the published review: “Even if some successes in treating BPH patients with α-adrenoblockers and 5-ARIs have been achieved, the combined use of the drugs is appropriate because the differences in mechanisms of action permit both to act on the smooth muscle tissue, producing its relaxation, and to reduce the size of prostate by the induction of apoptosis, which ultimately induces the maximum therapeutic effect . . . Therefore, the development of new therapeutic approaches for BPH requires the knowledge of the molecular pathways involved both in the proliferation and in the programmed death of prostate cells.”

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