Combined effect of terazosin and finasteride on apoptosis, cell proliferation, and transforming growth factor-beta expression in benign prostatic hyperplasia.

BACKGROUND: Medical treatment of benign prostatic hyperplasia (BPH) targets relief of symptoms by causing either relaxation of the prostatic smooth muscle with alpha1 adrenergic blockade, or shrinkage of the gland with 5alpha-reductase inhibitors. We recently demonstrated that alpha1-blockers, such as terazosin, induce apoptosis in prostatic cells. In this study, we examined the combined effect of finasteride and terazosin on the rate of apoptosis and cellular proliferation to investigate their potential synergy at the cellular level. METHODS: Prostate specimens were obtained from men who were treated with either finasteride (n = 24), terazosin (n = 42), or combination therapy (n = 10) for varying time periods (1 week to 36 months) for the relief of the symptoms of BPH. The proliferative and apoptotic indices of both stromal and epithelial prostatic cell populations were determined. Antibodies against TGF-beta1 and TbetaRII were used to examine the immunoreactivity of TGF-beta1 and TbetaRII, respectively, in all prostate tissue sections. RESULTS: The apoptotic index in both prostate cell populations was significantly higher following the combination treatment compared to terazosin or finasteride alone. There were no significant changes in the rate of cellular proliferation with any treatment. Furthermore, there was a significant increase in TGF-beta1 expression in the prostates of patients treated with terazosin or combination therapy, while there was no change in TbetaRII expression. CONCLUSIONS: These results support the concept that induction of prostate apoptosis is a potential molecular mechanism underlying the combination effect of alpha1 blockade with 5alpha-reductase inhibitors in the effective treatment of BPH. The upregulation of TGF-beta1 implies a role for this ligand as an effector of apoptosis induction in response to alpha1-blockade or finasteride therapy of BPH patients.

The cost value of medical versus surgical hormonal therapy for metastatic prostate cancer.

PURPOSE: The cost of luteinizing hormone releasing hormone analogue and antiandrogen for prostate cancer is being scrutinized by the Health Care Finance Administration and other insurers. We compared the discounted present value cost of medical hormonal therapy to that of orchiectomy as well as the value created by these treatments from the insurer and patient perspectives. MATERIALS AND METHODS: We performed a telephone survey of 42 patients receiving hormonal therapy to estimate the value created by medical versus surgical castration from the patient perspective. The cost of medical hormonal therapy was discounted back to the present value and compared with the cost of bilateral orchiectomy. RESULTS: The total cost of bilateral orchiectomy was $2,022, while the discounted present value cost using the average wholesale price for 30 months of medical hormonal therapy was $13,620. Therefore, medical hormonal therapy costs $11,598 more than orchiectomy ($13,620 - $2,022). A discounted payment of $386 per month for 30 months is necessary to recoup the $11,598 difference. All surveyed patients on medical hormonal therapy stated that avoiding orchiectomy was worth $386 per month and it was an appropriate insurer expense. If patients paid $386 per month out-of-pocket, 22 of the 42 (52%) would pay the additional monthly expense, while 20 (48%) indicated that they could not afford the additional expense. CONCLUSIONS: These results indicate that medical hormonal therapy costs significantly more than bilateral orchiectomy but creates positive value for men with prostate cancer by enabling them to avoid orchiectomy.

Alpha 1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia.

PURPOSE: Recent evidence indicated that an alpha 1 blocker, doxazosin, induces prostate apoptosis in patients with benign prostatic hyperplasia (BPH). In this study, to determine whether this apoptotic response was mediated by alpha 1 adrenoceptor-dependent mechanism or was specific to doxazosin, we examined the effect of another alpha 1 blocker, terazosin, in addition to doxazosin, on the dynamics of prostate cell growth. MATERIALS AND METHODS: Cell proliferation and apoptosis were evaluated in BPH patients, an untreated (control) group (n = 31), and men treated with terazosin (n = 42) and doxazosin (n = 61) for the relief of the obstructive symptoms. Terazosin (1 to 10 mg./day) and doxazosin (2 to 8 mg./day) treatment varied from 1 week to 3 years. Ki-67 immunostaining and the TUNEL assay were used to evaluate the proliferative and apoptotic indices, respectively, in both the epithelial and stromal components of prostate (biopsy and prostatectomy) specimens. The smooth muscle cell content of the prostatic stroma was identified on the basis of smooth muscle alpha-actin immunoreactivity. RESULTS: A significant induction of apoptosis was observed in both the prostatic epithelial and stromal cells within the first month of terazosin and doxazosin therapy, as compared with untreated controls (p < 0.05). Furthermore, the marked induction of prostatic stroma apoptosis in response to both alpha 1 adrenoceptor antagonists was paralleled by a significant decrease in the smooth muscle alpha-actin expression. This loss of prostatic smooth muscle cells correlated with morphological stromal regression (as detected by trichrome staining) and BPH symptom improvement. Neither terazosin nor doxazosin therapy resulted in significant changes in prostate cell proliferation. CONCLUSIONS: These findings demonstrate that alpha-blockers as a class may regulate prostate growth by inducing apoptosis in both the epithelial and stromal cells, with little effect on cell proliferation. Apoptosis-mediated prostate stromal regression appears as a molecular mechanism underlying the therapeutic response to alpha 1 blockade in the treatment of BPH.