Benign Prostatic Hyperplasia (BPH)

[Michael Scally MD]

Growth Hormone-Releasing Hormone (GHRH) Antagonists Reduce Prostate Size In Experimental Benign Prostatic Hyperplasia (BPH)

The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates the secretion of growth hormone (GH) from the anterior pituitary gland upon binding to its receptor (GHRH-R). In turn, GH stimulates the production of insulin-like growth factor 1 (IGF1), a major anabolic growth factor and a potent mitogen for many cancers. GHRH and its pituitary-type receptor as well as its truncated receptor splice variants (SV) are expressed in various normal human tissues including prostate, kidney, lung, and liver and on many human cancer cell lines and tumors. Pituitary-type GHRH-R and SV1 appear to mediate effects of GHRH and its antagonists on tumors. GHRH itself acts as an autocrine/paracrine growth factor in human cancers, including prostate.

To develop therapies for cancer, our laboratory has synthesized GHRH antagonists with high antiproliferative activity in numerous experimental cancer models. The inhibitory effect of these analogs is exerted in part by indirect endocrine mechanisms through the suppression of GHRH-evoked release of GH from the pituitary, which in turn results in the inhibition of the hepatic production of IGF1. Direct mechanisms involved in the main antitumor effects of GHRH antagonists appear to be based on blocking the action of autocrine GHRH on tumors and inhibition of autocrine IGF1/2. Recent studies also indicate that GHRH antagonists reduce generation of reactive oxygen species, which cause damage to prostatic stroma and epithelium. GHRH antagonists inhibit the growth of androgen-independent human prostatic cancers and also numerous other cancers xenografted into nude mice and suppress tumoral growth factors.

Benign prostatic hyperplasia (BPH) is a progressive hyperplasia of prostatic glandular and stromal tissues. BPH is an age-related disease and is present in 20% of 40-y-old men and in 70% of 60-y-old men. Currently, there is no completely effective treatment for BPH. Medical therapies consist of ?-adrenergic blockers, which lower adrenergic tone, and 5?-reductase inhibitors, which decrease levels of dihydrotestosterone (DHT). In some patients surgery, mostly transurethral resection of the prostate, is the only effective intervention.

Despite the enormous burden of BPH on public health, its pathogenesis is incompletely understood. Hyperplastic growth in BPH has been ascribed to an imbalance between androgen/estrogen signaling, tissue remodeling in the aging prostate, chronic inflammation, stem cell defects, overexpression of stromal and epithelial growth factors, hypoxia, epithelial–mesenchymal transition, and other obscure factors.

A model of BPH in male rats can be produced by repeated injections of testosterone. This model has been adapted for several studies. Because the mechanism of prostate growth is complex and heterogeneous in different species, and the testosterone-induced models of BPH show an epithelial hyperplasia, the androgen-induced models of BPH have limitations. It has been proposed that BPH is not a proliferative disease of the stroma but rather is an accumulation of mesenchymal-like cells derived from the prostatic epithelium and the endothelium. The description of human BPH as predominantly of epithelial origin supports the use of a testosterone-induced model of BPH with predominant epithelial hyperplasia.

This study estimated the therapeutic effect of the GHRH antagonists using a testosterone-induced rat model of BPH. The therapeutic effect of the 5?-reductase 2 (5AR2) inhibitor finasteride was estimated also. Researchers investigated the mechanisms of action of GHRH antagonists, including their in vivo effects on the expression levels of GHRH, GHRH-R and its splice variant SV1, 5AR2, ?1A-adrenoreceptor (?1A-AR), androgen receptor (AR), IL-1?, cyclooxygenase 2 (COX-2), and NF-?? in rat prostates. Quantitative PCR arrays for growth factors, inflammatory cytokines, and signal transduction genes were performed as well as analysis of the effect of GHRH antagonists on cell division and apoptosis.

The main finding of the study is that the GHRH antagonists reduce prostate size in an experimental model of BPH. In addition to prostate shrinkage in rats, multiple factors related to growth and inflammation, which are crucial in the pathogenesis and progression of BPH, were markedly reduced by treatment with GHRH antagonists. The antibody used to detect GHRH receptors identifies both pituitary-type GHRH-R and its splice variant SV1. Furthermore, the ligand competition assay detected specific high-affinity receptors for GHRH in rat prostate.

Changes in serum GH, IGF1, DHT, and PSA were not significant after treatment with GHRH antagonists. Recently, research showed that GHRH antagonists inhibit the proliferation of the human prostate epithelial BPH-1 cell line in vitro. These findings strongly suggest that prostate shrinkage is a result of direct inhibitory effects of GHRH antagonists exerted through prostatic GHRH receptors, not involving the GH/IGF1 axis.

The demonstration of the coexpression of GHRH and its receptors in rat prostate supports the hypothesis that GHRH produced locally in the prostate could act in an autocrine/paracrine manner through an interaction with the GHRH receptors. The presence of this pathway, which is disrupted by GHRH antagonists, provides a mechanistic explanation for the antiproliferative effects of such antagonists in prostate cell growth in culture and in nude mice xenograft models of prostate cancer. The data also imply that GHRH could be involved in the pathogenesis of BPH.


Rick FG, Schally AV, Block NL, et al. Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. Proceedings of the National Academy of Sciences 2011;108(9):3755-60. Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia

Growth hormone-releasing hormone (GHRH), a hypothalamic polypeptide, acts as a potent autocrine/paracrine growth factor in many cancers. Benign prostatic hyperplasia (BPH) is a pathologic proliferation of prostatic glandular and stromal tissues; a variety of growth factors and inflammatory processes are inculpated in its pathogenesis. Previously we showed that potent synthetic antagonists of GHRH strongly inhibit the growth of diverse experimental human tumors including prostate cancer by suppressing various tumoral growth factors. The influence of GHRH antagonists on animal models of BPH has not been investigated. We evaluated the effects of the GHRH antagonists JMR-132 given at doses of 40 ?g/d, MIA-313 at 20 ?g/d, and MIA-459 at 20 ?g/d in testosterone-induced BPH in Wistar rats. Reduction of prostate weights was observed after 6 wk of treatment with GHRH antagonists: a 17.8% decrease with JMR-132 treatment; a 17.0% decline with MIA-313 treatment; and a 21.4% reduction with MIA-459 treatment (P < 0.05 for all). We quantified transcript levels of genes related to growth factors, inflammatory cytokines, and signal transduction and identified significant changes in the expression of more than 80 genes (P < 0.05). Significant reductions in protein levels of IL-1?, NF-??/p65, and cyclooxygenase-2 (COX-2) also were observed after treatment with a GHRH antagonist. We conclude that GHRH antagonists can lower prostate weight in experimental BPH. This reduction is caused by the direct inhibitory effects of GHRH antagonists exerted through prostatic GHRH receptors. This study sheds light on the mechanism of action of GHRH antagonists in BPH and suggests that GHRH antagonists should be considered for further development as therapy for BPH.

 

[Michael Scally MD]

Dutasteride/Tamsulosin Fixed-Dose Combination For The Treatment Of Benign Prostatic Hyperplasia

In the CombAT (Combination of Avodart and Tamsulosin) trial a new assessment was developed and tested called the Patient's Perception of Study Medication (PPSM) which told the investigators if the patients, given free choice, would choose to take that combination of medication to treat their problem and stay on the medication. CombAT has clearly demonstrated that for the man with an enlarged prostate (>30 mL) and moderate symptom complaints, the combination of dutasteride and tamsulosin compared with monotherapy will provide the most effective and most durable long-term benefits. This was demonstrated in all parameters including symptom response, lack of progression, and the development of AUR or the need for surgery. Moreover, the combination is safe with very few significant side effects or adverse events. Finally, if given the choice a greater number of patients would choose and continue to regularly take the combination therapy over either monotherapy.


Barkin J. Review of dutasteride/tamsulosin fixed-dose combination for the treatment of benign prostatic hyperplasia: efficacy, safety, and patient acceptability. Patient Prefer Adherence 2011;5:483-90. Review of dutasteride/tamsulosin fixed-dose combination for the treatm

Lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) will usually affect older men, of whom 50% over the age 60 years and almost 90% in their nineties will be bothered enough by their symptoms that they request some type of treatment. However, symptomatic bother may also affect men in their forties with a prevalence rate of almost 18%. The International Prostate Symptom Score (IPSS) has become the most widely used and best validated questionnaire to allow the patient to quantify the severity of his LUTS/BPH symptoms. This score has become the cornerstone in demonstrating the "rate of symptom response" for the patient who has been exposed to any type BPH management. Question 8 on the IPSS score is what is defined as the "Quality of Life" question or what is also termed the "Bothersome Index." The score out of 6 as declared by the patient will reflect the degree of concern that the patient is feeling about his symptoms and the reduction of the score after treatment is a statement of their improved quality of life. There are 2 families of accepted medical therapy to treat the symptoms of BPH and potentially prevent the most worrisome long-term sequelae of progression of BPH: urinary retention or the need for surgery. When defining the impact of the main types of medical therapy, the alpha blockers have been termed the "openers" and the 5 alpha-reductase inhibitors are described as the "shrinkers." Since they each offer a different mechanism of effect, the concept of combination therapy was raised and trialed many times over recent years. The final aspect of any medical therapy is the patient's satisfaction with the treatment and the side effects. In the CombAT (Combination of Avodart and Tamsulosin) trial a new assessment was developed and tested called the Patient's Perception of Study Medication (PPSM) which told the investigators if the patients, given free choice, would choose to take that combination of medication to treat their problem and stay on the medication.

 

[Michael Scally MD]

Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms

Sarma AV, Wei JT. Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms. New England Journal of Medicine 2012;367(3):248-57. MMS: Error

Mechanisms of Action and Targets for Intervention in Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms. Lower urinary tract symptoms due to an overactive bladder, a bladder-outlet obstruction, or both may be treated pharmacologically. Selective agents have target receptors that are predominantly localized to the bladder and prostate. In contrast, nonselective agents may have more systemic effects.

 

[anonymous_475692]

so can someone with bph still take trt and cycle & what is an effective way to reduce prostate