Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia

Ferenc G. Rick, Andrew V Schally, Norman L Block, Mehrdad Nadji, Karoly Szepeshazi, Marta Zarandi, Irving Vidaurre, Roberto Perez, Gabor Halmos, Luca Szalontay

Research output: Contribution to journalArticle

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Abstract

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 μg/d, MIA-313 at 20 μg/d, and MIA-459 at 20 μg/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-1β, NF-κβ/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.

Original languageEnglish
Pages (from-to)3755-3760
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number9
DOIs
StatePublished - Mar 1 2011

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Growth Hormone-Releasing Hormone
Prostatic Hyperplasia
Hormone Antagonists
Prostate
Intercellular Signaling Peptides and Proteins
Cyclooxygenase 2
Interleukin-1
Genes
Testosterone
Wistar Rats
Weight Loss
Signal Transduction
Neoplasms
Prostatic Neoplasms
Animal Models
Cytokines
Weights and Measures

Keywords

  • Chronic prostatic inflammation
  • Prostatic cell death
  • Prostatic hypertrophy
  • Rodent benign prostatic hyperplasia model

ASJC Scopus subject areas

  • General

Cite this

Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. / Rick, Ferenc G.; Schally, Andrew V; Block, Norman L; Nadji, Mehrdad; Szepeshazi, Karoly; Zarandi, Marta; Vidaurre, Irving; Perez, Roberto; Halmos, Gabor; Szalontay, Luca.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 9, 01.03.2011, p. 3755-3760.

Research output: Contribution to journalArticle

Rick, Ferenc G. ; Schally, Andrew V ; Block, Norman L ; Nadji, Mehrdad ; Szepeshazi, Karoly ; Zarandi, Marta ; Vidaurre, Irving ; Perez, Roberto ; Halmos, Gabor ; Szalontay, Luca. / Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 9. pp. 3755-3760.
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abstract = "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 μg/d, MIA-313 at 20 μg/d, and MIA-459 at 20 μg/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-1β, NF-κβ/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.",
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