Benign prostatic hyperplasia (BPH) is the most common nonmalignant disease in men over 40 years of age of all races and cultures. BPH is the enlargement of the prostate as a consequence of the overproliferation of stromal and glandular elements. The etiology and natural history of BPH, however, remain obscure. Numerous studies support the role of aging, hormones, peptide growth factors, and genetic mutations in the onset and pathogenesis of BPH. Based on both current experimental and clinical data, a unifying hypothesis for the etiology of BPH was proposed: The initial stimulus for aberrant growth occurs when the epithelial or stromal cell has reached a critical threshold of accumulated genetic mutational events with aging and reverts to an embryonic clone. Under the permissive effects of androgen and estrogens, the embryonic clone acquires autonomous growth by the abnormal secretion peptide growth factors. Peptide growth factors directly mediate the epithelial and stromal interactions responsible for Phase I, the induction and maintenance of the BPH nodule. Androgens and estrogens probably play a more important role in Phase II, the diffuse acceleration of BPH nodular growth in later life. This working hypothesis will be tested in the chimpanzee, man's closest primate relative who shares 98% DNA sequence homology with humans, and like man develops spontaneous BPH, through the following Specific Aims: 1) To characterize Phase I and Phase II spontaneous BPH by cross sectional analysis of an aging chimpanzee colony; 2) To characterize Phase I and Phase II spontaneous BPH by longitudinal analysis of an aging chimpanzee colony; and 3) To determine the relationship of androgens and estrogens to peptide growth factors by experimentally inducing BPH in the chimpanzee by hormonal manipulation. The hypothesis that androgens and estrogens are permissive and that peptide growth factors are directly responsible for the abnormal epithelial and stromal interactions responsible for BPH will be tested in the aging chimpanzee by minimally invasive, survival approaches. More specifically, both the temporal and spatial expression of peptide growth factors[Transforming growth factor a (TGFa), Transforming growth factor b (TGFb) and basic fibroblast growth factor (bFGF)] and their receptors [Epidermal growth factor receptor (EGFR) and TGFb receptor type I and type II (TGFb RI and RII)] and their relationship to androgens (testosterone) and estrogens (estradiol and estrone) should provide important clues about the etiology and natural history of BPH. More importantly, these studies may hold future promise by serving as a basis to determine whether spontaneous BPH in the nonhuman primate may be modified by preventable or therapeutic manipulation which can be later applied to BPH in man.
| Steiner, M S; Couch, R C; Raghow, S et al. (1999) The chimpanzee as a model of human benign prostatic hyperplasia. J Urol 162:1454-61 |
