The effect of steroid hormones on the growth pattern and RNA synthesis in human benign prostatic hyperplasia in organ culture

Abstract

Summary.-The effect of testosterone, dihydrotestosterone, 3p-androstanediol and oestradiol-17p on the morphology and RNA synthesis in human benign prostatic hyperplasia (BPH) in organ culture has been investigated. In hormone treated and untreated explants alike, the epithelium multiplied to form several layers. This effect was most marked after exposure to dihydrotestosterone. In explants grown in non-supplemented medium the epithelium showed some squamous changes; testosterone or dihydrotestosterone preserved the secretory character of the epithelium while oestradiol-17p caused cellular degeneration. IThe incorporation of 3H-uridine into RNA was studied by autoradiography. In the epithelium, testosterone or dihydrotestosterone raised the uptake significantly over that measured in the control explants, oestradiol-17p reduced itwhile3p-androstanediol produced similar values to those found in the control explants. The incorporation of 3H-uridine in the smooth muscle cells was increased by testosterone and decreased by oestradiol-17p. A comparison with normal rat prostatic epithelium in organ culture showed that in the absence of androgens the incorporation of 3H-uridine was lower than in BPH and the effect of testosterone correspondingly greater.The results suggest that although the growth of human BPH in organ culture appears to be androgen dependent, it still remains hormone sensitive and can be influenced by steroid hormones in a similar manner to that in rat prostate gland. They further show that the smooth muscle of the stroma is also hormone sensitive, a point which should be considered in the hormonal management of benign prostatic hyperplasia.THE USE of organ culture for the evaluation of hormonal effects on human benign prostatic hyperplasia (BPH) has obvious advantages. In this system, the various components, their anatomical relationship and function are, under suitable conditions, preserved in vitro and the action of hormones can be assessed on several parameters such as proliferation as well as cell differentiation and the effects on epithelium and stroma studied separately. Schrodt and Foreman (1971) explanted human BPH in organ culture and found that the prostatic * Sir Halley Stewart Fellow. epithelium and its fine structure were well preserved in the absence of androgens but showed somne evidence of squamous metaplasia; the addition of testosterone caused much epithelial necrosis. MacMahon and Thomas (1973), using the same system also obtained good maintenance in androgen-free medium and showed that neither testosterone nor stilboestrol diphosphate altered the morphology of the epithelium. McRae et al. (1973) used DNA synthesis as a criterion of hormonal action and reported a slight increase in DNA synthesis in

Biochemical Investigations of Separated Epithelium and Stroma From Benign Hyperplastic Prostatic Tissue

“…The occurrence of an active 5a-reductase in human prostatic stroma might be taken as evidence that this tissue, has the capacity "to respond to androgens. Pertinent here are the observations of Lasnitzki, Whitaker <& Withycombe (1975) who showed by autoradiography that androgens stimulate RNA synthesis in smooth muscle cells of prostatic expiants in organ culture. Whether the 5a-reductase activity observed by us is confined to smooth muscle cells or also occurs in the fibroblasts of the stroma is not known.…”

The Influence of Oestradiol on the Metabolism of Androgens by Human Prostatic Tissue

“…The androstanediols have a lesser effect on growth (Lasnitzki, 1975;Lasnitzki et al 1975) and it is unlikely that the increase in the formation of the androstanediols would compensate for the decrease in DHT. The effect of oestrogen therapy on androgen metabolism in the prostate may therefore be less relevant than the fall in serum testosterone unless it is com¬ bined with orchidectomy.…”

“…The presence of specific, high-affinity, protein receptors for DHT in normal and hyperplastic tissue (Mainwaring & Milroy, 1973) and the ability of the DHT-receptor complex to bind to chromatin suggest strongly that DHT is the principal active androgen in man. DHT is also more effective than testosterone in enhancing RNA synthesis in hyper¬ plastic human prostatic tissue (Lasnitzki, Whitaker & Withycombe, 1975). Alteration in the metabolism of testosterone and androstenedione to DHT and other metabolites could influence the growth of the prostate and play a role in the genesis of both benign hyperplasia and carcinomas.…”

Androgen Binding in Cytosols and Nuclei of Human Benign Hyperplastic Prostatic Tissue

“…This is suggested by the requirement for functioning testes for the development of BPH (Mostofi, 1970), the clinical response of BPH to anti-androgen therapy (Scott, 1971) and the fact that testosterone is required for the maintenance of functional and structural integrity in BPH tissue expiants cultured in vitro (Lasnitzki, Whitaker & Withycombe, 1975). It is generally accepted that these responses to androgenic steroids are mediated by an androgen-specific intracellular receptor system ; this type of mechanism has been charac¬ terized to a considerable extent in the prostate gland of the rat (Mainwaring, 1977).…”