Abstract
Although dihydrotestosterone (DHT) is the principal androgen in the prostate, testosterone can also act as an androgen in this tissue. To determine the relative potencies of testosterone and DHT in preventing prostate regression, castrated rats were implanted for 4 d with varying doses of testosterone in the presence or absence of the 5alpha-reductase inhibitor finasteride. In the absence of finasteride, testosterone in the prostate is converted to DHT, creating an intraprostatic DHT dose response. In the presence of finasteride, this conversion is blocked, and an intraprostatic testosterone dose response is achieved. DHT was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass, a measure of epithelial cell function. The two androgens were equipotent at preventing DNA fragementation and expression of testosterone-repressed prostate message, two measures of apoptosis (cell death). The intraprostatic testosterone concentration that results from finasteride treatment in rats is sufficient to inhibit apoptosis but will not maintain normal epithelial cell activity. In conclusion, whereas DHT is more potent than testosterone at stimulating prostate epithelial cell function as measured by ductal mass, the two androgens are equipotent at preventing prostate cell death after castration. These results explain why finasteride causes prostate involution in the rat with minimal evidence of prostate cell death.
Full Text
The Full Text of this article is available as a PDF (156.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anderson K. M., Liao S. Selective retention of dihydrotestosterone by prostatic nuclei. Nature. 1968 Jul 20;219(5151):277–279. doi: 10.1038/219277a0. [DOI] [PubMed] [Google Scholar]
- Briehl M. M., Miesfeld R. L. Isolation and characterization of transcripts induced by androgen withdrawal and apoptotic cell death in the rat ventral prostate. Mol Endocrinol. 1991 Oct;5(10):1381–1388. doi: 10.1210/mend-5-10-1381. [DOI] [PubMed] [Google Scholar]
- Brodie A. M., Son C., King D. A., Meyer K. M., Inkster S. E. Lack of evidence for aromatase in human prostatic tissues: effects of 4-hydroxyandrostenedione and other inhibitors on androgen metabolism. Cancer Res. 1989 Dec 1;49(23):6551–6555. [PubMed] [Google Scholar]
- Brolin J., Skoog L., Ekman P. Immunohistochemistry and biochemistry in detection of androgen, progesterone, and estrogen receptors in benign and malignant human prostatic tissue. Prostate. 1992;20(4):281–295. doi: 10.1002/pros.2990200404. [DOI] [PubMed] [Google Scholar]
- Buttyan R., Olsson C. A., Pintar J., Chang C., Bandyk M., Ng P. Y., Sawczuk I. S. Induction of the TRPM-2 gene in cells undergoing programmed death. Mol Cell Biol. 1989 Aug;9(8):3473–3481. doi: 10.1128/mcb.9.8.3473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deslypere J. P., Young M., Wilson J. D., McPhaul M. J. Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene. Mol Cell Endocrinol. 1992 Oct;88(1-3):15–22. doi: 10.1016/0303-7207(92)90004-p. [DOI] [PubMed] [Google Scholar]
- Furuya Y., Isaacs J. T. Differential gene regulation during programmed death (apoptosis) versus proliferation of prostatic glandular cells induced by androgen manipulation. Endocrinology. 1993 Dec;133(6):2660–2666. doi: 10.1210/endo.133.6.8243289. [DOI] [PubMed] [Google Scholar]
- Grino P. B., Griffin J. E., Wilson J. D. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology. 1990 Feb;126(2):1165–1172. doi: 10.1210/endo-126-2-1165. [DOI] [PubMed] [Google Scholar]
- Imperato-McGinley J., Gautier T., Zirinsky K., Hom T., Palomo O., Stein E., Vaughan E. D., Markisz J. A., Ramirez de Arellano E., Kazam E. Prostate visualization studies in males homozygous and heterozygous for 5 alpha-reductase deficiency. J Clin Endocrinol Metab. 1992 Oct;75(4):1022–1026. doi: 10.1210/jcem.75.4.1400866. [DOI] [PubMed] [Google Scholar]
- Jung-Testas I., Groyer M. T., Bruner-Lorand J., Hechter O., Baulieu E. E., Robel P. Androgen and estrogen receptors in rat ventral prostate epithelium and stroma. Endocrinology. 1981 Oct;109(4):1287–1289. doi: 10.1210/endo-109-4-1287. [DOI] [PubMed] [Google Scholar]
- Kuiper G. G., Enmark E., Pelto-Huikko M., Nilsson S., Gustafsson J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5925–5930. doi: 10.1073/pnas.93.12.5925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kyprianou N., Isaacs J. T. Biological significance of measurable androgen levels in the rat ventral prostate following castration. Prostate. 1987;10(4):313–324. doi: 10.1002/pros.2990100405. [DOI] [PubMed] [Google Scholar]
- Kyprianou N., Isaacs J. T. Quantal relationship between prostatic dihydrotestosterone and prostatic cell content: critical threshold concept. Prostate. 1987;11(1):41–50. doi: 10.1002/pros.2990110106. [DOI] [PubMed] [Google Scholar]
- Lamb J. C., English H., Levandoski P. L., Rhodes G. R., Johnson R. K., Isaacs J. T. Prostatic involution in rats induced by a novel 5 alpha-reductase inhibitor, SK&F 105657: role for testosterone in the androgenic response. Endocrinology. 1992 Feb;130(2):685–694. doi: 10.1210/endo.130.2.1733716. [DOI] [PubMed] [Google Scholar]
- Léger J. G., Montpetit M. L., Tenniswood M. P. Characterization and cloning of androgen-repressed mRNAs from rat ventral prostate. Biochem Biophys Res Commun. 1987 Aug 31;147(1):196–203. doi: 10.1016/s0006-291x(87)80106-7. [DOI] [PubMed] [Google Scholar]
- Matzkin H., Soloway M. S. Immunohistochemical evidence of the existence and localization of aromatase in human prostatic tissues. Prostate. 1992;21(4):309–314. doi: 10.1002/pros.2990210407. [DOI] [PubMed] [Google Scholar]
- Oesterling J. E., Juniewicz P. E., Walters J. R., Strandberg J. D., Steele R. E., Ewing L. L., Coffey D. S. Aromatase inhibition in the dog. II. Effect on growth, function, and pathology of the prostate. J Urol. 1988 Apr;139(4):832–839. doi: 10.1016/s0022-5347(17)42657-7. [DOI] [PubMed] [Google Scholar]
- Rittmaster R. S., Magor K. E., Manning A. P., Norman R. W., Lazier C. B. Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate. Mol Endocrinol. 1991 Jul;5(7):1023–1029. doi: 10.1210/mend-5-7-1023. [DOI] [PubMed] [Google Scholar]
- Rittmaster R. S., Manning A. P., Wright A. S., Thomas L. N., Whitefield S., Norman R. W., Lazier C. B., Rowden G. Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5 alpha-reductase inhibitor finasteride. Endocrinology. 1995 Feb;136(2):741–748. doi: 10.1210/endo.136.2.7835306. [DOI] [PubMed] [Google Scholar]
- Russo P., Warner J. A., Huryk R., Perez G., Heston W. D. TRPM-2 gene expression in normal rat ventral prostate following castration and exposure to diethylstilbestrol, flutamide, MK-906 (finasteride), and coumarin. Prostate. 1994 May;24(5):237–243. doi: 10.1002/pros.2990240504. [DOI] [PubMed] [Google Scholar]
- Schulze H., Claus S. Histological localization of estrogen receptors in normal and diseased human prostates by immunocytochemistry. Prostate. 1990;16(4):331–343. doi: 10.1002/pros.2990160408. [DOI] [PubMed] [Google Scholar]
- Schweikert H. U., Tunn U. W., Habenicht U. F., Arnold J., Senge T., Schulze H., Schröder F. H., Blom J. H., Ennemoser O., Horniger W. Effects of estrogen deprivation on human benign prostatic hyperplasia. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):573–576. doi: 10.1016/0960-0760(93)90261-t. [DOI] [PubMed] [Google Scholar]
- Shao T. C., Kong A., Marafelia P., Cunningham G. R. Effects of finasteride on the rat ventral prostate. J Androl. 1993 Mar-Apr;14(2):79–86. [PubMed] [Google Scholar]
- Wilson J. D., Griffin J. E., Russell D. W. Steroid 5 alpha-reductase 2 deficiency. Endocr Rev. 1993 Oct;14(5):577–593. doi: 10.1210/edrv-14-5-577. [DOI] [PubMed] [Google Scholar]
- Zhou Z. X., Lane M. V., Kemppainen J. A., French F. S., Wilson E. M. Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol. 1995 Feb;9(2):208–218. doi: 10.1210/mend.9.2.7776971. [DOI] [PubMed] [Google Scholar]