Pharmacological Induction of 5α-Reductase Deficiency in the Rat: Separation of Testosterone-Mediated and 5α-Dihydrotestosterone-Mediated Effects*

Abstract

(5 alpha, 20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one, a mechanism-based inhibitor of testosterone 5 alpha-reductase, produced pronounced and long lasting inhibition of the enzyme in the prostate and preputial glands when administered orally to rats. Administration of the inhibitor to castrate rats bearing testosterone implants produced inhibition of growth of the prostate, seminal vesicles,and preputial glands, but had no effect on growth of the levator ani muscle. (5 alpha-20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one did not antagonize growth of the accessory sex organs induced by 5 alpha-dihydrotestosterone (5 alpha-DHT). The inhibitor thus produced a pure 5 alpha-reductase deficiency in the rat without detectable receptor-level antagonism, and with consequences similar to those occurring at puberty in the 5 alpha-reductase-deficient human male: reduction of 5 alpha-DHT-mediated processes and maintenance of those mediated by testosterone. The results emphasize the importance of the enzymatic profiles of individual organs in determining selective response to testosterone or 5 alpha-DHT. Evidence is presented which indicates that the testes are the source of circulating 5 alpha-DHT in the immature rat.

Natural variability and the influence of concurrent control values on the detection and interpretation of low-dose or weak endocrine toxicities.

“…The assays for FIN described in this article represent a continuation of previous experiments (Ashby and Lefevre 2000;Blohm et al 1986) and studies conducted as part of the current Organisation for Economic Co-operation and Development (OECD) validation of the Hershberger assay. The OECD studies demonstrated that a dose of FIN as low as 200 µg/kg/day inhibited the growth of the seminal vesicles, ventral prostate, and glans penis of TP-treated rats (J. Ashby, unpublished data).…”

Effects of Perinatal Exposure to Flutamide on Sex Hormone Responsiveness in F1 Male Rats

“…In addition, dependent organs produce DHT themselves using testosterone derived from testis Leydig cells. According to Blohm et al (1986), administration of a 5 alfa-reductase inhibitor to castrated animals bearing testosterone implants produced growth inhibition in the prostate and seminal vesicles, but had no effect on the growth of the levator ani muscles. Furthermore, they reported the latter to exhibit a growth response to exogenous DHT.…”

Aromatase inhibition reduces dendritic growth in a sexually dimorphic rat spinal nucleus

“…However, in contrast to many other androgen-dependent tissues, BC/LA growth is preferentially sensitive to circulating testosterone, and under normal conditions exhibits little trophic response to dihydrotestosterone. Low levels of muscle 5-alpha reductase preclude local formation of dihydrotestosterone, while high levels of catabolic enzymes rapidly inactivate dihydrotestosterone derived from circulation (Mooradian et al, 1987;Blohm et al, 1986;Kumar et al, 1992). This pattern of enzymatic expression, combined with the BC/LA muscle's trophic response to androgens, permits BC/LA muscle weight to serve as an indirect but sensitive indicator of alterations in circulating testosterone.…”