Disorders of peripheral formation and action in the male (androgen resistance and prostate hyperplasia), and in the female (hirsutism and acne), are associated with abnormalities in peripheral androgen formation. While it is generally agreed that dihydrotestosterone (DHT) is synthesized peripherally and is the nuclear androgen in sexual tissue, markers of these events, such as plasma DHT or even unconjugated androstanediol, have not been satisfactory. In earlier studies, we reported that androstanediol glucuronide (3 alpha diol G) in plasma was increased in a high percentage of idiopathic and PCO hirsute patients, but normal in nonhirsute PCO individuals. Likewise, levels are reduced in androgen resistance and 5 alpha reductase deficiency cases in genetic males, and the testosterone/3 alpha diol glucuronide ratio is markedly altered. Since the most efficient precursor of 3 alpha diol G is DHT, but only accounts when taken with testosterone for 1/2 of the circulating conjugate, we wish to persue the following 5 studies to explain the origin, structure, and relationship to DHT formation of androstanediol glucuronide. 1) The glucuronide could be at the 3 alpha or 17 position and this determines the metabolic pathway. The site will be determined by forming plasma 3H 3 diol G in patients after 3H DHT infusion. The compound can be isolated using extraction, derivative and HPLC techniques developed by us with P.N. Rao, PhD. Preliminary, but definite evidence, now indicates all activity is at the 17 position, confirming the use of this label in assay and kinetic studies underway. 2) Additional candidates as precursors of 3 alpha diol G are androstenedione and DHEA. The in vivo conversion of these androgen prehormones will be determined using tracer steroids under steady state conditions. 3) Another potential precursor is androsterone and its glucuronide. The conversion will be studied using specially synthesized 9,11 3H compounds. 4) A key project and concept of our work is that total body DHT formation exceeds blood production. Long-term 3H DHT infusions will be given to normal and hirsute subjects and the specific activity and production rates of DHT, 3 alpha diol, and 3 alpha diol G measured in blood and urine. A major difference from the two sites will suggest that peripheral production is not reflected in blood. 5) In collaboration with Drs. R. Lobo and R. Marrs we shall test whether skin minses and fibroblasts in culture synthesize 3 alpha diol G in vitro and whether formation parallels 5 alpha reductase activity in men, women, and in hirsute states.
| Warren, D W; Pasupuleti, V; Lu, Y et al. (1990) Tumor necrosis factor and interleukin-1 stimulate testosterone secretion in adult male rat Leydig cells in vitro. J Androl 11:353-60 |
