Nelson Vergel
Founder, ExcelMale.com
J Clin Endocrinol Metab. 1998 Aug;83(8):2749-57.
Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men--a clinical research center study.
Wang C1, Iranmanesh A, Berman N, McDonald V, Steiner B, Ziel F, Faulkner SM, Dudley RE, Veldhuis JD, Swerdloff RS.
Abstract
Twenty-five men, 60-80 yr old, participated in a pharmacokinetic study to compare three doses (16, 32, and 64 mg/day, n = 8 or 9 in each group) of 5alpha-dihydrotestosterone (DHT) gel (0.7% hydroalcoholic gel with 2.3 g gel delivering 16 mg DHT) applied daily over one upper arm (16 mg); both arms and shoulders (32 mg); and bilateral arms, shoulders, and upper abdomen (64 mg), respectively. Multiple blood samples for the pharmacokinetic profile for DHT and testosterone (T) were drawn over a 24-h period before application, after first application, and after 14 days of daily application of DHT gel. Additional blood samples for DHT, T, and estradiol were obtained 24 h after application on days 3, 5, 7, and 11 and after discontinuation of DHT gel for 3, 5, 7, and 14 days (days 17, 19, 21, and 28 after first instituting treatment). No skin irritation was observed in any of the subjects. Before treatment, mean serum DHT and T levels were not different among the three dose groups. The serum DHT levels increased gradually after gel application on the first day, reaching a plateau between 12-18 h. During the 14 days of daily application of DHT gel, the mean baseline DHT levels reached steady state by day 2 or 3 and were elevated considerably above baseline. Mean serum DHT levels varied between 8-11, 12-17, and 14-24 nmol/L in the 16-, 32-, and 64-mg groups, respectively. The area under curve (AUC) of serum DHT levels over 24 h on day 14 were 6.0-, 6.9-, and 16.1-fold above pretreatment levels for the three doses. Concomitant with the increase in serum DHT levels, the AUC produced by endogenous serum T levels decreased to 75, 56, and 36% of baseline after 14 days of 16, 32, and 64 mg/day DHT gel. Similar patterns of decreases in AUC of serum estradiol levels were found. The calculated mean total androgen levels (T + DHT) rose with DHT gel application in all groups (P < 0.0001) on both days 1 and 14. We conclude that the three doses of DHT gel tested might provide adequate androgen replacement in hypogonadal men at the low, middle, and high physiological androgen (T + DHT) range.
J Clin Invest. 1984 Dec;74(6):2272-8.
Antiestrogenic action of dihydrotestosterone in mouse breast. Competition with estradiol for binding to the estrogen receptor.
Casey RW, Wilson JD.
Abstract
Feminization in men occurs when the effective ratio of androgen to estrogen is lowered. Since sufficient estrogen is produced in normal men to induce breast enlargement in the absence of adequate amounts of circulating androgens, it has been generally assumed that androgens exert an antiestrogenic action to prevent feminization in normal men. We examined the mechanisms of this effect of androgens in the mouse breast. Administration of estradiol via silastic implants to castrated virgin CBA/J female mice results in a doubling in dry weight and DNA content of the breast. The effect of estradiol can be inhibited by implantation of 17 beta-hydroxy-5 alpha-androstan-3-one (dihydrotestosterone), whereas dihydrotestosterone alone had no effect on breast growth. Estradiol administration also enhances the level of progesterone receptor in mouse breast. Within 4 d of castration, the progesterone receptor virtually disappears and estradiol treatment causes a twofold increase above the level in intact animals. Dihydrotestosterone does not compete for binding to the progesterone receptor, but it does inhibit estrogen-mediated increases of progesterone receptor content of breast tissue cytosol from both control mice and mice with X-linked testicular feminization (tfm)/Y. Since tfm/Y mice lack a functional androgen receptor, we conclude that this antiestrogenic action of androgen is not mediated by the androgen receptor. Dihydrotestosterone competes with estradiol for binding to the cytosolic estrogen receptor of mouse breast, whereas 17 beta-hydroxy-5 beta-androstan-3-one (5 beta-dihydrotestosterone) neither competes for binding nor inhibits estradiol-mediated induction of the progesterone receptor. Dihydrotestosterone also promotes the translocation of estrogen receptor from cytoplasm to nucleus; the ratio of cytoplasmic-to-nuclear receptor changes from 3:1 in the castrate to 1:2 in dihydrotestosterone-treated mice. Thus, the antiestrogenic effect of androgen in mouse breast may be the result of effects of dihydrotestosterone on the estrogen receptor. If so, dihydrotestosterone performs one of its major actions independent of the androgen receptor.
