title: The effects of a brain-enhanced estradiol delivery system on testosterone and androgen-dependent tissues. I. Dose-response and time-course evaluation.
abstract: The primary objective underlying hormone treatment of prostatic adenocarcinoma is to induce an effective androgen deprivation, and high dose estrogen therapy is as effective as surgical castration in abolishing the growth-promoting effects of androgens on prostatic tissue. An estradiol-chemical delivery system (E2-CDS), with sustained release of E2 in the brain, may be potentially useful in the treatment of prostatic cancer by virtue of the need for lower or less frequent doses of the estrogen. In this study we evaluated the dose- and time-dependent effects of the E2-CDS vs. 17 beta-E2 on serum testosterone (T) and weights of androgen-dependent tissues in male rats. Rats received a single iv injection of E2-CDS (0.1, 0.5, or 1.0 mg/kg), equimolar doses of 17 beta-E2, or the drug's vehicle. Sera and tissues were collected 1, 7, 14, or 21 days later for determination of hormone levels and tissue weights. The E2-CDS exhibited a dose- and time-dependent suppression of serum T and weights of the ventral prostate and seminal vesicles. In contrast, 17 beta-E2 had no significant effect on serum T or growth of these androgen-dependent tissues. Serum T levels were significantly reduced by 98%, 82%, and 59% at 1, 7, and 14 days, respectively, with the 1.0 mg/kg dose of E2-CDS. The E2-CDS significantly reduced prostate weight by 45% and 50% (1.0- and 0.5-mg/kg doses, respectively) 7 days and by 27% (0.5 mg/kg dose) 14 days after treatment. Similarly, seminal vesicle weights were reduced by 14-20% on day 1, maximally reduced by 39-48% on day 7, and still reduced by 24-36% on day 14 compared with the control levels. Weights of these tissues returned to control levels by day 21. Serum E2 was elevated through 7 days by E2-CDS or on day 1 only by 17 beta-E2. PRL secretion was stimulated for 1 week by both forms of estrogen. Anterior pituitary weights were increased by the E2-CDS through 14 days, while 17 beta-E2 had no significant effect. These data indicate that the E2-CDS causes chronic suppression of serum T, which subsequently results in regression of androgen-dependent tissue weight.
authors.affiliation: Center for Drug Discovery University of Florida College of Pharmacy, Gainesville 32610.
authors.forename: M H
authors.initials: MH
authors.lastname: Rahimy
authors.forename: W R
authors.initials: WR
authors.lastname: Anderson
authors.forename: M E
authors.initials: ME
authors.lastname: Brewster
authors.forename: N
authors.initials: N
authors.lastname: Bodor
authors.forename: J W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001812:Blood-Brain Barrier; D003505:Cyclodextrins; D004095:Dihydropyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010903:Pituitary Gland, Anterior / Q000033:anatomy & histology; D011388:Prolactin / Q000378:metabolism; D011467:Prostate / Q000033:anatomy & histology* / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012669:Seminal Vesicles / Q000033:anatomy & histology* / Q000187:drug effects; D013739:Testosterone / Q000097:blood*; D047392:beta-Cyclodextrins
chemical_list: D003505:Cyclodextrins; D004095:Dihydropyridines; D004337:Drug Carriers; D047392:beta-Cyclodextrins; C051867:estradiol 17-dihydrotrigonelline; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D013739:Testosterone; D004958:Estradiol; D011388:Prolactin