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The Effects of a Brain-Enhanced Estradiol Delivery System on Testosterone and Androgen-Dependent Tissues. I. Dose-Response and Time-Course Evaluation

Center for Drug Discovery, and the Department of Pharnacidynamics, University of Florida College of Pharmacy Gainesville, Florida 32610
Center for Drug Discovery and Pharmatec, Inc. Alachua, Florida 32615
Center for Drug Discovery, University of Florida College of Pharmacy Gainesville, Florida 32610

Address all correspondence and requests for reprints to: James W. Simpkins, Department of Pharmacodynamics, Box J-487, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610.

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. 17β-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 17β-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, 17β-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 17β-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 17β-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.

Received January 14, 1991.