Effects of a brain-enhanced estrogen delivery system on tail-skin temperature of the rat: implications for menopausal...

The menopause results from the decreasing production of ovarian estrogens/progestins. This loss of ovarian hormones in 75-85% of women leads to a number of brain-mediated steroid-withdrawal symptoms, the most frequent being hot flushes. Thus, replacement therapy with a brain-enhanced estrogen delivery system (E2-CDS) with sustained release of estradiol (E2) in the brain may be more effective in the treatment of menopausal symptoms than currently used estrogens. The present study was designed to evaluate the effects of E2-CDS vs. E2, on the tail-skin temperature (TST) surge associated with administration of naloxone to morphine-dependent rats, an animal model for menopausal hot flush. Ovariectomized rats received a single or multiple doses of E2-CDS at 1.0 mg/kg body weight or E2 (0.5 mg pellet) weekly for 1 or 3 weeks before temperature recording. The mean maximal elevation in TST of the control animals was 6.4 +/- 0.2 degrees C. A single injection of E2-CDS attenuated the naloxone-induced rise in TST by 25%, while multiple injections resulted in significant attenuation of the rise in TST (3.4 +/- 0.6). By contrast, multiple implants of E2 pellet (3 pellets over 3 weeks) did not affect the surge of TST. Plasma E2 levels in animals treated with E2-CDS were slightly increased to 13 pg/ml for single-injected and to 44 pg/ml for multiple-injected rats. However, the E2-pellet treatment produced plasma E2 levels that were 2-fold greater than the E2 levels produced by multiple injections of E2-CDS. Plasma gonadotropins (LH and FSH) were significantly suppressed with the E2-pellet as well as the single and multiple E2-CDS treatment. Plasma prolactin levels were significantly elevated by E2 pellet and multiple injections of E2-CDS. The kinetic profiles of E2-CDS metabolites in plasma indicated an apparent t1/2 = 8 h for E2-Q+ and 3 h for E2. Collectively, these data support the view that E2-CDS may be potentially useful in the treatment of vasomotor hot flushes.