This application proposes to evaluate a series of novel steroid chemical delivery systems which we have shown are selectively """"""""locked-into"""""""" the central nervous system (CNS). The proposed selective CNS delivery of gonadal steroids is based upon the chemical attachment of estradiol of testosterone to the lipid soluble dihydropyridine carrier. This steroid-carrier system readily crosses the blood brain barrier (BBB) and the carrier is rapidly oxidized to the corresponding hydrophilic pyridinium salt, thus reducing its rate of egress from the CNS. The hydrolysis of the steroid from its carrier results in the sustain release of the steroid in the brain and the rapid clearance of the non-toxic carrier. Preliminary evaluations of one estradiol-chemical delivery system (E2 -CDS) resulted in a dose-dependent sustained suppression of LH in female rats and in male rats a chronic (at least 24 days) suppression of LH release following a single injection. In the present application, we proposed to evaluate both the testosterone-chemical delivery system (T-CDS) and E2- CDS for the dose-dependency and time-course of suppression LH and FSH secretion, and the corresponding levels of released testosterone or E2 in the brain and peripheral tissue. With the identification of the optimal doses and sampling times, we will assess the mechanism of action of the steroid-CDS in chronically suppressing gonadotropin release by assessing the activity of neurons which contain luteinizing hormone-releasing hormone- releasing hormone (LHRH), by determining the responsiveness of anterior pituitary gonadotrophs to LHRH, and by assessing parameters of this pulsatile release of LH. We will evaluate the capacity of brain-specific delivery of gonadal steroids to reduced endogenous steroid secretion from the ovaries and/or testes. Finally, we will evaluate the E2-CDS and the T-CDS for their efficacy in reducing the rate of growth of endometrial and prostatic tissue in animal models for endometriosis and prostatic cancer. The proposed evaluations may lead to (i) a useful tool for dissociating central from peripheral effects of gonadal steroids, (ii) a selective treatment of brain estradiol deficiencies in women with vasomotor symptoms and (iii) the selective reduction in gonadotropin secretion for fertility regulation and the treatment of peripheral steroid-dependent diseases, such as prostatic hypertrophy or cancer, as well as endometriosis.
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