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Dose and Time-Course Evaluation of a Redox-Based Estradiol-Chemical Delivery System for the Brain. II. Pharmacodynamic Responses

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Abstract

Clinically, brain-enhanced delivery and sustained release of estradiol (E2) are desirable for effective treatments of menopausal hot flushes and prostatic adenocarcinoma and for fertility regulation. Thus, we conducted studies to determine the dose- and time-dependent effects of a brain-enhanced estradiol-chemical delivery system (E2-CDS) on anterior pituitary hormones secretion in ovariectomized (OVX) rats. The E2-CDS has consistently demonstrated preferential retention of its intermediate metabolite (E2-Q+ ), with slow release of E2 in the brain but rapid clearance from peripheral tissues. Animals received a single iv injection of E2-CDS at doses of 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg on day 0. The responses of plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL) were then evaluated at 1, 7, 14, 21, or 28 days after drug administration. The E2-CDS caused a dose- and time-dependent suppression of LH and FSH throughout the time course studied. The maximum LH and FSH reduction occurred at 7 days postinjection. Plasma LH and FSH were significantly suppressed by 86 and 58% on day 7, respectively, and were suppressed by 35% (LH) or were at preinjection levels (FSH) at 28 days following the single injection of a 1.0-mg E2-CDS dose. An equimolar E2 dose suppressed LH and FSH by only 29 and 20% on day 7, respectively which were not significantly different from time 0 values. Plasma PRL increased significantly on day 14 with the 1.0-mg E2-CDS dose but levels returned to preinjection values by 28 days after drug administration. Lower doses of the E2-CDS did not affect PRL concentrations. Plasma GH concentrations were not altered in response to the E2-CDS at any dose or time. Also, anterior pituitary and uterine weights increased in a dose- and time-dependent manner in response to E2-CDS administration. Collectively, these data demonstrate that the E2-CDS effects on gonadotropins suppression are dose and time dependent and this duration of suppression is consistent with the long half-lives of the E2-CDS metabolites in the brain.

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Rahimy, M.H., Simpkins, J.W. & Bodor, N. Dose and Time-Course Evaluation of a Redox-Based Estradiol-Chemical Delivery System for the Brain. II. Pharmacodynamic Responses. Pharm Res 7, 1107–1112 (1990). https://doi.org/10.1023/A:1015967906433

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