Date of Award:

1990

Document Type:

Thesis

Degree Name:

Master of Science (MS)

Department:

Animal, Dairy, and Veterinary Sciences

Advisor/Chair:

Stanley D. Allen

Abstract

Ketoconazole is a broad-spectrum antifungal with oral activity and is documented to block steroid biosynthesis in fungi and mammals.

Estradiol-primed ovariectomized rats lose the estradiol-induced, cornified layer of the vaginal epithelium as a result of ketoconazole treatment. This effect is not explained by current knowledge of ketoconazole's mechanism of action.

Ketoconazole's effect on estradiol's binding to either receptors in target tissues (target-cell receptors) or serum-estradiol-carrying proteins in the aforementioned rats was investigated.

The uterus is responsive to estradiol treatment, which causes an increase in uterine size and weight. This tissue is a sensitive means of studying the effects of ketoconazole on target-cell estradiol receptors. Tamoxifen, documented to block the effects of estradiol by binding to target-cell estradiol receptors, was used as a control drug. Uterine weight and horn diameter were measured in estradiol-treated, ovariectomized rats after 7 days of oral, twice-a-day, drug treatment.

Ketoconazole had no effect on mean uterine weights and uterine horn diameters at any of the doses tested; however, tamoxifen at a dose of 10 mg/kg caused a significant reduction in uterine weight and horn diameter. Vaginal histopathology showed that ketoconazole and tamoxifen caused decornification.

The percentage of unbound estradiol in the serum was measured in estradiol-treated, ovariectomized rats treated with ketoconazole orally, twice-a-day for 3 days to determine the effects of ketoconazole on the serum binding of estradiol.

The results of vaginal cytology showed that ketoconazole caused normal decornification. In comparison with control animals, the results of the serum percent-unbound estradiol assays showed that ketoconazole caused a dose-related increase in the percent-unbound estradiol in the blood. The dose required to cause a 5 percent increase in serum unbound estradiol was approximately 6 times greater than the minimum dose required to cause decornification.

Ketoconazole's effects on target-cell estradiol receptors and serum estradiol-carrying proteins do not appear to have any relationship to its effects in causing vaginal decornification in this model.

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