Induction of Uterine Leiomyomas in Mice by Medroxalol and Prevention by Propranolol

Abstract

Medroxalol hydrochloride is an antihypertensive agent with β1 adrenergic cardiac blocking properties, and β2 and some α1 vasodilating activity. In previous carcinogenicity studies medroxalol was shown to induce leiomyomas of the uterus in CD-I mice but not in Long Evans rats. In addition, there was a significant increase in endometrial stromal sarcomas in mice receiving the lowest dose of medroxalol; however, the*** lack of a dose response made the relationship to treatment questionable. Because of these findings, additional 18-month drug diet studies were conducted in 3 parallel segments using female CD-1 mice to determine the effects of: 1) an expanded range of doses, 2) various durations of dosing, and 3) the effect of the β-blocker, propranolol, on leiomyoma induction. These studies confirmed the fact that chronic dietary treatment with medroxalol can lead to an increased incidence of leiomyomas in the mouse uterus, but failed to demonstrate any relationship between endometrial stromal sarcomas and medroxalol administration. A linear trend occurred in the incidence of leiomyomas and of smooth muscle hypertrophy/hyperplasia, a possible precursor to leiomyoma. Both findings were notably increased at 250 mg/kg/day or more. Doses of 50 mg/kg/day or less were considered no effect levels. At 500 mg/kg/day a treatment period of 12 months or more was required before a noticeable increase in leiomyomas occurred in mice examined after 18 months. The β-blocker, propranolol, prevented this increase in leiomyomas, and led to the conclusion that the β2 agonist activity of medroxalol was involved in their induction. Propranolol did not block the spontaneous occurrence of these tumors.