Subacute toxicity of diethylstilboestrol and hexoestrol in the female rat, and the effects of clomiphene pretreatment.

ABSTRACT

Two groups, each of ten female rats, were orally dosed with the synthetic oestrogens diethylstilboestrol (DES; 6 mg/kg day) and hexoestrol (60 mg/kg/day) for 6 wk. A further group of ten animals received clomiphene citrate (2 mg/kg/day) and DES (6 mg/kg/day), while two groups, each of ten animals, acted as controls. One animal treated with DES died within the 42-day study period. Its death was associated with a bleeding disorder related to severe liver damage. The remaining treated animals showed little overt toxicity. The major haematological finding in the treated animals that survived was a moderate, stable, normocytic, normochromic anaemia. The terminal bone marrows of these animals showed a modest degree of erythroid hypoplasia. There were stimulatory and other changes in the reproductive tract and there were gains in the liver, adrenal and pituitary weights. These effects were more marked in the rats treated with hexoestrol, the gains in the relative organ weights being particularly striking liver, 51%, adrenals, 210%, uterus, 79% and pituitary, 500%. The oestrogens caused reductions in body weight (18% in both cases) and appetite, a modest degree of fatty change in the liver, and alterations in the serum proteins. The Thrombotest clotting times of the hexoestrol-treated rats were prolonged. Clomiphene citrate decreased the adverse effects of DES on appetite and body weight, and sharply decreased the gains in the pituitary and uterine weights from 243 to 80% and 59 to 14%, respectively. The toxic effects of the oestrogens in the rat were more closely related to the dose administered than to their hormonal potency. Oestrogens are less toxic to the rat than they are to the cat, dog and ferret, and the toxic effects are in many respects qualitatively different.