Endocrine pathology of estrogens: species differences.

The clinical uses of estrogens are associated with serious adverse effects, so the experimental toxicology of these compounds is under continuous review. Structurally different estrogens have qualitatively similar effects in animals when given in amounts way above the rodent uterotrophic dose. Toxicity still tends, however, to be related to estrogenic potency. Carnivores are more susceptible than rodents. Changes in reproductive, mammary and endocrine tissues are consistent with hyperestrogenism. Growth rate is decreased in rats and mice, but weight gains have been reported in other species. The weights of the liver, spleen, thymus and other organs are changed. Liver damage can occur. Susceptibility declines in the order cat, ferret, rat and mouse, dog. Clotting changes seen in the rat are secondary to liver damage. Moderate doses elicit anemia in rats, but lethal bone marrow depression in dogs and ferrets. Death is associated with hemorrhage. Antiestrogens modify aspects of estrogen toxicity in the rat, but not in the ferret. The predictive value of animal studies for humans has been disappointing. Interspecies variations at the hypothalamic-pituitary axis appear to have an important bearing on the differential activities of estrogens and antiestrogens across the species.