Does anti-atherogenic estradiol valerate treatment cause adverse effects on liver and uterus in NZW rabbits?

The rabbit has been a widely accepted animal model for atherosclerosis research since Anitschkow first used this animal in 1913 in identifying dietary-induced hypercholesterolemia as a major risk factor for atherogenesis. Experiments with cholesterol-fed rabbits have demonstrated the beneficial effects of estrogen treatment on the development of atheroma for more than 50 y. Clinical trials have found a reduction in cardiovascular events of up to 50% in postmenopausal women receiving estrogen replacement therapy. However, metabolic conditions in rabbits, as well as physiological estrogen serum levels, differ in some aspects from those in humans. In rabbits, experimentally-induced hormone levels are about 5- to 10-fold higher than those found in untreated animals. Normal physiological estrogen levels in rabbits are not cardioprotective under dietary-induced hypercholesterolemia. We investigated whether replacement induced "hyperestrogenemia" causes adverse effects on organs other than the cardiovascular system. Twenty-nine female rabbits were divided into 4 different groups, 2 without and 2 with estrogen treatment (1 mg estradiol valerate/kg body weight/w over 12 w). Organ weights, transaminases and uterine histology were examined. In rabbits treated with estrogen, we did not see relevant adverse effects on heart, kidney and liver weights, or on liver enzymes. But there was a significant increase in spleen weights, as well as notable changes in the endometrium with moderate inflammation. These findings indicate that the dosage of estrogen commonly used for atherosclerosis research does not cause serious disorders in the major organs of cholesterol-fed rabbits.