Systemic and histopathologic changes in Beagle dogs after chronic daily oral administration of synthetic (ethinyl estradiol) or natural (estradiol) estrogens, with special reference to the kidney and thyroid

ABSTRACT Four groups of 3 male and 3 female sexually mature Beagle dogs were treated daily po with either ethinyl estradiol (EE) or estradiol (E2). A fifth group of 4 males and 4 females acted as a control group. Three groups of dogs were treated with EE: One group was treated at dose levels of 2.0, 1.5, and 1.0 mg/kg for 6 mo; the other 2 groups received either 0.5 mg/kg or 1.0 mg/kg for 1 yr. The fourth group was treated with 5.0 mg/kg E2 for 1 yr. Results obtained for the clinical, hematological, and biochemical parameters and the histopathologic findings of most organs and tissues in EE- and E2-treated dogs were essentially comparable to those documented in the literature for dogs treated with synthetic or natural estrogens. Chronic treatment with EE or E2 induced similar effects, with the exception of mesothelial proliferation of the genital serosa, which was observed in EE-treated dogs only. Additional new estrogen-related findings were observed in the kidneys and thyroid glands of EE- and E2-treated dogs. Increased interstitial fibrous tissue occurred at the corticomedullary junction and in the outer cortex of the kidney. It appeared to originate primarily from the perivascular fibrous tissue of branches of the renal arteries and veins. Extension of this lesion into the renal parenchyma resulted in secondary atrophic changes of tubules and glomeruli. The treatment relationship and specific characteristics of this renal alteration differentiated it from other chronic renal interstitial and vascular diseases. Squamous metaplasia of urogenital tract epithelia, including renal cortical tubule epithelium, occurred as expected in both EE- and E2-treated dogs. Unexpectedly, squamous metaplasia of thyroid follicular epithelium also occurred. It was present in scattered follicles of both EE- and E2-treated dogs. The renal and thyroid changes did not alter clinicopathological function tests for either of these organs. These 2 new findings extend the list of estrogen-related effects in the dog.