Prolonged effects of β-estradiol 3-benzoate on thyroid tumorigenesis in gonadectomized rats pretreated with N-bis(2-hydroxypropyl)nitrosamine

The prolonged modulatory effects of β-estradiol 3-benzoate (EB), a synthetic estrogenic compound, were investigated in a rat two-stage thyroid tumorigenesis model. One week after a single subcutaneous (s.c.) injection of N-bis(2-hydroxypropyl)nitrosamine, gonadectomized F344 rats of both sexes were s.c. implanted with fused pellets containing EB for 32 weeks. Doses of EB at 0, 0.004, 0.02 and 0.1 mg were achieved by varying the ratio of EB to cholesterol in the pellet. Major organs including the thyroid, pituitary, liver, kidneys, uterus and brain were weighed and histopathological observation was performed. Serum was assayed for triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH). Thyroid weights were increased by the EB pellet implantation in a dose-dependent manner and significantly (P<0.05) elevated in the 0.1 mg EB male group and in the 0.02 and 0.1 mg EB female groups. The EB treatments dose-dependently suppressed serum T4 levels and inversely elevated serum TSH levels in both sexes but without statistical significance in females. Histopathologically, EB increased the occurrence of thyroid proliferative lesions in males and showed a tendency for increase in females. Interestingly, the effect of EB was more intensive in males than in females, even the lowest dose inducing a follicular carcinoma in a male. These results, thus indicate the possible contribution of prolonged EB stimulation at lower doses to thyroid tumorigenesis without additional promotive condition.