REMODELING OF HYPERPLASTIC PITUITARIES IN HYPOTHYROID ALPHA-SUBUNIT KNOCKOUT MICE AFTER THYROXINE AND 17-BETA-ESTRADIOL TREATMENT - ROLE OFAPOPTOSIS

Hyperplasia of pituitary thyrotrophs is often associated with hypothyr oidism. In this study, the effects of thyroxine and 17 beta-estradiol on thyrotroph hyperplasia was analyzed using a hypothyroid mouse model resulting from targeted disruption of the glycoprotein hormone a-subu nit (alpha SU) gene, which leads to lack of functional thyroid-stimula ting hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) and underdevelopment of the thyroid and gonads. Thyroxi ne replacement for 2 mo resulted in a decrease in the relative percent of thyrotrophs and an increase of lactotrophs and somatotrophs number s to normal values. A twofold increase in the relative percent of gona dotrophs was observed compared to wild-type mouse pituitary. Treatment for 2 mo with 17 beta-estradiol led to an increase in lactotroph numb ers to normal levels, but had no influence on thyrotroph hyperplasia. Rearrangement of the hyperplastic pituitary phenotype after hormonal r eplacement proceeded without any evidence of pituitary cell necrosis. A slight increase in apoptotic cell death was observed in hormone-trea ted pituitaries, and this was localized to TSH cells by double-labelin g experiments. Chronic thyroxine treatment resulted in increased expre ssion of Bcl-2 protein in hypertrophied pituitary cells, whereas 17 be ta-estradiol increased expression of Bad protein in prolactin cells. T hese results suggest that apoptotic cell death is involved in reversal of thyrotroph hyperplasia in the presence of thyroid hormone. Thyroxi ne and 17 beta-estradiol may influence cell death in this model by reg ulating expression of the Bcl-2 protein family in a cell-type specific manner.