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Thyroid Hormone-Responsive Pituitary Hyperplasia Independent of Somatostatin Receptor 2

Department of Human Genetics (M.L.B., J.H.S., S.K.K., S.A.C.), Departments of Radiology and Biological Chemistry (B.D.R.), University of Michigan, Ann Arbor, Michigan 48109; Division of Endocrinology, Metabolism, and Diabetes (D.G., V.D.S., J.M.D., E.C.R.), University of Colorado Health Sciences Center, Denver, Colorado 80262; and Division of Anatomic Pathology (R.V.L.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. Sally Camper, Department of Human Genetics, University of Michigan Medical School, 1500 West Medical Center Drive, 4301 MSRB III, Ann Arbor, Michigan 48109-0638.

Mice homozygous for the targeted disruption of the glycoprotein hormone -subunit (Gsu) display hypertrophy and hyperplasia of the anterior pituitary thyrotropes. Thyrotrope hyperplasia results in tumors in aged Gsu^-/- mice. These adenomatous pituitaries can grow independently as intrascapular transplants in hypothyroid mice, suggesting that they have progressed beyond simple hyperplasia. We used magnetic resonance imaging to follow the growth and regression of thyrotrope adenomatous hyperplasia in response to thyroid hormone treatment and discovered that the tumors retain thyroid hormone responsiveness. Somatostatin (SMST) and its diverse receptors have been implicated in cell proliferation and tumorigenesis. To test the involvement of SMST receptor 2 (SMSTR2) in pituitary tumor progression and thyroid hormone responsiveness in Gsu^-/- mutants, we generated Smstr2^-/-, Gsu^-/- mice. Smstr2^-/-, Gsu^-/- mice develop hyperplasia of thyrotropes, similar to Gsu^-/- mutants, demonstrating that SMSTR2 is dispensable for the development of pituitary adenomatous hyperplasia. Thyrotrope hyperplasia in Smstr2^-/-, Gsu^-/- mice regresses in response to T₄ treatment, suggesting that SMSTR2 is not required in the T₄ feedback loop regulating TSH secretion.