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Simian Virus 40 T Antigen-Induced Gonadotroph Adenomas: A Model of Human Null Cell Adenomas¹

Vollum Institute (T.R.K., K.E.G., M.J.L.), and Division of Endocrinology (K.E.G.), Oregon Health Sciences University, Portland, Oregon 97201; and Department of Pathology, Mt. Sinai Hospital (S.L.A.), Toronto, Ontario, Canada M5G 1X5

Address all correspondence and requests for reprints to: Malcolm J. Low, M.D., Ph.D., Vollum Institute, L-474, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201. E-mail: low{at}ohsu.edu

The cell of origin of human null cell pituitary adenomas is disputed. Although these tumors, by definition, do not produce any of the anterior pituitary hormones in vivo, they have been shown to express gonadotropin subunit genes, release gonadotropin hormones in vitro, and express the gonadotroph-associated transcription factor steroidogenic factor-1. However, they demonstrate variable responses to releasing hormones in vitro, raising questions about their origin from differentiated gonadotrophs or pluripotent stem cells. In this set of experiments, transgenic mice carrying a temperature-sensitive mutant (TSA58) of simian virus 40 T antigen driven by human FSHß regulatory elements were produced. These animals developed slow growing, multifocal pituitary nodules that demonstrated secretion of FSH with serum FSH levels 10-fold higher in male transgenic animals and 5-fold higher in female transgenic animals than those in nontransgenic controls. Anterior pituitary pathology progressed from diffuse gonadotroph hyperplasia to nodular adenomas with persistent, but decreasing, immunoreactivity for FSHß and LHß. Ultrastructural characteristics of the tumors were identical to those of human null cell adenomas. These results support the hypothesis that human null cell adenomas are derived from gonadotrophs and provide an animal model for further study of this disease.

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