Expression of the Pituitary Transcription Factor Ptx-1, But Not That of the Trans-Activating Factor Prop-1, Is Reduced in Human Corticotroph Adenomas and Is Associated with Decreased a-Subunit Secretion*

We have studied the expression of the pituitary transcription factors Ptx-1 and Prop-1 in a series of 34 pituitary adenomas fully characterized for in vitro hormone secretion and histological staining. In studies involving mammalian cell lines, the pituitary transcription factor Ptx-1 has been shown to be a pituitary hormone panactivator, whereas more recent studies have shown that it plays an important role in a-subunit gene expression. Its expression has not been examined previously in human pituitary adenomas characterized by in vitro hormone secretory profiles. Of the 34 pituitary adenomas studied, Ptx-1 expression was reduced by more than 50% compared to that of the housekeeping gene human glyceraldehyde-3-phosphate dehydrogenase in the 6 corticotroph adenomas, which also had significantly reduced a-subunit production (all 6 tumors secreting #0.5 ng/24 h). Mutations of the pituitary transcription factor Prop-1, which is responsible for the syndrome of Ames dwarfism in mice, are being increasingly recognized as a cause of combined pituitary hormone deficiency in humans, although ACTH deficiency has been described only once. Prop-1 expression was detected in all 34 pituitary adenomas, including 6 corticotroph adenomas and 5 gonadotroph adenomas. The expression of Prop-1 has not been described previously in these cell phenotypes. (J Clin Endocrinol Metab 85: 2537–2542, 2000) T PITUITARY gland has a carefully orchestrated spatial and temporal sequence of hormone development in concert with DNA-binding trans-activating factors exerting control over the promoter elements of specific pituitary hormones to effect their cell specific expression (1–4). These cell-specific transcription factors may act either alone or in combination with other transcription factors to exert their tissue-specific action (1, 2). In an attempt to dissect out a role for pituitary transcription factors in pituitary tumorigenesis it seems logical to focus on transcription factors that are expressed at a very early stage in pituitary development. The first of these pituitary transcription factors, prophet of Pit-1 (Prop-1) (5), is involved in the transcription of GH, PRL, TSHb, and LH/FSH genes and in the proliferation and differentiation of somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs, but not corticotrophs (6–8). Mutations in the Prop-1 gene cause the syndrome of Ames dwarfism in mice and a similar phenotype in humans (7–9). Previous studies in patients who have mutations in the Prop-1 gene demonstrate that phenotypic characteristics of the gene mutation in affected families are highly variable, but all demonstrate to some degree GH, PRL, TSH, LH, and FSH deficiencies as well as lower LH, FSH (7–9), and ACTH levels in the circulation (10), a finding not present in Pit-1 gene mutations. Constitutively active gene mutations in pituitary transcription factors have not been described to date in pituitary adenomas, and a connection between phenotype expression in pituitary ontogeny and actual hormone hypersecretion remains tenuous. Nevertheless, in light of a previous observation suggesting no difference in Prop-1 expression in a limited variety of pituitary adenomas (11), we sought to examine the expression of this transcription factor in a large series of pituitary adenomas, including corticotroph and gonadotroph adenomas (not previously studied), for which there was full histological and in vitro characterization of