MAMMOSOMATOTROPH ADENOMA AND GIGANTISM IN AN 8-Y OLD BOY: PATHOPHYSIOLOGICAL ASPECTS

Abstract

We studied an 8-year old prepubertal boy with growth acceleration (without bone age advancement) from age 3 y. Past history was remarkable for onset of strabismus (age 2 y) and progressive loss of vision, coarsening of features, and no galactorrhea. CT-scan and MRI showed a large intra- and suprasellar mass. Elevated basal GH (x = 28 μg/L) and PRL (x = 120 μg/L) were observed, as well as paradoxical responses of GH to L-Dopa, TRH and OGTT. PRL was reduced by L-Dopa but not modified by TRH. GHRH stimulated release of GH, as well as PRL to a lesser degree. Transsphenoidal partial tumor resection was performed, and subsequent treatment with bromocriptine decreased GH and PRL levels. Complete tumor removal was later achieved by a transcranial approach. Immunohistochemistry and electron microscopy using the immunogold technique confirmed the diagnosis of mammosomatotroph adenoma. Occasional tumor cells were also positive for the α-subunit of glycoprotein hormones and β-TSH. Immunoblots of G-protein subunits in tumoral tissue showed increased αs-42 and αs-47, decreased αi-3 and αq, and no change in αO levels when compared to normal human pituitary tissue. Adenylate cyclase activity was markedly elevated in tumoral tissue and could be further stimulated. Using the polymerase chain reaction and single-strand conformational polymorphism analysis, no mutations in the Gsα gene were found. Tumor explants continued to secrete high levels of GH and PRL, as well as α-subunit of glycoprotein hormones and β-TSH, for up to 22 days in culture. The stimulatory factors (GHRH, TRH) induced dose-related responses. In contrast, the inhibitory factors (SRIF, L-Dopa) were effective in suppressing either basal or stimulated hormone release only at high (μM) concentrations, possibly due to the G-protein anomalies. These results are compatible with an oncogenic process induced by excessive GHRH stimulation of adenylate cyclase-regulated cell hyperactivity, although constitutive activation of specific regulatory factors such as Pit-I may also play an important role.