The molecular basis of hypopituitarism

Abstract

Hypopituitarism is defined as the deficiency of one or more of the hormones secreted by the pituitary gland. Several developmental factors necessary for pituitary embryogenesis and hormone secretion have been described, and mutations of these genes in humans provide a molecular understanding of hypopituitarism. Genetic studies of affected patients and their families provide insights into possible mechanisms of abnormal pituitary development; however, mutations are rare. This review characterizes several of these developmental proteins and their role in the pathogenesis of hypopituitarism. Continuing research is required to better understand the complexities and interplay between these pituitary factors and to make improvements in genetic diagnosis that can lead to early detection and provide a future cure.

Figure 1

A modified overview of pituitary development adapted from previous embryological studies performed in murine species. The development of the mature pituitary gland is dependent on the contact of the oral ectoderm with the ventral diencephalon (neural ectoderm) followed by a cascade of events consisting of both signaling molecules and transcription factors expressed in a specific temporal and spatial fashion. At approximately embryological day 9.5 (e9.5), BMP-4 and Nkx2.1 along with sonic hedgehog (Shh) participate with the initial evagination of ventral diencephalon and invagination of oral ectoderm to from the primordial Rathke’s pouch (RP). In addition, expression of Gli 1,2, Lhx3 and Pitx 1,2 plays an important role in the development of progenitor pituitary cell types. This is closely followed by the expression of Hesx1, Isl1, Pax6 and Six3, 6, which are also implicated in cellular development, proliferation and migration. Interactions between factors is illustrated by the attenuation of Hesx1 (hashed arrows at approximately e12.5) that is required for the expression of Prop1. By e12.5, RP has formed and by e17.5, differentiation of specific pituitary cell types has been completed. The expression of Pit1 is also marked with the attenuation of Prop1 expression (hashed arrows).The mature pituitary gland is marked by the differentiated cell types: somatotrophs (S), lactotrophs (L), thyrotrophs (T), gonadotrophs (G) and corticotrophs (C). Also shown are the posterior and intermediate lobe of the pituitary and the location of melanotropes (M) [–9].