Aged PROP1 Deficient Dwarf Mice Maintain ACTH Production

Igor O Nasonkin,Catherine E Keegan,David L Bavers,Gary D Hammer,Felix Beuschlein,Sally A Camper,Robert D Ward,Amanda H Mortensen,Giovambattista Pani

doi:10.1371/journal.pone.0028355

Igor O Nasonkin, Catherine E Keegan + Show 7 more

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https://doi.org/10.1371/journal.pone.0028355

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Abstract

Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1null (Prop1-/-) and the Ames dwarf (Prop1df/df) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism.

Highlights

Congenital pituitary hormone deficiency in humans occurs with a frequency of approximately 1 in 4000 live births and is caused primarily by mutations in genes important for pituitary development [1,2]
Our evidence for up regulation of the pituitary-adrenal axis in Prop1 deficient mice is consistent with previous reports of elevated corticosterone in Ames dwarf mice [31,32], and the increased corticosterone levels we reported in Prop1-/- newborns [19]
The main goal of this research was to study the pituitaryadrenal axis in two different mutant Prop1 alleles on different genetic backgrounds to detect any evidence of adrenocorticotropic hormone (ACTH) deficiency and subsequent hypocortisolism

Summary

Introduction

Congenital pituitary hormone deficiency in humans occurs with a frequency of approximately 1 in 4000 live births and is caused primarily by mutations in genes important for pituitary development [1,2]. The hormone deficiencies are similar to those caused by POU1F1 mutations, except that the deficiencies include reduced gonadotropin production requiring sex hormone substitution and there is a strong tendency toward progressive hormone loss leading to lower circulating adrenocorticotropic hormone (ACTH) later in life, requiring glucocorticoid replacement therapy [8,9,10, 11,12,13] Another interesting difference between PROP1 and POU1F1 patients is the tendency of patients with PROP1 mutations to undergo apparent degeneration of the pituitary gland during childhood [14,15]. The progressive hormone loss and transient pituitary hyperplasia associated with PROP1 mutations are not well understood

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