Role of Pituitary POMC-Peptides and Insulin-Like Growth Factor II in the Developmental Biology of the Adrenal Gland

Abstract

During fetal life, it is critical that there is coordinate regulation of the growth, zonation and differentiation of the fetal adrenal cortex to ensure that cells in key tissues and organs are exposed in a programmed temporal sequence to the actions of glucocorticoids. Glucocorticoids are essential for maturation of key target organs before birth, including the lung, brain, liver, gut, kidney and adrenal, and the prepartum increase in glucocorticoid synthesis and secretion by the fetal adrenal gland is critical for the successful transition to postnatal life. It is also evident that premature or abnormal exposure of embryonic or fetal tissues to glucocorticoids during critical windows of development can irreversibly alter the programmed development of organ systems. Premature or abnormal exposure of the fetus to excess glucocorticoids may occur either as a consequence of endogenous stimulation of the fetal hypothalamo-pituitary-adrenal axis (HPAA) or as a consequence of exposure to exogenous glucocorticoids in a therapeutic context. Administration of synthetic glucocorticoids to women at risk of preterm labour, for example, is a routine clinical practice designed to improve respiratory function and neonatal outcome. It is clearly important to understand what endogenous factors regulate the growth and functional maturation of the adrenal cortex during development and the consequent likelihood of exposure of developing tissues to excess corticosteroids. To date, investigations have centred on the role of ACTH 1-39 in the stimulation of adrenal growth and steroidogenesis in long gestation species, such as the primate and sheep, where maturation and differentiation of organ systems occurs predominantly before birth. In this review, we will focus on the evidence that in addition to ACTH 1-39, other pro-opio-melanocortin (POMC) derived peptides, which are synthesized, processed and secreted by the fetal pituitary, play a role in the coordinate regulation of the specific phases of growth and functional development of the fetal adrenal gland in vivo. We will discuss our recent findings on the direct in vivo actions of N-POMC 1-77 and separately, insulin like growth factor II (IGF-II), as adrenal growth factors. These studies provide an understanding of the separate regulatory mechanisms which control activation of adrenal growth and stimulation of adrenal steroidogenesis in the late gestation fetus.

Adrenocortical responses to ACTH in neonatal rats: effect of hypoxia from birth on corticosterone, StAR, and PBR

“…We were unable, however, to demonstrate an increase in ACTH at 7 days of age. It remains possible that other posttranslational products of proopiomelanocortin may be involved (6).…”

“…Our initial hypothesis was that plasma ACTH was increased at some time during the exposure to hypoxia and that its trophic effects were responsible (6,19). Consistent with that was the increase in relative adrenal weight we observed.…”

Endocrine Regulation of Feto-Placental Growth

“…Glucocorticoids also affect expression of IGF-I and IGF-II in the placenta and other fetal tissues, such as the liver, skeletal muscle and adrenal, in a tissue-specific manner [3,19]. In fetal ovine adrenals, cortisol decreases IGF2 gene expression, which is associated with cytodifferentiation of the adrenal cortex and activation of the enzymes involved in cortisol synthesis [41]. Consequently, there may be a local regulatory loop operating between adrenal cortisol and IGF-II that ensures an exponential rise in cortisol secretion and, hence, tissue maturation in the period immediately before delivery.…”

Functional maturation of growth hormone cells in the anterior pituitary gland of the fetus

“…As noted above, the differentiation of ACTH cells in the anterior pituitary gland and the secretion of ACTH occur earlier than that of GH in rats as well as in mice [82] and humans [83]. ACTH plays a pivotal role in maturation of the steroid genesis of the adrenal cortex [84]. In the rat fetus, the serum ACTH level increases in late gestation [85], and this change is considered to induce an increased corticosterone secretion from the fetal adrenal cortex with a peak on E19 [85][86][87].…”