Development of the Hypothalamus-Pituitary-Adrenal Axis in the Fetus

Corticotropin-Releasing Hormone

The hypothalamus develops from the ventral diencephalon and is differentiated by 9 to 10 weeks of gestation in the human fetus. The anterior pituitary derives from the Rathke pouch, an invagination of oral ectoderm, and is present at approximately 5 weeks gestation. The neurovascular link between the hypothalamus and the pituitary is evident as early as 11 weeks of gestation. By 12 to 13 weeks of gestation, the fetal hypothalamus shows immunoactivity and bioactivity of CRH. Therefore the fetal hypothalamus can provide the stimulus for ACTH secretion from the anterior pituitary starting from early in the second trimester. However, based on the hormone levels seen in preterm infants, the regulated axis of hypothalamic CRH, ACTH, and cortisol secretion (HPA) may not be fully developed until late gestation.

CRH is a 41–amino acid neuropeptide synthesized in the paraventricular nucleus of the hypothalamus. ^, CRH is secreted, along with arginine vasopressin (AVP), into the hypophyseal portal blood and regulates the release of ACTH from the anterior pituitary gland. CRH acts by binding G protein–coupled receptors located on corticotroph cells of the anterior pituitary gland, leading to the activation of adenylate cyclase resulting in increased levels of intracellular cyclic adenine monophosphate (cAMP). The induction of cAMP activates protein kinase A, which ultimately stimulates the secretion of ACTH from the corticotroph cells.

Studies in fetal sheep reveal that there is a progressive elevation in CRH that is particularly notable during the second half of gestation. The expression of hypothalamic CRH messenger RNA (mRNA) during this time appears to be regulated by a glucocorticoid-mediated negative feedback signal, as is the case postnatally. However, the sensitivity of this feedback may decrease with increasing gestational age. This could explain how, despite the presence of high levels of cortisol that stimulate parturition, CRH-stimulated ACTH secretion persists in late-gestation fetuses.

In addition to the central nervous system, CRH is produced in peripheral sites, including the adrenal medulla, ovaries, uterus, and placenta. Placental expression of CRH is unique to primates and, as a source of both maternal and fetal serum CRH, has an important role in the development of the placenta and fetus and the progression to parturition. ^, Placental CRH increases exponentially during pregnancy, with expression increasing 100-fold during the last 6 to 8 weeks of pregnancy. CRH from the placenta stimulates the production of fetal ACTH, leading to the production of dehydroepiandrosterone (DHEA) and cortisol by the fetal adrenal gland. ^, Fetal DHEA serves as the predominant precursor for the synthesis of estradiol by the placenta, which increases throughout the course of pregnancy up to the time of birth, when the rise in estrogen, particularly in amniotic fluid, promotes myometrial contractility. This is essential because the primate placenta does not express significant levels of 17α-hydroxylase-17,20-lyase, which is required for conversion of progesterone to estrogen, as is seen in the placenta of other mammals. In human pregnancies, the rise in estrogen comes from the conversion of DHEA secreted from the fetal adrenal.

The rise in placental CRH during pregnancy increases cortisol from both the fetal and maternal adrenal glands. In turn, placental CRH is paradoxically stimulated by cortisol such that a positive feedback system is created ( Fig. 143.1 ). The surge in fetal cortisol secretion that precipitates parturition is crucial in fetal organ maturation, preparing the fetus for extrauterine life. Cortisol is of particular importance to maturation of the fetal lungs, as indicated by the frequent occurrence of respiratory distress syndrome in preterm infants and the risk of which is reduced by antenatal corticosteroids. Placental CRH stimulation of both cortisol and DHEA tethers the effects of cortisol on fetal organ maturation to the timing of parturition. ^,

Increasing placental CRH contributes to the rise in maternal serum CRH. ^, Maternal plasma levels of CRH increase steadily in the second trimester, reaching up to 1000-fold above the levels of nonpregnant women. ^, However, abnormally elevated maternal CRH levels are associated with complications during pregnancy, including preterm labor, preeclampsia, intrauterine growth restriction (IUGR), and postpartum depressive symptoms. ^{, , ,} High levels of cortisol from prenatal maternal stress can stimulate placental CRH secretion, leading to premature birth. Together, these clinical findings suggest that the timing of birth can be altered by modulation of the HPA axis.

Adrenocorticotropic Hormone

Maternal plasma ACTH levels increase moderately during pregnancy, with corresponding increases in cortisol concentrations. ^, By 16 weeks gestation, ACTH is detectable in fetal blood, and studies report that levels of ACTH increase slightly as gestation progresses. ^, However, the extent of the increase in ACTH during pregnancy is disproportionate to the massive increase in circulating placental-derived CRH. ACTH is synthesized and secreted by corticotroph cells in the anterior pituitary gland, and it is a hormone end product of its precursor, proopiomelanocortin (POMC) ( Fig. 143.2 ). Depending on the site of origin, POMC is converted, through a series of enzyme-induced cleavages, to various peptides. In the anterior pituitary, the enzyme prohormone convertase 1/3 acts on POMC to form pro-ACTH and β-lipotropin. Pro-ACTH is processed further to yield other peptides, including ACTH and α-melanocyte-stimulating hormone (αMSH). The action of αMSH, through the melanocortin-1 receptor (MC1R), stimulates production of melanin, resulting in darkening of skin cells. This explains why individuals with primary adrenal insufficiency, such as Addison disease, develop hyperpigmentation. The loss of negative feedback from cortisol results in excessive production of ACTH along with other POMC peptides, including αMSH. It is also likely that the precursors of αMSH, including POMC, at high enough concentrations can act at the MC1R to cause hyperpigmentation.

The action of ACTH occurs when the hormone binds to its receptor, the melanocortin-2 receptor (MC2R), located in all zones of the adrenal cortex. The primary site of ACTH action is in the zona fasciculata, where binding results in activation of the adenylate cyclase system, which induces the synthesis of cortisol. ^, Cortisol has negative feedback on its own secretion by fast inhibition of ACTH secretion and delayed inhibition of CRH and ACTH production. The stimulatory actions of ACTH at the fetal adrenal are also inhibited by other POMC peptides that contain the ACTH sequence, namely, POMC itself and pro-ACTH. Consequently, the precursor peptide levels in the adrenal may be as important as levels of ACTH. Immunoreactive ACTH, as measured by some assays, may reflect levels of both ACTH and the precursors.

ACTH is required for normal structure and function of the adrenal cortex. In mice with complete absence of POMC, the adrenal glands fail to proliferate, resulting in atrophic adrenals. High-dose replacement of ACTH in these mice rescues the adrenal glands in terms of weight, morphology, and cortisol secretion, but this may be due to hypertrophy of the zona fasciculata, not full regeneration of the glands. Similarly, human babies born with agenesis of the pituitary gland or hypopituitarism often have atrophic or malformed and unresponsive adrenal glands. In addition, the presence of excess exogenous or endogenous glucocorticoids suppresses ACTH secretion and can also cause atrophic and hyporesponsive adrenal glands.