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CURRENT TOPIC
The fetal and neonatal hypothalamic–pituitary–
adrenal axis
P C Ng
The hypothalamus, pituitary, and adrenal glands are dynamic endocrine organs during fetal development.1–3^ The adrenal glands, in particular, exhibit remarkable transformation in size, morphology, and function during the prenatal and neonatal periods.2 3^ It is now rec- ognised that normal development of the hypothalamic–pituitary–adrenal (HPA) axis is essential for: (1) the regulation of intrauterine homeostasis; and (2) the timely diVerentiation and maturation of vital organ systems includ- ing the lungs, liver, and central nervous system necessary for immediate neonatal survival after birth. In addition, acting together with the pla- centa, the HPA axis might indirectly control the normal timing of parturition in primates.1– The liberal use of exogenous antenatal and postnatal corticosteroids during pregnancy and early neonatal life have also raised concerns about potential adverse eVects on the HPA axis and subsequent neurodevelopment.^4 Thus, an understanding of the physiology and function of the HPA axis in intrauterine and extrauter- ine life is important for neonatologists. This article aims to provide an overview on the physiology of the glucocorticoid axis and the eVects that exogenous corticosteroids have on this system.
Basic physiology Hormone activity in the HPA axis can be detected between eight and 12 weeks of gesta- tion, early in fetal development.1–3^ Cortico- trophin releasing hormone (CRH) is produced from the fetal hypothalamus and the placenta during pregnancy. It is the primary secreta- gogue controlling pro-opiomelanocortin (POMC) mRNA expression and pituitary cor- ticotroph secretion of adrenocorticotrophin (ACTH).1 3^ CRH regulates the growth of pituitary corticotrophs, adrenocortical diVer- entiation, and steroidogenic maturation of the fetal HPA axis.^3 It is also a potent vasodilator of the fetoplacental circulation and can potentiate the function of local mediators and hormones, such as prostaglandins and oxytocin, in in- creasing myometrial contractility during labour.^1 The progressive increase in the con- centration of CRH in fetal and maternal circu- lations at late gestation suggests a pivotal role of placental CRH in modulating the timing of parturition (see below).^3 ACTH is principally produced by the anterior pituitary cortico-
trophs and is the prime trophic hormone con- trolling fetal adrenocortical growth, diVerentia- tion, and steriodogenesis.1 3^ ACTH acts via local mediators or growth factors, such as the vascular endothelial growth factor and epider- mal growth factor, in synchronising fetal adrenocortical growth and angiogenesis. The functional development of the fetal adrenal cortex is a highly complex process that involves the ontogenical expression of specific steroidogenic enzymes in diVerent zones and at diVerent times in gestation.^3 The fetal zone is the principal site of dehydroepiandrosterone sulphate (DHEA-S) production, whereas the definitive zone is the main site of mineralocor- ticoid synthesis. The transitional zone is functionally similar to the fetal zone early in development and is believed to be the site of de novo cortisol production after 28 weeks of gestation.^3 Cortisol is important in maintaining intrauterine homeostasis. It also influences the structural and functional development of a wide variety of fetal tissues, and is essential for the antepartum maturation of organ systems including the lungs, gastrointestinal tract, liver, and central nervous system, which are vital for neonatal survival.^2
Regulation of the HPA axis The regulation of the fetal HPA axis and its interaction with the placenta are illustrated in fig 1. The fetal hypothalamus responds to acute stressful situations such as arterial hypotension and haemorrhage by releasing CRH. CRH stimulates the production of ACTH from the fetal corticotrophs. The latter hormone en- hances adrenal cortisol secretion, which in turn inhibits excessive CRH and ACTH release from the fetal hypothalamic–pituitary centres. ACTH also promotes DHEA-S secretion from the adrenocortical fetal zone, which provides substrates for oestrogen synthesis. Placental oestrogens indirectly influence the fetal HPA axis by facilitating the conversion of active cor- tisol into inactive cortisone, thereby reducing the concentration of cortisol in the fetus. This results in decreasing the negative feedback eVects of cortisol on the fetal hypothalamic– pituitary centres and causes an increase in fetal POMC mRNA, ACTH, and adrenal cortisol production. An increase in fetal ACTH secre- tion further stimulates DHEA-S production.^5 This positive feedback loop has been proposed
F250 Arch Dis Child Fetal Neonatal Ed 2000; 82 :F250–F
Department of Paediatrics, Level 6, Clinical Science Building, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, NT, Hong Kong, Peoples Republic of China P C Ng
Correspondence to: Professor Ng
to be the mechanism underlying the rapid growth of the fetal adrenal cortex and the eY- cient production of DHEA-S at midgestation.^5 Finally, the cortisol produced downregulates the positive feedback loop by exerting a negative control on the hypothalamic–pituitary centres (fig 1). Paradoxically, adrenal glucocorticoid stimu- lates the release of CRH from the placenta.3 6 Placental CRH, which is identical to hypotha- lamic CRH in structure, bioactivity, and immunoreactivity, stimulates the expression of fetal pituitary ACTH and eVectively estab- lishes another positive feedback circuit, result- ing in concomitant increase of CRH, ACTH, and cortisol towards the end of gestation (fig 1).3 6^ This self perpetuating mechanism reaches its peak at the onset of labour and the positive feedback loop is eventually terminated by delivery of the placenta and the fetus.^3 Hence, it is possible that environmental stress might stimulate a precocious rise in fetal hypothalamic and placental CRH production, which triggers the cascade of changes resulting in preterm delivery. This theory is supported by the observation that premature infants have significantly higher concentrations of maternal
CRH in the early third trimester than those who deliver at term.^7
Adaptation to extrauterine life Because successful adaptation of newborns to extrauterine life relies on the exact timing of parturition and maturation of vital organ systems, the steroidogenic compartments of the fetal adrenal cortex must develop ad- equately and produce suYcient endogenous cortisol for perinatal survival towards the end of gestation. Despite the dramatic remodelling of the adrenal cortex that occurs immediately after birth, there is no evidence of clinical adrenocortical insuYciency in term infants during this crucial period. 3 In contrast, ill and extremely premature infants form a unique group because of their potentially decreased ability to produce stress induced release of glucocorticoid. 8 9^ Recent studies suggest that some preterm very low birth weight infants, in particular those less than 1000 g, have inap- propriately low serum cortisol concentrations 8–10 (^) but greatly raised concentrations of the cortisol precursors 11-deoxycortisol, 17-hydroxyprogesterone, and 17- hydroxypregnenolone when compared with term infants, indicating that the activity of some adrenal steroidogenic enzymes might be reduced as a result of adrenocortical immaturity. 9 10^ A large proportion of very low birth weight infants do not respond satis- factorily to stimulation by a physiological dose of ACTH (0.1 μg/kg). 11 An inverse relation between gestational age and serum cortisol concentrations has also been described during the first 7 days of life in premature infants.12 13 In contrast to the above findings, Hanna and colleagues 14 and Ng and colleagues 15 have investigated the pituitary–adrenal function of very low birth weight infants using ovine and human CRH (1 μg/kg), respectively, and the results suggest that both ACTH and cortisol responses are adequate in most patients, with the configuration of the stimulation curves, the magnitude of responses, and the timing of the peak concentrations being comparable with those seen in the mature axis. 15 Hence, it has been postulated that the relative inadequacy of cortisol production in some sick premature infants might be related to their inability to “recognise” stress or a failure of the hypotha- lamus to secrete CRH in stressful situations.^14 Very low birth weight infants with low or suboptimal serum cortisol concentrations might have a higher risk of developing chronic lung disease and of requiring prolonged oxygen supplementation.11 16^ Transient adrenocortical insuYciency has also been described in very low birth weight infants who present with pro- found hypotension and shock, which are resist- ant to volume expansion and inotrope treat- ment, but respond promptly to glucocorticoid replacement.^8 In this condition, the pituitary release of ACTH in response to exogenous human CRH stimulation appears to be intact but the adrenals fail to produce adequate corti- sol to maintain normal blood pressure (PC Ng et al , unpublished data). This phenomenon, however, appears to be short lived and normal
Figure 1 A schematic model to illustrate the neuroendocrine interaction between the fetal hypothalamic–pituitary–adrenal axis and the placenta. The solid arrows represent positive stimulatory pathways and the broken arrows represent negative inhibitory pathways. ACTH, corticotrophin; CRH, corticotrophin releasing hormone; CRH-BP, corticotrophin releasing hormone binding protein; DHEA-S, dehydroepiandrosterone sulphate; IGF, insulin-like growth factor; POMC, pro-opiomelanocortin; pro-ACTH, pro-corticotrophin; VEGF, vascular endothelial growth factor.
Inhibitors: 1 Exogenous corticorteroids 2 Vagal stimuli
Cortisol concentration (positive feedback loop)
Converts cortisol into cortisone
Stimulates prostaglandin production and influences myometrial contraction
Placenta CRH-BP
Liver 16 α-hydroxy-DHEA-S DHEA-S
CRH
Oestrogens
Cortisol (positive feedback loop)
Cortisol (negative feedback loop)
DHEA-S 16 α-hydroxy- DHEA-S
Stimulators: 1 Acute physical stress: acute hypoxic-ischaemic episode, systemic hypotension, haemorrhage, etc 2 Psychological stress 3 Noxious stimulus 4 Neuropeptides Fetal hypothalamus CRH
—
—
Fetal anterior pituitary POMC
Fetal adrenal Definitive zone
Transitional zone
Fetal zone DHEA-S
Cortisol
Maturation of vital organ systems eg lung, gastrointestinal tract, liver, brain, etc
Mineralocorticoid
ACTH (via local growth factors or mediators eg VEGF, IGF, etc)
Pro-ACTH ACTH
β endorphin
β endorphin
Fetal and neonatal hypothalamic–pituitary–adrenal axis F
concentrations when compared with larger fetuses and newborns of equivalent gestations.41 42^ Cortisol values in adults were found to be highest in those who were lightest at birth.^43 Low birth weight and raised serum cortisol concentrations are positively correlated with high blood pressure, but inversely related to glucose tolerance.35–38 43^ Therefore, it has been postulated that perinatal stress and expo- sure to corticosteroids might induce long last- ing changes in the HPA axis and alter an indi- vidual’s sensitivity to later environmental manipulations.32 34^ Hence, the long term eVects of antenatal and postnatal corticosteroids on the HPA axis and their potential to predispose to specific diseases in later life should be stud- ied longitudinally, and carefully monitored.
Summary Regulation of the fetal HPA axis is a highly complicated process and is under the control of positive and negative feedback circuits (fig 1), placental hormones, and local autocrine/ paracrine mediators or growth factors.^3 The primary aims of this complex system are to ensure appropriate coordination of tissue growth and diVerentiation, orderly maturation of vital organ systems, and ultimately to act together with the placenta to determine the exact timing of parturition most suitable for successful transition from intrauterine to ex- trauterine life. Undoubtedly, the understand- ing of basic fetal and neonatal neuroendocrine physiology and development has been clinically exploited and translated into new measures for revolutionising the management of preterm and newborn infants. Current evidence suggests that the antenatal and postnatal use of corticosteroids causes only transient suppres- sion of the HPA axis, and endocrine function recovers within one week and four to eight weeks, respectively, in most infants after corticosteroid treatment has been stopped.12 23–26^ However, because early treat- ment with exogenous corticosteroids might potentially influence the programming of the HPA axis,^32 clinicians should monitor the long term eVects of such exposure in treated cases.
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