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Adrenocortical function and dysfunction in the fetus and neonate
Seminars in Neonatology (2004) 9, 13–21
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
REVIEW ARTICLE
Adrenocortical function and dysfunction in the fetus and neonate Kristi L. Watterberg * Division of Neonatology, MSC10 5590, University of New Mexico, Albuquerque, NM 87131-0001, USA
KEYWORDS Cortisol; Adrenal insufficiency; Adrenal cortex; Infant; Premature infant; Hypotension; Adrenal development; Fetal
Summary Under normal circumstances, the fetus is exposed to very low concentrations of cortisol until late in gestation. Perturbations of the intra-uterine environment resulting in fetal exposure to increased cortisol may have consequences not only in infancy, but also into adult life. In the postnatal period, developmental immaturity and/or the effects of critical illness on adrenal function may result in insufficient cortisol production to maintain homeostasis in the face of acute stress or illness, a situation that has been labelled ‘relative adrenal insufficiency’ in other acutely ill populations. The definition of inadequate adrenal function in the newborn and its possible relationship to adverse outcomes in both premature and term infants are only beginning to be characterized. © 2003 Elsevier Ltd. All rights reserved.
Introduction The activation of the hypothalamic-pituitaryadrenal (HPA) axis is critical to maintain homeostasis in response to stress, and the effects of adrenal insufficiency have been well described.1 However, for many years, clinical interest in newborn adrenocortical function was primarily limited to the effects of absolute steroid deficiencies produced by inborn errors of metabolism. Recently, fetal and neonatal adrenal function and dysfunction have become areas of intense interest and controversy. Although part of this increased interest results from a new focus on the potential effects of adrenal function on clinical disease and outcomes in the extremely premature infant, an additional driving force has been the hypothesis that exposure of the fetus to abnormal cortisol concentrations may lead to a broad range of adult diseases, including hypertension, coronary heart disease, type II diabetes, chronic renal failure and depression.2–4 * Tel.: +1-505-272-6753; fax: +1-505-272-1539 E-mail address: [email protected] Watterberg).
(K.L.
Increasing survival of extremely immature infants first provided new incentive for investigation of adrenal function in the newborn. Two abstracts, in 1989 and 1991, first described cortisol insufficiency, or ‘Addisonian crisis’, in extremelylow-birthweight infants,5,6 and many studies have followed, exploring the relationship of adrenal function to clinical illness and outcomes in these infants. In addition, the recent emergence of an entity labelled ‘relative adrenal insufficiency’ in other critically ill patient populations7,8 obliges us to consider and explore the effects of acute illness on adrenal function in critically ill infants of all gestational ages who exhibit cardiovascular instability and other signs consistent with adrenal insufficiency. The primary focus of this review of fetal and neonatal adrenocortical function, therefore, will not be on the effects of inborn errors of steroidogenesis or exogenous glucocorticoid administration, prenatally or postnatally. Instead, the objectives are: (1) to briefly review normal fetal adrenal development and to consider the effects of increased fetal cortisol exposure resulting from
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Table 1
Factors affecting fetal adrenal function
Maternal: cortisol passively transferred to the fetus suppresses the fetal HPA axis – Increased production during maternal stress – Increased transfer during early gestation – Increased transfer in the presence of decreased placental 11-HSD2 activity Placental: 11-HSD2 – Converts maternal cortisol to cortisone – Modulates exposure of fetus to maternal cortisol Placental CRH – Stimulates fetal HPA axis – Is in turn stimulated by increased fetal cortisol – Increases exponentially prior to delivery Chorioamnionitis – Pro-inflammatory cytokines stimulate fetal HPA axis Fetal: responds to maternal and placental signals during development – HPA axis is suppressed by maternal cortisol – HPA axis is stimulated by placental CRH or chorioamnionitis HPA axis, hypothalamic-pituitary-adrenal axis; CRH, corticotrophin-releasing hormone.
perturbations of the intra-uterine environment; (2) to review current literature concerning adrenal function in the newborn, particularly the extremely immature infant; and (3) to consider the possible effects of critical illness on adrenal function in the newborn.
Fetal adrenocortical development The development of the fetal adrenal cortex takes place in a complex milieu of maternal, placental and fetal interactions that, under normal circumstances, combine to shield the fetus from significant cortisol exposure until late in gestation. This situation promotes continuing growth and proliferation of fetal tissues, and defers the differentiating effects of glucocorticoids until late in gestation, when increased fetal cortisol concentrations induce the maturation necessary for postnatal life.9,10 All three components of this system—maternal, placental and fetal—are essential for normal fetal adrenal development, and perturbation of any of them can affect the outcome. Below is a brief capsule of these complex interactions, summarized in Table 1 (for an extensive review, see Refs. 9 and 11).
Maternal Early in gestation, the placenta has little capacity to convert maternal cortisol to the biologically inactive cortisone (see section below). Therefore, through midgestation, a small percentage of maternal cortisol is passively transmitted into the fetal circulation, exerting negative feedback on the fetal HPA axis and suppressing fetal cortisol production.11 Late in gestation, as placental metabolic activity matures during the third trimester, less maternal cortisol reaches the fetus, resulting in increased fetal adrenocorticotrophic hormone (ACTH) secretion and cortisol production.11
Placental The placenta performs a myriad of endocrine functions throughout gestation. Two placental factors crucial to fetal adrenal development are 11 hydroxysteroid dehydrogenase type 2 (11-HSD2) and placental corticotrophin-releasing hormone (CRH). The enzyme 11-HSD2 oxidizes cortisol to the biologically inactive cortisone, and is a primary regulator of fetal exposure to maternal cortisol. The activity of this enzyme is very low during the first half of gestation, allowing passive transmission of maternal cortisol through the placenta to the fetus. As the placenta matures during the last trimester, 11-HSD2 activity increases markedly, converting an increasing percentage of maternal and fetal cortisol to cortisone, thereby decreasing negative feedback to the fetal HPA axis and stimulating production of fetal ACTH and cortisol.11,12 The placenta is also the source of large quantities of CRH. In contrast to hypothalamic CRH, which is inhibited by high cortisol concentrations, placental CRH appears to be stimulated by cortisol.13 Placental CRH is released into both the fetal and the maternal circulation, and increases exponentially as gestation progresses toward term,13 stimulating fetal adrenal steroid production. The primary product of the fetal zone of the adrenal gland, dehydroepiandrosterone sulphate (DHEAS), circulates back to the placenta, where it becomes a key substrate for the synthesis of placental oestrogens, which in turn stimulate further production of 11-HSD2 in the placenta.11 This becomes a continuing ‘feed-forward’ loop as the third trimester progresses, where exponentially increasing placental CRH and decreasing maternal cortisol stimulate increasing fetal DHEAS and cortisol production, in turn resulting in increased placental oestrogen production which stimulates more 11-HSD2, and so forth, eventually culminating in parturition.11,13 Early elevation of placental CRH in the maternal
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circulation has been associated with preterm delivery, implicating the neuro-endocrine axis in this process.13,14
Fetal In response to the hormonal signals above, the fetal adrenal gland undergoes massive hypertrophy during the latter part of gestation, reaching weights at term that will not be achieved again until adulthood.9 However, this hypertrophy primarily takes place in the ‘fetal zone’ of the adrenal cortex, whose primary product is not cortisol, but dehydroepiandrosterone and its sulphate, DHEAS, a primary substrate for production of placental oestrogens (see above). Through most of gestation, the fetal adrenal gland is deficient in the enzyme 3 hydroxysteroid dehydrogenase (3HSD), which catalyses an essential step in the production of cortisol and other adrenal steroids from cholesterol. Immunohistochemical staining for 3HSD is almost absent in human fetal adrenal tissue at midgestation, then begins to increase in intensity during the third trimester, staining most heavily at term.15 Numerous studies indicate that the human fetal adrenal cortex cannot produce cortisol de novo before 23 weeks of gestation, and normally does not do so until as late as 30 weeks of gestation.9 Instead, the fetus synthesizes cortisol from the abundant placental progesterone, bypassing the need for 3HSD.9 Passive exposure to maternal cortisol contributes to suppression of fetal ACTH secretion during the first part of gestation. Diminishing placental transmission of maternal cortisol late in gestation, together with increasing CRH exposure, stimulates fetal ACTH secretion, which in turn results in the necessary development of the adrenal neocortex and maturation of 3HSD activity. As a consequence of these interactions, fetal cortisol concentrations are normally quite low until well into the third trimester.16,17 Considering the normal time line for fetal adrenocortical maturation, we should be surprised, not that extremely premature infants may have limited ability to maintain homeostasis in response to postnatal stress, but that such infants can maintain homeostasis at all. It is possible that they owe this precocious ability, at least in part, to the very perturbation of the intra-uterine environment that led to their premature delivery. For example, in the above histologic study, the adrenal gland of a 22week-gestation fetus delivered after 10 weeks of ruptured membranes showed unexpected, dense staining for 3HSD.15
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Perturbations of the intra-uterine environment In the normal pregnancy, very low concentrations of cortisol are present in the fetal circulation until late in gestation, as above. However, perturbation in any of the three compartments affecting the fetus—maternal, placental or fetal—can result in exposure of the fetus to elevated cortisol concentrations. On the one hand, the fetus may be passively exposed to excess maternal cortisol, either from increased maternal production (from, for example, increased maternal stress or undernutrition14) or from decreased activity of 11-HSD2 in the placenta.12 On the other hand, the fetus may actively secrete increased amounts of cortisol in response to stimulatory factors, such as proinflammatory cytokines produced by chorioamnionitis.18 In some ways, these two pathways—active and passive—may produce similar effects, since both result in the exposure of the fetus to increased cortisol concentrations inappropriately early in gestation. Other effects may be quite different. Passive exposure to excess glucocorticoid suppresses the fetal HPA axis,19 whereas activation of the fetal axis can enhance postnatal cortisol production.20 Fetal exposure to excess exogenous glucocorticoid causes decreased birth weight and organ weights in animals.21 In one elegant study of the direct effect of increased cortisol concentrations on cellular growth and differentiation, Rudolph et al. infused cortisol directly into the left coronary artery of fetal sheep at about two-thirds of gestation, achieving local concentrations of cortisol in the left ventricle equal to those normally present at the end of gestation. These authors found that premature exposure to increased cortisol produced premature differentiation, inhibiting myocyte replication and resulting in markedly decreased total DNA, i.e. hypoplasia.10 In human studies, decreased birth weight has been seen following exogenous glucocorticoid exposure.21 In addition, both maternal stress and decreased 11-HSD2 activity, which passively increase fetal cortisol exposure, have been linked to lower birth weights in term and preterm infants.12,14,17 In premature infants, lower birth weight has also been associated with both decreased ACTH in fetal blood16 and decreased response to ACTH stimulation in the newborn,22 both indicating fetal HPA axis suppression. The primary trigger for increased active fetal cortisol production is prenatal inflammation, i.e. chorioamnionitis. Histologic chorioamnionitis is quite common in preterm deliveries, occurring in
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more than half of the pregnancies delivered before 30 weeks' gestation.20 Chorioamnionitis generates pro-inflammatory cytokines, including interleukin 1 and interleukin 6, which stimulate the HPA axis.18,20 In 1971, a series of 387 autopsies showed that premature infants with chorioamnionitis had larger adrenal glands than those without, and that infants who died of respiratory distress syndrome had smaller adrenal glands than those dying of other causes.23 More recently, premature infants exposed to histologic chorioamnionitis were found to have increased cortisol concentrations and increased response to ACTH stimulation during the first week of postnatal life, as well as decreased requirements for respiratory support.20 These findings may suggest a beneficial effect of inflammation-induced precocious maturity of the fetal HPA axis. However, the same systemic inflammatory response that stimulates the fetal HPA axis may produce its own short- and long-term adverse effects, such as hypotension, bronchopulmonary dysplasia (BPD) or neurodevelopmental abnormalities.24–26 The effects of increased fetal exposure to cortisol may even persist into adulthood. The first link reported between low birth weight and hypertension in adulthood was quickly followed by an explosion of interest in the relationship of fetal growth and growth restriction to adverse outcomes in adult life.2–4 This new field, dubbed the ‘fetal origins’ or ‘fetal programming’ of adult disease, has now linked fetal growth restriction to other cardiovascular diseases, type II diabetes and insulin resistance syndrome, depression and end-stage renal disease.2–4 The postulated mechanism linking low birth weight with these widely diverse adverse outcomes is increased fetal exposure to cortisol, with resultant life-long changes in total organ cell numbers, as well as an altered ‘set-point’ and exaggerated sensitivity of the HPA axis to stress.2 At present, these links between intra-uterine growth restriction and adult disease remain epidemiologic, providing fertile ground for continuing research— although following the HPA axis prospectively from infancy to adulthood will present a real challenge of long-term follow-up!
Postnatal adrenal function Adrenal physiology Activation of the HPA axis is critical to maintain homeostasis in response to stress. Although “the reasons why elevated glucocorticoid levels protect the organism under stress are not well
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understood . glucocorticoid deficiency . may cause hypotension, shock and death.”1 Among its many actions, cortisol: (1) regulates protein, carbohydrate, lipid and nucleic acid metabolism; (2) maintains vascular responsiveness to circulating vasoconstrictors and opposes the increase in capillary permeability during acute inflammation; (3) regulates extracellular water by reducing movement of water into cells and by promoting free water excretion; (4) suppresses the inflammatory response; and (5) modulates central nervous system (CNS) processing and behaviour.1,27 Following logically from the above paragraph, signs of acute adrenal insufficiency can include hypoglycaemia (although this may not be seen in patients with continuous intravenous dextrose infusion), amplified responses to inflammatory stimuli, hyponatraemia with oliguria, and, perhaps most notably, cardiovascular dysfunction and circulatory collapse. Although classic glucocorticoid physiology teaches that steroids act through gene transcription, the rapidity of some responses to cortisol replacement, particularly cardiac function, demonstrates that they must also act through other, ‘nongenomic’ mechanisms. For example, premature infants with vasopressor-resistant hypotension showed significantly increased blood pressure within 2 h of receiving hydrocortisone.28 Such a prompt response may result from an immediate increase in cytosolic calcium availability caused by the interaction of cortisol with membrane-bound receptors.28 Cortisol may also improve cardiac function by reversing the downregulation of adrenergic receptors, inhibiting nitric oxide synthase expression and/or prostacyclin production, decreasing the re-uptake of norepinephrine, improving capillary integrity, or other mechanisms.28 In addition to its crucial metabolic effects, cortisol also modulates CNS function, especially in the hippocampus where it affects learning and memory.27 There is extensive documentation of the adverse effects of prolonged high glucocorticoid concentrations on the CNS at all stages of development; however, it is also clear that adrenal insufficiency is detrimental to CNS function and that both situations result in apoptosis and neurodegeneration.27 Thus, cortisol and the CNS interact in a delicate balance, where too much or too little glucocorticoid adversely affects structure and function.
Relative adrenal insufficiency Although the incidence of absolute adrenal insufficiency in critically ill patients is rare, a phenomenon labelled ‘relative adrenal insufficiency’ or
Adrenocortical function and dysfunction Table 2
Features of relative adrenal insufficiency
Described in acutely stressed adults and children (e.g. illness, surgery, trauma) Basal cortisol values may be within normal range, but are insufficient for the situation Patients have decreased response to ACTH stimulation Primary presentation is cardiovascular instability, with hypotension and shock May result in increased mortality Aetiology, definition and prevalence unclear ACTH, adrenocorticotrophic hormone.
‘relative AI’ has recently been described in both adult and paediatric populations.7,8,29,30 These patients present with cardiovascular instability and shock, and have higher mortality rates (Table 2). Such patients have detectable, even apparently normal, cortisol concentrations; however, these cortisol concentrations are inadequate for the severity of their illness, and their response to ACTH stimulation is diminished.7,8,29,30 The aetiology of this relative AI in the face of acute illness is unclear; postulated mechanisms have included cytokine-related suppression of ACTH or cortisol synthesis, cytokine-induced tissue resistance to cortisol actions, inadequate perfusion of the adrenal gland, or a limited adrenocortical reserve.7,8,29,31 The definition of relative AI has not been well established. One recent review suggested that a critically ill adult with a random cortisol value of <414 nmol/l (15 µg/dl) should be considered to have relative AI, and that individuals with concentrations between 15 and 34 µg/dl should have ACTH stimulation performed.8 A rise in serum cortisol of <250 nmol/l (<9 µg/dl) after stimulation is also likely to represent relative AI, and such patients may benefit from hydrocortisone therapy.8,30 Since the definition of this entity is not well established, its prevalence is also unclear; however, it appears to be quite common in septic shock and variable in other conditions.7,8,29,30 Low-dose hydrocortisone treatment of patients with septic shock has been shown to decrease serum concentrations of proinflammatory cytokines, attenuate the systemic inflammatory response syndrome, and improve survival.30,31 Adrenal function in the premature infant Considering the abrupt interruption of the normal intra-uterine influences on adrenal development, it would seem reasonable to expect that premature infants, particularly those born before 29–30 weeks
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of gestation, would have limited capacity to maintain homeostasis in an extra-uterine environment. Considering also the severity of illness frequently present in these patients, the premature infant could have two factors contributing to inadequate adrenal function: developmental immaturity and relative adrenal insufficiency in the face of acute illness. Therefore, the extremely premature infant may be able to produce enough cortisol to maintain homeostasis under non-stressful conditions, but insufficient cortisol to respond appropriately to stress. As more such infants survive, assessing and supporting adrenal function in this group acquire increasing clinical importance. The assessment of adrenal function and adrenal insufficiency in premature infants has been complicated by the difficulty of defining appropriate cortisol values for this population. After the cortisol surge at delivery, clinically well infants may have very low basal cortisol values without apparent compromise;32 however, such values cannot be considered appropriate for sick, stressed patients. Similar difficulties hamper efforts to define normal values for response to ACTH stimulation. First, stimulation studies in the literature are difficult to compare. Most have used the ACTH analogue cosyntropin (1–24 corticotropin), but at doses ranging from 0.1 to 36 µg/kg.33,34 Other studies have used CRH, testing pituitary as well as adrenal function. The entire HPA axis can only be tested with metyrapone suppression or induction of hypoglycaemia, neither of which is acceptable in these fragile patients. Whichever test has been used, many sick premature infants have typically shown low basal cortisol concentrations and blunted response to stimulation compared with other populations. In clinically well adults, the peak cortisol value after stimulation is considered the most reliable parameter for assessing adrenal response to ACTH stimulation, and a stimulated value of ≥500 nmol/l (>18 µg/dl) is often considered normal.1 A number of authors have found that perhaps only half of sick premature infants achieve that value after ACTH or CRH stimulation.19,33–36 Although the concentration of cortisol-binding globulin (CBG) in preterm infants is somewhat lower than in adults, the low basal cortisol concentrations and reduced response to stimulation seen in preterm infants cannot be explained by variations in CBG concentrations.33,37,38 The high incidence in these infants of a response that would be considered inadequate in other populations creates a dilemma: should a lower response to ACTH or CRH testing be considered ‘normal’ for
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this population? Or is this a normal fetal response, which may be inadequate for the stresses of postnatal life, predisposing these infants to adrenal insufficiency when faced with acute illness? To address this question, the relationship of cortisol values to measures of acute illness and outcome must be considered.
Adrenal function and acute illness in preterm infants Two abstracts first described functional consequences of inadequate adrenal function in extremely-low-birthweight infants, presenting two series of infants with clinical cortisol insufficiency, or ‘Addisonian crisis’.5,6 These infants exhibited hypotension, oliguria and hyponatraemia, with cortisol values of <414 nmol/l (<15 µg/dl). All responded to hydrocortisone supplementation with improvement in blood pressure, urine output and sodium concentrations. Subsequent studies of the relationship of cortisol values to acute illness in preterm infants have shown that, instead of the higher cortisol values expected in sick patients, lower cortisol values are often seen in sicker infants,35,38 including those who require mechanical ventilation19,35,37 and those with hypotension.37,39 The relationship of cortisol values to hypotension is of particular interest, both because hypotension is associated with adverse outcomes in the premature infant,40 and also because it is a primary presentation of adrenal insufficiency in other populations. Many premature infants are treated with vasopressors for hypotension, yet the aetiology of this common phenomenon has been unclear. Studies in baboons and human infants have now shown that arterial blood pressure correlates with cortisol production.39,41 Response to hydrocortisone therapy in premature infants with vasopressor-resistant hypotension is rapid and convincing,28 further implicating inadequate adrenal function in its pathogenesis. One randomized trial compared the efficacy of dopamine with hydrocortisone for primary treatment of hypotension in very-low-birthweight infants, and found them to be similarly effective.42 These authors did not find a relationship between cortisol values and blood pressure response; however, their study was performed on the first day of life, and the cortisol surge at delivery might have obscured any differences. The average rise in cortisol after ACTH in these infants was <250 nmol/l (<9 µg/dl), a value suggested to be inadequate in other sick populations (see above).8
Figure 1 Basal and stimulated cortisol values in very-lowbirthweight infants during the second half of the first week of life (mean±SEM). Infants developing bronchopulmonary dysplasia (filled bar), defined as receiving supplemental oxygen at 36 weeks’ postmenstrual age, had significantly lower basal cortisol concentrations (P<0.05) and lower response to ACTH stimulation (P<0.02) than those who did not (open bar). Cumulative data from previous studies, analysed by multiple regression including gestational age.20,36,37
Adrenal function and outcome The first study investigating the relationship of adrenal function in premature infants to a clinical outcome explored its association with the development of BPD.36 Infants who develop BPD show early increases in markers of lung inflammation.25 As cortisol is essential to control the body's response to inflammation, the hypothesis of the study was that inadequate cortisol activity led to amplified inflammatory responses, resulting in chronic lung disease. ACTH stimulation testing performed at the end of the first week of life showed that infants who developed BPD had a significantly lower response to ACTH, with a median poststimulation cortisol of 367 nmol/l (13.3 µg/dl) compared with 520 nmol/l (18.8 µg/dl) in those who did not develop BPD.36 Fig. 1 shows basal and ACTHstimulated cortisol values during the first week of life; values in infants developing BPD are significantly lower than those in infants who recover without BPD. Several subsequent studies have shown lower basal and/or stimulated cortisol values in infants developing BPD,33,35,43,44 although one study did not find this association.45 Other findings supporting the link between decreased adrenal function and BPD include: (1) an inverse correlation of serum cortisol values with markers of lung inflammation; (2) significantly lower cortisol values in infants with patent ductus arteriosus, a condition almost universally cited as a factor predisposing to BPD; and
Adrenocortical function and dysfunction Table 3
19
Randomized studies of hydrocortisone therapy in infants
Reference Bourchier and Weston Watterberg et al.43
42
Purpose
Design
Sample size
Outcome
Treat hypotension Prevent BPD
Randomized, blinded Randomized, blinded
40 40
Efficacy similar to dopamine Improved survival without BPD
BPD, bronchopulmonary dysplasia.
(3) increased precursors to cortisol synthesis in such infants, again indicating decreased capacity to synthesize cortisol.46,47 The observation that decreased early adrenal function was associated with the subsequent development of BPD led to a pilot study of 40 infants, testing the effect of prophylaxis of early adrenal insufficiency on its development (Table 3). Hydrocortisone was given during the first two weeks of life, at a dose intended to achieve serum levels seen in acutely ill patients in other populations.7,8,29,30 Preliminary pharmacokinetic studies led to the use of a dose of 1 mg/kg/day, equivalent to about 5% of the previously used dexamethasone dose of 0.5 mg/kg/day, and lower than doses often given to hypotensive premature infants.5,6,28,42 A median serum concentration of 717 nmol/l (26 µg/ dl) was achieved without suppression of adrenal function when tested three days after the end of therapy.43 The 20 infants treated with hydrocortisone showed a significant increase in survival without oxygen dependence at 36 weeks' postmenstrual age.43 In addition, and in contrast to many dexamethasone studies, the infants treated with hydrocortisone showed no impairment of head growth or weight gain at 36 weeks' postmenstrual age compared with placebo. Although these results are promising, the study was far too small to adequately evaluate possible adverse effects. A large, multicentre trial is now under way to test this hypothesis in a much larger population and to monitor neurodevelopmental outcomes. Until the effects of hydrocortisone replacement therapy can be evaluated in large clinical trials, clinical use in the preterm infant should probably be restricted to those infants with vasopressor-resistant hypotension, since persistent hypotension has been linked to adverse outcomes.40 In summary, considering the possible adverse effects of adrenal insufficiency on one hand, and the possible links between excess fetal or neonatal glucocorticoid exposure and adverse long-term outcomes on the other, the very premature infant finds himself or herself caught in a very difficult situation. Cortisol is essential to maintain homeostasis
in response to extra-uterine stressors, yet exposure to increased glucocorticoid activity at a time when such exposure should be low could have long-term adverse effects. At a minimum, this would argue in favour of decreasing environmental and other stressors in the neonatal intensive care unit wherever possible to decrease unnecessary cortisol secretion.
The term infant While adrenal function in the preterm infant has received increasing attention over the past years, extremely little work has thus far been published investigating the effect of critical illness on adrenal function in term infants. Small studies have recently suggested that these patients, too, may exhibit a relative adrenal insufficiency in the face of critical illness. Tantivit et al. reported seven term infants with vasopressor-resistant hypotension, all of whom responded to hydrocortisone therapy. Cortisol concentrations were obtained in six of the seven infants, and five of the six values were <276 nmol/l (<10 µg/dl).48 Subsequently, Pittinger and Sawin reported that 79% of 34 cortisol values obtained in 10 infants with congenital diaphragmatic hernia were <200 nmol/l (<7 µg/dl).49 A recent abstract evaluating the prevalence of adrenal insufficiency in mechanically ventilated term infants found that 11 of 16 infants (69%) with vasopressor-resistant hypotension had cortisol values of <276 nmol/l (<10 µg/dl), and seven of those values were <138 nmol/l (<5 µg/dl).50 In the infants with low cortisol values, blood pressure improved after hydrocortisone administration.50 These findings suggest that some term infants, like patients in other populations, may exhibit a relative adrenal insufficiency in the face of acute illness. These small studies in acutely ill term infants are reminiscent of the first studies demonstrating decreased adrenal function in preterm infants, reminding us how much work remains to be done. In conclusion, the effects of abnormal fetal adrenal development appear to have consequences far beyond those previously thought, both in infancy and adult life. Cortisol concentrations in
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many acutely ill infants—term as well as preterm—are quite low, and would be considered clearly inadequate in other populations. Observational and small interventional studies suggest that these low cortisol values correlate with abnormal function, particularly of the cardiovascular system, and with the development of BPD. Although one multicentre clinical trial is known to be under way further evaluating the use of low-dose hydrocortisone to prevent BPD, additional investigation is needed, especially in the term infant in whom adrenal function has received minimal attention thus far. Also, as we have repeatedly been reminded, all interventional studies in infants must include assessment of neurodevelopmental and other long-term outcomes for a full understanding of their risks and benefits.
Practice points • Vasopressor-resistant hypotension may represent adrenal insufficiency. • High doses of glucocorticoid are not necessary to treat adrenal insufficiency. • Stress increases cortisol, and sustained increases in cortisol are detrimental; wherever possible, we should decrease infant stress in the neonatal intensive care unit.
Research directions • Effects of prenatal and postnatal growth restriction on HPA axis reactivity and long-term outcomes in premature infants. • Short- and long-term effects of cortisol replacement therapy in extremely premature infants. • Effects of stress on cortisol concentrations in premature infants, and correlation with growth parameters. • Incidence and consequences of relative adrenal insufficiency in acutely ill term infants.
References 1. Williams HW, Dluhy RG. Diseases of the adrenal cortex. In: Fauci AS, Braunwald E, Isselbacher KJ et al., editors. Harrison's principles of internal medicine. The McGraw-Hill Companies Inc., 1998;2035–57.
2. Reynolds RM, Walker BR, Syddall HE et al. Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 2001; 86:245–50. 3. Thompson C, Syddall H, Rodin I et al. Birth weight and the risk of depressive disorder in late life. Br J Psychiatry 2001; 179:450–5. 4. Lackland DT, Bendall HE, Osmond C et al. Low birth weights contribute to the high rates of early-onset chronic renal failure in the southeastern United States. Arch Intern Med 2000;160:1472–6. 5. Colasurdo MA, Hanna CE, Gilhooly JT et al. Hydrocortisone replacement in extremely premature infants with cortisol insufficiency. Clin Res 1989;37:180A. 6. Ward RM, Kimura RE, Rich-Denson C. Addisonian crisis in extremely premature neonates. Clin Res 1991;39:11A. 7. Lamberts SWJ, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997;337:1285–92. 8. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727–34. 9. Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 1997; 18:378–403. 10. Rudolph AM, Roman C, Gournay V. Perinatal myocardial DNA and protein changes in the lamb: effect of cortisol in the fetus. Pediatr Res 1999;46:141–6. 11. Pepe GJ, Albrecht ED. Actions of placental and fetal adrenal steroid hormones in primate pregnancy. Endocr Rev 1995; 16:608–48. 12. McTernan CL, Draper N, Nicholson H et al. Reduced placental 11-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab 2001;86:4979–83. 13. McLean M, Smith R. Corticotrophin-releasing hormone and human parturition. Reproduction 2001;121:493–501. 14. Wadhwa PD, Sandman CA, Garite TJ. The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Prog Brain Res 2001;133:131–42. 15. Parker CR Jr, Faye-Peterson O, Stankovic AK et al. Immunohistochemical evaluation of the cellular localization and ontogeny of 3-hydroxysteroid dehydrogenase/delta 5–4 isomerase in the human fetal adrenal gland. Endocr Res 1995;21:69–80. 16. Economides DL, Nicolaides KH, Linton EA et al. Plasma cortisol and adrenocorticotropin in appropriate and small for gestational age fetuses. Fetal Ther 1988;3:158–64. 17. Kajantie E, Dunkel L, Turpeinen U et al. Placental 11hydroxysteroid dehydrogenase-2 and fetal cortisol/ cortisone shuttle in small preterm infants. J Clin Endocrinol Metab 2003;88:493–500. 18. Falkenberg ER, Davis RO, DuBard M et al. Effects of maternal infections on fetal adrenal steroid production. Endocr Res 1999;25:239–49. 19. Ng PC, Lam CWK, Lee CH et al. Reference ranges and factors affecting the human corticotropin-releasing hormone test in preterm, very low birth weight infants. J Clin Endocrinol Metab 2002;87:4621–8. 20. Watterberg KL, Scott SM, Naeye RL. Chorioamnionitis, cortisol and acute lung disease in very low birth weight infants. Pediatrics 1997;99 (URL http://www.pediatrics.org/cgi/content/full/99/2/e6. 21. Newnham JP, Moss TJM, Nitsos I et al. Antenatal steroids: the good, the bad and the unknown. Curr Opin Obstet Gynecol 2002;14:607–12.
Adrenocortical function and dysfunction 22. Bolt RJ, van Weissenbruch MM, Popp-Snijders C et al. Fetal growth and the function of the adrenal cortex in preterm infants. J Clin Endocrinol Metab 2002;87:1194–9. 23. Naeye RL, Harcke HT Jr, Blanc WA. Adrenal gland structure and the development of hyaline membrane disease. Pediatrics 1971;47:650–7. 24. Yanowitz TD, Jordan JA, Gilmour CH et al. Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res 2002;51:310–6. 25. Watterberg KL, Demers LM, Scott SM et al. Chorioamnionitis and early lung inflammation in babies who develop bronchopulmonary dysplasia. Pediatrics 1996;97:210–5. 26. Yoon BH, Jun JK, Romero R et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997;177:19–26. 27. De Kloet ER, Vreugdenhil E, Oitzl MS et al. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269–301. 28. Seri I, Tan R, Evans J. Cardiovascular effects of hydrocortisone in preterm infants with pressor-resistant hypotension. Pediatrics 2001;107:1070–4. 29. Joosten KFM, De Kleijn ED, Westerterp M et al. Endocrine and metabolic responses in children with meningococcal sepsis: striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab 2000;85:3746–53. 30. Annane D, Sebille V, Charpentier C et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862–71. 31. Briegel J, Jochum M, Gippner-Steppert C et al. Immunomodulation in septic shock: hydrocortisone differentially regulates cytokine responses. J Am Soc Nephrol 2001; 12:S70–4. 32. Al Saedi S, Dean H, Dent W et al. Reference ranges for serum cortisol and 17-hydroxyprogesterone levels in preterm infants. J Pediatr 1995;126:985–7. 33. Korte C, Styne D, Merritt TA et al. Adrenocortical function in the very low birth weight infant: improved testing sensitivity and association with neonatal outcome. J Pediatr 1996; 128:257–63. 34. Hingre RV, Gross SJ, Hingre KS et al. Adrenal steroidogenesis in very low birth weight preterm infants. J Clin Endocrinol Metab 1994;78:266–70. 35. Huysman MWA, Hokken-Koelega ACS, DeRidder MAJ et al. Adrenal function in sick very preterm infants. Pediatr Res 2000;48:629–33.
21 36. Watterberg KL, Scott SM. Evidence of early adrenal insufficiency in babies who develop bronchopulmonary dysplasia. Pediatrics 1995;85:120–5. 37. Scott SM, Watterberg KL. Effect of gestational age, postnatal age, and illness on plasma cortisol concentrations in premature infants. Pediatr Res 1995;37:112–6. 38. Hanna CE, Jett PL, Laird MR et al. Corticosteroid binding globulin, total serum cortisol and stress in extremely low birth weight infants. Am J Perinatol 1997;14:201–4. 39. Arnold JD, Bonacruz G, Leslie GI et al. Antenatal steroids modulate the amplitude of pulsatile cortisol secretion in premature neonates. Pediatr Res 1998;44:876–81. 40. Goldstein RF, Thompson RJ Jr, Oehler JM et al. Influence of acidosis, hypoxemia and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics 1995;95:238–43. 41. Yoder BA, Martin H, McCurnin DC et al. Impaired urinary cortisol excretion and early cardiopulmonary dysfunction in immature baboons. Pediatr Res 2002;51:426–32. 42. Bourchier D, Weston PJ. Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birth weight infants. Arch Dis Child 1997; 76:F174–8. 43. Watterberg KL, Gerdes JS, Gifford KL et al. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 1999;104:1258–63. 44. Banks BA, Stouffer N, Cnaan A et al. Association of plasma cortisol and chronic lung disease in preterm infants. Pediatrics 2001;107:494–8. 45. Merz U, Pfaffle R, Peschgens T et al. The hypothalamicpituitary-adrenal axis in preterm infants weighing ≤1250 g: association with perinatal data and chronic lung disease. Acta Paediatr 1998;87:313–7. 46. Watterberg KL, Scott SM, Backstrom C et al. Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus. Pediatrics 2000;105:320–4. 47. Watterberg KL, Gerdes JS, Cook KL. Impaired glucocorticoid synthesis in premature infants developing chronic lung disease. Pediatr Res 2001;50:190–5. 48. Tantivit P, Subramanian N, Garg M et al. Low serum cortisol in term newborns with refractory hypotension. J Perinatol 1999;19:352–7. 49. Pittinger TP, Sawin RS. Adrenocortical insufficiency in infants with congenital diaphragmatic hernia: a pilot study. J Pediatr Surg 2000;35:223–6. 50. Fernandez EF, Watterberg KL. Evidence of adrenal insufficiency in term infants with refractory hypotension. Pediatric Res 2002;51:288A.
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
REVIEW ARTICLE
Adrenocortical function and dysfunction in the fetus and neonate Kristi L. Watterberg * Division of Neonatology, MSC10 5590, University of New Mexico, Albuquerque, NM 87131-0001, USA
KEYWORDS Cortisol; Adrenal insufficiency; Adrenal cortex; Infant; Premature infant; Hypotension; Adrenal development; Fetal
Summary Under normal circumstances, the fetus is exposed to very low concentrations of cortisol until late in gestation. Perturbations of the intra-uterine environment resulting in fetal exposure to increased cortisol may have consequences not only in infancy, but also into adult life. In the postnatal period, developmental immaturity and/or the effects of critical illness on adrenal function may result in insufficient cortisol production to maintain homeostasis in the face of acute stress or illness, a situation that has been labelled ‘relative adrenal insufficiency’ in other acutely ill populations. The definition of inadequate adrenal function in the newborn and its possible relationship to adverse outcomes in both premature and term infants are only beginning to be characterized. © 2003 Elsevier Ltd. All rights reserved.
Introduction The activation of the hypothalamic-pituitaryadrenal (HPA) axis is critical to maintain homeostasis in response to stress, and the effects of adrenal insufficiency have been well described.1 However, for many years, clinical interest in newborn adrenocortical function was primarily limited to the effects of absolute steroid deficiencies produced by inborn errors of metabolism. Recently, fetal and neonatal adrenal function and dysfunction have become areas of intense interest and controversy. Although part of this increased interest results from a new focus on the potential effects of adrenal function on clinical disease and outcomes in the extremely premature infant, an additional driving force has been the hypothesis that exposure of the fetus to abnormal cortisol concentrations may lead to a broad range of adult diseases, including hypertension, coronary heart disease, type II diabetes, chronic renal failure and depression.2–4 * Tel.: +1-505-272-6753; fax: +1-505-272-1539 E-mail address: [email protected] Watterberg).
(K.L.
Increasing survival of extremely immature infants first provided new incentive for investigation of adrenal function in the newborn. Two abstracts, in 1989 and 1991, first described cortisol insufficiency, or ‘Addisonian crisis’, in extremelylow-birthweight infants,5,6 and many studies have followed, exploring the relationship of adrenal function to clinical illness and outcomes in these infants. In addition, the recent emergence of an entity labelled ‘relative adrenal insufficiency’ in other critically ill patient populations7,8 obliges us to consider and explore the effects of acute illness on adrenal function in critically ill infants of all gestational ages who exhibit cardiovascular instability and other signs consistent with adrenal insufficiency. The primary focus of this review of fetal and neonatal adrenocortical function, therefore, will not be on the effects of inborn errors of steroidogenesis or exogenous glucocorticoid administration, prenatally or postnatally. Instead, the objectives are: (1) to briefly review normal fetal adrenal development and to consider the effects of increased fetal cortisol exposure resulting from
1084-2756/04/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2003.08.003
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Table 1
Factors affecting fetal adrenal function
Maternal: cortisol passively transferred to the fetus suppresses the fetal HPA axis – Increased production during maternal stress – Increased transfer during early gestation – Increased transfer in the presence of decreased placental 11-HSD2 activity Placental: 11-HSD2 – Converts maternal cortisol to cortisone – Modulates exposure of fetus to maternal cortisol Placental CRH – Stimulates fetal HPA axis – Is in turn stimulated by increased fetal cortisol – Increases exponentially prior to delivery Chorioamnionitis – Pro-inflammatory cytokines stimulate fetal HPA axis Fetal: responds to maternal and placental signals during development – HPA axis is suppressed by maternal cortisol – HPA axis is stimulated by placental CRH or chorioamnionitis HPA axis, hypothalamic-pituitary-adrenal axis; CRH, corticotrophin-releasing hormone.
perturbations of the intra-uterine environment; (2) to review current literature concerning adrenal function in the newborn, particularly the extremely immature infant; and (3) to consider the possible effects of critical illness on adrenal function in the newborn.
Fetal adrenocortical development The development of the fetal adrenal cortex takes place in a complex milieu of maternal, placental and fetal interactions that, under normal circumstances, combine to shield the fetus from significant cortisol exposure until late in gestation. This situation promotes continuing growth and proliferation of fetal tissues, and defers the differentiating effects of glucocorticoids until late in gestation, when increased fetal cortisol concentrations induce the maturation necessary for postnatal life.9,10 All three components of this system—maternal, placental and fetal—are essential for normal fetal adrenal development, and perturbation of any of them can affect the outcome. Below is a brief capsule of these complex interactions, summarized in Table 1 (for an extensive review, see Refs. 9 and 11).
Maternal Early in gestation, the placenta has little capacity to convert maternal cortisol to the biologically inactive cortisone (see section below). Therefore, through midgestation, a small percentage of maternal cortisol is passively transmitted into the fetal circulation, exerting negative feedback on the fetal HPA axis and suppressing fetal cortisol production.11 Late in gestation, as placental metabolic activity matures during the third trimester, less maternal cortisol reaches the fetus, resulting in increased fetal adrenocorticotrophic hormone (ACTH) secretion and cortisol production.11
Placental The placenta performs a myriad of endocrine functions throughout gestation. Two placental factors crucial to fetal adrenal development are 11 hydroxysteroid dehydrogenase type 2 (11-HSD2) and placental corticotrophin-releasing hormone (CRH). The enzyme 11-HSD2 oxidizes cortisol to the biologically inactive cortisone, and is a primary regulator of fetal exposure to maternal cortisol. The activity of this enzyme is very low during the first half of gestation, allowing passive transmission of maternal cortisol through the placenta to the fetus. As the placenta matures during the last trimester, 11-HSD2 activity increases markedly, converting an increasing percentage of maternal and fetal cortisol to cortisone, thereby decreasing negative feedback to the fetal HPA axis and stimulating production of fetal ACTH and cortisol.11,12 The placenta is also the source of large quantities of CRH. In contrast to hypothalamic CRH, which is inhibited by high cortisol concentrations, placental CRH appears to be stimulated by cortisol.13 Placental CRH is released into both the fetal and the maternal circulation, and increases exponentially as gestation progresses toward term,13 stimulating fetal adrenal steroid production. The primary product of the fetal zone of the adrenal gland, dehydroepiandrosterone sulphate (DHEAS), circulates back to the placenta, where it becomes a key substrate for the synthesis of placental oestrogens, which in turn stimulate further production of 11-HSD2 in the placenta.11 This becomes a continuing ‘feed-forward’ loop as the third trimester progresses, where exponentially increasing placental CRH and decreasing maternal cortisol stimulate increasing fetal DHEAS and cortisol production, in turn resulting in increased placental oestrogen production which stimulates more 11-HSD2, and so forth, eventually culminating in parturition.11,13 Early elevation of placental CRH in the maternal
Adrenocortical function and dysfunction
circulation has been associated with preterm delivery, implicating the neuro-endocrine axis in this process.13,14
Fetal In response to the hormonal signals above, the fetal adrenal gland undergoes massive hypertrophy during the latter part of gestation, reaching weights at term that will not be achieved again until adulthood.9 However, this hypertrophy primarily takes place in the ‘fetal zone’ of the adrenal cortex, whose primary product is not cortisol, but dehydroepiandrosterone and its sulphate, DHEAS, a primary substrate for production of placental oestrogens (see above). Through most of gestation, the fetal adrenal gland is deficient in the enzyme 3 hydroxysteroid dehydrogenase (3HSD), which catalyses an essential step in the production of cortisol and other adrenal steroids from cholesterol. Immunohistochemical staining for 3HSD is almost absent in human fetal adrenal tissue at midgestation, then begins to increase in intensity during the third trimester, staining most heavily at term.15 Numerous studies indicate that the human fetal adrenal cortex cannot produce cortisol de novo before 23 weeks of gestation, and normally does not do so until as late as 30 weeks of gestation.9 Instead, the fetus synthesizes cortisol from the abundant placental progesterone, bypassing the need for 3HSD.9 Passive exposure to maternal cortisol contributes to suppression of fetal ACTH secretion during the first part of gestation. Diminishing placental transmission of maternal cortisol late in gestation, together with increasing CRH exposure, stimulates fetal ACTH secretion, which in turn results in the necessary development of the adrenal neocortex and maturation of 3HSD activity. As a consequence of these interactions, fetal cortisol concentrations are normally quite low until well into the third trimester.16,17 Considering the normal time line for fetal adrenocortical maturation, we should be surprised, not that extremely premature infants may have limited ability to maintain homeostasis in response to postnatal stress, but that such infants can maintain homeostasis at all. It is possible that they owe this precocious ability, at least in part, to the very perturbation of the intra-uterine environment that led to their premature delivery. For example, in the above histologic study, the adrenal gland of a 22week-gestation fetus delivered after 10 weeks of ruptured membranes showed unexpected, dense staining for 3HSD.15
15
Perturbations of the intra-uterine environment In the normal pregnancy, very low concentrations of cortisol are present in the fetal circulation until late in gestation, as above. However, perturbation in any of the three compartments affecting the fetus—maternal, placental or fetal—can result in exposure of the fetus to elevated cortisol concentrations. On the one hand, the fetus may be passively exposed to excess maternal cortisol, either from increased maternal production (from, for example, increased maternal stress or undernutrition14) or from decreased activity of 11-HSD2 in the placenta.12 On the other hand, the fetus may actively secrete increased amounts of cortisol in response to stimulatory factors, such as proinflammatory cytokines produced by chorioamnionitis.18 In some ways, these two pathways—active and passive—may produce similar effects, since both result in the exposure of the fetus to increased cortisol concentrations inappropriately early in gestation. Other effects may be quite different. Passive exposure to excess glucocorticoid suppresses the fetal HPA axis,19 whereas activation of the fetal axis can enhance postnatal cortisol production.20 Fetal exposure to excess exogenous glucocorticoid causes decreased birth weight and organ weights in animals.21 In one elegant study of the direct effect of increased cortisol concentrations on cellular growth and differentiation, Rudolph et al. infused cortisol directly into the left coronary artery of fetal sheep at about two-thirds of gestation, achieving local concentrations of cortisol in the left ventricle equal to those normally present at the end of gestation. These authors found that premature exposure to increased cortisol produced premature differentiation, inhibiting myocyte replication and resulting in markedly decreased total DNA, i.e. hypoplasia.10 In human studies, decreased birth weight has been seen following exogenous glucocorticoid exposure.21 In addition, both maternal stress and decreased 11-HSD2 activity, which passively increase fetal cortisol exposure, have been linked to lower birth weights in term and preterm infants.12,14,17 In premature infants, lower birth weight has also been associated with both decreased ACTH in fetal blood16 and decreased response to ACTH stimulation in the newborn,22 both indicating fetal HPA axis suppression. The primary trigger for increased active fetal cortisol production is prenatal inflammation, i.e. chorioamnionitis. Histologic chorioamnionitis is quite common in preterm deliveries, occurring in
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more than half of the pregnancies delivered before 30 weeks' gestation.20 Chorioamnionitis generates pro-inflammatory cytokines, including interleukin 1 and interleukin 6, which stimulate the HPA axis.18,20 In 1971, a series of 387 autopsies showed that premature infants with chorioamnionitis had larger adrenal glands than those without, and that infants who died of respiratory distress syndrome had smaller adrenal glands than those dying of other causes.23 More recently, premature infants exposed to histologic chorioamnionitis were found to have increased cortisol concentrations and increased response to ACTH stimulation during the first week of postnatal life, as well as decreased requirements for respiratory support.20 These findings may suggest a beneficial effect of inflammation-induced precocious maturity of the fetal HPA axis. However, the same systemic inflammatory response that stimulates the fetal HPA axis may produce its own short- and long-term adverse effects, such as hypotension, bronchopulmonary dysplasia (BPD) or neurodevelopmental abnormalities.24–26 The effects of increased fetal exposure to cortisol may even persist into adulthood. The first link reported between low birth weight and hypertension in adulthood was quickly followed by an explosion of interest in the relationship of fetal growth and growth restriction to adverse outcomes in adult life.2–4 This new field, dubbed the ‘fetal origins’ or ‘fetal programming’ of adult disease, has now linked fetal growth restriction to other cardiovascular diseases, type II diabetes and insulin resistance syndrome, depression and end-stage renal disease.2–4 The postulated mechanism linking low birth weight with these widely diverse adverse outcomes is increased fetal exposure to cortisol, with resultant life-long changes in total organ cell numbers, as well as an altered ‘set-point’ and exaggerated sensitivity of the HPA axis to stress.2 At present, these links between intra-uterine growth restriction and adult disease remain epidemiologic, providing fertile ground for continuing research— although following the HPA axis prospectively from infancy to adulthood will present a real challenge of long-term follow-up!
Postnatal adrenal function Adrenal physiology Activation of the HPA axis is critical to maintain homeostasis in response to stress. Although “the reasons why elevated glucocorticoid levels protect the organism under stress are not well
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understood . glucocorticoid deficiency . may cause hypotension, shock and death.”1 Among its many actions, cortisol: (1) regulates protein, carbohydrate, lipid and nucleic acid metabolism; (2) maintains vascular responsiveness to circulating vasoconstrictors and opposes the increase in capillary permeability during acute inflammation; (3) regulates extracellular water by reducing movement of water into cells and by promoting free water excretion; (4) suppresses the inflammatory response; and (5) modulates central nervous system (CNS) processing and behaviour.1,27 Following logically from the above paragraph, signs of acute adrenal insufficiency can include hypoglycaemia (although this may not be seen in patients with continuous intravenous dextrose infusion), amplified responses to inflammatory stimuli, hyponatraemia with oliguria, and, perhaps most notably, cardiovascular dysfunction and circulatory collapse. Although classic glucocorticoid physiology teaches that steroids act through gene transcription, the rapidity of some responses to cortisol replacement, particularly cardiac function, demonstrates that they must also act through other, ‘nongenomic’ mechanisms. For example, premature infants with vasopressor-resistant hypotension showed significantly increased blood pressure within 2 h of receiving hydrocortisone.28 Such a prompt response may result from an immediate increase in cytosolic calcium availability caused by the interaction of cortisol with membrane-bound receptors.28 Cortisol may also improve cardiac function by reversing the downregulation of adrenergic receptors, inhibiting nitric oxide synthase expression and/or prostacyclin production, decreasing the re-uptake of norepinephrine, improving capillary integrity, or other mechanisms.28 In addition to its crucial metabolic effects, cortisol also modulates CNS function, especially in the hippocampus where it affects learning and memory.27 There is extensive documentation of the adverse effects of prolonged high glucocorticoid concentrations on the CNS at all stages of development; however, it is also clear that adrenal insufficiency is detrimental to CNS function and that both situations result in apoptosis and neurodegeneration.27 Thus, cortisol and the CNS interact in a delicate balance, where too much or too little glucocorticoid adversely affects structure and function.
Relative adrenal insufficiency Although the incidence of absolute adrenal insufficiency in critically ill patients is rare, a phenomenon labelled ‘relative adrenal insufficiency’ or
Adrenocortical function and dysfunction Table 2
Features of relative adrenal insufficiency
Described in acutely stressed adults and children (e.g. illness, surgery, trauma) Basal cortisol values may be within normal range, but are insufficient for the situation Patients have decreased response to ACTH stimulation Primary presentation is cardiovascular instability, with hypotension and shock May result in increased mortality Aetiology, definition and prevalence unclear ACTH, adrenocorticotrophic hormone.
‘relative AI’ has recently been described in both adult and paediatric populations.7,8,29,30 These patients present with cardiovascular instability and shock, and have higher mortality rates (Table 2). Such patients have detectable, even apparently normal, cortisol concentrations; however, these cortisol concentrations are inadequate for the severity of their illness, and their response to ACTH stimulation is diminished.7,8,29,30 The aetiology of this relative AI in the face of acute illness is unclear; postulated mechanisms have included cytokine-related suppression of ACTH or cortisol synthesis, cytokine-induced tissue resistance to cortisol actions, inadequate perfusion of the adrenal gland, or a limited adrenocortical reserve.7,8,29,31 The definition of relative AI has not been well established. One recent review suggested that a critically ill adult with a random cortisol value of <414 nmol/l (15 µg/dl) should be considered to have relative AI, and that individuals with concentrations between 15 and 34 µg/dl should have ACTH stimulation performed.8 A rise in serum cortisol of <250 nmol/l (<9 µg/dl) after stimulation is also likely to represent relative AI, and such patients may benefit from hydrocortisone therapy.8,30 Since the definition of this entity is not well established, its prevalence is also unclear; however, it appears to be quite common in septic shock and variable in other conditions.7,8,29,30 Low-dose hydrocortisone treatment of patients with septic shock has been shown to decrease serum concentrations of proinflammatory cytokines, attenuate the systemic inflammatory response syndrome, and improve survival.30,31 Adrenal function in the premature infant Considering the abrupt interruption of the normal intra-uterine influences on adrenal development, it would seem reasonable to expect that premature infants, particularly those born before 29–30 weeks
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of gestation, would have limited capacity to maintain homeostasis in an extra-uterine environment. Considering also the severity of illness frequently present in these patients, the premature infant could have two factors contributing to inadequate adrenal function: developmental immaturity and relative adrenal insufficiency in the face of acute illness. Therefore, the extremely premature infant may be able to produce enough cortisol to maintain homeostasis under non-stressful conditions, but insufficient cortisol to respond appropriately to stress. As more such infants survive, assessing and supporting adrenal function in this group acquire increasing clinical importance. The assessment of adrenal function and adrenal insufficiency in premature infants has been complicated by the difficulty of defining appropriate cortisol values for this population. After the cortisol surge at delivery, clinically well infants may have very low basal cortisol values without apparent compromise;32 however, such values cannot be considered appropriate for sick, stressed patients. Similar difficulties hamper efforts to define normal values for response to ACTH stimulation. First, stimulation studies in the literature are difficult to compare. Most have used the ACTH analogue cosyntropin (1–24 corticotropin), but at doses ranging from 0.1 to 36 µg/kg.33,34 Other studies have used CRH, testing pituitary as well as adrenal function. The entire HPA axis can only be tested with metyrapone suppression or induction of hypoglycaemia, neither of which is acceptable in these fragile patients. Whichever test has been used, many sick premature infants have typically shown low basal cortisol concentrations and blunted response to stimulation compared with other populations. In clinically well adults, the peak cortisol value after stimulation is considered the most reliable parameter for assessing adrenal response to ACTH stimulation, and a stimulated value of ≥500 nmol/l (>18 µg/dl) is often considered normal.1 A number of authors have found that perhaps only half of sick premature infants achieve that value after ACTH or CRH stimulation.19,33–36 Although the concentration of cortisol-binding globulin (CBG) in preterm infants is somewhat lower than in adults, the low basal cortisol concentrations and reduced response to stimulation seen in preterm infants cannot be explained by variations in CBG concentrations.33,37,38 The high incidence in these infants of a response that would be considered inadequate in other populations creates a dilemma: should a lower response to ACTH or CRH testing be considered ‘normal’ for
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this population? Or is this a normal fetal response, which may be inadequate for the stresses of postnatal life, predisposing these infants to adrenal insufficiency when faced with acute illness? To address this question, the relationship of cortisol values to measures of acute illness and outcome must be considered.
Adrenal function and acute illness in preterm infants Two abstracts first described functional consequences of inadequate adrenal function in extremely-low-birthweight infants, presenting two series of infants with clinical cortisol insufficiency, or ‘Addisonian crisis’.5,6 These infants exhibited hypotension, oliguria and hyponatraemia, with cortisol values of <414 nmol/l (<15 µg/dl). All responded to hydrocortisone supplementation with improvement in blood pressure, urine output and sodium concentrations. Subsequent studies of the relationship of cortisol values to acute illness in preterm infants have shown that, instead of the higher cortisol values expected in sick patients, lower cortisol values are often seen in sicker infants,35,38 including those who require mechanical ventilation19,35,37 and those with hypotension.37,39 The relationship of cortisol values to hypotension is of particular interest, both because hypotension is associated with adverse outcomes in the premature infant,40 and also because it is a primary presentation of adrenal insufficiency in other populations. Many premature infants are treated with vasopressors for hypotension, yet the aetiology of this common phenomenon has been unclear. Studies in baboons and human infants have now shown that arterial blood pressure correlates with cortisol production.39,41 Response to hydrocortisone therapy in premature infants with vasopressor-resistant hypotension is rapid and convincing,28 further implicating inadequate adrenal function in its pathogenesis. One randomized trial compared the efficacy of dopamine with hydrocortisone for primary treatment of hypotension in very-low-birthweight infants, and found them to be similarly effective.42 These authors did not find a relationship between cortisol values and blood pressure response; however, their study was performed on the first day of life, and the cortisol surge at delivery might have obscured any differences. The average rise in cortisol after ACTH in these infants was <250 nmol/l (<9 µg/dl), a value suggested to be inadequate in other sick populations (see above).8
Figure 1 Basal and stimulated cortisol values in very-lowbirthweight infants during the second half of the first week of life (mean±SEM). Infants developing bronchopulmonary dysplasia (filled bar), defined as receiving supplemental oxygen at 36 weeks’ postmenstrual age, had significantly lower basal cortisol concentrations (P<0.05) and lower response to ACTH stimulation (P<0.02) than those who did not (open bar). Cumulative data from previous studies, analysed by multiple regression including gestational age.20,36,37
Adrenal function and outcome The first study investigating the relationship of adrenal function in premature infants to a clinical outcome explored its association with the development of BPD.36 Infants who develop BPD show early increases in markers of lung inflammation.25 As cortisol is essential to control the body's response to inflammation, the hypothesis of the study was that inadequate cortisol activity led to amplified inflammatory responses, resulting in chronic lung disease. ACTH stimulation testing performed at the end of the first week of life showed that infants who developed BPD had a significantly lower response to ACTH, with a median poststimulation cortisol of 367 nmol/l (13.3 µg/dl) compared with 520 nmol/l (18.8 µg/dl) in those who did not develop BPD.36 Fig. 1 shows basal and ACTHstimulated cortisol values during the first week of life; values in infants developing BPD are significantly lower than those in infants who recover without BPD. Several subsequent studies have shown lower basal and/or stimulated cortisol values in infants developing BPD,33,35,43,44 although one study did not find this association.45 Other findings supporting the link between decreased adrenal function and BPD include: (1) an inverse correlation of serum cortisol values with markers of lung inflammation; (2) significantly lower cortisol values in infants with patent ductus arteriosus, a condition almost universally cited as a factor predisposing to BPD; and
Adrenocortical function and dysfunction Table 3
19
Randomized studies of hydrocortisone therapy in infants
Reference Bourchier and Weston Watterberg et al.43
42
Purpose
Design
Sample size
Outcome
Treat hypotension Prevent BPD
Randomized, blinded Randomized, blinded
40 40
Efficacy similar to dopamine Improved survival without BPD
BPD, bronchopulmonary dysplasia.
(3) increased precursors to cortisol synthesis in such infants, again indicating decreased capacity to synthesize cortisol.46,47 The observation that decreased early adrenal function was associated with the subsequent development of BPD led to a pilot study of 40 infants, testing the effect of prophylaxis of early adrenal insufficiency on its development (Table 3). Hydrocortisone was given during the first two weeks of life, at a dose intended to achieve serum levels seen in acutely ill patients in other populations.7,8,29,30 Preliminary pharmacokinetic studies led to the use of a dose of 1 mg/kg/day, equivalent to about 5% of the previously used dexamethasone dose of 0.5 mg/kg/day, and lower than doses often given to hypotensive premature infants.5,6,28,42 A median serum concentration of 717 nmol/l (26 µg/ dl) was achieved without suppression of adrenal function when tested three days after the end of therapy.43 The 20 infants treated with hydrocortisone showed a significant increase in survival without oxygen dependence at 36 weeks' postmenstrual age.43 In addition, and in contrast to many dexamethasone studies, the infants treated with hydrocortisone showed no impairment of head growth or weight gain at 36 weeks' postmenstrual age compared with placebo. Although these results are promising, the study was far too small to adequately evaluate possible adverse effects. A large, multicentre trial is now under way to test this hypothesis in a much larger population and to monitor neurodevelopmental outcomes. Until the effects of hydrocortisone replacement therapy can be evaluated in large clinical trials, clinical use in the preterm infant should probably be restricted to those infants with vasopressor-resistant hypotension, since persistent hypotension has been linked to adverse outcomes.40 In summary, considering the possible adverse effects of adrenal insufficiency on one hand, and the possible links between excess fetal or neonatal glucocorticoid exposure and adverse long-term outcomes on the other, the very premature infant finds himself or herself caught in a very difficult situation. Cortisol is essential to maintain homeostasis
in response to extra-uterine stressors, yet exposure to increased glucocorticoid activity at a time when such exposure should be low could have long-term adverse effects. At a minimum, this would argue in favour of decreasing environmental and other stressors in the neonatal intensive care unit wherever possible to decrease unnecessary cortisol secretion.
The term infant While adrenal function in the preterm infant has received increasing attention over the past years, extremely little work has thus far been published investigating the effect of critical illness on adrenal function in term infants. Small studies have recently suggested that these patients, too, may exhibit a relative adrenal insufficiency in the face of critical illness. Tantivit et al. reported seven term infants with vasopressor-resistant hypotension, all of whom responded to hydrocortisone therapy. Cortisol concentrations were obtained in six of the seven infants, and five of the six values were <276 nmol/l (<10 µg/dl).48 Subsequently, Pittinger and Sawin reported that 79% of 34 cortisol values obtained in 10 infants with congenital diaphragmatic hernia were <200 nmol/l (<7 µg/dl).49 A recent abstract evaluating the prevalence of adrenal insufficiency in mechanically ventilated term infants found that 11 of 16 infants (69%) with vasopressor-resistant hypotension had cortisol values of <276 nmol/l (<10 µg/dl), and seven of those values were <138 nmol/l (<5 µg/dl).50 In the infants with low cortisol values, blood pressure improved after hydrocortisone administration.50 These findings suggest that some term infants, like patients in other populations, may exhibit a relative adrenal insufficiency in the face of acute illness. These small studies in acutely ill term infants are reminiscent of the first studies demonstrating decreased adrenal function in preterm infants, reminding us how much work remains to be done. In conclusion, the effects of abnormal fetal adrenal development appear to have consequences far beyond those previously thought, both in infancy and adult life. Cortisol concentrations in
20
K.L. Watterberg
many acutely ill infants—term as well as preterm—are quite low, and would be considered clearly inadequate in other populations. Observational and small interventional studies suggest that these low cortisol values correlate with abnormal function, particularly of the cardiovascular system, and with the development of BPD. Although one multicentre clinical trial is known to be under way further evaluating the use of low-dose hydrocortisone to prevent BPD, additional investigation is needed, especially in the term infant in whom adrenal function has received minimal attention thus far. Also, as we have repeatedly been reminded, all interventional studies in infants must include assessment of neurodevelopmental and other long-term outcomes for a full understanding of their risks and benefits.
Practice points • Vasopressor-resistant hypotension may represent adrenal insufficiency. • High doses of glucocorticoid are not necessary to treat adrenal insufficiency. • Stress increases cortisol, and sustained increases in cortisol are detrimental; wherever possible, we should decrease infant stress in the neonatal intensive care unit.
Research directions • Effects of prenatal and postnatal growth restriction on HPA axis reactivity and long-term outcomes in premature infants. • Short- and long-term effects of cortisol replacement therapy in extremely premature infants. • Effects of stress on cortisol concentrations in premature infants, and correlation with growth parameters. • Incidence and consequences of relative adrenal insufficiency in acutely ill term infants.
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