KEY POINTS
- 1.
Normal hypothalamic-pituitary-adrenal (HPA) axis production of cortisol and a normal renin-angiotensin-aldosterone axis are needed for the normal regulation of volume status, blood pressure, and serum sodium, potassium and glucose levels in the neonate. Disorders of these axes can be life-threatening.
- 2.
Cortisol deficiency can be due to a disorder of the adrenal gland itself or to impaired ACTH secretion from the pituitary gland.
- 3.
Mineralocorticoid deficiency can result from deficient production of aldosterone from the adrenal gland or from impaired mineralocorticoid signaling.
- 4.
A disorder of sex development, resulting in virilization of a 46,XX fetus or undervirilization of a 46,XY fetus, may indicate an underlying disorder of adrenal steroid synthesis.
- 5.
Transient, relative glucocorticoid deficiency can occur in all newborns in the transition to extrauterine life. This may be exacerbated in the premature infant due to immaturity of the HPA axis and as a consequence of critical illness.
Introduction
The adrenal glands sit on top of the upper pole of each kidney. The inner adrenal medulla produces catecholamines, predominantly epinephrine, which protect against hypotension and hypoglycemia. There are no significant disorders of the adrenal medulla during infancy. The adrenal cortex produces steroid hormones: aldosterone (a mineralocorticoid); cortisol (a glucocorticoid); and androgens, predominantly dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Mineralocorticoid action regulates the body’s fluid volume and serum potassium level, whereas glucocorticoids have a wide range of actions, including controlling the immune response and protecting against hypoglycemia and hypotension. The role of glucocorticoids to protect against hypoglycemia and hypotension are particularly important during times of stress, when healthy individuals will increase cortisol secretion by as much as 10-fold. Neonatal disorders of the adrenal cortex include those that result in deficiency of mineralocorticoid and glucocorticoid action and those that cause excessive mineralocorticoid and androgen action.
Embryology and Development of the HPA Axis
The cells of the adrenal cortex are of mesodermal origin whereas the cells of the adrenal medulla are from the neuroectoderm. Adreno-gonadal progenitor cells appear around the 4th week of gestation, and these cells give rise to steroidogenic cells of the gonads and adrenal cortex around the 7th to 8th weeks of gestation. The complete hypothalamic-pituitary-adrenal (HPA) axis is established by 20 weeks of gestation. The fetal adrenal cortex ( Fig. 27.1A ) consists of a relatively small outer definitive zone and a larger fetal zone. At about midgestation, a transitional zone develops between the definitive and fetal zones. During fetal life, the fetal zone produces large amounts of DHEA and DHEAS, which serve as precursors for placental estrogen production. The definitive zone of the fetal adrenal can produce glucocorticoid and mineralocorticoid. The role of the transitional zone is unclear, although it may be a site of fetal cortisol synthesis. Fetal adrenal glands grow through the third trimester. At birth, they are the same size as adult adrenal glands, that is, they are very large relative to body size. After birth the fetal zone involutes and disappears by about 6 to 12 months of age, with a concomitant decrease in the size of the infant adrenal gland. After birth, while the fetal zone is involuting, the definitive zone slowly enlarges and ultimately forms the three distinct zones of the fully developed adrenal cortex ( Fig. 27.1B ): the outer zona glomerulosa, which produces aldosterone; the middle zona fasciculata, which produces cortisol; and the inner zona reticularis, which produces DHEA, DHEAS, and androstenedione. The glomerulosa and fasciculata zones are not fully differentiated until about 3 years of age, whereas the zona reticularis does not begin to differentiate until after 3 years of age and is not fully developed until 15 years of age.
Steroid hormones are produced using cholesterol as the precursor. Although the adrenal gland can make cholesterol de novo from acetate, most of the cholesterol for postnatal steroid synthesis comes from plasma low-density lipoprotein from dietary cholesterol. The synthetic pathway of adrenal steroid synthesis is shown in Fig. 27.2 . The expression of a subset of the enzymes in the synthetic pathway results in temporal and zone-specific expression of the steroid hormones. Note that although the postnatal adrenal gland makes little or no testosterone, there is evidence that the fetal adrenal gland can synthesize testosterone through the expression of 17β-hydroxysteroid dehydrogenase 5 (17βHSD5). In virilizing forms of congenital adrenal hyperplasia, this adrenal testosterone production can be significant and contributes to the virilization of female fetuses.
In the first half of gestation, maternal cortisol crosses the placenta, inhibiting the fetal HPA axis ( Fig. 27.3A ). However, starting at midgestation and increasing through the last trimester, there is increased expression of placental 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), whose activity converts cortisol to the inactive cortisone ( Fig. 27.3B ). This limits exposure of the fetus to maternal glucocorticoid, decreasing the negative feedback effect on the fetal HPA axis and resulting in an increase in fetal ACTH production. , Although all the enzymes necessary for the synthesis of cortisol are expressed in the developing adrenal gland very early in gestation, by 14 weeks of gestation, 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) is no longer expressed. Until expression of 3βHSD2 returns in the definitive zone (and possibly the intermediate zone) later in gestation, the fetal adrenal cannot synthesize cortisol from cholesterol. This lack of 3βHSD2 expression drives the production of DHEA and DHEAS by the fetal zone. Prior to expression of 3βHSD2 later in gestation, the fetal adrenal can synthesize cholesterol, but it does so by utilizing placental progesterone as the substrate. It is not until after 30 weeks’ gestation that the fetal adrenal typically produces cortisol de novo from cholesterol. Thus infants born at less than 27 to 30 weeks’ gestational age may have more impairment in the HPA axis than infants born at a later gestational age. For infants born after 27 weeks’ gestational age, serum cortisol levels over the first week of life change in response to illness, with infants who are ill showing a rise in serum cortisol and well infants having a decline in serum cortisol. In contrast, serum cortisol levels decrease in infants born prior to 27 weeks’ gestational age, whether they are ill or well. This transient adrenal insufficiency of prematurity seems to be limited to the first 2 weeks of life. A final unique aspect of the fetal HPA axis is that the placenta produces corticotropin releasing hormone (CRH), with the production increasing through the end of gestation (see Fig. 27.3C ). At that time, fetal ACTH is stimulated by the high circulating levels of placental CRH, with suppression of fetal hypothalamic CRH.
Although the enzymes necessary for the production of aldosterone are present in the fetus, mineralocorticoid production is only required postnatally.
Clinical Features of Adrenal Insufficiency
The presentation of neonates and infants with disorders of the adrenal gland and the HPA axis depends on which class of adrenal hormone production is disrupted. If there is impairment of mineralocorticoid signaling, the infant may present with acute life-threatening dehydration and hyponatremia and hyperkalemia. Mineralocorticoid deficiency can also present in infancy with a subacute or chronic presentation of failure to thrive. Glucocorticoid deficiency can present with hypotension and hypoglycemia; the hypotension is compounded by the dehydration that occurs with mineralocorticoid deficiency if that is also present. When the adrenal insufficiency is due to hypopituitarism, there is glucocorticoid deficiency, but there is not mineralocorticoid deficiency, because aldosterone production is under control of the renin-angiotensin system, not ACTH. Disorders of adrenal androgen production can result in a disorder of sexual development, presenting as ambiguous genitalia in the newborn.
Causes of Adrenal Insufficiency
Primary adrenal insufficiency refers to disorders of the adrenal cortex, whereas central adrenal insufficiency refers to glucocorticoid deficiency as a result of impaired ACTH secretion. Depending on the underlying cause, primary adrenal insufficiency can result in mineralocorticoid deficiency in addition to glucocorticoid deficiency. The main causes of adrenal insufficiency in the neonate are listed in Table 27.1 . Primary adrenal insufficiency can occur because of underdevelopment of the adrenal gland or impaired function of the adrenal gland.
| Primary adrenal insufficiency |
| Disorders of adrenal gland development |
| Adrenal hypoplasia congenital (AHC): DAX1 mutation |
| Isolated DAX1 mutation |
| Xp21 continuous gene deletion |
| Mutations of SF1 |
| IMAGe syndrome |
| MIRAGE syndrome |
| Impaired adrenal gland function |
| Isolated glucocorticoid deficiency |
| Familial glucocorticoid deficiency |
| Metabolic disorders |
| Congenital adrenal hyperplasia |
| 21-Hydroxylase deficiency |
| 11-Hydroxylase deficiency |
| 3BHSD-deficiency |
| 17-Hydroxylase deficiency |
| Congenital lipoid adrenal hyperplasia |
| StAR deficiency |
| P450SCC deficiency |
| P450 Oxidoreductase Deficiency (Antler-Bixley Syndrome) |
| Smith-Lemli-Opitz Syndrome |
| Adrenal hemorrhage |
| Disorders of the renin-angiotensin-aldosterone axis |
| Aldosterone synthase deficiency |
| Pseudohypoaldosteronism (PHA) |
| Autosomal dominant PHA, NR3C2 mutations |
| Autosomal recessive, systemic PHA, ENaC mutations |
| Secondary to renal disease |
| Central adrenal insufficiency |
| Hypopituitarism |
| Developmental |
| Postinjury |
| Suppression of HPA axis from exogenous glucocorticoid treatment |
| Treatment of the infant |
| Maternal treatment during gestation |
| Relative adrenal insufficiency |
| Illness-associated |
| Immaturity of the HPA axis |
Disorders of Adrenal Gland Development
X-linked adrenal hypoplasia congenita (AHC) is caused by mutation of the NROB1 gene encoding DAX1 on chromosome Xp21. AHC may be caused by a specific mutation of DAX1 but can also be part of a contiguous gene syndrome along with glycerol kinase deficiency and Duchenne muscular dystrophy. In the most common form the definitive zone of the fetal adrenal gland does not develop. Half of the boys present with salt loss and glucocorticoid insufficiency early in infancy and the rest with adrenal insufficiency throughout childhood. AHC is also associated with hypogonadotropic hypogonadism because DAX1 is involved in pituitary gonadotrope development. Heterozygous mutations in steroidogenic factor 1(SF1, coded for by NR5A1 ) result in complete or partial gonadal dysgenesis, resulting in ambiguous genitalia or a female phenotype in 46,XY infants. There have been rare reports of individuals with NR5A1 mutations also having primary adrenal failure (in at least one case due to a homozygous NR5A1 mutation), although in most patients with heterozygous NR5A1 mutations, adrenal steroidogenesis appears normal. IMAGe syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, and genitourinary anomalies) and MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) are also associated primary adrenal insufficiency from impaired adrenal gland development. IMAGe syndrome is due to a dominant missense mutation of the CDKN1C gene on the maternal allele ( CDKN1C is paternally imprinted). This gene encodes the tumor suppressor P57KIP2. Different mutations in this gene cause Beckwith-Wiedemann syndrome. MIRAGE syndrome is caused by heterozygous missense mutations in the SAMD9 gene.
Familial glucocorticoid deficiency (also called hereditary unresponsiveness to ACTH) is an autosomal recessive condition of impaired cortisol synthesis caused by mutations in a number of genes including MC2R (which codes for the ACTH receptor), MRAP (melanocortin receptor accessory protein gene), MCM4 , TXNRD2 , and NNT. Classically, these patients do not have mineralocorticoid deficiency, although mineralocorticoid deficiency has been described in patients with mutations in NNT. The first symptoms of familial glucocorticoid deficiency typically occur in early infancy and include recurrent hypoglycemia, failure to thrive, or an adrenal crisis precipitated by an illness. The patients often are hyperpigmented at presentation due to the effects of an elevated ACTH level.
Impaired Adrenal Gland Function
A number of metabolic disorders affecting steroid hormone synthesis result in adrenal insufficiency—in some cases affecting just glucocorticoid production, in others affecting both glucocorticoid and mineralocorticoid production. Congenital adrenal hyperplasia, which impairs the synthesis of cortisol from cholesterol, is the most common metabolic disorder causing adrenal insufficiency. Smith-Lemli-Opitz syndrome impairs adrenal function due to a defect in cholesterol synthesis.
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive diseases caused by mutations in the enzymes that are necessary for the production of cortisol (see chapter 27 for further details on these disorders). The impaired fetal production of cortisol results in a rise in ACTH, driving adrenal gland hyperplasia and the overproduction of adrenal steroids that are not dependent on the mutated enzyme. Depending on the type of CAH, this can result in an infant being born with ambiguous genitalia due to virilization of the 46,XX fetus or to undervirilization of the 46,XY fetus. When the infant is not born with ambiguous genitalia (or when the ambiguous genitalia are not recognized, as in the severely virilized 46,XX infant with 21-hydroxylase deficiency who is mistaken for a male without ambiguous genitalia), the infant is at risk of presenting with an acute adrenal crisis with hypotension and hypoglycemia from cortisol deficiency, along with dehydration, hyponatremia, and hyperkalemia if mineralocorticoid deficiency is also present. In part because infants are born in a relatively volume-expanded state, the presentation with a salt-wasting adrenal crisis (from combined glucocorticoid and mineralocorticoid deficiency) classically occurs in the second week of life, although it can occur both earlier and later.
Virilization of the 46,XX fetus with CAH occurs due to the overproduction of DHEA and (in some forms of CAH) androstenedione. These adrenal androgens are converted into testosterone and dihydrotestosterone either in the adrenal gland (due to the expression of 17βHSD5 in the fetal adrenal or outside the adrenal gland due the peripheral expression of 3βHDS1, 17βHSD5, and 5α-reductase). CAH due to deficiency of 21-hydroxylase causes over 90% of CAH. The presentation of 21-hydroxylase deficiency depends on the degree of enzyme deficiency. The mildest form (attenuated or nonclassic) presents in adolescent females with hirsutism and menstrual irregularity. With greater enzyme deficiency (simple virilizing form), 46,XX newborns will present with ambiguous genitalia at birth, and 46,XY children will present as a boy with peripheral precocious puberty in later infancy or early childhood. The most severe form (salt-wasting CAH) will present with ambiguous genitalia in the 46,XX infant, with the virilization sometimes severe enough to appear as a male with bilateral undescended testes. 46,XY infants with salt-wasting 21-hydroxylase deficiency are born with normal male genitalia, presenting with a salt-wasting adrenal crisis in the first week or two of life. Other, rarer forms of CAH that can virilize the 46,XX fetus are those due to mutations in 3βHSD2 ( 3BHSD2 gene) and 11-β-hydroxylase ( CYP11B1 gene). Mutations that result in severe deficiency of 3βHSD2 activity will lead to a risk of a salt-wasting crisis, just as in 21-hydroxylase deficiency. In the 46,XY infant, 11-β-hydroxylase deficiency presents with peripheral precocious puberty. Although this enzyme defect impairs the production of aldosterone, there is overproduction of deoxycorticosterone, which, at the high concentrations achieved, activates the mineralocorticoid receptor. Although these infants can have a salt-wasting crisis in infancy, it is less common than in 21-hydroxylase deficiency. These infants are, however, at risk of having an adrenal crisis from glucocorticoid deficiency, such as during an intercurrent illness or other stress. The unregulated activation of the mineralocorticoid receptor by deoxycorticosterone leads to hypertension in these individuals, although this generally does not occur until after the neonatal period.
Some of the same enzymes that produce cortisol from cholesterol in the adrenal gland are needed to produce testosterone in the testis. Therefore some forms of CAH also impair testosterone production in the 46,XY fetus. Because a high fetal concentration of dihydrotestosterone, derived from a high concentration of testosterone, is needed for the development of normal male genitalia, these forms of CAH result in ambiguous genitalia in the 46,XY fetus. The forms of CAH that result in undervirilization of the 46,XY fetus are those due to mutations in 3BHSD2 and mutations that impair the 17-hydroxylase activity of CYP17A1. Note that 3BHSD2 CAH can cause ambiguous genitalia in both the 46,XX and 46,XY fetus: the overproduction of DHEA in the adrenal virilizes the 46,XX fetus, and the impaired testosterone production in the testis results in undervirilization of the 46,XY fetus. CYP17A1 CAH will not virilize the 46,XX fetus (because there is no overproduction of adrenal DHEA) and also does not put infants at risk of a salt-wasting crisis (because aldosterone synthesis is not impaired.)
Another form of CAH that both virilizes the 46,XX fetus and results in undervirilization of the 46,XY fetus is that due to mutations in P450 oxidoreductase (POR). POR transfers electrons to all microsomal cytochrome P450 enzymes, including P450c17, P450c21, and P450aro; impairing 17-hydroxylase, 17,20-lyase, 21-hydroxylase, and aromatase activities in steroid synthesis (aromatase converts androgens to estrogens). Presumably related to impairment of other P450 enzymes, these patients have the Antley-Bixler skeletal malformation syndrome (ABS), which includes craniosynostosis, brachycephaly, radio-ulnar or radio-humeral synostosis, femoral bowing, midface hypoplasia, and choanal atresia. ABS can also be caused by heterozygous gain-of-function mutations of fibroblast growth factor receptor 2 (in this case, ABS is not associated with abnormal steroid synthesis). POR deficiency does not impair aldosterone production, and glucocorticoid deficiency is variable but is generally mild, with normal baseline cortisol levels but subnormal cortisol levels after ACTH stimulation. Because of impaired placental aromatization of fetal androgens to estrogens, there can be virilization of the mother of a fetus with POR deficiency.
Disorders of Cholesterol Metabolism
Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive defect in cholesterol biosynthesis due to mutations in the steroid delta-7 reductase gene, DHCR7. Features include microcephaly, developmental delay, proximal thumbs, syndactyly of of the second and third toes, cardiac abnormalities, and undervirilized genitalia in 46,XY infants (due to impaired in utero production of dihydrotestosterone). Low serum cholesterol with elevated 7-dehydrocholesterol and 8-dehydrocholesterol and decreased steroid delta 7 reductase activity are found in these patients, with genetic analysis of DHCR7 confirming the diagnosis. In addition to adrenal insufficiency, SLO patients may also have hypoparathyroidism, hypothyroidism, and immunodeficiency. Most patients with SLO have normal-sized adrenal glands, although adrenal hyperplasia has been reported. Milder forms of SLO may not have adrenal insufficiency. In more severe forms of SLO, it is possible that cholesterol deficiency and accumulation of 7DHC and other oxysterols alter the cell membrane and cell membrane rigidity. This leads to absence or malformation of vesicles needed for endocrine and exocrine functioning. One study showed that adrenal function was preserved in patients with mild or moderate SLO treated with dietary cholesterol supplementation.
Other metabolic disorders, including peroxisomal disorders such as Zellweger syndrome, and mitochondrial disorders such as Kearns-Sayre syndrome can have adrenal insufficiency as part of their features. However, the adrenal insufficiency may not be present in infancy, and the other aspects of these diseases predominate.
Adrenal Hemorrhage
Because the neonatal adrenals are large and highly vascular, they are at risk of developing adrenal hemorrhage. In most cases, this is asymptomatic. However, adrenal hemorrhage can also present with marked jaundice, anemia, or a large flank mass. Adrenal insufficiency rarely occurs from adrenal hemorrhage, perhaps only 1% to 2% of the time, in large part because it is only bilateral about 10% of the time. When bilateral adrenal hemorrhage causes adrenal insufficiency, there will be both glucocorticoid and mineralocorticoid deficiency. Risk factors for the development of adrenal hemorrhage include asphyxia, sepsis, coagulation disorders, traumatic deliveries, and perinatal injuries.
Isolated Disorders of Mineralocorticoid Signaling
Aldosterone synthase deficiency is caused by mutations of the CYP11B2 gene that produces the aldosterone synthase enzyme p450C11aldo. These infants present in the first weeks of life with nausea, vomiting, and feeding problems with failure to thrive. Laboratory investigation reveals metabolic acidosis, hyponatremia, hyperkalemia, and a high renin level, with a low or inappropriately normal level of aldosterone.
Aldosterone resistance (pseudohypoaldosteronism [PHA]) can present similar to aldosterone deficiency (nausea, vomiting, failure to thrive, hyponatremia, and hyperkalemia) but with an elevated serum aldosterone level. There are two congenital forms for this. Heterozygous mutations in the NR3C2 gene coding for the mineralocorticoid receptor cause aldosterone resistance that typically has resolution of a need for salt supplementation by 18 to 24 months of age. Mutations in the genes encoding the epithelial sodium channel subunits ( SCNN1A , SCNN1B , and SCNN1G ) cause an autosomal recessive form of PHA that results in a more systemic disorder that includes significant pulmonary and skin disease. This systemic form does not ameliorate with age. Transient PHA is secondary to renal disease, including pyelonephritis and obstructive uropathy.
Central adrenal insufficiency, resulting in deficient ACTH secretion from the pituitary, may be due to developmental hypopituitarism, hypopituitarism from perinatal central nervous system (CNS) injury, or from temporary impairment of ACTH secretion. Central adrenal insufficiency impacts glucocorticoid synthesis, but mineralocorticoid function is normal.
Hypopituitarism
Hypopituitarism as a cause of adrenal insufficiency is discussed in detail in Chapter 27 . Neonates with hypopituitarism may present with direct hyperbilirubinemia or hypoglycemia from the hormone deficiency and with midline defects such as cleft palate or an absent septum pellucidum, which point to a risk for hypopituitarism.
Suppression From Exogenous Glucocorticoid
Prolonged use of systemic or inhaled glucocorticoids can suppress ACTH secretion, which results in atrophy of the adrenal cortex. Both of these issues take time to resolve after withdrawal of exogenous glucocorticoid treatment, and until they do, the patient will have a form of central adrenal insufficiency (the renin-angiotensin-aldosterone axis is not affected). The risk of adrenal suppression in infants appears to be the same as that in older children and adults: if there is use of supraphysiologic doses of systemic glucocorticoid for more than 2 weeks, this places the infant at risk of adrenal suppression. The data on how much inhaled corticosteroids can suppress the HPA axis in infants are incomplete. One study found that 21 days of inhaled beclomethasone (starting at an expected delivered dose of 40 mcg/kg/day) in infants born at a mean gestational age of 26.2 to 26.4 weeks resulted in lower baseline serum cortisol levels but no difference in cortisol levels after an ACTH stimulation test. In older children, moderate or higher doses of inhaled corticosteroids result in a risk of adrenal suppression. ,
Maternal use of glucocorticoids can cause adrenal suppression in the newborn if the glucocorticoid is not inactivated by placental 11βHSD2 and the treatment extends until close to the time of delivery. Thus, this will occur with maternal treatment with dexamethasone or betamethasone or with extremely high doses of other glucocorticoids that then overwhelm the capacity of placental 11βHSD2. Because placental 11βHSD2 expression is low early in gestation, maternal glucocorticoid treatment can more easily result in suppression of the HPA axis of infants born extremely prematurely. Although the effect of a particular maternal glucocorticoid regimen is difficult to predict, recovery of the infant HPA axis typically occurs within about 2 weeks after birth. However, some studies have shown a decreased HPA axis response to painful stress for up to 4 months after birth.
Relative Adrenal Insufficiency
Relative adrenal insufficiency refers to the inability of a patient to generate sufficient cortisol needed during a state of physiologic stress in the absence of a permanent, underlying disorder of the HPA axis. This has been best described in critically ill adults but also occurs in critically ill neonates. The mechanism for this critical illness–associated relative adrenal insufficiency includes cytokine-induced suppression of ACTH and cortisol synthesis and possibly decreased adrenal gland perfusion. Additionally, in the first week of life the HPA axis may be relatively sluggish in responding to stress due at least in part to the fact that the fetal hypothalamic production of corticotropin releasing factor is quiescent because of the large amount of corticotropin releasing factor produced by the placenta at the end of gestation, which can induce a lag in the recovery of the infant’s production of hypothalamic CRH after birth. In premature infants, there may also be transient adrenal insufficiency due to immaturity of the HPA axis. As discussed previously, the 3βHSD2 that is necessary for synthesis of cortisol from cholesterol is not fully expressed until after about 30 weeks’ gestation, although the increase in 3βHSD2 expression can be accelerated by premature birth. Nonetheless, with premature birth, the progesterone source that is utilized for fetal cortisol synthesis is cut off, potentially further impairing the capacity for cortisol synthesis of premature newborns. For all of these reasons, clinicians must be cautious about attributing adrenal insufficiency in infants to a permanent disorder. One challenge when evaluating for relative adrenal insufficiency is the difficulty in quantitating the physiologic stress. Because cortisol levels increase with stress, it is not surprising that higher cortisol levels may be a marker for increased morbidity and mortality as in a study by Rameshbabu et al., where basal serum cortisol levels at 24 to 36 hours of life were significantly higher in preterm infants (<30 weeks’ gestational age or <1250 g birth weight) who died or developed vasopressor refractory hypotension.
Studies have attempted to correlate cortisol levels, either baseline or ACTH-stimulated levels, with outcomes in premature infants. These have given conflicting results. Some have found that higher cortisol concentrations correlate with an increase in short-term adverse outcomes, suggesting the higher cortisol concentrations are a marker for disease severity. , Other studies have found that lower levels correlate with worse outcomes, raising the possibility of adrenal insufficiency as a potential contributor to worse outcomes. However, a number of other studies found no correlation of cortisol levels with clinical outcome. ,
Evaluation
Evaluation of primary or central adrenal insufficiency involves testing the adrenal axis. If the concern is for primary adrenal insufficiency, both mineralocorticoid and glucocorticoid insufficiency are expected. In older children, there is a circadian variation in serum cortisol levels through the day. Neonates do not initially have this circadian variation. Although some studies have demonstrated circadian variation as early as the first few days of life, the classic circadian variation of peak serum cortisol concentration in the early morning and a nadir at midnight typically develops starting around 2 months of age, becoming fully established in most infants by about 9 months of age. Therefore, in neonates, time of day generally does not matter when measuring basal cortisol levels. A baseline cortisol level above 10 mcg/dL (285 nmol/L) is generally a good indication of a normal HPA axis. Baseline cortisol levels below 10 mcg/dL do not always indicate adrenal insufficiency, however, and in some situations (such as a critically ill infant), a level above 10 mcg/dL may not exclude adrenal insufficiency. When primary adrenal insufficiency is being evaluated, a serum ACTH level should be measured with the serum cortisol, because the combination of an ACTH concentration more than twice the upper limit of the reference range with a cortisol concentration less than 5 mcg/dL is diagnostic. In situations where the baseline cortisol level does not give a definitive answer, ACTH stimulation testing may need to be performed to further evaluate for adrenal insufficiency. This testing can be used to evaluate for both primary and central adrenal insufficiency, with the important caveat that it will miss the diagnosis of acute (<2–4 weeks) central adrenal insufficiency (as might occur after a CNS injury) because a positive result in the case of central adrenal insufficiency relies on the atrophy of the adrenal gland that occurs in the absence of normal ACTH stimulation. The standard ACTH stimulation test uses 250 mcg of synthetic ACTH in adults, with the equivalent dose for infants being 15 mcg/kg. The low-dose ACTH stimulation test uses a 1-mcg dose of ACTH in adults (0.1 mcg/kg or 1 mg/m 2 in infants) and is proposed to have a higher sensitivity for central adrenal insufficiency. There is significant risk of false positives with the low-dose test, particularly in settings were the testing is not done frequently. The 2016 Endocrine Society Clinical Practice Guidelines recommend the standard-dose ACTH stimulation test over the low-dose test until more evidence demonstrates superiority of the low dose-test. In the past, a peak cortisol value more than 18 mcg/dL (500 nmol/L) made adrenal insufficiency unlikely. However, newer cortisol assays, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and newer, highly specific immunoassays, result in lower cortisol results than the assays that were used to define the 18 mcg/dL threshold. Although specific validation of the proper threshold to define adrenal insufficiency in infants using these newer assays has not been performed, a threshold of 12.5 to 14.5 mcg/dL (350–400 nmol/L) is more appropriate, because this is the level that corresponds to the 18 mcg/dL on the older assays.
Blood electrolytes should be obtained to identify hyponatremia and hyperkalemia when primary adrenal insufficiency is suspected. Hyponatremia (but not hyperkalemia) can also occur with isolated glucocorticoid deficiency (as in central adrenal insufficiency), although in this case it is due to impaired water excretion rather than the sodium loss that occurs with mineralocorticoid deficiency.
If cortisol deficiency is being evaluated because of hypoglycemia, a serum cortisol level should be obtained at the time of hypoglycemia (when the serum glucose concentration is less than 50 mg/dL or 2.8 mmol/L) to look for the appropriate counterregulatory response with a rise in cortisol to above the same threshold considered normal on the ACTH stimulation test. Because hyperinsulinism is a common cause of neonatal hypoglycemia, and in this case, the hypoglycemia can develop so quickly that the serum cortisol has not yet increased at the time the hypoglycemia is detected, a subsequent serum cortisol level 30 minutes after the detection of the hypoglycemia should be measured.
To evaluate for CAH, the appropriate steroid precursors proximate to the enzyme deficiency are measured (e.g., 17-hydroxyprogesterone in 21-hydroxylase deficiency).
If there is concern about adrenal hemorrhage, imaging with abdominal ultrasound can be obtained but is not necessary to diagnose primary adrenal insufficiency. Similarly, if adrenal insufficiency from hypopituitarism is suspected, magnetic resonance imaging of the hypothalamus and pituitary should be obtained.
Management
Treatment of adrenal insufficiency consists of replacing the missing cortisol and/or aldosterone ( Table 27.2 ). The usual daily requirement for cortisol is 6 to 8 mg/m 2 /day. Hydrocortisone is preferred for replacement therapy over synthetic glucocorticoids because the risk of side effects from overtreatment is substantial when synthetic glucocorticoids are used. In congenital adrenal hyperplasia, a slightly higher dose than the usual 6 to 8 mg/m 2 /day dose may be needed because the goal of treatment is to lower adrenal androgen production in addition to replacing the cortisol deficiency. Oral bioavailability of hydrocortisone is close to 100%, so the same dose may be used for both oral and parenteral delivery.
