Glucocorticoid secretion

Glucocorticoid excess and deficiency states are often difficult to diagnose because cortisol levels normally fluctuate widely according to the time of day and degree of stress (Table 8.1). Glucocorticoid excess results in normal or high random cortisol levels, loss of the normal circadian rhythm, an increase in urinary free cortisol and failure of plasma cortisol to suppress with low‐dose dexamethasone.

Glucocorticoid deficiency is easy to diagnose if the defect is in the adrenal gland itself (primary adrenal insufficiency) because this will result in elevated ACTH levels and low cortisol levels with absent or impaired rise following synthetic ACTH (Cortrosyn^® or Synacthen^®) stimulation. The diagnosis is more difficult when the defect lies in the hypothalamus or pituitary gland (central adrenal insufficiency, CAI). In suspected secondary adrenal insufficiency, the low‐dose synthetic ACTH test may be helpful. The rationale for this test is that the adrenal glands, if under‐stimulated for months or years, will respond subnormally to quasi‐physiological stimulation. A peak stimulated cortisol greater than 550 nmol/L is considered normal, while a peak of less than 400 nmol l⁻¹ is considered too low, and a great many patients fall in the grey zone in between. We regard a peak‐stimulated cortisol level of >500 nmol l⁻¹ as ‘normal’ (see Table 8.1) while recognizing that any chosen cut‐off level will be somewhat arbitrary and that the biochemical data must be interpreted in the clinical context.

Mineralocorticoid secretion

Mineralocorticoid deficiency is assessed by the measurement of plasma and urinary electrolytes, and of plasma renin and aldosterone (Table 8.2).

Adrenal androgen secretion

Adrenal androgen status is assessed by plasma steroid analysis under basal and stimulated conditions (Table 8.3). Monitoring of patients with 21 hydroxylase deficiency is routinely based on the measurement of plasma 17‐hydroxyprogesterone (17‐OHP) and androstenedione at the time of clinic visits. If available, salivary or capillary profiles collected at home may add information about adherence to treatment.

Causes

The causes of CAI are as follows:

• Congenital:
  
  
  
  • idiopathic congenital hypopituitarism;
    
  • septo‐optic dysplasia;
    
  • other mid‐line central nervous system (CNS) disorders;
    
  • isolated ACTH deficiency (mutations in TPit, POMC, or NFKB2).
  
  
• Acquired
  
  
  
  • craniopharyngioma;
    
  • cranial irradiation (e.g. for head and neck tumours);
    
  • surgery to hypothalamic–pituitary area;
    
  • steroid therapy
    
  • vascular insult, trauma, meningitis.

Clinical features

ACTH deficiency is usually seen in association with several other anterior pituitary hormone deficiencies. Severe ACTH deficiency at birth causes hypoglycaemia, poor feeding, convulsions and jaundice. The jaundice is of the cholestatic type and resolves once hydrocortisone is started.

In older children, the symptoms of CAI are non‐specific. Cortisol deficiency is responsible for tiredness and lack of energy, with increased susceptibility to and a longer recovery period from minor illnesses. Children with POMC deficiency also have severe obesity and red hair. Some POMC mutations lead to high, not low, plasma ACTH. NFKB2 mutations are also associated with common variable immunodeficiency.

Investigations

In the newborn infant, dynamic studies are difficult to perform. If congenital hypopituitarism is strongly suspected (hypoglycaemia, jaundice, micropenis, low plasma free thyroxine (FT4) and random plasma cortisol levels less than 50 nmol/L [1.4 μg dL]), then replacement should be instituted without delay. In more doubtful cases where the child is reasonably stable, 1 μg ACTH can be given intravenously and the cortisol response assessed at 30 minutes. Peak values of <550 nmol/L [<19 μg/dL] are suggestive of prenatal hypostimulation of the adrenal glands.

In children with suspected CAI, especially survivors of cancer, investigation depends on the severity of symptoms and the clinical context. Children who have received doses of >3000 cGy are particularly at risk. Cortisol secretion can be assessed by carrying out a low‐dose ACTH test, or a salivary cortisol profile. An undetectable plasma dehydroepiandrosterone sulphate (DHEAS) level at an age when adrenarche should have occurred (>8 years) is indirect evidence of at least partial ACTH deficiency.

Treatment

Hydrocortisone, 10 mg/m² per day should be given divided in two or three doses per day. Treatment during an intercurrent illness or during surgery is as for 21‐hydroxylase deficiency (see section ‘Treatment’). Once the child is on glucocorticoid replacement, biochemical monitoring is not usually necessary.

Causes

• Congenital:
  
  
  
  • adrenal hypoplasia – X‐linked (DAX‐1 mutation) or autosomal recessive;
    
  • CAH;
    
  • familial glucocorticoid deficiency (FGD) (autosomal recessive) or resistance.
  
  
• Acquired:
  
  
  
  • isolated autoimmune adrenalitis (Addison’s disease);
    
  • adrenalitis associated with other autoimmune endocrinopathies;
    
  • adrenoleukodystrophy (ALD);
    
  • tuberculosis;
    
  • bilateral adrenalectomy;
    
  • drugs (e.g. cyproterone).

Congenital adrenal hypoplasia

In the newborn period, cortisol deficiency will cause hypoglycaemia and jaundice, while aldosterone deficiency will result in hyponatraemia, hyperkalaemia, poor feeding, vomiting, and failure to thrive. Investigations will show elevated renin and ACTH, but low or normal 17‐OHP. Symptoms usually start from day 10 onwards. Boys with a DAX‐1 (dosage‐sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) mutation may have bilateral cryptorchidism in infancy and gonadotrophin deficiency in adolescence.

Familial glucocorticoid deficiency

Familial glucocorticoid deficiency (FGD, also known as ‘hereditary unresponsiveness to ACTH’) is an autosomal recessive disorder in which the adrenal cortex is unable to respond to ACTH. In about 25% of cases, a mutation on the ACTH receptor MC2‐R can be identified. These children, who tend to be tall, are classified as having FGD type 1. FGD without an MC2‐R mutation is termed FGD type 2. Recently, mutations in a new gene encoding a protein called melanocortin 2 receptor accessory protein (MRAP) have been identified in some cases of FGD type 2. MRAP is required for the expression of MC2‐R at the cell membrane. More recently identified causes include mutations in NNT (some with associated mineralocorticoid deficiency and insulin‐dependent diabetes) or in TXNRD2.

Patients present with jaundice, poor feeding, failure to thrive, and hypoglycaemia in infancy. Older children may present with collapse and coma, sometimes with fatal consequences so that the diagnosis is only made post mortem. Investigations show elevated ACTH, low cortisol with poor or no response to ACTH and normal renin levels. Plasma potassium is usually normal but a degree of hyponatraemia may be present. This is attributable to cortisol deficiency causing impaired water secretion at the renal tubule.

Treatment

Congenital adrenal hypoplasia should be treated similarly to 21‐hydroxylase deficiency (see section ‘Treatment’), although the dose of hydrocortisone used can be somewhat lower (as there is no need to suppress ACTH to prevent hyperandrogenism). FGD should be treated with hydrocortisone but not fludrocortisone or salt.

Causes

Autoimmune adrenalitis (Addison’s disease) is the most common cause of acquired primary adrenal deficiency. Although seen in isolation, it may also be associated with other autoimmune disorders, such as diabetes mellitus and Hashimoto’s thyroiditis, and with the polyglandular autoimmune (PGA) syndromes. PGA 1, also known as autoimmune polyendocrinopathy with endocrinopathy, muco‐cutaneous candidiasis and ectodermal dystrophy (APECED), is a recessive condition caused by mutations in the AIRE (autoimmune regulator) gene on chromosome 21 and has its onset in childhood and adolescence. Components of APECED syndrome include the following:

• Endocrine:
  
  
  
  • Addison’s disease;
    
  • hypoparathyroidism;
    
  • primary ovarian failure;
    
  • diabetes mellitus;
    
  • hypophysitis.
  
  
• Non‐endocrine:
  
  
  
  • vitiligo;
    
  • alopecia;
    
  • malabsorption;
    
  • hepatitis;
    
  • keratitis;
    
  • immune deficiency – increased prevalence of infections, particularly mucocutaneous candidiasis.

ALD is an X‐linked recessive disorder affecting both the CNS and the adrenal cortex. Onset may be in childhood or early adulthood. The phenotype is highly variable, even within families, so that the presence and severity of neurological impairment and adrenal failure vary from case to case. Severely affected individuals suffer progressive neurological disability, and ultimately death. The neurological symptoms may precede those of adrenal insufficiency, or vice versa. Therefore, in all males with primary adrenal insufficiency other than CAH, plasma very long chain fatty acids must be measured.

Clinical features of primary adrenal insufficiency

Symptoms include tiredness, weight loss, and, in the final stages, vomiting, drowsiness, and coma. Examination shows increased pigmentation (Figure 8.5), especially in the skin creases, old scars and buccal mucosa, with signs of recent weight loss, and low or normal blood pressure.

Investigations

Fasting glucose is normal or low. In acute adrenal insufficiency, sodium is low, potassium is high, and there may be severe hypoglycaemia. Basal cortisol is low or normal with no rise following ACTH administration. Plasma ACTH and renin activity are high. Given the association between Addison’s disease and other autoimmune diseases and ALD, the following is recommended at diagnosis and yearly thereafter:

• autoantibody screen (adrenal, thyroid, islet cell, parietal cell);
  
• calcium, phosphate, complete blood count (CBC), vitamin B₁₂, folate, thyroid‐stimulating hormone (TSH), and alanine amino transferase (ALT).

Treatment

Acute adrenal insufficiency is managed by intravenous (IV) fluids with 0.9% saline and added 5% glucose, IV hydrocortisone (see p. 182) and conversion to oral hydrocortisone and fludrocortisone once recovery has occurred (Table 8.4).

Follow‐up

Once a patient is on established treatment with hydrocortisone and fludrocortisone, clinical monitoring and adjusting the dosage as body surface area increases are usually sufficient and there is no need for laboratory investigations.

Aldosterone deficiency

• Congenital adrenal hypoplasia.
  
• Addison’s disease.
  
• Enzyme disorders:
  
  
  
  • StAR protein deficiency;
    
  • 3‐βHSD deficiency;
    
  • CYP 21 (21‐hydroxylase) deficiency; or
    
  • CYP 11B2 (aldosterone synthase) deficiency.

Aldosterone resistance (pseudohypoaldosteronism)

• Autosomal dominant or sporadic – affects renal tubule.
  
• Recessive – affects kidneys, colon, and sweat and salivary glands.

Adrenal causes of androgen excess

• Adrenocortical adenoma and carcinoma.
  
• CAH:
  
  
  
  • CYP 21 (21‐hydroxylase) deficiency and CYP 11β1 (11‐hydroxylase) deficiency;
    
  • 3‐βHSD deficiency in females;
    
  • 11‐βHSD 1 deficiency.

Isolated premature pubarche is common (see Chapter 5) but virilization in girls or prepubertal boys suggests an androgen‐secreting tumour or an enzyme defect.

Clinical features

Virilization develops over a period of weeks or months and accelerated linear growth and bone maturation then become apparent. In boys, the testes are prepubertal (Figure 8.6).

Investigations

These show a marked elevation of one or more of the adrenal androgens, androstenedione, and DHEAS. Abdominal ultrasound, followed by CT or MRI scanning, should be obtained without delay.

Treatment

Treatment is by surgical removal wherever possible. If the tumour is well circumscribed and <5 cm in diameter, the prognosis is good. Pathological features are usually not helpful in predicting the risk of recurrence or of metastases.

Incidence

In most populations, the incidence is about one in 15 000 births.

Pathogenesis and classification

21‐hydroxylase deficiency results from mutations in the CYP21B gene, which is situated on chromosome 6. The phenotype of 21‐hydroxylase deficiency correlates reasonably well with the following genotype:

• Salt‐wasting 21‐hydroxylase deficiency (SW 21‐OHD) results from a child inheriting two severe mutations, leading to complete or near‐complete loss of 21‐B function, with <1% of normal 21‐hydroxylase activity.
  
• Simple virilizing 21‐hydroxylase deficiency (SV 21‐OHD) occurs if one of the two mutations (e.g. point mutation Ile172Asn) is relatively mild with 1–5% preservation of 21‐hydroxylase activity. Significant salt loss does not occur, although plasma renin activity is often elevated.
  
• Non‐classical or late onset 21‐hydroxylase deficiency (NC 21‐OHD) results if one mutation is mild (e.g. Val 281Leu). Likely an ascertainment bias, it is diagnosed more often in females.

Clinical features

SW 21‐OHD females present with virilization at birth. The clitoris is enlarged and there generally is posterior fusion of the labia majora (Figure 8.7). The vagina and urethra usually enter a common urogenital sinus, with the distal end of the vagina becoming increasingly more distant from the pelvic floor with the severity of virilization. Virilization can be graded in severity according to the Prader classification (Figure 8.8).

Males with SW 21‐OHD usually present in the second week of life, with a salt‐losing crisis heralded by poor feeding, vomiting, poor weight gain, and listlessness. Examination shows dehydration with pigmentation of the scrotum. Biochemistry reveals hyponatraemia and hyperkalaemia. Death may occur before the diagnosis is considered. For this reason, neonatal screening for SW 21‐OHD is being implemented in an increasing number of countries. However, this is not yet universal because the positive predictive value of a high 17‐OHP is very low, especially in premature or stressed neonates.

Boys with SV 21‐OHD, and girls with SV 21‐OHD in whom virilization at birth has been mild and/or missed, will present later in childhood (usually two to four years) with signs of androgen excess – long‐standing growth acceleration and advanced bone age, enlarged penis or clitoris, and pubic hair. Both girls and boys with SV 21‐OHD enter true puberty early when treated with glucocorticoids because of priming of the hypothalamic–pituitary axis. This leads to premature closure of the epiphyses and an adult height below target.

NC 21‐OHD is a rare cause of hyperandrogenism in adolescent and adult females and should be considered in the differential diagnosis of the polycystic ovary syndrome.

Diagnosis

SW 21‐OHD is diagnosed in females with ambiguous genitalia, no palpable gonads, hyperpigmentation of the labia majora and a uterus on ultrasound, and in boys with a salt‐wasting crisis. Biochemical confirmation is based on high plasma androgens and 17‐OHP (values usually >100 nmol l⁻¹ [>3300 ng dl⁻¹]).

In SV and NC 21‐OHD, 17‐OHP elevation is milder. Levels are higher between 8.00 a.m. and 9.00 a.m. In this context, 17‐OHP at 0 and 60 minutes after standard ACTH stimulation (250 μg), can be compared to the nomogram published by New et al. in 1983.

Prenatal management

After the birth of a child affected with 21‐OHD, the genotype of parents, affected child, and healthy siblings can be determined. The main purpose of prenatal testing is to assist with maternal dexamethasone treatment. Pre‐pregnancy counselling as to the pros and cons of this intervention is important. If the mother chooses to be treated, dexamethasone 20 μg/kg per day should be started by four to six weeks’ gestation. This should be continued throughout pregnancy if the foetus is an affected female, but stopped if the foetus is male or an unaffected female. Determining the sex of the embryo and CYP21B genotyping based on free embryonic DNA in maternal blood will allow shortening unnecessary treatments. The demonstrated benefit of reducing or preventing virilization in girls must be offset against hypertension, weight gain, striæ, and mood changes in the mother. The possible long‐term physical and psychological deleterious consequences of in utero dexamethasone exposure have led to this treatment no longer being even suggested to the couple by some clinicians.

Neonatal management

Diagnosis and management of 21‐OHD in newborn females are part of disorders of sex development (DSD) management (see Chapter 7).

Once the diagnosis has been confirmed, treatment must be started as follows:

1. Fludrocortisone 0.05–0.100 mg per day.
   
2. Sodium chloride 5 mmol kg per day in three divided doses given as either 6% (1 mmol/ml), 15% (2.5 mmol/ml), or 30% (5 mmol/ml) solution. The solution may be added to milk feeds or given separately (e.g. if mother is breast‐feeding).
   
3. Hydrocortisone 20 mg/m² per day in three divided doses.

If clinical evidence of salt‐wasting is present (weight loss >10%), manage as follows:

1. Measure electrolytes and 17‐OHP. Hyperkalaemia usually precedes hyponatremia and hypoglycaemia.
   
2. Give 10–30 ml/kg of 0.9% saline over one to three hours depending on the degree of dehydration, then 0.9% saline at a rate sufficient to provide maintenance, and correct any deficit over 24 hours. Monitor capillary glucose.
   
3. Give hydrocortisone 25 mg intravenously immediately, then 12.5 mg six hourly until enteral administration can be started.
   
4. When plasma sodium is normal and the infant is stable, start fludrocortisone, sodium chloride and hydrocortisone as above.

Glucocorticoid Therapy

Treatment consists of oral hydrocortisone, approximately 15 mg/m² per day in three divided doses. Suspensions are unreliable and 10 mg hydrocortisone tablets should be given halved or quartered, asking the pharmacy to prepare powder if needed.

Fludrocortisone Therapy

Fludrocortisone 0.05–0.100 mg per day, with blood pressure monitoring.

Salt Therapy

The dosage of 5 mmol/kg per day should be maintained for the first 12 months of life and is usually discontinued at, or shortly before, the first birthday.

Education and Surveillance

A great deal of time must be invested in counselling the parents at diagnosis. Parent information leaflets are very useful. Contact with a family with an affected child of similar sex can also be very helpful. Management of acute illness should be carefully discussed, and the parents instructed in the administration of intramuscular hydrocortisone in an emergency.

The infant should be reviewed weekly until the parents are comfortable with management, thereafter one‐ to three‐monthly during infancy. Weight and length are measured on each occasion with blood pressure, plasma steroids, and renin at least three‐monthly. Routine measurement of electrolytes is not indicated if the child is thriving.

Management of Acute Illness

Infancy is a prime time for acute illness, including gastroenteritis. The key to successful management is correct parental instruction (see Table 8.5), facilitated by provision of a CAH therapy card (similar to the asthma card). A CAH therapy card is shown in Appendix 2. In North America, it is common practice to prescribe a Medic‐Alert^® bracelet to all patients who are glucocorticoid‐dependent. If the following procedure is followed, children with CAH rarely need admission to hospital and duration of hospital stay will be minimized:

1. If the child has an intercurrent illness but is well, feeding and playing normally, and is not febrile, then no change in dosage is required.
   
2. If the child is unwell with fever, reduced activity, etc., then the oral total daily dosage of hydrocortisone is doubled and given in three divided doses.
   
3. If the child is particularly unwell, especially if there is vomiting, drowsiness, or diarrhoea – in which case oral hydrocortisone will not be reliably absorbed – give hydrocortisone intramuscularly in a dose of 12.5 mg for infants up to 6 months, 25 mg from 6 months to 5 years, 50 mg from 5 to 10 years, and 100 mg thereafter (see Table 8.5). If the parents are unable or unwilling to give intramuscular hydrocortisone, then the child should be taken to hospital immediately.
   
4. If the child does not respond to the intramuscular injection, parents should take the child immediately to hospital. Under these circumstances:
   
   
   
   • Take blood for electrolytes, glucose and full blood count.
     
   • Give hydrocortisone intravenously if not given intramuscularly by parents (dosage as above).
     
   • Give 10–30 ml kg⁻¹ 0.9% saline over one to three hours depending on the degree of dehydration, followed by 0.9% saline and 5% dextrose to provide maintenance and correct any deficit.
     
   • Give hydrocortisone injections six hourly (dosage given in Table 8.5) until the child is able to tolerate oral medications.
     
   • Genital surgery is discussed in Chapter 7 on DSD.

Medical Management of Children Undergoing Surgery

On the day of surgery, hydrocortisone should be given intravenously at the doses stated in Table 8.5 as soon as an IV line is established. Thereafter, half of this initial dose should be given six hourly (see Table 8.5). This high dose hydrocortisone treatment also covers the mineralocorticoid needs of these patients.

Management of Linear Growth

Chronic treatment consists of daily or twice‐daily fludrocortisone therapy to replace aldosterone, and twice‐ or thrice‐daily hydrocortisone to suppress ACTH secretion and thus prevent acceleration of bone maturation and virilization. The limitation of this approach is that the glucocorticoid regimen fails to mimic normal cortisol secretion. Moreover, even if ACTH secretion is normalized, the presence of the enzyme block will still cause androgen excess. Therefore, to achieve satisfactory adrenal suppression, a slightly supraphysiological dose of glucocorticoid is needed. Conversely, insufficient glucocorticoid dosage will result in androgen excess, early epiphyseal fusion, and decreased adult height. Central precocious puberty resulting from priming of the hypothalamus (see Chapter 5 on puberty) can be treated with gonadotrophin‐releasing hormone (GnRH) agonists but is not always easy to document with a GnRH stimulation test in children with CAH.

It is also evident that frankly excessive glucocorticoid administration will result in Cushingoid features, obesity, and slow growth with decreased adult height. What is less obvious is that lesser degrees of glucocorticoid overdosage will cause hyperphagia resulting in obesity with normal or increased height velocity and advancing bone age, tempting the clinician to make a further increase in hydrocortisone dosage.

With these considerations in mind, the clinician needs to make a careful judgement as to the optimal glucocorticoid dose, taking the clinical assessment, height velocity, bone age, and biochemical profile into account, and being mindful that adherence problems are common, especially during adolescence.

Hydrocortisone – 10–15 mg/m² per day –is usually given in two to three doses, titrating the dosage so that the height velocity is 4–7 cm per year. The manner in which the daily glucocorticoid dose should be administered is controversial. Some favour giving a thrice‐daily dose, equally divided, in pre‐school children, then a twice‐daily dose from school age (when adherence with a thrice‐daily regime becomes problematic). Fludrocortisone should be given at 0.150 mg/m² per day to bring plasma renin into the reference range.

At clinic visits (no less than every six months), the following should be done:

• Measurement of height, weight, height velocity, and body mass index (BMI) and (in older children) pubertal stage.
  
• Examination for features of over‐treatment (Cushing’s syndrome) and under‐treatment (including pigmentation and signs of androgen excess).
  
• Measurement of blood pressure (to monitor fludrocortisone dosage).
  
• Bone age should be evaluated yearly.
  
• Most practitioners also measure plasma 17‐OHP, androgens and renin activity biannually; this should ideally be done in the morning before taking the tablets. Some centres also measure 17‐OHP and androstenedione on capillary samples taken by the patient throughout the day. Normalization of 17‐OHP and androstenedione may reflect over‐treatment with glucocorticoid and suppression of renin may reflect over‐treatment with mineralocorticoid. However, there is great individual variation in biochemical profiles, and surveillance is based primarily on clinical parameters (growth in height and weight, bone age, pubertal progression, and blood pressure).

Morbidity

The sources of morbidity for parents and individuals with CAH are as follows:

1. Parents:
   
   
   
   1. Shock of initial diagnosis.
      
   2. In female infants, distress at the genital anomaly and uncertainty about sex at birth.
      
   3. Anxiety over possible genital surgery and sequellae.
   
   
2. Patients:
   
   
   
   1. Acute illness.
      
   2. Learning disability in some salt‐wasting patients.
      
   3. Growth:
      
      
      
      • poor growth 0–2 years;
        
      • overgrowth 2–10 years;
        
      • early puberty;
        
      • decreased adult height;
        
      • obesity.
      
      
   4. Urogenital problems:
      
      
      
      • In males: testicular adrenal rest tumours reducing fertility
        
      • In females:
        
      • urinary tract infection;
        
      • incontinence;
        
      • vaginal stenosis (haematocolpos, difficulty with tampon insertion and later with penovaginal intercourse).
      
      
   5. Psychosexual:
      
      
      
      • self‐esteem/confidence;
        
      • sexual activity;
        
      • sexual orientation;
        
      • gender identity development;
        
      • fertility.

The principal causes of morbidity are the complications of surgery in girls, and of obesity in both sexes. Strategies to minimize these problems include the use of prenatal dexamethasone, bilateral adrenalectomy during infancy in those with SW 21‐OHD associated with severe genotype, adding growth hormone, anti‐androgens and aromatase inhibitors, or using sustained‐release hydrocortisone. However, none of these options has become standard, despite having been under discussion for many years.

Causes

• Adrenal hypoplasia.
  
• Enzyme disorders:
  
  
  
  • StAR protein deficiency;
    
  • 3‐βHSD deficiency;
    
  • 17‐hydroxylase deficiency;
    
  • 17,20‐desmolase deficiency;
    
  • 17‐βHSD deficiency.

The androgen deficiency in boys with adrenal hypoplasia is insignificant because gonadal androgen synthesis is intact. However, severe enzyme deficiency affecting both adrenal and gonadal androgen synthesis results in under‐masculinization with complete sex reversal in the more severe cases, and ambiguous genitalia in less severe cases. Management is discussed in Chapter 7.