Adrenal Disorders
The adrenal gland is composed of two embryologically distinct tissues, the cortex and medulla, arising from the mesoderm and neuroectoderm, respectively. Adrenal cortex consists of three anatomically distinct zones
1. The outer zona glomerulosa: site of mineralocorticoid production (aldosterone), regulated mainly by renin-angiotensin system, and partially by ACTH.
2. The central zona fasciculata: responsible for glucocorticoid synthesis, regulated by ACTH.
3. The inner zona reticularis: site of adrenal androgen (predominantly dehydroepiandrostenedione (DHEA, DHEA sulfate and androstenedione) secretion.
With regard to function, there is no strict separation between the steroid-producing adrenal cortex and the catecholamine-producing medulla. Recent studies have provided evidence that chromaffin cells once thought to be located exclusively in the medulla, are found in all zones of the adult adrenal cortex, and that cortical cells are found in the medulla.
Congenital Adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is a family of inherited enzyme deficiencies that impair normal corticosteroid synthesis by the adrenal cortex. The most common enzyme deficiency is 21-hydroxylase deficiency, which accounts for over 90% of cases. CAH due to 21-hydroxylase deficiency can be classified as either classical (simple virilizing or salt-wasting types) or non-classical. Other rare enzyme deficiencies resulting in CAH include 17-alpha-hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and 11-beta-hydroxylase deficiency. Compensatory increase in adrenocorticotrophic hormone secretion leads to overproduction of steroid precursors in the adrenal cortex, resulting in adrenal hyperplasia. Excess precursors may be converted to androgens that may result in virilization of female fetuses. The phenotype is determined by the severity of the cortisol deficiency and the nature of the steroid precursors that accumulate proximal to the enzymatic block. The most common abnormality, which is responsible for greater than 90% of patients with CAH, is caused by a deficiency of the 21-hydroxylase enzyme. Less common causes for CAH include deficiencies in 11β-hydroxylase and 17α-hydroxylase. Reduced 21-hydroxylase activity results in accumulation of 17-hydroxyprogesterone as a result of impaired conversion to 11-deoxycorticosterone. Excess 17-hydroxyprogesterone is then converted through androstenedione to androgens, levels of which can increase by as much as several hundred fold. Excess androgens virilizing the undifferentiated female external genitalia, ranging from mild clitoral hypertrophy to complete formation of a phallus and scrotum. In contrast, genital development in male fetuses is normal, although excess androgens cause postnatal virilization in both genders and may manifest in precocious puberty. A severe enzyme deficiency or even a complete block of enzymatic activity produces the classic form of CAH. Two thirds to three fourths of cases have salt loss, which may be life threatening.
It has been known that the fetal adrenal gland can be pharmacologically suppressed by maternal replacement doses of dexamethasone. Suppression can prevent masculinization of affected female fetuses in couples who are carriers of classic CAH. Differentiation of the external genitalia begins at about 7 weeks of gestation. Chorionic villus sampling has traditionally been the earliest approach for determining gender, although earlier detection should now be possible by molecular testing for Y-sequences in maternal blood. Pharmacologic therapy can be initiated before diagnosis, but therapy is continued only if the fetus is an affected female. Hundreds of fetuses have been treated successfully with prevention or amelioration of masculinization.
Screening studies indicate a worldwide incidence of classical 21-hydroxylase deficient CAH as 1 in 14,000 live births. Incidences vary among different populations, ranging from 1 in 600 live births in Alaska, to 1 in 5,000 live births in Saudi Arabia, to 1 in 23,000 live births in New Zealand. The prevalence frequency of non-classical 21-hydroxylase deficient CAH is considerably higher at 1 in 1,000 in white populations, with an even higher frequency among selected ethnic groups most notably, Ashkenazi Jews. Prevalence of non-classical CAH is 1 in 27 Ashkenazi Jews, 1 in 40 Hispanics, 1 in 50 Yugoslavs, 1 in 300 Italians, and 1 in 100 in a heterogeneous New York population. The fertility rate among untreated females with non-classical CAH is reported to be 50%.
CAH is an autosomal recessive disorder and the gene encoding 21-hydroxylase enzyme, CYP21A2, is mapped to the short arm of chromosome 6 (6p21.3). To date, more than 100 mutations have been described. Approximately 95% to 98% of the mutations causing 21-hydroxylase deficiency have been identified through molecular genetic studies of gene rearrangement and point mutations arrays.
Deficiency of 21-hydroxylase enzyme causes insufficient cortisol production, stimulating increased production of corticotropin-releasing hormone and ACTH. High ACTH levels lead to adrenal hyperplasia and production of excess androgens (e.g., delta-4-androstenedione), which do not require 21-hydroxylation for synthesis. Symptoms of excessive androgens are found in varied degrees in classical and non-classical forms of 21-hydroxylase deficiency and are attributable to the severity of the enzyme defect.
The internal female reproductive tract remains normal, as the ovaries do not produce anti-Mullerian hormone. Postnatal virilization includes rapid growth, premature development of pubic hair, and advanced body maturation leading to secondary precocious puberty, early epiphysis fusion, and short final adult height. Short stature may be the combined result of elevated adrenal androgens causing advanced epiphyseal maturation and premature epiphyseal fusion, with glucocorticoid overproduction inducing growth suppression, leading to short stature. Gonadal dysfunction usually occurs, as the excess adrenal androgens suppress pituitary gonadotropins and thus impair testicular growth and function.
When the loss of 21-hydroxylase function is severe, adrenal aldosterone secretion is insufficient to stimulate sodium reabsorption by the distal renal tubules, resulting in salt-wasting as well as cortisol deficiency, in addition to androgen excess.
Clinical characteristics of different enzyme deficiency forms of CAH
21-hydroxylase deficiency
· Non-classical CAH
o Mild-to-moderate enzyme deficiency
o Females do not have virilized genitalia at birth
o May present in a child as precocious development of axillary hair or odor, pubic hair, acne, or tall stature as a child with an advanced bone age that may eventually result in short stature as an adult.
o Adolescent females may also present with oligomenorrhoea, amenorrhea, polycystic ovaries, acne, hirsutism, or alopecia.
· Classical CAH: salt-loser
o Most severe form of the disease
o Approximately 75% of classical cases
o commonly present with ambiguous genitalia in the female
o Characterized by insufficient aldosterone, with vomiting and dehydration occurring early (1-4 weeks) in infant life and risk of life-threatening adrenal crises.
· Classical CAH: simple virilized (non salt-loser)
o Enzyme defect is moderate
o Approximately 25% of classical cases
o Retain ability to conserve salt.
17-alpha-hydroxylase deficiency
· Hypertension (HTN) and Hypokalemia
· Delayed puberty in females and virilization in males
· No salt-wasting occurs.
3-beta-hydroxysteroid dehydrogenase deficiency
· Ambiguous genitalia in both males and females
· Salt-wasting (rare).
11-beta-hydroxylase deficiency
· Hypertension (HTN)
· Hyperandrogenism, causing ambiguous genitalia in female infants and childhood virilization in both sexes.
Antenatal diagnosis can be performed in the first trimester by molecular genetic analysis of fetal DNA from chorionic villus sampling or amniocentesis.
Dexamethasone treatment of the affected female fetus does not prevent the development of CAH, but helps in prevention of antenatal virilization in affected girls.
Newborn screening is performed by measuring 17-hydroxyprogesterone on a filter paper blood spot sample obtained by the heel-prick technique. Screening serves several important purposes:
· Identifying the classical form of 21-hydroxylase CAH
· Determining patients at risk for life-threatening salt-wasting crises
· Expediting the diagnosis of females with ambiguous genitalia
· Detecting some (though not all) people with the non-classical form.
Diagnosis at birth of a female usually is made immediately due to the apparent genital ambiguity. As differentiation of the external genitalia is unaffected in newborn males, only hyperpigmentation may suggest increased ACTH secretion. Diagnosis at birth in males usually depends on antenatal or newborn screening. A positive family history is common. Infertility, both male and female, is commonly identified when a couple attempts to have a child.
Signs of hyperandrogenism in affected children include precocious puberty or early onset of facial, axillary, and pubic hair, adult body odor, and rapid somatic growth. This early growth spurt is accompanied by premature epiphyseal maturation and closure, resulting in a final height that is below that expected from parental heights. Patients tend to be tall children, but short adults. In adolescence and adult age, signs of hyperandrogenism may include temporal balding, severe acne, irregular menses, hirsutism, and infertility. Menstrual irregularity and secondary amenorrhea with or without hirsutism occur in a subset of post-menarche females, especially those in poor hormonal control. Primary amenorrhea or delayed menarche can occur if females with classical CAH if untreated, inadequately treated, or over treated with glucocorticoid.
Infants with salt-wasting have poor feeding, weight loss, failure to thrive, vomiting, dehydration, hypotension, hyponatraemia, and hyperkalaemic metabolic acidosis progressing to adrenal crisis (azotaemia, vascular collapse, shock, and death). Adrenal crisis can occur as early as 1 to 4 weeks of age.
Non-classical CAH
· A positive family history is common.
· Symptoms include acne, premature development of pubic hair, accelerated growth, advanced bone age, and reduced adult stature as a result of premature epiphyseal fusion. Acne tends to be severe with pustules and red papules on the face, back, and other regions of the body.
· Females are born with normal genitalia; postnatal symptoms may include hirsutism, temporal baldness, delayed menarche, menstrual irregularities, and infertility. Among adult females, most present with hirsutism only, with rare presentations of only hirsutism and menstrual disorder or menstrual disorder only.
· Males may have early beard growth and an enlarged phallus with relatively small testes. Symptoms in adult males may be limited to short stature or oligozoospermia and diminished fertility.
Diagnosis
Classic 21-hydroxylase deficiency
The characteristic biochemical abnormality is an elevated serum concentration of 17-hydroxyprogesterone. False positive results from neonatal screening are common with premature infants, and many screening programs have established reference ranges that are based upon weight and gestational age. High serum androstenedione, testosterone, 08:00 am serum cortisol level will be low and serum ACTH will be high, and increased urinary excretion of metabolites of cortisol precursors, particularly pregnanetriol, pregnanetriol glucuronide, and 17-ketosteroids. (Pregnanetriol and its glucuronide are the major metabolites of 17-hydroxyprogesterone, and 17-ketosteroids are metabolites of androgens).
Patients with the salt-losing form of 21-hydroxylase deficiency have low serum concentrations of aldosterone and 11-deoxycorticosterone and increased plasma renin activity. The mineralocorticoid deficiency can lead to volume depletion, hyponatremia, and hyperkalemia. Patients are also at risk for hypoglycemia during an adrenal crisis. To assess borderline cases, the standard high-dose (250 mcg cosyntropin) test, not the low-dose (1 mcg) test, should be used. Genetic testing also can be used to evaluate borderline cases. Genetic testing detects approximately 95 percent of mutant alleles.
Newborns or infants with ambiguous genitalia are recommended for karotyping or FISH (fluorescence in situ hybridization) for X and Y chromosome detection, and an ultrasound of the pelvis to identify internal female genitalia and adrenal glands to look for the large size.
Prader score for genital ambiguity
Genital ambiguity can be evaluated by the Prader score in newborn females. The scores range on a scale of 1 to 5 (I to V). The genitalia can be scored from slightly virilized (score of 1) to indistinguishable from a male (score of 5). Most females with classical 21-hydroxylase deficiency are born with Prader IV genitalia.
Ferriman-Gallwey score for hirsutism
The scoring system quantifies the extent of hair growth in nine key anatomical sites. Hair growth is graded using a scale from zero (no terminal hair) to 4 (maximal growth), for a maximum score of 36. A score of 8 or more indicates the presence of androgen excess. The degree of facial and body hair excess can be objectively scored by this method.
Treatment
Adrenal crisis
The initial goals are treatment of hypotension and dehydration, reversal of electrolyte abnormalities, and correction of cortisol deficiency. Normal (0.9 percent) saline solution or 5 percent dextrose in normal saline should be infused intravenously as quickly as possible. An intravenous bolus of 10 to 20 mL/kg of normal saline should be administered. An intravenous bolus of 2 to 4 mg/kg of 10 percent dextrose should be considered if there is significant hypoglycemia. Hypotonic saline should not be usedbecause it can worsen the hyponatremia; the same is true of 5 percent dextrose without the addition of normal saline. Hyperkalemia should be corrected with the administration of glucose and insulin if necessary.
Glucocorticoid is usually administered as hydrocortisone(cortisol) in a dose of 12 to 15 mg/m2 body surface area per day. In the early phase of treatment, infants may require up to 25 mg/m2/day of hydrocortisone to reduce markedly elevated adrenal hormones. This dose range exceeds the daily cortisol secretory rate of normal infants and children, which is estimated to be 7 to 9 mg/m2 body surface area in neonates and 6 to 7 mg/m2 body surface area in children and adolescents.
For older adolescents and adults, long-acting glucocorticoids such as dexamethasone or prednisoloneare the preferred treatment. When given at bedtime, these drugs effectively suppress ACTH secretion for much of the next day. However, the longer duration of action and greater potency of dexamethasone may increase the risk of over treatment, restricting linear growth if given prior to epiphyseal closure. Dexamethasone is given as a bedtime dose of 0.25 to 0.50 mg.
The usual pediatric dose of fludrocortisoneis 0.05 to 0.20 mg per day. Infants with the salt-losing form may require higher doses of fludrocortisone (occasionally up to 0.30 mg per day) and also require sodium chloride supplementation of 1 to 3 g per day (about 17 to 51 mEq per day) distributed in several feedings. Fludrocortisone doses may be decreased after 6 to 12 months of age because sensitivity to mineralocorticoid increases as the kidneys mature in the first year of life. Salt tablets can be discontinued as the child begins to eat table food and the taste for salty food increases. Additional salt intakemay be needed with exposure to hot weather or with intense exercise.
CAH is associated with short stature in adults even when optimal adrenal hormonal control is maintained throughout childhood and puberty. It has been shown that growth hormone therapy, alone or in combination with a gonadotropin-releasing hormone analogue, is effective in improving growth rate, height deficit, and final height in children. Dosing is determined and delivered by an endocrinologist familiar with the use of these hormones.