AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Congenital adrenal hyperplasia (CAH) is a general term used to describe a group of inherited disorders in which a defect in cortisol biosynthesis is present with consequent overproduction of ACTH and secondary adrenal hyperplasia as a consequence. An enzymatic defect in 11-beta-hydroxylase is the second most common variant of CAH and accounts for approximately 5-8% of cases.

Patients with 11-beta-hydroxylase deficiency present with features of androgen excess, including masculinization of female newborns and precocious puberty in male children. Approximately two thirds of patients also have hypertension, which may or may not be associated with mineralocorticoid excess, hypokalemia, and metabolic alkalosis. The association of CAH with hypertension was first noted in the 1950s. The hypertension is initially responsive to glucocorticoid replacement, but it may become a chronic condition subsequently requiring standard antihypertensive therapy.

Pathophysiology

The zona fasciculata normally secretes cortisol, predominantly under the trophic effect of adrenocorticotropic hormone (ACTH). The steroid biosynthetic pathway is shown in Image 1. Knowledge of this pathway is vital to understanding the clinical presentation of 11-beta-hydroxylase deficiency and the other variants of CAH.

In the zona fasciculata, the typical end product of the steroid biosynthetic pathway is cortisol (see Image 1), and cortisol regulates pituitary ACTH production through negative feedback inhibition. Loss of 11-beta-hydroxylase activity in the adrenal gland blocks the synthesis of cortisol and results in an increase in ACTH production. Aldosterone is the main mineralocorticoid produced by the adrenal zona glomerulosa, and its production is regulated by the renin-angiotensin-system. A 17-hydroxy pathway similar to the active pathway in the zona glomerulosa occurs in the zona fasciculata; however, the final product is corticosterone rather than aldosterone. Corticosterone is hydroxylated and oxidized at the 18 position to produce aldosterone in the glomerulosa, but not in the fasciculata.

The adrenal fasciculata production of corticosterone, a weak glucocorticoid, and deoxycorticosterone (DOC), a potent mineralocorticoid, is minimal and relatively unimportant in healthy normal individuals, but it is important in patients with 11-beta-hydroxylase deficiency. In these patients, a new steady state is achieved and excess DOC production occurs due to elevated ACTH levels.

Humans have two 11-beta-hydroxylase isoenzymes that are 93% identical. CYP11B1 is responsible for cortisol biosynthesis, expressed in the zona fasciculata, and regulated by ACTH. CYP11B2 is responsible for aldosterone synthesis, expressed in the zona glomerulosa, and regulated by the renin-angiotensin system and potassium levels. The genetic elements responsible for the differential regulation of CYP11B1 and CYP11B2 have not been elucidated completely. CAH due to 11-hydroxylase deficiency is due to genetic defects of CYP11B1 characterized by impaired conversion of 11-deoxycortisol to cortisol, reduced cortisol, impaired conversion of DOC to corticosterone, and increased 11-deoxycortisol, DOC, and ACTH secretion.

Mutations of the CYP11B2 gene cause aldosterone deficiency with characteristic features of mineralocorticoid deficiency. No associated cortisol deficiency or consequent adrenal hyperplasia is present, and isolated aldosterone synthetase deficiency is not a type of CAH.

Patients with 11-beta-hydroxylase deficiency have clinical features of androgen excess such as premature sexual maturation observed in boys and virilization of females. These symptoms are the result of excess adrenal androgen production and are similar to those observed in the more common virilizing form of CAH, 21-hydroxylase deficiency. Accumulated cortisol precursors are shunted into the pathway of adrenal androgen production (see Image 1). Affected girls are born with some degree of virilization of their external genitalia, while the internal genital structures derived from the müllerian ducts (fallopian tubes, uterus, and cervix) are unaffected. Postnatally, both sexes may experience rapid somatic growth, accelerated skeletal maturation and premature development of sexual and body hair. Affected boys present with premature sexual maturation.

About two-thirds of patients with the severe classic variant of 11-beta-hydroxylase deficiency have early-onset hypertension. This hypertension generally is mild to moderate but, in as many as one third of cases, is associated ultimately with left ventricular hypertrophy, retinopathy, and macrovascular events. The exact cause of the hypertension is unclear and is presumed to be due to excessive secretion of DOC, a mineralocorticoid. Overall however, the degree of DOC excess does not correlate with the degree or severity of hypertension. Possibly, the 18-hydroxy and the 19-nor metabolites of DOC, which are mineralocorticoids, may play an additional role.

Rarely, patients with 11-beta-hydroxylase deficiency may have salt wasting, especially during infancy. The exact pathophysiology of this is unclear. In some cases, excess glucocorticoid administration appears to play a role through suppression of DOC secretion. If the zona glomerulosa is chronically suppressed by excess DOC, a sudden decrease in DOC associated with glucocorticoid therapy may not be compensated for by an adequate increase in aldosterone secretion. In cases that have been described prior to beginning therapy with glucocorticoids, the suggested mechanisms include abnormal sensitivity to the natriuretic effects of various putative natriuretic factors.

A milder, late-onset or nonclassic form of CYP 11B1 deficiency with symptoms of androgen excess is rare, but has been described. These patients are not hypertensive. It is not a significant cause of hyperandrogenism in women, and stringent criteria should be used for diagnosis. ACTH-stimulated levels of 11-deoxycortisol should be at least 5 times the upper limit of normal to establish the diagnosis of nonclassic 11-beta-hydroxylase deficiency.

Frequency

United States

Prevalence is approximately 1 case per 100,000 live births.

International

Prevalence is similar to US rates in most reported series worldwide. However, the reported rates in Israel and Morocco are much higher, 1 case per 5000-7000 live births.

Mortality/Morbidity

• The classic hypertensive variants have the greatest potential for long-term morbidity.

Race

• 11-beta-hydroxylase deficiency is most commonly found in Jewish people of Moroccan descent.

Sex

• Although the condition is more easily recognizable in females, no sex predilection exists.

Age

• This is a genetic disease. Patients are affected throughout life.
• The peak age at diagnosis is infancy and early childhood. Females present as neonates with ambiguous external genitalia, and males present as toddlers with virilization.
• The mild form of 11-beta-hydroxylase deficiency is rare and may present with menstrual irregularities and hirsutism in adolescent or adult women.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Virilization
  
  
  • Classic 46,XX patients present at birth with some degree of masculinization of their external genitalia.
  
  
  
  • Classic 46,XY patients typically present at 2-4 years of age with signs and symptoms of androgen excess, including increased growth velocity, advanced bone age, pubic hair, increased penile length, and aggressive behavior.
  
  
  
  • Later in life, males may have poor spermatogenesis that may manifest as azoospermia, oligospermia, and subsequent infertility.
  
  
  
  • Nonclassic 11-beta-hydroxylase deficiency is more subtle and presents later in life. Adolescent or adult females may present with amenorrhea, oligomenorrhea, or hirsutism.
     
• Hypertension
  
  
  • Hypertension occurs in approximately two thirds of patients with the severe classic form of 11-beta-hydroxylase deficiency.
  
  
  
  • It often begins in the first few years of life. Because the blood pressure elevation is mild to moderate, comparing the blood pressures of patients to age-appropriate levels is vital.
  
  
  
  • Patients are usually asymptomatic.
  
  
  
  • Consequences of hypertension include left ventricular hypertrophy, retinopathy, cardiovascular accidents, and hypertensive nephrosclerosis.
  
  
  
  • Excess mineralocorticoids in patients can cause hypokalemia and metabolic alkalosis, which may present as muscle weakness and ileus.
  
  
  
  • Patients with mild (nonclassic) varieties typically have normal blood pressure.
     
• Salt wasting
  
  
  • Salt wasting is a rare, but distinct, presentation.
  
  
  
  • Patients present with hyperkalemia, hyponatremia, and hypovolemia.
  
  
  
  • The exact pathophysiology is unclear, but it may be precipitated by glucocorticoid therapy.

Physical

• Ambiguous genitalia in XX patients is the most distinctive finding on physical examination.
  
  
  • The genital examination findings of XX patients vary depending on the degree of virilization.
  
  
  
  • Findings can include clitoromegaly that can be severe enough to simulate a male penis or partial-to-full labioscrotal fold fusion that can simulate a scrotum (in the absence of palpable testicles).
  
  
  
  • Despite virilized external genitalia, patients who are 46,XX have normal female internal genitalia. For this reason, fertility is possible and these patients should be raised as girls.
     
• In children, other signs of androgen excess include early puberty, pubic hair, axillary hair, and adult body odor, and growth acceleration. Accelerated growth and early epiphyseal fusion result in short stature as adults.



• Adult women may have signs of virilization including muscular body habitus and hirsutism.



• Hyperpigmentation may occur due to the accompanying excess of ACTH akin to that observed in Addison disease. The hyperpigmentation may be more prominent at pressure points, around the areolae, the buccal mucosa or other mucous membranes, the scrotum, and scar tissue.



• Clinical features of uncontrolled hypertension, such as S₄, heart failure, elevated blood pressure, and hypertensive retinopathy, may be present.



• Affected young boys (aged 2-5 y) may have evidence of an enlarged phallus (both in length and thickness) inappropriate for chronologic age as well as advanced pubic and axillary hair. However, the testicular size in these boys tends to be small and firm (generally less than 5 mL in volume) and more consistent in size to their chronologic age. Palpable testicular masses in affected boys should raise the possibility of coexisting adrenal rest tumors. Apart from the testicles, these lesions can also arise in retroperitoneal locations where they are generally clinically asymptomatic and often only found on routine radiologic imaging tests.

Causes

• 11-beta-hydroxylase deficiency is an autosomal recessive disease due to mutations in the CYP11B1 gene. Moroccan Jews almost always show the same mutation—arginine (Arg) 448 to histidine (His), R448H.
• Thus far, no consistent phenotype-genotype correlations have been made.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Stein-Leventhal syndrome
Genetic syndromes with ambiguous genitalia
Genetic syndromes with precocious puberty (male children)
Congenital hypertrophic pyloric stenosis
C-21-hydroxylase deficiency variant of CAH

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Based on the excess precursors formed by the enzyme deficiency, diagnosis is made by measuring 11-deoxycortisol.
  
  

  • Random levels of 11-deoxycortisol are markedly elevated (to several thousand ng/dL) in the classic form. In subjects with the late-onset/nonclassical variants, random levels of 11-deoxycortisol may be normal; thus, an ACTH stimulation test to demonstrate elevated post stimulation values is then indicated.

  • In the classic form, other hormones that may be elevated include DOC; urinary 17-ketosteroids; urinary tetra hydrometabolites; adrenal androgens including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione; and testosterone.

  • Because DOC and other precursors associated with this deficiency have mineralocorticoid activity, plasma renin activity is suppressed.
  
  
  
  • Neonates may lack the diagnostic features of hypertension and suppressed renin.
  
  
  
  • Mild-to-moderate elevations of 17-hydroxyprogesterone may be observed, thus diagnosis of 11-beta-hydroxylase deficiency may be missed in neonates if 11-deoxycortisol is not specifically measured. Although 17-hydroxyprogesterone levels are not markedly elevated, an erroneous diagnosis of 21-hydroxylase deficiency is possible.
  
  
  
  • In contrast to other forms of CAH, carriers of 11-beta-hydroxylase deficiency (heterozygotes) do not have elevation of the metabolite precursors.
  
  
  
  • Once a case is identified, additional familial cases can be identified using biochemical or genetic markers.
  
  
  
  • Increased understanding of the genetic basis of this condition has enabled the medical community to establish the diagnosis prenatally.
  
  
  
  • Techniques include estimating amniotic fluid 11-deoxycortisol and oligonucleotide hybridization of DNA obtained from chorionic villus biopsies.
  
  
  
  • DNA analysis is used routinely in Israel where the single His R448H mutation is prevalent.
  
  
  
  • In addition to enabling genetic counseling, prenatal diagnosis of the condition offers the opportunity to consider prenatal treatment with dexamethasone to prevent virilization of the external genitalia of XX fetuses.
  
  
  
  • ACTH-stimulated levels of 11-deoxycortisol should be 5 times normal in the mild nonclassic variants.

Imaging Studies

• Pelvic or testicular ultrasonography is useful to visualize adnexal structures in the pelvis of females, to check for normal gonads, and to exclude testicular masses.



• Testicular adrenal rest tumors (ectopic adrenal tissue) have been described in males. They usually are bilateral, located in the mediastinum testes, and detected by ultrasonography.



• Abdominal CT scan may be useful for evaluating the adrenal glands, excluding mass lesions, and diagnosing adrenal hyperplasia, which typically is symmetrical and bilateral. It also may be nodular in long-standing cases. Occasionally, adrenal rests can also be found in ectopic retroperitoneal locations.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Treatment is similar to that of all the other variants of CAH. It centers on suppressing the ACTH-driven adrenal hyperplasia and subsequent mineralocorticoid and/or androgen excess.

• Glucocorticoid replacement therapy
  
  
  • Glucocorticoid replacement is vital because it reduces ACTH secretion and thus reduces the production of ACTH-dependent androgens and mineralocorticoids.
  
  
  
  • Clues that suggest inadequate glucocorticoid replacement include persistent hypertension, suppressed renin activity, elevated deoxycorticosterone or 11-deoxycortisol levels, and continued virilization in women or children.
  
  
  
  • Clues that suggest excess glucocorticoid replacement include obesity, decreased growth velocity in children, hyperlipidemia, osteoporosis, and suppressed 11-deoxycortisol levels.
  
  
  
  • Oral hydrocortisone is the ideal glucocorticoid for replacement therapy in children. A typical dose is 12-25 mg/m²/d in 2-3 divided doses.
  
  
  
  • Monitor patients for both inadequate (virilization) and excess (cushingoid features) steroid treatment, even if the dose is within indicated range.
  
  
  

  • If the response to hydrocortisone is poor, dexamethasone may be used in adults. The major problem associated with dexamethasone use is its relative short duration of action, thus necessitating multiple daily dosing (ideally q4-6h). Other glucocorticoid formulations also may be used, and prednisone has a significantly longer duration of action than dexamethasone, making bid to tid dosing adequate in most cases.

  • In situations involving fever or non–life-threatening illness, increase glucocorticoid dosages 2-3 times above the maintenance dose.
  
  
  

  • Treat patients with high doses of glucocorticoids for surgical procedures, life-threatening illness (eg, sepsis), and/or major trauma (hydrocortisone at 100 mg/m² IV q6h as needed).

• Antihypertensive therapy often is needed. Potassium-sparing diuretics, such as spironolactone or amiloride, with or without a calcium channel blocker, such as nifedipine, often are used.



• Prenatal treatment
  
  
  • Prenatal treatment is an option for fetuses known to be at risk for classic 11-beta-hydroxylase deficiency. The only setting in which this therapy should be considered is if both parents are known carriers of virilizing CAH.
  
  
  
  • Prenatal therapy is controversial because the long-term effects on the child are unknown.
  
  
  

  • Dexamethasone may be used in mothers during pregnancy at a dose of 20 mcg/kg/day in multiple divided doses initiated as soon as the pregnancy is confirmed, starting at approximately 4-5 weeks’ gestation.

  • Genetic testing is performed on the fetus, typically via chorionic villus sampling or less ideally by amniocentesis. Dexamethasone is discontinued if the fetus is XY or unaffected XX.
  
  
  

  • Once such therapy is initiated, the mother and fetus must be monitored closely. While this sort of therapy has the potential of reducing virilization in affected female babies, it does not obviate the need for subsequent CAH therapy in the child and the price is often great for the mother as the dose of dexamethasone needed to be administered invariably results in a cushingoid state in the pregnant mother.

• Several preliminary trials of gene therapy for CAH in animal models of 21-hydroxylase deficiency are ongoing. Trials include gene transfer experiments in 21-hydroxylase–deficient mice and adenoviral vector/direct intra-adrenal transfer of the CYP21 gene in other animal models. At present, no human studies are underway.

Surgical Care

• Surgical care generally is limited to reconstruction of ambiguous genitalia in female patients and this is the subject of continuing debate.
• The surgical procedure usually involves both clitoroplasty and vaginoplasty in infancy or clitoroplasty in infancy with vaginoplasty in late adolescence. Use of vaginal dilators sometimes is necessary to prevent restenosis.
• Recent suggestions for treatment options for CAH include the use of bilateral adrenalectomy. This has been proposed for both infants and older patients. It is still considered experimental and should be reserved for cases that are difficult to control using standard medical therapy.

Consultations

• Because this condition often is associated with ambiguous genitalia or precocious puberty, patients and families may require psychologic counseling and support.
• A small number of studies suggest that women with CAH have a higher incidence of negative body self-image and less sexual thought, fantasy, and activity. Endocrine, anatomical, surgical, and psychological factors all may contribute to this observed reduced sexual activity.

Diet

Hypertensive phenotypic variants may require a low-salt diet.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The medical therapy for all variants of CAH centers on adequate glucocorticoid replacement. This will reduce the ACTH-driven adrenal hyperplasia and production of the various hormone precursors. The recommended medications are hydrocortisone for children and hydrocortisone, prednisone, or dexamethasone for adults.

Potassium-sparing diuretics may be used. These agents are often not sufficient if hypertension is severe, in which case calcium channel blockers (nifedipine and verapamil) typically are used as first-choice antihypertensives.

Oral contraceptive pill preparations may be used in adult women with mild forms of the disease to ameliorate some of the virilizing symptoms associated with the condition.

Drug Category: Corticosteroids

These agents are used for glucocorticoid hormone replacement and for androgen suppression associated with CAH.

Drug Name	Prednisone (Deltasone, Orasone, Sterapred)
Description	Recommended for use in older patients because it is longer acting than hydrocortisone.
Adult Dose	5-7.5 mg/d divided bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Dexamethasone (Decadron, AK-Dex)
Description	Synthetic adrenocortical steroid. Dexamethasone is a white, odorless, crystalline powder that is stable in air and practically insoluble in water. Lacks virtually any mineralocorticoid activity.
Adult Dose	0.25-0.5 mg/d PO qd or divided bid; may be used in mothers during pregnancy at a dose of 20 mcg/kg initiated as soon as pregnancy is confirmed, starting at 4-5 weeks' gestation
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Effects decrease with coadministration of barbiturates, phenytoin, and rifampin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Category: Dihydropyridine calcium channel blockers

This and other calcium channel blockers (both dihydropyridine and nondihydropyridine) have particular utility in the management of hypertension related to mineralocorticoid excess. They are among the most efficacious antihypertensives used in hypertension associated with CAH, such as occurs in 11-beta-hydroxylase deficiency.

Drug Category: Potassium-sparing diuretics

These agents are used to treat hypertension associated with 11-beta hydroxylase deficiency. 

Drug Name	Spironolactone (Aldactone)
Description	Specific pharmacologic antagonist of aldosterone that acts primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule.
Adult Dose	25-200 mg PO qd
Pediatric Dose	1-3 mg/kg/d PO divided bid/qid
Contraindications	Documented hypersensitivity; anuria; renal failure; hyperkalemia
Interactions	Excessive potassium intake may cause hyperkalemia in patients receiving spironolactone (should not be administered concurrently with other potassium-sparing diuretics); use with ACE inhibitors or indomethacin, even in presence of a diuretic, has been associated with severe hyperkalemia (use caution when administered concomitantly); use with caution in impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate a hepatic coma; lithium generally should not be administered with diuretics; alcohol, barbiturates, or narcotics may cause orthostatic hypotension; corticosteroids may be associated with intensified electrolyte depletion (hypokalemia may occur); has been shown to increase half-life of digoxin; may result in increased serum digoxin levels and subsequent digitalis toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Shown to be tumorigenic in chronic toxicity studies in rats (use only in indicated circumstances); observe all patients receiving diuretic therapy for evidence of fluid or electrolyte imbalance (hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hyperkalemia)

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

• Complications result from inadequate or excess glucocorticoid therapy.



• Inadequate glucocorticoid therapy in these patients could result in exacerbation of the symptomatology associated with the disease including virilization in females; hyperpigmentation; and accelerated growth in early childhood with consequent early epiphysial fusion and, thus, adult short stature.
  
  

  • For males, inadequate treatment could encourage the growth of adrenal rest tumors that, when present, in the testicles are known to be associated with oligospermia and consequently infertility.
    

  • The problems of virilization and precocious puberty associated with poorly treated cases also result in myriad adjustment, self-image, identity, and mood disorders that often require long-term treatment and counseling by mental health professionals.

  • Patients with poorly controlled conditions may also have poorly controlled hypertension with the well-known cardiovascular sequelae that may accompany this.

• Excessive glucocorticoid therapy is also associated with a litany of potential medical problems typified in patients with Cushing syndrome. Among the major ones that need to be carefully looked for include increased risk for diabetes, truncal obesity, poor wound healing, increased risk for dyspeptic ulcer disease with bleeding, increased risk for glaucoma, osteoporosis, and chronic insomnia.

Patient Education

• Patients should wear medic alert bracelets stating the potential for adrenal insufficiency.



• Patients should have emergency intramuscular hydrocortisone at home. The patient and family members should be properly educated in its administration in case oral intake is not possible.



• Patients should know the features of both glucocorticoid excess and glucocorticoid deficiency and should be educated on their early detection.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Prenatal treatment with dexamethasone is an option for fetuses known to be at risk for classic 11-beta-hydroxylase deficiency.
• • The only setting in which this therapy should be considered is if both parents are known carriers of virilizing CAH.

  • Prenatal therapy is controversial because the long-term effects on the child are unknown.

  • Surgical intervention aimed at correcting genital anomalies is the subject of continuing debate.

  • Some adult patients with intersex conditions have advocated postponing genital surgery until the affected individual is able to provide informed consent. This option should be presented to parents. However, raising a child with ambiguous genitalia is a complex psychosocial issue and it is unclear if children and their families would accept this alternative.

Special Concerns

• Fertility and pregnancy
• • Many women with CAH wish to have children.
  
  
  
  • Reduced fertility may be caused by inadequately suppressed adrenal androgen production.
  
  
  
  • Polycystic ovarian syndrome (PCOS) may develop secondary to adrenal hyperandrogenism.
  
  
  
  • The effect of ovarian exposure to adrenal androgens prenatally and during childhood is unknown, but may predispose these women to PCOS.
  
  
  
  • Other reasons for reduced fertility may include an inadequate vaginal vault for coitus and psychological factors leading to reduced sexual activity.
  
  
  
  • Whether the increased adrenal androgens associated with pregnancy require increased glucocorticoid therapy is unclear. Placental aromatase appears to have a large reserve and is able to convert large amounts of ambient androgen to estrogen. This may prevent virilization of the fetus, even in cases of poorly controlled CAH in the mother.
  
  
  
  • The ideal glucocorticoid for use in patients with 11-hydroxylase deficiency and other CAH variants during pregnancy is prednisone. Dexamethasone or any other semisynthetic glucocorticoid crosses the placenta and suppresses the fetal hypothalamic-pituitary-adrenal (HPA) axis. This is distinct and different from prenatal therapy in pregnant mothers at high risk of having a child with virilizing variants of CAH. In this case, suppression of the fetal HPA axis is desirable.
  
  
  
  • During pregnancy, monitor glucocorticoid dosages and hormone levels closely.
     
• Routine prenatal screening for CAH presently is available only for the 21-hydroxylase variety.



• Polycystic ovary syndrome
  
  
  • PCOS is one of the most important differential diagnoses of late-onset or nonclassic variants of virilizing CAH.
  
  
  
  • PCOS is a heterogenous disorder characterized by hirsutism, virilism, hyperandrogenism, menstrual irregularities, chronic anovulation, obesity, insulin resistance, acanthosis nigricans, multiple ovarian cysts, and an elevated luteinizing hormone (LH) to follicular-stimulating hormone (FSH) ratio.
  
  
  
  • The elevated LH-to-FSH ratio and significant insulin resistance are useful discriminant laboratory findings.
  
  
  
  • CAH is far less common than PCOS.
  
  
  
  • The best means of distinguishing CAH from PCOS is by measuring the levels of the appropriate metabolite after 250 mcg of ACTH (11-deoxycortisol in 11-beta-hydroxylase deficiency).

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Steroidogenesis pathways in the adrenal cortex.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Azziz R. Nonclassic adrenal hyperplasia. In: Bardin CW, ed. Currrent Therapy in Endocrinology and Metabolism. 6th ed. 1997. Mosby Year:175-78.
• Azziz R, Boots LR, Parker CR Jr. 11 beta-hydroxylase deficiency in hyperandrogenism. Fertil Steril. Apr 1991;55(4):733-41. [Medline].
• Carlson AD, Obeid JS, Kanellopoulou N. Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J Steroid Biochem Mol Biol. Apr-Jun 1999;69(1-6):19-29. [Medline].
• Cathelineau G, Brerault JL, Fiet J, et al. Adrenocortical 11 beta-hydroxylation defect in adult women with postmenarchial onset of symptoms. J Clin Endocrinol Metab. Aug 1980;51(2):287-91. [Medline].
• Cerame BI, Newfield RS, Pascoe L, et al. Prenatal diagnosis and treatment of 11beta-hydroxylase deficiency congenital adrenal hyperplasia resulting in normal female genitalia. J Clin Endocrinol Metab. Sep 1999;84(9):3129-34. [Medline].
• Deaton MA, Glorioso JE, McLean DB. Congenital adrenal hyperplasia: not really a zebra [published erratum appears in Am Fam Physician 1999 Sep 15;60(4):1107]. Am Fam Physician. Mar 1 1999;59(5):1190-6, 1172. [Medline].
• Garner PR. Congenital adrenal hyperplasia in pregnancy. Semin Perinatol. Dec 1998;22(6):446-56. [Medline].
• Ghazi AA, Hadayegh F, Khakpour G, et al. Bilateral testicular enlargement due to adrenal remnant in a patient with C11 hydroxylase deficiency congenital adrenal hyperplasia. J Endocrinol Invest. Jan 2003;26(1):84-7. [Medline].
• Joehrer K, Geley S, Strasser-Wozak EM. CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Hum Mol Genet. Oct 1997;6(11):1829-34. [Medline].
• Kalaitzoglou G, New MI. Congenital adrenal hyperplasia. Molecular insights learned from patients. Receptor. Fall 1993;3(3):211-22. [Medline].
• Lucky AW, Rosenfield RL, McGuire J, et al. Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche. J Clin Endocrinol Metab. May 1986;62(5):840-8. [Medline].
• Mantero F, Opocher G, Armanini D. 11 Beta-hydroxylase deficiency. J Endocrinol Invest. Jul-Aug 1995;18(7):545-9. [Medline].
• Mantero F, Opocher G, Rocco S. Long-term treatment of mineralocorticoid excess syndromes. Steroids. Jan 1995;60(1):81-6. [Medline].
• Merke DP, Tajima T, Chhabra A. Novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency. J Clin Endocrinol Metab. Jan 1998;83(1):270-3. [Medline].
• Meyer-Bahlburg HF. What causes low rates of child-bearing in congenital adrenal hyperplasia?. J Clin Endocrinol Metab. Jun 1999;84(6):1844-7. [Medline].
• Miller WL. Congenital adrenal hyperplasia in the adult patient. Adv Intern Med. 1999;44:155-73. [Medline].
• Miller WL. Early steps in androgen biosynthesis: from cholesterol to DHEA. Baillieres Clin Endocrinol Metab. Apr 1998;12(1):67-81. [Medline].
• Moran C, Knochenhauer ES, Azziz R. Non-classic adrenal hyperplasia in hyperandrogenism: a reappraisal. J Endocrinol Invest. Nov 1998;21(10):707-20. [Medline].
• Mornet E, Dupont J, Vitek A. Characterization of two genes encoding human steroid 11 beta- hydroxylase (P-450(11) beta). J Biol Chem. Dec 15 1989;264(35):20961-7. [Medline].
• New MI, Newfield RS. Congenital adrenal hyperplasia. In: Bardin CW, ed. Current Therapy in Endocrinology and Metabolism. 6th ed. 1997. Mosby Year:179-187.
• Pang S. Congenital adrenal hyperplasia. Baillieres Clin Obstet Gynaecol. Jun 1997;11(2):281-306. [Medline].
• Pang S, Levine LS, Lorenzen F. Hormonal studies in obligate heterozygotes and siblings of patients with 11 beta-hydroxylase deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab. Mar 1980;50(3):586-9. [Medline].
• Panitsa-Faflia C, Batrinos ML. Late-onset congenital adrenal hyperplasia. Ann N Y Acad Sci. Jun 17 1997;816:230-4. [Medline].
• Pascoe L, Curnow KM, Slutsker L. Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc Natl Acad Sci U S A. Jun 1 1992;89(11):4996-5000. [Medline].
• Rosler A, Leiberman E, Cohen T. High frequency of congenital adrenal hyperplasia (classic 11 beta- hydroxylase deficiency) among Jews from Morocco. Am J Med Genet. Apr 1 1992;42(6):827-34. [Medline].
• Rosler A, Leiberman E, Rosenmann A, et al. Prenatal diagnosis of 11beta-hydroxylase deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab. Oct 1979;49(4):546-51. [Medline].
• Storr HL, Barwick TD, Snodgrass GA, et al. Hyperplasia of adrenal rest tissue causing a retroperitoneal mass in a child with 11 beta-hydroxylase deficiency. Horm Res. 2003;60(2):99-102. [Medline].
• Stratakis CA, Rennert OM. Congenital adrenal hyperplasia: molecular genetics and alternative approaches to treatment. Crit Rev Clin Lab Sci. Aug 1999;36(4):329-63. [Medline].
• White PC. Genetic diseases of steroid metabolism. Vitam Horm. 1994;49:131-95. [Medline].
• White PC. Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am. Mar 2001;30(1):61-79, vi. [Medline].
• White PC, Curnow KM, Pascoe L. Disorders of steroid 11 beta-hydroxylase isozymes. Endocr Rev. Aug 1994;15(4):421-38. [Medline].
• White PC, Obeid J, Agarwal AK. Genetic analysis of 11 beta-hydroxysteroid dehydrogenase. Steroids. Feb 1994;59(2):111-5. [Medline].
• White PC, Speiser PW. Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am. Jun 1994;23(2):325-39. [Medline].
• Zachmann M, Tassinari D, Prader A. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients. J Clin Endocrinol Metab. Feb 1983;56(2):222-9. [Medline].
• Zhu YS, Cordero JJ, Can S, et al. Mutations in CYP11B1 gene: phenotype-genotype correlations. Am J Med Genet A. Oct 15 2003;122(3):193-200. [Medline].

Article Last Updated: May 26, 2006