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Guideline Summary
Guideline Title
Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline.
Bibliographic Source(s)
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC, Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Sep;95(9):4133-60. [275 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency

Guideline Category
Diagnosis
Management
Screening
Treatment
Clinical Specialty
Endocrinology
Family Practice
Internal Medicine
Surgery
Intended Users
Advanced Practice Nurses
Nurses
Physician Assistants
Physicians
Guideline Objective(s)

To provide clinical practice guidelines for congenital adrenal hyperplasia (CAH)

Target Population

Patients with congenital adrenal hyperplasia

Interventions and Practices Considered

Screening

  1. 21-hydroxylase deficiency screening with initial immunoassay and further evaluation of positive tests by liquid chromatography/tandem mass spectrometry
  2. Standardization of first-tier screening tests
  3. Cosyntropin (ACTH) stimulation test
  4. Ultrasound for testicular adrenal rest tumors from adolescence in males

Diagnosis

  1. Early morning baseline serum 17-hydroxyprogesterone (17-OHP) in symptomatic individuals
  2. Complete adrenocortical profile following a cosyntropin stimulation test
  3. Genotyping, as applicable
  4. Gynecological history and examination, in adolescent females

Management/Treatment

  1. Prenatal therapy (only through protocols approved by Institutional Review Boards)
  2. Maintenance therapy with hydrocortisone tablets
  3. Monitor patients for signs of glucocorticoid (GC) excess, as well as for signs of inadequate androgen suppression
  4. Fludrocortisone and sodium chloride supplements
  5. Increasing the GC dosage, in select populations
  6. Wearing or carrying by patient of medical identification of adrenal insufficiency
  7. Monitoring treatment with consistently timed hormone measurements
  8. Incomplete suppression of endogenous adrenal steroid secretion
  9. Monitoring of height, weight, physical examination, and bone age x-ray assessment
  10. Treatment of nonclassic (NC) CAH in children with inappropriate early onset and rapid progression of pubarche or bone age and in adolescents with overt virilization
  11. Discontinuing therapy when symptoms resolve
  12. Close monitoring for iatrogenic Cushing syndrome
  13. Adrenal imaging, in select populations
  14. Neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization
  15. Experimental treatment within clinical trials
  16. Bilateral adrenalectomy, in select populations
  17. Hydrocortisone or long-acting GCs, in adults
  18. Monitoring of GC and mineralocorticoid (MC) treatment with annual physical examination and hormone measurements
  19. Genetic counseling
  20. Referral to reproductive endocrinologist and/or fertility specialist, as appropriate
  21. Joint care by endocrinologists and obstetricians for pregnant patients
  22. Hydrocortisone/prednisolone and fludrocortisone, with adjustment of GC doses as needed and stress doses of GCs during labor and delivery in pregnant patients
  23. Referral to mental health staff, as appropriate

Note: The use of oral hydrocortisone suspension and the chronic use of long-acting potent GCs in growing patients; the use of increased GC doses in mental and emotional stress, minor illness, and before physical exercise; the use of stress doses of GC in patients with nonclassic CAH unless their adrenal function is suboptimal or iatrogenically suppressed; treatment in asymptomatic individuals with NCCAH; routine evaluation of bone mineral density in children; and the routine use of pelvic ultrasound in patients with regular menstrual cycles are not recommended.

Major Outcomes Considered
  • Positive predictive value of screening tests
  • Morbidity and mortality associated with congenital adrenal hyperplasia (CAH)
  • Signs and symptoms of CAH
  • Growth rates

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

The Endocrine Society's Task Force commissioned two systematic reviews (see the "Availability of Companion Documents" field) to support their guidelines on congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency.

Adult Height in Patients with Congenital Adrenal Hyperplasia

Eligibility Criteria

Eligible studies enrolled individuals with classic congenital adrenal hyperplasia (CAH) who started treatment in the first five years of life, followed and treated until final height. Studies were eligible regardless of design, language or sample size. The reviewers excluded studies in which they could not ascertain the timing of diagnosis or height outcomes.

Search Strategy

The reviewers searched electronic databases (MEDLINE, EMBASE, Cochrane Library, ISI Web of Science and Scopus) from inception through September 2008 utilizing a combination of subject headings and textwords that referred to congenital adrenal hyperplasia and glucocorticoids. The reviewers also requested references from content experts and searched the bibliographies of included studies.

Study Selection

Reviewers working independently and in duplicate reviewed abstracts and titles and subsequently full text articles for eligibility. Disagreements were resolved by consensus or arbitration.

Prenatal Dexamethasone Use for the Prevention of Virilization in Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia due to 21 Hydroxylase (CYP21A2) Deficiency

Eligibility Criteria

Eligible studies were comparative studies that enrolled pregnancies at risk of classical CAH in which dexamethasone was given to one group and included a comparison unexposed group. Eligible studies had to measure either fetal or maternal outcomes, such as fetal death, fetal malformations, fetal growth parameters and need for neonatal intensive care, obstetric complications (need for instrumentation or caesarian section, bleeding complications, infections), new maternal hyperglycemia requiring treatment or new maternal hypertension requiring treatment. Studies were included if reporting long term physical, metabolic and neuropsychological outcomes, such as growth, dyslipidemia, dysglycemia, cardiovascular outcomes (including hypertension, carotid intima media thickness, and cardiovascular events) and neuropsychological outcomes, or school performance. The reviewers excluded studies using other glucocorticoids and studies not measuring the fetal and maternal outcomes of interest. Language of publication and random allocation were not eligibility criteria.

Study Identification

An expert reference librarian (P.J.E.) designed and conducted the electronic search strategy with input from an endocrinologist (V.M.M.) with expertise in conducting systematic reviews. The systematic search included MEDLINE, EMBASE, and Cochrane CENTRAL electronic databases from their inception through August 2009. The detailed strategy is available in the appendix of the clinical review (see the "Availability of Companion Documents" field). To identify additional candidate studies, the reviewers reviewed the reference lists of the eligible primary studies, narrative reviews, and systematic reviews, and they queried the expert members of the commissioning task force.

Study Selection

Working independently and in duplicate, reviewers screened all abstracts and titles. After obtaining all potentially eligible studies in full text, these reviewers, again working independently and in duplicate, determined eligibility with acceptable chance-adjusted interobserver agreement mean kappa = 0.87 (range 0.77-0.97). Disagreements were resolved by consensus or arbitration.

Number of Source Documents

Adult Height in Patients with Congenital Adrenal Hyperplasia

Initial search of the literature yielded 1088 publications and 35 eligible studies with sufficient data for meta-analysis.

Prenatal Dexamethasone Use for the Prevention of Virilization in Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia due to 21 Hydroxylase (CYP21A2) Deficiency

The search identified 1083 candidate studies for review, of which only 4 studies were confirmed eligible and were published in 8 manuscripts contributing to 12 comparisons.

Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Quality of Evidence

+OOO Denotes very low quality evidence

++OO Denotes low quality evidence

+++O Denotes moderate quality evidence

++++ Denotes high quality evidence

Methods Used to Analyze the Evidence
Meta-Analysis of Observational Trials
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Adult Height in Patients with Congenital Adrenal Hyperplasia

Quality Assessment

Two reviewers working independently and in duplicate assessed the quality of eligible studies, i.e., the risk of bias. The Newcastle-Ottawa scale was used to assess the quality of observational studies. Funding source of the studies was noted as well.

Data Extraction

Reviewers working independently and in duplicate extracted data from each of the eligible trials using an electronic structured extraction form. Data extraction included full description of participants enrolled including their sex and age at diagnosis, criteria for congenital adrenal hyperplasia (CAH) diagnosis, time of initiation, type, dose, route, duration, and adherence related to glucocorticoid replacement, details of mineralocorticoid replacement, age at onset of puberty, age at menarche, target height or mid-parental height, final height achieved and the use of growth enhancing drugs. The reviewers also extracted data on patient and parent satisfaction with achieved height. When the reports presented individual patient data, the reviewers selected eligible patients, collected their data and grouped these data in a cohort. Foreign language articles were translated by multi-lingual reviewers.

Statistical Analysis

Standard deviation score (SDS) for final height and corrected height were estimated from each study and pooled using random-effects meta-analysis. SDS expresses height differences in terms of the standard deviation for height of the reference population. Most studies reported SDS in reference to their national databases. Where SDS was not reported, it was computed by the authors using the final adult height of the subjects and the control group or other reference populations (the average national gender specific height and the mid-parental height). Where individual patient data or several groups of patients were reported in a study, the patients that met the inclusion criteria were selected and grouped. Corrected height refers to the final height SDS – mid-parental height SDS and thus compares the final height to the genetic height potential. Mid-parental height was calculated using the formula: (father height + mother height)/2 + 6.5 cm for boys and -6.5 cm for girls. The reviewers assessed the degree of inconsistency in the results between studies using the I2 statistic. This statistic explains the proportion of inconsistency between studies that cannot be explained by chance alone and is likely due to real differences in the population or the conduct of the studies.

Subgroup and Sensitivity and Meta-regression Analyses

To explain the observed inconsistency, the reviewers explored several subgroups. The reviewers tested for subgroup-height interactions considering a 2-tailed p value <0.05 to be statistically significant. These subgroups were defined as: (a) patients diagnosed before or after 1 year of age; (b) patient sex, male or female; (c) patient age at onset of puberty, 8-11 vs 11.1-14 years in boys, 8-10 vs 10.1-12 years in girls; (d) type of glucocorticoid used in treatment; (e) dose of glucocorticoid, as hydrocortisone equivalent relative to body surface area, 14-19 vs 19.1-24 mg/m2/day; (f) use of mineralocorticoid; (g) exposure to height enhancing drugs (growth hormone, leuprolide acetate, aromatase inhibitors [e.g., anastrozole, letrozole], androgen receptor blockers [e.g., flutamide], and estrogen receptor blockers [e.g., tamoxifen]); (h) loss to follow-up; (i) adherence to treatment; (j) quality of outcome measure (self-report vs. clinical measure); and (k) quality of exposure ascertainment (self-report vs. chart review). The reviewers conducted weighted meta-regression using the final SDS as the dependent variable and the year of publication as the independent variable to determine whether secular trends in height over time have affected study conclusions. The reviewers explored in sensitivity analyses how the results of the meta-analyses would change when borderline eligible studies were excluded.

Prenatal Dexamethasone Use for the Prevention of Virilization in Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia due to 21 Hydroxylase (CYP21A2) Deficiency

Data Collection

Using a standardized data extraction form and working in duplicate, the reviewers abstracted the following descriptive data from every study: description of the mothers (age), and characteristics of treatment and control interventions (medication type, indication, dose, frequency, route, and duration).

The reviewers also abstracted the outcomes of interest from every study. They collected fetal death, fetal malformations, birth weight, height and head circumference, need for neonatal intensive care, long term complications (school performance, psychoneurological outcomes, metabolic outcomes [dyslipidemia, dysglycemia], cardiovascular outcomes [including metabolic outcomes, hypertension, carotid intima media thickness, and cardiovascular events]). As for maternal outcomes the reviewers recorded: new hyperglycemia requiring treatment, new hypertension requiring treatment, symptoms of hypercortisolism (edema, striae) and obstetric complications (gestational age at delivery, need for instrumentation or c-section, bleeding complications, infections).

Outcomes collected were at the longest point of complete follow-up while patients were still exposed to the interventions. The reviewers contacted authors for missing data when needed.

Quality Assessment

The reviewers employed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate the quality of research evidence, taking into account the elements that can strengthen the quality of observational studies such as strong associations, direction of confounding and dose-response relationships. For each study, the reviewers assessed how the population was selected, how the exposure (hormone therapy) documented (self-report vs. medical chart documentation), whether outcomes were assessed via self-report or clinical/structured interview, the duration and adequacy of study follow up, and the proportion of participants lost to follow up. The reviewers assessed their chance-adjusted agreement on study quality using the kappa statistic with disagreements resolved by consensus or arbitration.

Statistical Analyses

Meta Analyses

The reviewers determined the pooled weighted mean difference (WMD) between treatment and control interventions and the associated 95% confidence interval (CI) using a DerSimonian and Laird random-effects meta-analysis as implemented in RevMan 4.2 (Cochrane Collaboration), and in Stats-Direct statistical software (StatsDirect Ltd., Altrincham, UK; http://www.statsdirect.com External Web Site Policy).

The reviewers quantified inconsistency using the I2 statistic, which describes the proportion of heterogeneity across studies that is not due to chance, thus describing the extent of true inconsistency in results across trials: I2 less than 25% and more than 50% reflect small and significant inconsistency, respectively. I2 is not estimable when the number of included studies is <3.

Subgroup Analyses

To explore causes of inconsistency and subgroup-treatment interactions, we planned the following subgroup analyses defined by risk of 21-hydroxylase (CYP21A2) deficiency in pregnancy, timing (1st trimester or later start) and duration (1st trimester, all pregnancy) of glucocorticoid treatment, and study quality descriptors (comparability of cohorts, objective and blind assessment of outcomes, loss to follow-up). The reviewers planned to assess treatment-subgroup interactions by univariate analyses.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Participants

The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating congenital adrenal hyperplasia (CAH), a methodologist, and a medical writer. Additional experts were also consulted.

Evidence

Using the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (+OOO), low (++OO), moderate (+++O), or high (++++) and the strength of recommendations is described.

Consensus Process

Consensus was guided by systematic reviews of evidence and discussions.

Rating Scheme for the Strength of the Recommendations

Strength of Recommendation

1 - Indicates a strong recommendation and is associated with the phrase "The Task Force recommends."

2 - Denotes a weak recommendation and is associated with the phrase "The Task Force suggests."

Cost Analysis

The developers reviewed published cost analyses.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

The guidelines were reviewed and approved sequentially by The Endocrine Society's Clinical Guidelines Subcommittee (CGS) and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments.

Recommendations

Major Recommendations

Definitions for the quality of the evidence (+OOO, ++OO, +++O, and ++++); the strength of the recommendation (1 or 2); and the difference between a "recommendation" and a "suggestion" are provided at the end of the "Major Recommendations" field.

Newborn Screening

The Task Force recommends that screening for 21-hydroxylase deficiency be incorporated into all newborn screening programs (1|++OO), using a two-tier protocol (initial immunoassay with further evaluation of positive tests by liquid chromatography/tandem mass spectrometry).

The Task Force recommends standardization of first-tier screening tests to a common technology with a single consistent set of norms stratified by gestational age (1|++OO).

The Task Force recommends that infants with positive newborn screens for congenital adrenal hyperplasia (CAH) be followed up according to specific regional protocols (1|++OO).

Prenatal Treatment of CAH

The Task Force recommends that prenatal therapy continue to be regarded as experimental. Thus the Task Force does not recommend specific treatment protocols.

The Task Force suggests that prenatal therapy be pursued through protocols approved by Institutional Review Boards at centers capable of collecting outcomes data on a sufficiently large number of patients so that risks and benefits of this treatment can be defined more precisely (2|++OO).

Diagnosis of Nonclassic CAH (NCCAH)/CAH after Infancy

The Task Force recommends obtaining with an early morning baseline serum 17-hydroxyprogesterone (17-OHP) in symptomatic individuals (1|++OO).

The Task Force recommends obtaining a complete adrenocortical profile following a cosyntropin stimulation test to differentiate 21-hydroxylase deficiency from other enzyme defects, and to make the diagnosis in borderline cases (1|++OO).

The Task Force suggests genotyping only when results of the adrenocortical profile following cosyntropin stimulation test are equivocal or for purposes of genetic counseling (2|+OOO).

Medical Treatment of CAH in Growing Patients

The Task Force recommends maintenance therapy with hydrocortisone tablets in growing patients with classic CAH (1|+++O).

The Task Force recommends against the use of oral hydrocortisone suspension, and against the chronic use of long-acting potent glucocorticoid (GCs), in growing patients (1|++OO).

The Task Force recommends monitoring patients for signs of GC excess, as well as for signs of inadequate androgen suppression (1|++OO).

The Task Forces recommends that all patients with classic CAH be treated with fludrocortisone and sodium chloride supplements in the newborn period and early infancy (1|++OO).

The Task Force recommends increasing the GC dosage of CAH patients in situations such as febrile illness (>38.5°C), gastroenteritis with dehydration, surgery accompanied by general anesthesia, and major trauma (1|++OO).

The Task Force recommends against the use of increased GC doses in mental and emotional stress, minor illness, and before physical exercise (1|+OOO).

The Task Force recommends against the use of stress doses of GC in patients with nonclassic CAH unless their adrenal function is suboptimal or iatrogenically suppressed (1|+OOO).

The Task Force suggests that patients who require treatment always wear or carry medical identification indicating that they have adrenal insufficiency (2|+OOO).

The Task Force recommends monitoring treatment by consistently timed hormone measurements (1|+OOO).

The Task Force recommends that endogenous adrenal steroid secretion not be completely suppressed in order to avoid adverse effects of over-treatment (1|++OO).

The Task Force suggests regular monitoring of height, weight, and physical examination; annual bone age x-ray assessment is also suggested after age 2 years (2|+OOO).

Treatment of NCCAH

The Task Force suggests treating NCCAH children with inappropriately early onset and rapid progression of pubarche or bone age, and adolescent patients with overt virilization (2|++OO).

The Task Force recommends against treatment in asymptomatic individuals with NCCAH (1|++OO).

The Task Force suggests that previously treated NCCAH patients be given the option of discontinuing therapy when symptoms resolve (2|++OO).

Complications of CAH

The Task Force recommends close monitoring for iatrogenic Cushing syndrome in all GC-treated patients (1|++OO).

The Task Force suggests against the routine evaluation of bone mineral density in children (2|+OOO).

The Task Force suggests that adrenal imaging be reserved for those patients who have an atypical clinical or biochemical course (2|+OOO).

Feminizing Surgery

The Task Force suggests that for severely virilized (Prader stage ≥3) females clitoral and perineal reconstruction be considered in infancy, and performed by an experienced surgeon in a center with similarly experienced pediatric endocrinologists, mental health professionals, and social work services (2|++OO).

The Task Force suggests neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization (2|+OOO).

The Task Force suggests continued long-term outcome studies of early surgery.

Experimental Therapies

The Task Force suggests that children with CAH who have a predicted height standard deviation (SD) ≤-2.25 be considered for experimental treatment in appropriately controlled trials (2|+OOO).

The Task Force recommends against use of experimental treatment approaches outside of formally approved clinical trials (1|++OO).

The Task Force suggests further prospective, randomized, and carefully controlled studies to determine whether the use of growth-promoting drugs increases adult height in patients with CAH (2|+OOO).

The Task Force suggests that bilateral adrenalectomy be considered only in select cases that have failed medical therapy, especially in rare cases of adult females with salt-wasting (SW) CAH and infertility. Risk for noncompliance must be evaluated prior to surgery (2|+OOO).

The Task Force suggests the development of new treatment approaches that minimize daily GC exposure and aim to achieve physiological cortisol replacement.

The Task Force suggests additional research concerning epinephrine deficiency in the stress response.

The Task Force suggests continued research concerning novel therapies.

The Task Force suggests that further study of alternative treatment approaches consider growth, metabolic, reproductive and neuropsychiatric endpoints.

CAH in Adulthood

The Task Force recommends that NCCAH screening with an early morning serum measurement of 17-OHP be confirmed when needed through a cosyntropin (ACTH) stimulation test (1|++OO).

The Task Force suggests treatment of adults with NCCAH with patient-important hyperandrogenism or infertility (2|+OOO). The Task Force suggests clinicians not prescribe daily GC substitution in adult males with NCCAH (2|+OOO).

The Task Force suggests that adult patients with classic CAH be treated with hydrocortisone or long-acting GCs (2|+OOO).

The Task Force suggests the monitoring of GC and mineralocorticoid (MC) treatment include at least annual physical examination and appropriate hormone measurements.

The Task Force recommends that genetic counseling be given to parents at birth of a CAH child, and to adolescents at the transition to adult care (1|+OOO).

The Task Force suggests that pediatric and adult endocrinologists, reproductive endocrinologists, gynecologists, and urologists have joint clinics for transfer of patients with CAH to adult care (2|+OOO).

The Task Force suggests a gynecological history and examination under anesthesia in adolescent females with CAH.

The Task Force suggests against the routine use of pelvic ultrasound in CAH patients with regular menstrual cycles (2|+OOO).

The Task Force suggests all males with classic CAH be periodically screened from adolescence for testicular adrenal rest tumors by ultrasound (2|+OOO).

The Task Force suggests that CAH patients with impaired fertility consult a reproductive endocrinologist and/or fertility specialist (2|+OOO).

The Task Force suggests that pregnant women with CAH be followed jointly by endocrinologists and obstetricians.

The Task Force recommends that patients with CAH who become pregnant continue their pre-pregnancy doses of hydrocortisone/prednisolone and fludrocortisone therapy (1|++OO). GC doses should be adjusted if symptoms and signs of GC insufficiency occur. The Task Force recommends against the use of GCs that traverse the placenta, such as dexamethasone, for treatment of pregnant patients with CAH (1|++OO). Stress doses of GCs should be used during labor and delivery.

Mental Health

The Task Force suggests that patients with CAH and psychosocial problems associated with disorders of sexual development be referred to mental health staff with specialized expertise in managing such problems (2|++OO).

The Task Force suggests the development, evaluation, and implementation in long-term clinical trials and in clinical practice of valid and responsive patient-reported assessments of their quality of life in response to treatment regimens (2|+OOO).

Definitions:

Quality of Evidence

+OOO Denotes very low quality evidence

++OO Denotes low quality evidence

+++O Denotes moderate quality evidence

++++ Denotes high quality evidence

Strength of Recommendation

1 - Indicates a strong recommendation and is associated with the phrase "The Task Force recommends."

2 - Denotes a weak recommendation and is associated with the phrase "The Task Force suggests."

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is specifically stated for most recommendations (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits
  • Screening markedly reduces the time to diagnosis of infants with congenital adrenal hyperplasia (CAH). Morbidity and mortality are reduced due to early diagnosis and prevention of severe salt wasting.
  • Administering glucocorticoids (GCs) to the mother prenatally aims to reduce female genital virilization, the need for reconstructive surgery, and the emotional distress associated with the birth of a child with ambiguous genitalia.
  • The goal of therapy is to reduce excessive androgen secretion by replacing the deficient hormones. Proper treatment with glucocorticoids prevents adrenal crisis and virilization, allowing normal growth and development.
  • All patients with elevated plasma renin activity (PRA) or aldosterone to PRA ratio benefit from fludrocortisone therapy and adequate dietary sodium. Maintenance of sodium balance reduces vasopressin and cosyntropin (ACTH) levels, contributing to lower GC doses, leading to better auxological outcomes.
  • Bilateral adrenalectomy reduces the risk of virilization in females and allows for treatment with lower GC doses.
  • Adults with classic CAH are treated to avoid symptoms of adrenocortical deficiency in both sexes; hyperandrogenism, voice changes, and infertility in women; and testicular tumors in men.
Potential Harms
  • False-positive screening results are costly and may entail a large amount of physician time for evaluation and counseling, plus nursing time and additional laboratory tests if cosyntropin testing is undertaken. Moreover, parents of infants with positive screens may suffer significant psychological distress at the prospect of their children having a potentially life-threatening chronic disease.
  • Multiple studies indicate that prenatal treatment with glucocorticoids is associated with modest but manageable maternal complications that do not appear to pose a major risk to the mother.
  • Many reports of teratogenic effects, especially orofacial clefts, produced by high doses of dexamethasone administered to pregnant animals and in human patients led the U.S. Food and Drug Administration to classify dexamethasone as a category B drug, whose safety in pregnancy is not established.
  • Clinical management of classic CAH is a difficult balance between hyperandrogenism and hypercortisolism. Undertreatment carries the risk of adrenal crisis and allows increased adrenal androgen production, with accelerated bone age and loss of growth potential; overtreatment may suppress growth, increase blood pressure, and cause iatrogenic Cushing's syndrome.
  • Glucose and electrolyte supplementation should be given to young children due to risk of hypoglycemia and electrolyte imbalance with hydrocortisone.
  • Objections to adrenalectomy are based on surgical risk, possible increased risk of adrenal crisis due to loss of protective residual adrenal function, and possible loss of hormones that may have beneficial effects such as epinephrine and dehydroepiandrosterone (DHEA).
  • Overtreatment with glucocorticoids (GCs) will cause Cushingoid features and may lead to osteoporosis, and excess mineralocorticoids (MCs) will cause hypertension.

Qualifying Statements

Qualifying Statements
  • Clinical Practice Guidelines are developed to be of assistance to endocrinologists and other health care professionals by providing guidance and recommendations for particular areas of practice. The Guidelines should not be considered inclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the independent judgment of health care providers and each patient's individual circumstances.
  • The Endocrine Society makes no warranty, express or implied, regarding the Guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. The Society shall not be liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained herein.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Patient Resources
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC, Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Sep;95(9):4133-60. [275 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2010 Sep
Guideline Developer(s)
The Endocrine Society - Professional Association
Source(s) of Funding

The Endocrine Society

Guideline Committee

Congenital Adrenal Hyperplasia Task Force

Composition of Group That Authored the Guideline

Authors: Phyllis W. Speiser, Ricardo Azziz, Laurence S. Baskin, Lucia Ghizzoni, Terry W. Hensle, Deborah P. Merke, Heino F. L. Meyer-Bahlburg, Walter L. Miller, Victor M. Montori, Sharon E. Oberfield, Martin Ritzen, and Perrin C. White

Financial Disclosures/Conflicts of Interest

Phyllis W. Speiser, M.D. (chair)—Financial or Business/Organizational Interests: Pediatric Endocrine Society, Society for Pediatric Research, and American Association of Clinical Endocrinologists; Significant Financial Interest or Leadership Position: Medical Advisory Board, CARES Foundation, and National Adrenal Diseases Foundation

Ricardo Azziz, M.B.A., M.D., M.P.H.—Financial or Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: none declared

Laurence S. Baskin, M.D.—Financial or Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: none declared

Lucia Ghizzoni, M.D., Ph.D.—Financial or Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: none declared

Terry W. Hensle, M.D.—Financial or Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: none declared;

*Deborah P. Merke, MS, M.D.—Financial or Business/Organizational Interests: Phoqus Pharmaceuticals and CARES Foundation; Significant Financial Interest or Leadership Position: none declared

Heino F. L. Meyer-Bahlburg, Dr. rer. Nat.—Financial or Business/Organizational Interests: Pediatric Endocrine Society, World Professional Association of Transgender Health, and Gender Identity Disorders for DSM-V of the American Psychiatric Association; Significant Financial Interest or Leadership Position: none declared

Walter L. Miller, M.D.—Financial or Business/Organizational Interests: CARES Foundation and Pediatric Endocrine Society; Significant Financial Interest or Leadership Position: Medical Advisory Board and CARES Foundation

†Victor M. Montori, M.D.—Financial or Business/Organizational Interests: KER unit (Mayo Clinic); Significant Financial Interest or Leadership Position: none declared

Sharon E. Oberfield, M.D.—Financial or Business/Organizational Interests: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Significant Financial Interest or Leadership Position: Pediatric Endocrine Society, Medical Advisory Board, and CARES Foundation

Martin Ritzen, M.D.—Financial or Business/Organizational Interests: Biopartners AG and Acta Paediatrica; Significant Financial Interest or Leadership Position: none declared

Perrin C. White, M.D.— Financial or Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: none declared.

* This work was supported by the Intramural Research Program of the National Institutes of Health.

† Evidence-based reviews for this guideline were prepared under contract with The Endocrine Society.

Guideline Endorser(s)
American Academy of Pediatrics - Medical Specialty Society
Androgen Excess and PCOS Society - International Agency
CARES Foundation - Nonprofit Organization
European Society for Paediatric Endocrinology - Medical Specialty Society
European Society of Endocrinology - Medical Specialty Society
Pediatric Endocrine Society - Medical Specialty Society
Society of Pediatric Urology - Medical Specialty Society
Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from The Endocrine Society Web site External Web Site Policy.

Print copies: Available from The Endocrine Society, Phone: (301) 941.0210; Email: Societyservices@endo-society.org.

Availability of Companion Documents

The following are available:

  • Muthusamy K, Elamin MB, Smushkin G, Murad MH, Lampropulos JF, Elamin KB, Abu Elnour NO, Gallegos-Orozco JF, Fatourechi MM, Agrwal N, Lane MA, Albuquerque FN, Erwin PJ, Montori VM. Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2010 Sep;95(9):4161-72.
  • Mercè Fernández-Balsells M, Muthusamy K, Smushkin G, Lampropulos JF, Elamin MB, Abu Elnour NO, Elamin KB, Agrwal N, Gallegos-Orozco JF, Lane MA, Erwin PJ, Montori VM, Murad MH. Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses. Clin Endocrinol (Oxf). 2010 Oct;73(4):436-44.

Print copies: Available from The Endocrine Society, Phone: (301) 941.0210; Email: Societyservices@endo-society.org

Patient Resources

The following is available:

  • Patient guide to congenital adrenal hyperplasia. The Hormone Foundation. 2010 Sep. 2 p. Electronic copies: Available in Portable Document Format (PDF) from The Hormone Foundation Web site External Web Site Policy.
  • Fact sheet: congenital adrenal hyperplasia. The Hormone Foundation. 2010 Feb. 1 p. Electronic copies: Available in Portable Document Format (PDF) from The Hormone Foundation Web site External Web Site Policy.

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

NGC Status

This NGC summary was completed by ECRI Institute on March 10, 2011. The information was verified by the guideline developer on June 6, 2011.

Copyright Statement

This is an author manuscript copyrighted by The Endocrine Society. This may not be duplicated or reproduced, other than for personal use or within the rule of "Fair Use of Copyrighted Materials" (section 107, Title 17, U.S. Code) without permission of the copyright owner, The Endocrine Society. From the time of acceptance following peer review, the full text of this manuscript is made freely available by The Endocrine Society at http://www.endo-society.org/guidelines/Current-Clinical-Practice-Guidelines.cfm External Web Site Policy.

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