Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline

Abstract

Objective: We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH).

Participants: The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration.

Consensus process: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's 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.

Conclusions: We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing's syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients' quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.

Figure 1

A, Normal fetal adrenal steroidogenesis. Because the fetal adrenal has low levels of 3β-HSD, most steroidogenesis is directed toward DHEA (and thence to DHEA-sulfate), but small amounts of steroid enter the pathways toward aldosterone and cortisol. The adrenal 21-hydroxylase, P450c21, is essential in both pathways. The adrenal can make small amounts of testosterone via 17β-HSD. B, In the absence of the 21-hydroxylase activity of P450c21, three pathways lead to androgens. First, the pathway from cholesterol to DHEA remains intact. Although much DHEA is inactivated to DHEA-sulfate, the increased production of DHEA will lead to some DHEA being converted to testosterone and dihydrotestosterone (DHT). Second, although minimal amounts of 17-OHP are converted to androstenedione in the normal adrenal, the huge amounts of 17-OHP produced in CAH permit some 17-OHP to be converted to androstenedione and then to testosterone. Third, the proposed backdoor pathway depends on the 5α and 3α reduction of 17-OHP to 17OH-allopregnanolone. This steroid is readily converted to androstanediol, which can then be oxidized to DHT by the reversible 3α-HSD enzyme. Although first discovered in marsupials, mass spectrometric examinations of human urinary steroid metabolites indicate this pathway may also occur in the human adrenal (7,8).

Figure 2

Diagnosis of CAH after infancy. Reference standards for hormonal diagnosis derived from Refs. ,, and . Note that randomly measured 17-OHP levels can be normal in NCCAH; hence, a screening 17-OHP level should be measured in the early morning (before 0800 h). Steroid measurements may differ with the assay employed. Classic CAH includes both salt-wasting and simple virilizing forms of 21-hydroxylase deficiency.