Approach to the patient: the adult with congenital adrenal hyperplasia

Abstract

The most common form of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency (21OHD). When the nonclassical (mild) form is included, 21OHD is the most common genetic disease in human beings. With the advent of pharmaceutical preparation of glucocorticoids starting in the 1960s and newborn screening starting in the 1990s, the majority of children with 21OHD are reaching adulthood, which has yielded a cohort of patients with, in essence, a new disease. Only recently have some data emerged from cohorts of adults with 21OHD, and in some centers, experience with the management of these patients is growing. These patients suffer from poor health, infertility, characteristic tumors in the adrenal glands and gonads, and consequences of chronic glucocorticoid therapy. Their care is fragmented and inconsistent, and many stop taking their medications out of frustration. Internal medicine residents and endocrinology fellows receive little training in their care, which further discourages their seeking medical attention. Adults with 21OHD have a different physiology from patients with Addison's disease or other androgen excess states, and their needs are different than those of young children with 21OHD. Consequently, their care requires unorthodox treatment and monitoring strategies foreign to most endocrine practitioners. Our goal for this article is to review their physiology, complications, and needs in order to develop rational and effective treatment and monitoring strategies.

Figure 1.

Adrenal steroid biosynthesis pathways and enzymatic defects causing CAH. The enzymes and proteins required for normal cortisol synthesis are shown: StAR, the steroid acute regulatory protein; CYP11A1, cholesterol side chain cleavage enzyme or P450scc; CYP17A1, steroid 17-hydroxylase/17,20-lyase or P450c17; 3βHSD2, 3β-hydroxysteroid dehydrogenase/isomerase type 2; POR, P450-oxidoreductase; and CYP21A2, steroid 21-hydroxylase or P450c21. Also shown are Fdx and FdxR, ferredoxin and ferredoxin reductase, respectively, which are the electron transfer proteins for the mitochondrial cytochrome P450 enzymes in the CYP11 family; SULT2A1, steroid sulfotransferase type 2A1 or DHEA sulfotransferase; and STS, steroid sulfatase. The 19-carbon androgen precursors DHEA and DHEAS are metabolized to active androgens and estrogens via other enzymes in the adrenal and peripheral tissues. Dotted line from 17OHP to AD indicates poor conversion by human CYP17A1, even in the presence of cytochrome b₅ (b₅), compared to conversion of 17OH-pregnenolone (17-hydroxypregnenolone) to DHEA.

Figure 2.

Altered steroidogenesis in 21OHD. The block at CYP21A2 (bold X) and raised ACTH cause 21-deoxysteroids to accumulate and to undergo conversion to androgens and estrogens (darkened lines), as well as significant amounts of 21-deoxycortisol due to conversion of 17OHP by CYP11B1, a reaction that is insignificant in the presence of a functional CYP21A2 enzyme. Some 11-deoxycorticosterone is formed by peripheral conversion of P4 by hepatic cytochrome P450 (CYP) enzymes.