Management of the Adult with Congenital Adrenal Hyperplasia

Hindawi Publishing Corporation International Journal of Pediatric Endocrinology Volume 2010, Article ID 614107, 9 pages doi:10.1155/2010/614107 Review Article Management of the Adult with Congenital Adrenal Hyperplasia Richard J. Auchus Division of Endocrinology and Metabolism, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8857, USA Correspondence should be addressed to Richard J. Auchus, Received 13 February 2010; Accepted 9 March 2010 Academic Editor: Peter Allen Lee Copyright © 2010 Richard J. Auchus. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Congenital adrenal hyperplasia (CAH), most commonly due to 21-hydroxylase deficiency (21OHD), has been studied by pediatric endocrinologists for decades. Advances in the care of these patients have enabled many of these children to reach adulthood. In contrast to the course and management of the disease in childhood, little is known about CAH in adults. In many patients, the proclivity to salt-wasting crises decreases. Linear growth ceases, and reproductive function becomes an issue. Most importantly, management must minimize the potential for long-term consequences of conventional therapies. Here we review the existing literature regarding comorbidities of adults with 21OHD, goals of treatment, and approaches to therapy, with an emphasis on need for improved management strategies. 1. Introduction As discussed elsewhere, the congenital adrenal hyperplasias (CAHs) are genetic defects in cortisol biosynthesis. Low cortisol removes feedback inhibition of adrenocorticotropin (ACTH) secretion, which causes adrenal hyperplasia. The clinical consequences of CAH derive from both the shunting of cortisol precursors along other pathways and the biological activities of these precursors and their unusual metabolites, which accumulate above the block. Treatments will ideally replace the glucocorticoid deficiency and normalize both mineralocorticoid and androgen biosynthesis without inducing untoward effects from the drugs themselves. The most common cause of CAH is 21-hydroxylase deficiency (21-OHD) [1], which afflicts about 1 : 15,000 live births [2]. Since the introduction of cortisone therapy by Wilkins et al. in the early 1950s [3], these children have been able to survive into adulthood. Now that over a half century has passed, one would think that abundant information would have accumulated on the care of adults with CAH, as is now the case for children [4]. Regrettably, very little is known about the physiology and management of adults with CAH, and what is known is essentially limited to 21OHD. 1.1. Why Is So Little Known? Genetic disorders, which manifest with congenital disease, are largely the providence of pediatrics. With the completion of the Human Genome Project, internists have become more aware of genetic disorders, but largely the focus has been on susceptibility genes for cancer, diabetes, and cardiovascular diseases. Training in the care of patients with congenital biosynthetic defects, such as glycogen storage diseases and CAH, is generally not considered an important component of internal medicine residencies and endocrinology fellowships. Consequently, few doctors who care for adults, even those at academic medical centers, are adequately trained or interested in rare genetic diseases. This scenario is evidently the case for CAH. Most internal medicine endocrinology trainees will see only a few patients with CAH, mainly if they rotate in the pediatric endocrinology clinic, and many will never see a single adult with CAH during their training. A search of the NIH CRISP database revealed only a few grants awarded to the study of CAH in the last 5 years, none of which were awarded to investigators in departments of internal medicine. Without interest and research in academic centers, there is little chance that internal medicine endocrinology fellows will receive adequate training in CAH. 2 1.2. Children Are Not Little Adults. The endocrine physiology of childhood is dominated by growth and pubertal development. Adults do neither, but they do age, and many have children or at least wish to become parents. With age, they are prone to all the maladies of adult life, including heart disease, osteoporosis, and cancer. Consequently, the focus and goals of treatment are quite different in adults and children. Treatment of CAH in infancy and early childhood strives first to prevent salt-wasting and hypotensive crises due to adrenal insufficiency. Treatment of adults with CAH should be tailored to meet the needs of the patient at the present time, but with a long-term view of mitigating consequences of therapy. As a rule, the medications used and intensity of monitoring will vary as the objectives change with time [5]. 1.3. Young Adults with Chronic Diseases Are Weary of Seeing Doctors. This feeling is particularly true if the doctor knows very little about their condition and shows little interest or concern for their specific needs. Many patients with CAH have stopped seeing physicians altogether and have discontinued corticosteroid replacement for long periods of time [6]. Women may become comfortable living in a state of androgen excess and may even experience fatigue from testosterone withdrawal if therapy is resumed. Men with CAH of experience few symptoms from reducing or stopping therapy, until they become seriously ill or their testicular rests become uncomfortably large. These considerations are important in understanding the approach to the adult with CAH, both medically and psychologically. 2. Physiology of CAH in Adults Many of the general principles are the same as for children with CAH, but the importance of the various factors is considerably different. All subsequent discussion will be limited to 21-OHD. 2.1. Basic Adrenal Physiology. Cytochrome P450c21 (CYP21A2) deficiency precludes aldosterone and cortisol synthesis, limiting steroidogenesis to the reactions catalyzed by 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2), cytochrome P450c17 (CYP17A1), and a bit to cytochrome P450c11β (CYP11B1) (Figure 1(a)). Low cortisol increases ACTH production, flooding the adrenal steroidogenic machinery with upstream precursors (Figure 1(b)). Over time, the adrenals enlarge due to the chronic trophic stimulus of ACTH. Consequently, the adult adrenal of a patient with 21-OHD makes large amounts of a few steroids, mainly progesterone (P4), 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone and its sulfate (DHEA[S]), plus lesser amounts of androstenedione (AD), testosterone (T) [7], and 21-deoxycortisol—which has little glucocorticoid or mineralocorticoid activity. Due to zonation, two critical enzyme activities required for T synthesis are physically separated in the adrenal gland. The (...truncated)