When the nonclassical (mild) form is included, 21OHD is the most common genetic disease in human beings. A typical sequence is a switch from hydrocortisone to prednisone for convenience, but often the prednisone is ineffectivedue to poor conversion to prednisoloneand then dexamethasone is started, with good androgen suppression but horrific physical consequences. In severely virilized girls, traditional skin or bowel grafts do not always give satisfactory long-term results (61), whereas buccal mucosa grafts appear promising but lack long-term outcomes (62, 63). The medical history should include lapses in medication (intentional or otherwise), recent episodes of adrenal crisis and/or increased glucocorticoids, reasons for switching from hydrocortisone to longer-acting glucocorticoids if relevant, and training in emergency hydrocortisone injection. . In addition, adults with 21OHD require cancer screening, immunizations, and general health maintenance like any other adult. Nandagopal R , Sinaii N , Avila NA, et al. Because women with 21OHD often develop a secondary polycystic ovary syndrome (40), a high T does not necessarily mean poor control. Richard J. Auchus, Wiebke Arlt, Approach to the Patient: The Adult With Congenital Adrenal Hyperplasia, The Journal of Clinical Endocrinology & Metabolism, Volume 98, Issue 7, 1 July 2013, Pages 26452655, https://doi.org/10.1210/jc.2013-1440. It is likewise critical to gauge how much the patient understands about the disease and to establish the goals, concerns, and limitations to compliance with therapy. Our goal for this article is to review their physiology, complications, and needs in order to develop rational and effective treatment and monitoring strategies. . About 3050% of men with 21OHD develop testicular adrenal rest tumors (TARTs) (7, 16), and the prevalence increases when control is poor, particularly for men with the most severe deficiency. See Table 6 and Supplemental Data (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org). Therrell BL , Berenbaum SA , Manter-Kapanke V, et al. In men, the AD/T ratio is normally <0.2 because most of the T derives from the testis, in which AD is almost completely reduced to T by 17-hydroxysteroid dehydrogenase type 3 (17HSD3) (42, 43). . She collapsed while watching a sporting event on a hot, humid day and was rushed by ambulance to the emergency department; she was poorly responsive, with a systolic blood pressure of 85 mm Hg, heart rate of 135 beats/min, and temperature of 37C. In women with 21OHD who are infertile or who have chronic amenorrhea, progesterone (P4), which accumulates upstream of 17OHP in the adrenal, should be assessed as well. One-year clinical evaluation of single morning dose prednisolone therapy for 21-hydroxylase deficiency, Improvement of semen quality in an infertile man with 21-hydroxylase deficiency, suppressed serum gonadotropins and testicular adrenal rest tumours, Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone, Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia, Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Unilateral adrenal tumor, erectile dysfunction and infertility in a patient with 21-hydroxylase deficiency: effects of glucocorticoid treatment and surgery, Outcome of bilateral adrenalectomy in congenital adrenal hyperplasia: one unit's experience, Giant bilateral myelolipomas in a man with congenital adrenal hyperplasia, Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia, Impaired sexual and reproductive outcomes in women with classical forms of congenital adrenal hyperplasia, The long term outcome of feminizing genital surgery for congenital adrenal hyperplasia: anatomical, functional and cosmetic outcomes, psychosexual development, and satisfaction in adult female patients, Use of autologous buccal mucosa for vaginoplasty: a study of eight cases, Autologous buccal mucosa vulvovaginoplasty for high urogenital sinus, Copyright 2013 by The Endocrine Society, Comparison of Hormonal Response to a Mixed Meal Challenge in Hypoglycemia after Sleeve Gastrectomy versus Gastric Bypass, Determination of Half-Lives of Circulating FSH and LH Glycoforms in Women during GnRH Receptor Blockade, Crescent, an independent risk factor for the progression of type 2 diabetic kidney disease, Hypogonadism in males with genetic neurodevelopmental syndromes, The Journal of Clinical Endocrinology & Metabolism, About The Journal of Clinical Endocrinology & Metabolism, https://www.endocrine.org/education-and-practice-management/continuing-medical-education/journal-cme, Special Features - Approach to the Patient, Receive exclusive offers and updates from Oxford Academic, The Response of Pituitary Gonadotropes to Synthetic LRF in Children with Glucocorticoid-Treated Congenital Adrenal Hyperplasia: Lack of Effect of Intrauterine and Neonatal Androgen Excess, Late-Onset Steroid 21-Hydroxylase Deficiency: A Variant of Classical Congenital Adrenal Hyperplasia, Evidence for Reduced 3-ol-Hydroxysteroid Dehydrogenase Activity in Some Hirsute Women Thought to Have Poly cystic Ovary Syndrome, Impaired Cognitive Function in Women with Congenital Adrenal Hyperplasia. Although the adrenal androgen excess does not cause contrasexual changes in men, gonadotropin suppression occurs and causes testicular atrophy and infertility (22). Transition of care and coordination of services among providers for adults with 21OHD remains a major problem, particularly for those who require psychological attention due to impaired body image and issues of sexuality consequent to the manifestations of disordered sex development and associated surgeries. Whereas virtually all patients with classic 21OHD are ascertained as children, primarily in the first year of life and now often by newborn screening (2), nonclassic 21OHD is diagnosed occasionally in childhood or at newborn screening, most commonly in adolescence and young adulthood, and sometimes in adulthood. Excessive adrenal-derived P4 creates a functional chronic luteal phase, even despite ovulation, which impairs both fertility and menses. The diagnosis and treatment of nonclassic CAH has been reviewed in detail elsewhere (30, 31). Common symptoms and conditions, such as fatigue and obesity, might be incorrectly attributed to their adrenal disease or their treatment, either by the physician or the patient. Herein lies one of the paradoxes of classic 21OHD: unlike children with the same disease or adults with autoimmune Addison's disease, many adults with 21OHD maintain relatively normal blood pressure and functional capacity without treatment. Adults with 21OHD tend to be short and are often obese, which might predispose to the metabolic syndrome and adverse cardiovascular risk (11). As a rule of thumb, the AD/T ratio in regularly cycling women is <2, but in hyperthecosis or with T-producing tumors, the ratio is <1. Disclosure Summary: R.J.A. Gastaud F , Bouvattier C , Duranteau L, et al. Although bilateral adrenalectomy has been suggested as a definitive therapy for children with classic 21OHD in poor control, this approach has fallen out of favor and should be used only in exceptional circumstances. If a patient is in good control during adolescence taking hydrocortisone and demonstrates the insight and commitment to remain strictly compliant, we encourage them to continue this regimen. Once again, the range in dose requirements varies considerably among genotypically similar adults with classic 21OHD, based on diet, concurrent medications, and other factors; mineralocorticoid requirements also change in an individual between childhood and adulthood. The generic hydrocortisone 20-mg scored pills, however, are only slightly more costly than dexamethasone. Scaroni C , Favia G , Lumachi F, et al. Unskilled providers might reinforce their nonadherence to medication by erroneously concluding that patients who stop therapy without spontaneous crisis have been misdiagnosed and are not vulnerable to adrenal crisis. In the United States, the smallest dexamethasone tablet is 0.5 mg, so patients must quarter tiny tablets or use a liquid form to take such low doses. Abbreviations: 21dF, 21-deoxycortisol; 19C, 19-carbon steroids; Aldo, aldosterone; DOC, 11-deoxycorticosterone; B, corticosterone; S, 11-deoxycortisol; F, cortisol; Delta-5, 3-hydroxy-5-ene steroids; Delta-4, 3-keto-4-ene steroids. is supported by grants R01-GM086596from the National Institutes of Health and a Clinician Scientist Award in Translational Research (no. . Bilateral adrenalectomy trades 1 form of adrenal insufficiency for a more severe form, and the patient should not be promised that androgen excess is permanently cured. Laboratory monitoring for the adult with CAH due to classic 21OHD. Laboratory data for adults with 21OHD are only a guide, which is less important than the clinical evaluation. . Treatment decisions should be based on the needs and desires of the patient, with internally consistent data from careful physical examination and appropriate laboratory evaluation. It is important to reassess mineralocorticoid requirements at the point of transition because this need might differ significantly between the adult and childhood phases. . For unknown reasons, dehydroepiandrosterone (DHEA) sulfate (DHEAS), the dominant ACTH-dependent 19-carbon steroid product of the adrenal, is easily suppressed by almost any glucocorticoid therapy (37) and cannot be used to gauge control. Samuel Dagogo-Jack, M.D., is a Consultant for Merck and Novo Nordisk; a Grantee for the American Diabetes Association, AstraZeneca, Boehringer Ingelheim, National Institutes of Health, and Novo Nordisk; and a Grant Reviewer for the American Diabetes Association and National Institutes of Health. Upon completion of pubertal development and attainment of adult height, the auxological and clinical parameters used to guide therapy are no longer germane, but the need for lifelong treatment persists. Merke DP , Keil MF , Jones JV , Fields J , Hill S , Cutler GB. The 19-carbon androgen precursors DHEA and DHEAS are metabolized to active androgens and estrogens via other enzymes in the adrenal and peripheral tissues. Adults with 21OHD receive a wide range of glucocorticoid treatment regimens, which does not correlate with CYP21A2 genotype or disease severity as children (7, 33, 47). Reisch N , Scherr M , Flade L, et al. Ogilvie CM , Rumsby G , Kurzawinski T , Conway GS. As a result, androgens can be normal or slightly high despite markedly elevated 17OHP. Consequently, a major priority when managing adults with CAH is to minimize long-term consequences of both the disease itself and its treatment. Although 17OHP and androgens tend to correlate, 17OHP is typically 100 to 1000 times higher and much more variable than androgens. Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships. Claahsen-van der Grinten HL , Otten BJ , Takahashi S, et al. . Although most adults with classic 21OHD will already have received a diagnosis, many women with nonclassic 21OHD are not diagnosed until they are evaluated for androgen excess and irregular menses and/or subfertility. Protocol for a living systematic review for the management of concussion in adults. Tiosano D , Vlodavsky E , Filmar S , Weiner Z , Goldsher D , Bar-Shalom R. Crocker MK , Barak S , Millo CM, et al. Upon completion of this educational activity, participants should be able to: interpret laboratory data for men and women with CAH and determine if their control is at goal. The most common form of CAH, found in 1:16 000 newborns, is 21OHD (1). 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. . Their care is fragmented and inconsistent, and many stop taking their medications out of frustration. If recent comprehensive laboratory test results are not available, a good baseline assessment is appropriate for the first visit. Most importantly, laboratory data are always secondary to clinical judgment in making treatment decisions. In 1 study, bone mass correlated inversely with the cumulative dose of glucocorticoid (12). Surgical TART removal effectively treats the mass effect in the testes but has not been shown to improve fertility (45). The patient agreed to resume adrenal replacement therapy and was scheduled to see a new endocrinologist 3 weeks later. Women with 21OHD often develop a secondary polycystic ovary syndrome with ovarian androgen excess (40); consequently, menstrual irregularity and elevated androgens do not always indicate poor control. R.J.A. A young adult male with classic 21OHD in poor control might appear healthy and normally virilized, but if testicular atrophy and suppressed gonadotropins are found, this man might still be paradoxically prepubertal due to adrenal-derived androgen excess. TARTs originate in the rete testis (19) and are thought to expand after chronic ACTH stimulation, just like the adrenal cortex itself. Speiser PW , Azziz R , Baskin LS, et al. The focus of this article is adults with classic 21OHD, and we will include a limited discussion of nonclassic 21OHD. We learn a tremendous amount from both of these groups at every encounter, and these interactions have shown us that we have only begun this journey. Consequently, an AD level greater than the T level in the presence of testicular masses in a man with 21OHD is a sign that current therapy is inadequate to maintain fertility. A second use of dexamethasone is in women with nonclassic 21OHD who suffer from prominent androgen excess, irregular menses, and infertility. . Miraculously, most of these patients appear relatively well and nicely tanned, with the exception of salt craving and heat intolerance, until they become seriously ill and suffer an adrenal crisis (24). She noted that she had more energy on treatment again but that the androgen excess and daily shaving did not bother her. As a rule of thumb, patients who have been consistently well-controlled since childhood do not need routine adrenal imaging, whereas imaging should be considered for patients with a long history of poor control, inconsistent therapy, or difficult-to-control disease. Her treatment goals were met, and no changes were made. The main obstacle to hydrocortisone is adherence to multiple daily doses, but most patients with Addison's disease take 23 daily hydrocortisone doses without difficulty. In addition, the cortisol precursor steroids accumulating above the enzymatic block might have biological activities of their own or follow other overflow pathways to alternative steroid products (Figure 1). 
1005954) from the Burroughs-Wellcome Fund. As a result of this expansion, the testis suffers from compression, functional impairment, and eventually fibrosis. Efforts to improve transitions and coordination of care have begun (25, 26) but are not widely implemented. . Hyperandrogenemic oligoanovulation is common in women with 21OHD (40), and even when ovulating regularly, persistently high adrenal-derived P4 prevents withdrawal bleeding (48) and renders the endometrial tissue and cervical mucus unfavorable for fertilization (55). 32). . Another contribution derives from antecedent control and the amount of adrenal hyperplasia upon reaching adulthood; patients who have remained poorly controlled throughout life require higher glucocorticoid doses to manage subsequently throughout adulthood. For women with all forms of 21OHD attempting to conceive, these alternative therapies are contraindicated, and glucocorticoid therapy must be intensified. Instructions for completing this activity can be found at https://www.endocrine.org/education-and-practice-management/continuing-medical-education/journal-cme.
1005954) from the Burroughs-Wellcome Fund. As a result of this expansion, the testis suffers from compression, functional impairment, and eventually fibrosis. Efforts to improve transitions and coordination of care have begun (25, 26) but are not widely implemented. . Hyperandrogenemic oligoanovulation is common in women with 21OHD (40), and even when ovulating regularly, persistently high adrenal-derived P4 prevents withdrawal bleeding (48) and renders the endometrial tissue and cervical mucus unfavorable for fertilization (55). 32). . Another contribution derives from antecedent control and the amount of adrenal hyperplasia upon reaching adulthood; patients who have remained poorly controlled throughout life require higher glucocorticoid doses to manage subsequently throughout adulthood. For women with all forms of 21OHD attempting to conceive, these alternative therapies are contraindicated, and glucocorticoid therapy must be intensified. Instructions for completing this activity can be found at https://www.endocrine.org/education-and-practice-management/continuing-medical-education/journal-cme.