In the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive cohort, 4 of 65 adult men with CAH had previously undergone unilateral orchidectomy for presumed testicular cancer or Leydig cell tumor, with histology findings consistent with TARTs (5). This observation suggests that either other adrenal-derived steroids substitute for aldosterone and/or cortisol, or that a physiological compensation for low corticosteroid activity at the target organs has occurred over time. Moran C , Azziz R , Weintrob N, et al. For adults with 21OHD, this subtyping of classic 21OHD is misleading and should be avoided (Table 3). Silvio Inzucchi, M.D., is a Consultant/Advisor for Boehringer Ingelheim, Genentech, Janssen, Merck, and Takeda; has DSMB Activity with Amgen, Esai, and Gilead; and receives CME support from Abbott, Amylin, Boeringher-Ingelheim, Merck, and Takeda. The most common form of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency (21OHD). No prospective studies are available either to support or to refute the utility of genotype as a guide to treatment. Reisch N , Scherr M , Flade L, et al. A second use of dexamethasone is in women with nonclassic 21OHD who suffer from prominent androgen excess, irregular menses, and infertility.
Scaroni C , Favia G , Lumachi F, et al. Consequently, the approach to the adult with 21OHD requires knowledge of the patient's prior treatment, the natural history of the disease, and the influence of various treatments on adrenal and gonadal steroid flux. The patient agreed to resume adrenal replacement therapy and was scheduled to see a new endocrinologist 3 weeks later. Consequently, an AD/T ratio >0.5 in a man with 21OHD indicates that a significant fraction of T is of adrenal origin, and if LH and FSH are suppressed with AD/T >1, most of the T is of adrenal origin. . Krone N , Braun A , Roscher AA , Knorr D , Schwarz HP. 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. In women, total T and SHBG are used to determine free and bioavailable T by calculation (38, 39), and these values are the most important parameters to gauge androgen excess. The needs and concerns shift as well to include family planning and long-term health quality. Alternative means of controlling androgen excess and menstrual irregularity, including antiandrogens and oral contraceptives, should be considered for long-term management during times when fertility is not desired. In fact, 3 or sometimes 2 divided doses of hydrocortisone daily provide good control in most adults with 21OHD who have been compliant with treatment throughout adolescence. 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. A complete laboratory panel is shown in Table 5, paired with the information gained from each analyte. Laboratory data for adults with 21OHD are only a guide, which is less important than the clinical evaluation. Her laboratory data showed a plasma renin activity of 3.5 ng/mL/h (1 ng/L/s), normal electrolytes, and total T of 62 ng/dL (2.2 nmol/L). In order to administer enough dexamethasone at bedtime to provide complete adrenal suppression and replacement throughout the following day, supraphysiological doses (>0.75 mg) must be used, but high doses are not necessary to restore sperm production if given in divided doses such as 0.25 mg twice daily. Finkielstain GP , Chen W , Mehta SP, et al. The adrenals, ovary, and peripheral tissues lack 17HSD3, and secondary enzymes such as 17HSD5 (AKR1C3) and 17HSD1 convert AD to T or DHEA to androst-5-ene-3,17-diol poorly in comparison. Testis-sparing surgery affords long-term control of TART growth but usually does not restore fertility (45), probably because the mass effect impairs blood flow to the spermatic tubules enough to cause severe damage (16). The term adrenal rest tumor should not be construed as a neoplasm because these cells are hyperplastic and do not show increased proliferation. 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. As a result, androgens can be normal or slightly high despite markedly elevated 17OHP. Altered steroidogenesis in 21OHD. . 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. Women with both classic and nonclassic 21OHD often suffer from infertility, even when having regular monthly menses, for reasons discussed below. . Some women with 21OHD who have undergone vaginal reconstruction suffer frequent bladder infections or require surgical resection of abscesses, cysts, or scar tissue. See Table 6 and Supplemental Data (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org). She had no Cushingoid stigmata, and she was wearing medical alert identification. Medication need not be interrupted for laboratory testing if results are interpreted in the context of medication schedule. Merke DP , Keil MF , Jones JV , Fields J , Hill S , Cutler GB. For men with classic 21OHD, TART tissue is not cured by adrenalectomy, and they still require corticosteroid replacement to prevent TART growth and to maintain normal physiology. . The evaluation should include a review of any adrenal or gonadal imaging studies and a brief sexual history with open-ended questions. Khan N , Sharma KK , Andersson S , Auchus RJ. With adolescence, the patient must gradually assume primary responsibility for his/her care and eventually stop seeing the pediatric endocrinologist. 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. The challenges we face to achieve these goals include improving the training of providers, developing new medical or surgical treatment strategies, and delivering coordinated care throughout the patients' lifetime. Furthermore, many patients with nonclassic 21OHD are never diagnosed, and those with cryptic disease rarely require treatment. Tiosano D , Vlodavsky E , Filmar S , Weiner Z , Goldsher D , Bar-Shalom R. Crocker MK , Barak S , Millo CM, et al. Thus, initial doses of dexamethasone should be 0.250.375 mg/d. 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). We discourage the use of the prodrug prednisone because at the low doses used for adrenal replacement, its conversion to the active drug prednisolone by 11-hydroxysteroid dehydrogenase activity is inconsistent. When control is poor, androgens will be high before and after each dose; when control is good, the differences will be slight. The Endocrine Society has achieved Accreditation with Commendation. 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. Only anecdotal information exists for the use of 5-reductase inhibitors or other androgen antagonists in women with 21OHD. ; Constantine Stratakis, M.D. Patients who take dexamethasone or prednisolone generally require more 9FCA than those who take hydrocortisone (cortisol), which also acts as a mineralocorticoid, with 40 mg hydrocortisone having equivalent mineralocorticoid activity as 0.1 mg 9FCA (53). Lastly, patient preference, related to frequency of dosing and tolerance of androgen or glucocorticoid excess, is likewise an important factor. 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. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Barnes RB , Rosenfield RL , Ehrmann DA, et al. If recent comprehensive laboratory test results are not available, a good baseline assessment is appropriate for the first visit. Treatment regimens and goals should be individualized, and these targets often change throughout a patient's life. Claahsen-van der Grinten HL , Otten BJ , Sweep FC , Hermus AR. Search for other works by this author on: Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia, Genetics of congenital adrenal hyperplasia, Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology, Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients, Metabolic profile and body composition in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia, Observation of hypertension in children with 21-hydroxylase deficiency: a preliminary report, Fractures and bone mineral density in adult women with 21-hydroxylase deficiency, Reduced bone mineral density and increased bone metabolism rate in young adult patients with 21-hydroxylase deficiency, Cardiovascular disease risk in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency, Congenital adrenal hyperplasia presenting as massive adrenal incidentalomas in the sixth decade of life: report of two patients with 21-hydroxylase deficiency, Total adrenal volume but not testicular adrenal rest tumor volume is associated with hormonal control in patients with 21-hydroxylase deficiency, High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency, Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia can cause severe testicular damage, Ovarian adrenal rest tumor in a congenital adrenal hyperplasia patient with adrenocorticotropin hypersecretion following adrenalectomy, Use of PET/CT with cosyntropin stimulation to identify and localize adrenal rest tissue following adrenalectomy in a woman with congenital adrenal hyperplasia, Prevalence of testicular adrenal rest tissue in neonates, Long term outcome in adult males with classic congenital adrenal hyperplasia, High prevalence of reduced fecundity in men with congenital adrenal hyperplasia, Primary infertility in 45-year-old man with untreated 21-hydroxylase deficiency: successful outcome with glucocorticoid therapy, The challenge of delivering endocrine care and successful transition to adult services in adolescents with congenital adrenal hyperplasia: experience in a single centre over 18 years, Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency, Guidelines for the development of comprehensive care centers for congenital adrenal hyperplasia: guidance from the CARES Foundation Initiative, Transition from pediatric to adult healthcare: assessment of specific needs of patients with chronic endocrine conditions, Anatomical and functional outcomes of feminizing genitoplasty for ambiguous genitalia in patients with virilizing congenital adrenal hyperplasia, Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline, Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia, Nonclassic congenital adrenal hyperplasia, Predicting phenotype in steroid 21-hydroxylase deficiency? TARTs originate in the rete testis (19) and are thought to expand after chronic ACTH stimulation, just like the adrenal cortex itself. For women with all forms of 21OHD attempting to conceive, these alternative therapies are contraindicated, and glucocorticoid therapy must be intensified. Charmandari E , Matthews DR , Johnston A , Brook CG , Hindmarsh PC. Patients with 21OHD might be at increased risk for other health problems, due both to their underlying disease and to their treatments. The Endocrine Society designates this JCEM Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credits. These patients require normalizationbut not complete suppressionof adrenal androgens in the early morning yet do not require adrenal replacement by day. We have observed marked and symptomatic reductions in blood pressure after bilateral adrenalectomy in adults with classic 21OHD, suggesting that adrenal-derived mineralocorticoids defend against volume depletion common in Addison's disease. . Excessive adrenal-derived P4 creates a functional chronic luteal phase, even despite ovulation, which impairs both fertility and menses. Although 17OHP and androgens tend to correlate, 17OHP is typically 100 to 1000 times higher and much more variable than androgens. In contrast to the vulnerability to hypotension as children, the prevalence of hypertension appears to be increased in adolescents (8) and adults (6, 7) with 21OHD. Our patient did return for follow-up, and she explained that she feared the side effects of prednisone, which she read on the patient information from the pharmacy. 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. In 1 study, bone mass correlated inversely with the cumulative dose of glucocorticoid (12). Epidemiologic Study of Epidural Analgesia for Lung Cancer Surgery from 2011 to 2018 in South Korea: A National Health Insurance Database Cohort Study. Internal medicine residents and endocrinology fellows receive little training in their care, which further discourages their seeking medical attention. Prednisolone, 0.52 mg, is usually sufficient to achieve the desired control, and a good starting dose is 1 mg. 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. Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships. . Rosner W , Auchus RJ , Azziz R , Sluss PM , Raff H. Vermeulen A , Verdonck L , Kaufman JM. Exploring the epidemiology of disseminated intravascular coagulation: protocol for the DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study. 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. 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. Therrell BL , Berenbaum SA , Manter-Kapanke V, et al. Glucocorticoid and mineralocorticoid replacement is therefore not only administered to restore fluid and electrolyte balance but also to reduce ACTH production, thereby attenuating the adrenal 19-carbon steroid synthesis. Oxford University Press is a department of the University of Oxford. It is important to reassess mineralocorticoid requirements at the point of transition because this need might differ significantly between the adult and childhood phases. . Adrenal steroid biosynthesis pathways and enzymatic defects causing CAH. The manifestations of 21OHD derive not only from cortisol and aldosterone deficiency, but also from androgen excess due to shunting of accumulating precursors to 19-carbon steroids. Each form of CAH has its unique clinical and biochemical features, which derive from the lack of cortisol but sometimes also from excess and/or deficiency of mineralocorticoids and androgens. Consequently, a major priority when managing adults with CAH is to minimize long-term consequences of both the disease itself and its treatment. 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. Surgical TART removal effectively treats the mass effect in the testes but has not been shown to improve fertility (45). 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. Cost is sometimes cited as a reason for using prednisone or dexamethasone in the United States, where a month's supply costs only a few dollars, whereas even generic hydrocortisone is 10 times more costly for 5- and 10-mg tablets. She noted that she had more energy on treatment again but that the androgen excess and daily shaving did not bother her. Reisch N , Flade L , Scherr M, et al. The dangers of chronic overtreatment are probably the major threat to the long-term health of these adults, but adrenal crises occur with undertreatment, which makes patients also more prone to suffering from TARTs and adrenal tumors. Instructions for completing this activity can be found at https://www.endocrine.org/education-and-practice-management/continuing-medical-education/journal-cme. Nordenskjld A , Holmdahl G , Frisen L, et al. If you have questions about this JCEM Journal-based CME activity, please direct them to education@endocrine.org. Because women with 21OHD often develop a secondary polycystic ovary syndrome (40), a high T does not necessarily mean poor control. Perhaps the greatest misconception among providers for adults with 21OHD concerns the importance of serum 17OHP as a guide to therapy. Her care had then been transferred to an internal medicine endocrinologist who 4 years earlier had prescribed prednisone, 10 mg twice daily, and 9-fludrocortisone acetate (9FCA), 0.1 mg/d. In the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive cohort, 4 of 65 adult men with CAH had previously undergone unilateral orchidectomy for presumed testicular cancer or Leydig cell tumor, with histology findings consistent with TARTs (5). This observation suggests that either other adrenal-derived steroids substitute for aldosterone and/or cortisol, or that a physiological compensation for low corticosteroid activity at the target organs has occurred over time. Moran C , Azziz R , Weintrob N, et al. For adults with 21OHD, this subtyping of classic 21OHD is misleading and should be avoided (Table 3). Silvio Inzucchi, M.D., is a Consultant/Advisor for Boehringer Ingelheim, Genentech, Janssen, Merck, and Takeda; has DSMB Activity with Amgen, Esai, and Gilead; and receives CME support from Abbott, Amylin, Boeringher-Ingelheim, Merck, and Takeda. The most common form of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency (21OHD). No prospective studies are available either to support or to refute the utility of genotype as a guide to treatment. Reisch N , Scherr M , Flade L, et al. A second use of dexamethasone is in women with nonclassic 21OHD who suffer from prominent androgen excess, irregular menses, and infertility.
In the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive cohort, 4 of 65 adult men with CAH had previously undergone unilateral orchidectomy for presumed testicular cancer or Leydig cell tumor, with histology findings consistent with TARTs (5). This observation suggests that either other adrenal-derived steroids substitute for aldosterone and/or cortisol, or that a physiological compensation for low corticosteroid activity at the target organs has occurred over time. Moran C , Azziz R , Weintrob N, et al. For adults with 21OHD, this subtyping of classic 21OHD is misleading and should be avoided (Table 3). Silvio Inzucchi, M.D., is a Consultant/Advisor for Boehringer Ingelheim, Genentech, Janssen, Merck, and Takeda; has DSMB Activity with Amgen, Esai, and Gilead; and receives CME support from Abbott, Amylin, Boeringher-Ingelheim, Merck, and Takeda. The most common form of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency (21OHD). No prospective studies are available either to support or to refute the utility of genotype as a guide to treatment. Reisch N , Scherr M , Flade L, et al. A second use of dexamethasone is in women with nonclassic 21OHD who suffer from prominent androgen excess, irregular menses, and infertility.