Glucocorticoid therapy should be minimized to accomplish the goal for the requisite period of time, such as restoring fertility, and 1 retrospective series found better outcomes when hydrocortisone is continued until delivery (29). Scaroni C , Favia G , Lumachi F, et al. Due to her job, she did not think that she could take several doses of hydrocortisone each day. Recommendations for adrenal imaging and for bone densitometry have not been established. We have a great deal to learn about the management of adults with 21OHD. Merke DP , Keil MF , Jones JV , Fields J , Hill S , Cutler GB. Women with 21OHD also develop adrenal rests in or near the ovaries, particularly after bilateral adrenalectomy (17, 18). 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. 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. 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. Their care is fragmented and inconsistent, and many stop taking their medications out of frustration. Most patients starting in good control will remain in good control with this treatment, but others will not, mainly because hydrocortisoneeven a large dose at bedtimedoes not last long enough to blunt the rise of ACTH early in the morning (4850). TARTs are thought to arise from cells of adrenal origin, which travel with the primordial gonad after the adrenal and gonadal cells separate within the urogenital ridge during fetal development. 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. In one clinic, less than half of the referred young adults with 21OHD attended 2 or more appointments with the adult endocrinologist (23). 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). These patients suffer from poor health, infertility, characteristic tumors in the adrenal glands and gonads, and consequences of chronic glucocorticoid therapy. Although 17OHP and androgens tend to correlate, 17OHP is typically 100 to 1000 times higher and much more variable than androgens. Consequently, a major priority when managing adults with CAH is to minimize long-term consequences of both the disease itself and its treatment. 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. DHEAS is often paradoxically low or low-normal even in 21OHD patients under poor control; consequently, poor compliance or low drug exposure should be considered if the DHEAS is not suppressed. 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). The needs and concerns shift as well to include family planning and long-term health quality. Patients rarely tolerate higher dexamethasone doses chronically due to sleep disturbance, weight gain, and skin changes, and these doses should only be used when lower doses are tolerated but ineffective. Using this approach, with 2 or 3 divided doses of prednisolone or hydrocortisone, 1 study found the fecundity rate for women with classic 21OHD to be 91%, not different from the general population (41). 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. She had neither taken these medications nor returned for follow-up because, she said, he wanted me to take too much medicine. The staff called the office of her former pediatric endocrinologist, who explained that the patient has classic 21OHD. 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. 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. 1005954) from the Burroughs-Wellcome Fund. Among parents of children with classic 21OHD, 4% are affected with cryptic or undiagnosed nonclassic 21OHD (36). Electrolytes and plasma renin activity or concentration, in conjunction with orthostatic blood pressures, assess volume status, and thus the need for and adequacy of fludrocortisone therapy. Long-term consequences of vaginal reconstruction surgery in women with 21OHD include vaginal strictures and fistulas as well as frequent urinary tract infections (27). A very simple, effective, and safe regimen for this purpose utilizes the fact that dexamethasone suppresses adrenal androgen production longer than cortisol synthesis. Traditionally, 21OHD is defined as classic if the defect is severe enough to cause cortisol insufficiency or nonclassic if cortisol production is normal but with excessive precursor accumulation to overcome the partial enzymatic block (Figure 2), yielding the characteristic elevation of 17-hydroxyprogesterone (17OHP) and more specifically 21-deoxycortisol, which is only generated in large amounts in the absence of substantial CYP21A2 function. In normal females, AD originates from both the adrenals and the ovaries, but in patients with 21OHD, most AD is usually of adrenal origin. The estimated time to complete each JCEM Journal-based CME activity, including review of material, is 1 hour. 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. Women require an evaluation of androgen-dependent body hair growth and acne in the context of depilation treatments, whereas only a brief external genital examination is necessary initially. Adults with 21OHD tend to be short and are often obese, which might predispose to the metabolic syndrome and adverse cardiovascular risk (11). She had no Cushingoid stigmata, and she was wearing medical alert identification. Men should have a testicular examination to assess atrophy and presence of TARTs, although most TARTs will only be identified with ultrasound imaging. 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 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). Genotype-phenotype analysis has revealed a strong correlation between genotype and the presence and severity of glucocorticoid and mineralocorticoid deficiency; however, the correlation with the severity of virilization at birth in girls with 46,XX disordered sex development is not as strong (for review, see Ref. In addition, adults with 21OHD require cancer screening, immunizations, and general health maintenance like any other adult. The diagnosis and treatment of nonclassic CAH has been reviewed in detail elsewhere (30, 31). Prednisolone, 0.52 mg, is usually sufficient to achieve the desired control, and a good starting dose is 1 mg. Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory? 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. A few patients tolerate 0.5 mg/d or more with minimal untoward consequences, but many become floridly Cushingoid with marked weight gain and disfiguring violaceous striae, which never resolve completely. . 32). 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. Laboratory monitoring for the adult with CAH due to classic 21OHD. The chronic enlargement of the adrenal glands in 21OHD is associated with increased prevalence of adrenal tumors, including massive myelolipomas (1315). Most sources recommend annual testicular sonography in males with 21OHD to screen for TARTs, which is more sensitive than physical examination (46). This monogenic disease with a clearly defined pathophysiology and biochemistry demonstrates the inherently polygenic nature of all diseases and the importance of individualizing therapy based on each patient's goals and responses. A normal semen analysis is the gold standard for normal androgen physiology in the male; however, the semen analysis will remain abnormal for months to years in the man with 21OHD and TARTs or testicular atrophy after an extended period of poor control (44) and might never return to normal despite good control (21). Finkielstain GP , Chen W , Mehta SP, et al. The following JCEM Editors reported no relevant financial relationships: Paolo Beck-Peccoz, M.D. 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. She was a short, overweight woman with excessive facial and body hair, frontal balding, and small hands and feet. A complete laboratory panel is shown in Table 5, paired with the information gained from each analyte. She noted that she had more energy on treatment again but that the androgen excess and daily shaving did not bother her. 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. 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. Exploring the epidemiology of disseminated intravascular coagulation: protocol for the DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study. 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. Androstenedione (AD) and the AD/T ratio help to ascertain how much T derives from the adrenal vs the ovary. After reviewing the options, she agreed to take 2.5 mg prednisolone upon arising and again at suppertime, plus 9FCA 0.1 mg daily. . . Alternatively, 0.1 mg dexamethasone at night plus daytime hydrocortisone 10 mg three times a day successfully shrank TARTs and improved semen quality without side effects in 1 man with 21OHD and infertility (52). If recent comprehensive laboratory test results are not available, a good baseline assessment is appropriate for the first visit. Even women with classic 21OHD can develop adrenal rest tumors in the pelvic area after bilateral adrenalectomy, with recurrent androgen excess (17, 18). 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 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. . 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. Many patients reach adulthood not understanding why they require chronic adrenal replacement therapy, and often these patients stop all treatment for years, similar to J.W. We thank our pediatric, internal medicine, and reproductive endocrinology colleagues, surgeons, urologists, gynecologists, psychologists, and others with whom we have shared discussions and management challenges for adults with 21OHD. Laboratory values obtained the following morning are shown in Table 1. is supported by grants R01-GM086596from the National Institutes of Health and a Clinician Scientist Award in Translational Research (no. Analogously, dual-photon x-ray absorptiometry should be considered for patients taking chronic dexamethasone 0.5 mg/d or higher, having Cushingoid stigmata, or following a long period of suppressed 17OHP and androgens. ; Merrily Poth, M.D. 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). has nothing to disclose. 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). Rosner W , Auchus RJ , Azziz R , Sluss PM , Raff H. Vermeulen A , Verdonck L , Kaufman JM. Auchus RJ , Witchel SF , Leight KR, et al. 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. . . Only anecdotal information exists for the use of 5-reductase inhibitors or other androgen antagonists in women with 21OHD. Adults with 21OHD have many unmet medical needs, and additional research to the natural history and optimal interventions is urgently needed to improve outcomes. Gastaud F , Bouvattier C , Duranteau L, et al. Because women with 21OHD often develop a secondary polycystic ovary syndrome (40), a high T does not necessarily mean poor control.

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