Considerable genetic and biochemical evidence suggests that this route contributes to DHT formation and genital virilization in female fetuses with cytochrome P450-oxidoreductase deficiency, presumably due to the accumulation of 17-OHP [1518]. Journal of Clinical Endocrinology and Metabolism. Article Advances in the care of these patients have enabled many of these children to reach adulthood. Evaluation of adrenomedullary function in patients with congenital adrenal hyperplasia. 1992, 89 (1): 293-300. In fact, children [29] and adults [30] with 21-OHD are prone to develop hypertension, prompting reduction or rarely discontinuation of mineralocorticoid dosing, or the paradoxical need for antihypertensive drugs plus fludrocortisone acetate. Traditional skin or bowel grafts often give suboptimal results, particularly in severely virilized girls [47]. First, massive adrenal myelolipomas may develop [34] and can be bilateral [59] and require surgical removal. Reduced bone mineral density has been found in 21-OHD in most studies [35, 36], but the degree is moderate, and frank osteoporosis is uncommon. 2000 Jun;21(3):245-91. doi: 10.1210/edrv.21.3.0398. 2001, 86 (7): 3070-3078. Wilson JD, Auchus RJ, Leihy MW: 5-androstane-3 ,17-diol is formed in tammar wallaby pouch young testes by a pathway involving 5 -pregnane-3 ,17-diol-20-one as a key intermediate. 2008, 13: 55-66. 2007, 92 (12): 4643-4649. 2007, 92 (2): 612-615. 2003, 18 (3): 604-607. 2021 Oct 29;22(21):11735. doi: 10.3390/ijms222111735. DHEA can be reduced by 17-HSD1, which is an efficient enzyme [22], to androst-5-ene-3, 17-diol, a substrate for 3-HSDs, yielding T (Figure 2(a)). Ghayee H, Auchus R: Clinical implications of androgen synthesis via 5-reduced precursors. Journal of Clinical Endocrinology and Metabolism. Salt appetite was investigated in 14 patients with congenital adrenal hyperplasia of the salt-wasting form (SW group), 12 patients with the simple virilized form who are not salt losing, and 18 healthy siblings. These routes involve the 5-reduction of 21-carbon pregnanes P4 and 17-OHP, followed by 3-reduction, to yield 5-pregnan-3-ol-20-one (allopregnanolone) and its 17-hydroxy derivative, 5-pregnane-3, 17-diol-20-one (Pdiol). 2001, 142 (2): 778-787. Journal of Clinical Endocrinology and Metabolism. This scenario is evidently the case for CAH. Since the introduction of cortisone therapy by Wilkins et al. Endocr Rev. Lo JC, Schwitzgebel VM, Tyrrell JB: Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. (a): the alternate or "backdoor" pathway to DHT, with intra- and extra-adrenal compartments demarcated. Google Scholar. Casters A, De Silva P, Rumsby G, Conway GS: Reassessing fecundity in women with classical congenital adrenal hyperplasia (CAH): normal pregnancy rate but reduced fertility rate. 10.1210/en.142.2.778. Most importantly, management must minimize the potential for long-term consequences of conventional therapies. Sciannamblo M, Russo G, Cuccato D, Chiumello G, Mora S: Reduced bone mineral density and increased bone metabolism rate in young adult patients with 21-hydroxylase deficiency. Arlt W, Walker EA, Draper N: Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Journal of Clinical Endocrinology and Metabolism. Dexamethasone needs only to be given once daily, with bedtime administration being the most effective means to suppress ACTH and adrenal 19-carbon steroid production [31]. 2020 Dec;133(12):1391-1402. doi: 10.1016/j.amjmed.2020.06.018. These TARTs can become large and cause pain in addition to impaired testicular function. If pregnancy is not desired, oral contraceptive pills provide several benefits, including lowering ovarian androgen production, maintaining monthly menses, and raising sex hormone binding globulin (SHBG), which lowers free testosterone and mitigates some of the hyperandrogenism with lower doses of glucocorticoid therapy. American Journal of Medical Genetics. Journal of Pediatric and Adolescent Gynecology. Consequently, if preservation of fertility is a priority, the TARTs should be managed early and aggressively with medical therapy. 2003, 16 (5): 289-296. Sakaki M, Izaki H, Fukumori T: Bilateral adrenal myelolipoma associated with adrenogenital syndrome. Journal of Clinical Endocrinology and Metabolism. Buccal mucosa grafts have shown good results in series with limited followup and may become a procedure of choice in the future [48, 49]. 10.1677/JOE-08-0337. Journal of Clinical Endocrinology and Metabolism. Epub 2014 Oct 7. Treatments will ideally replace the glucocorticoid deficiency and normalize both mineralocorticoid and androgen biosynthesis without inducing untoward effects from the drugs themselves. It is likely that, when a large TART is present, the testis is already damaged from increased pressure in the testicular capsule, which reduces testicular blood flow and obstructs the seminiferous tubules [52, 53]. 2006, 91 (11): 4453-4458. Mineralocorticoid replacement with 9-fludrocortisone acetate, 0.050.2mg/d, is usually continued, with the goal of a suppressed or low-normal plasma renin activity, which blunts the hypovolemic drive to ACTH production. Barnes RB, Rosenfield RL, Ehrmann DA: Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. Often staged procedures are employed with the goal of urinary hygiene and appropriate clitoral reduction in the neonate. 10.1016/S1083-3188(03)00155-4. Endocrinol Metab Clin North Am. California Privacy Statement, The reasons for their not attempting pregnancy include vaginal abnormalities, such as inadequate caliber for coitus or strictures following repair [43] and dyspareunia [42]. The https:// ensures that you are connecting to the Measurement of adrostenedione and gonadotropins is appropriate if gonadal dysfunction becomes evident to determine if the adrenals or testes are the dominant source of androgens. The goal is to have a normal testosterone and normal gonadal function in the absence of TARTs, and men with a 17-OHP 3,000 are unlikely to have large TARTs [57]. 2006, 91 (7): 2643-2649. For these reasons, not only the control of steroids exiting the adrenal, but also the extra-adrenal metabolism of these steroids is an important consideration in understanding the physiology of CAH in the adult. 10.1046/j.1365-2265.2002.01466.x. Antiandrogen therapy is a logical approach for treatment of 21-OHD, but with the exception of multidrug regimens [41], has received little attention. Dietary Sodium Restriction for Heart Failure: A Systematic Review of Intervention Outcomes and Behavioral Determinants. Sustained-release hydrocortisone preparations administered once daily with promising pharmacokinetics have been developed [32], but these products currently are not widely available. 10.1210/jc.2008-2374. Consequently, the route(s) from DHEA to T even in normal women are not obvious, and the biochemistry is even more complex in 21-OHD, as androgen precursor production is very high. Debono M, Ghobadi C, Rostami-Hodjegan A: Modified-release hydrocortisone to provide circadian cortisol profiles. Despite years of work and innovative surgical approaches, vaginal reconstruction remains a major problem in girls with 21-OHD. FOIA Journal of Endocrinology. Furthermore, the adrenal gland lacks 17-HSD3, the enzyme responsible for reduction of AD to T in the testis, but contains AKR1C3 (17-HSD5) [7], which has weak activity in catalyzing this reaction [10]. In the first place, a minority of women with 21-OHD even attempt to become pregnant [42], especially those with the most severe or "salt-wasting" disease [43]. 2007, 107 (1-2): 22-29. Sensitivity to the taste of NaCl was not altered. In contrast, the zona reticularisin which ACTH also stimulates steroid productionhas abundant CYP17A1, b5, and thus high 17,20-lyase activity, but these cells are deficient in 3-HSD2 and have robust DHEA-sulfotransferase activity (SULT2A1). Journal of Clinical Endocrinology and Metabolism. 1994, 79 (5): 1328-1333. 2006, 154 (3): 405-408. 2006, 13 (6): 801-802. Auchus, R.J. Management of the Adult with Congenital Adrenal Hyperplasia. 2003, 349 (8): 776-788. The Lancet. Avila NA, Premkumar A, Merke DP: Testicular adrenal rest tissue in congenital adrenal hyperplasia: comparison of MR imaging and sonographic findings. Nebesio TD, Eugster EA: Observation of hypertension in children with 21-hydroxylase deficiency: a preliminary report. Shackleton C, Marcos J, Arlt W, Hauffa BP: Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype. The prevalence of TART in men with 21-OHD is as high as 50%, if ascertained by sensitive ultrasonography or magnetic resonance imaging [51, 54]. Journal of Clinical Investigation. 2004, 15 (9): 432-438. Samuelson ML, Baker LA: Autologous buccal mucosa vulvovaginoplasty for high urogenital sinus. 2006, 91 (2): 447-453. Trends in Endocrinology and Metabolism. Google Scholar. Many of the general principles are the same as for children with CAH, but the importance of the various factors is considerably different. Endocrinology. Androgen excess is always a problem for these women, but the degree and its clinical consequences vary tremendously, and there is no reason to expose the woman to higher doses of corticosteroids if no benefit will be derived. Journal of Clinical Endocrinology and Metabolism. PubMed Richard J. Auchus. 2010, 95 (5): 2065-2072. Signal Transduction of Mineralocorticoid and Angiotensin II Receptors in the Central Control of Sodium Appetite: A Narrative Review. 2004, 222: 113-120. Journal of Pediatric Urology. Fertility and Sterility. Turgeon D, Carrier JS, Levesque E, Hum DW, Belanger A: Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members. Journal of Clinical Endocrinology and Metabolism. (a): Normal steroid biosynthetic pathways within each zone of the human adrenal gland. As discussed elsewhere, the congenital adrenal hyperplasias (CAHs) are genetic defects in cortisol biosynthesis. 10.1016/S0140-6736(04)16503-3. Division of Endocrinology and Metabolism, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8857, USA, You can also search for this author in Mahendroo MS, Wilson JD, Richardson JA, Auchus RJ: Steroid 5-reductase 1 promotes 5-androstane-3,17-diol synthesis in immature mouse testes by two pathways. Journal of Clinical Endocrinology and Metabolism. Consequently, the adrenal gland of a patient with 21-OHD has high capacity to synthesize DHEAS, but little of this 19-carbon precursor escapes the adrenal as T. Alternative routes to 5-reduced, 19-carbon steroids have been described in other species [11, 12]. 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. 10.1210/jcem-56-1-104. An official website of the United States government. PubMed Central Journal of Clinical Endocrinology and Metabolism. Men and women should have blood pressure and cholesterol screening, colon cancer screening, education to avoid smoking and to follow a healthy lifestyle, and care for acute illnesses. Br J Nutr. Morimoto I, Yamamoto S, Tateishi H, Ueda S, Toda Y, Zeki K, Watanabe K, Nakano Y, Kashimura M, Eto S. Intern Med. 8600 Rockville Pike Women may become comfortable living in a state of androgen excess and may even experience fatigue from testosterone withdrawal if therapy is resumed. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Provided by the Springer Nature SharedIt content-sharing initiative. 1980, 56 (2): 208-215. Journal of Clinical Endocrinology and Metabolism. Would you like email updates of new search results? The New England Journal of Medicine. Other reports note a higher prevalence of glucose intolerance, obesity, and dyslipidemia in adults with 21-OHD compared to controls [30], raising their risk for cardiovascular disease [37]. 1996, 81 (5): 1776-1779. Low cortisol increases ACTH production, flooding the adrenal steroidogenic machinery with upstream precursors (Figure 1(b)). 2002, 87 (6): 2442-2445. The site is secure. The New England Journal of Medicine. Ogilvie CM, Rumsby G, Kurzawinski T, Conway GS: Outcome of bilateral adrenalectomy in congenital adrenal hyperplasia: one unit's experience. 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. Disclaimer, National Library of Medicine Consequently, many adult women with 21-OHD face the need for definitive reconstruction surgery. Rosenfield RL, Bickel S, Razdan AK: Amenorrhea related to progestin excess in congenital adrenal hyperplasia. 2009, 94 (1): 89-95. Nguyen AD, Mapes SM, Corbin CJ, Conley AJ: Morphological adrenarche in rhesus macaques: development of the zona reticularis is concurrent with fetal zone regression in the early neonatal period. The findings suggest that salt appetite in humans is determined by interdependent, innate, physiological, and acquired attributes. International Journal of Pediatric Endocrinology PubMed Central Glucocorticoid doses should be increased for surgery and for acute illness when volume depletion from high fever, vomiting, diarrhea, or poor oral intake occursbut not for any minor illness or injury. The disadvantage of such a two-dose regimen is the tendency for ACTH to rise robustly in the early morning hours prior to the first dose, which worsens control, at least for a few hours until the first dose. Am J Med. 10.1016/j.jpurol.2005.09.001. 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]. Unfortunately, well-designed and controlled studies comparing various regimens are lacking, so the clinician is advised to generally try the safest and most physiologic replacement regimen, and then to intensify therapy gradually if symptoms and signs of undertreatment become evident. Regrettably, very little is known about the physiology and management of adults with CAH, and what is known is essentially limited to 21-OHD. The extent and routes of peripheral metabolism vary considerably amongst individuals and might explain to some degree the differences in disease control for adults with 21-OHD. Tiitinen A, Vlimki M: Primary infertility in 45-year-old man with untreated 21-hydroxylase deficiency: successful outcome with glucocorticoid therapy. Google Scholar. Biochemical Journal. Scaroni C, Favia G, Lumachi F: Unilateral adrenal tumor, erectile dysfunction and infertility in a patient with 21-hydroxylase deficiency: effects of glucocorticoid treatment and surgery. 1996, 81 (9): 3180-3190. in the early 1950s [3], these children have been able to survive into adulthood. Steroid biosynthesis in 21-OHD. 10.1016/j.fertnstert.2007.03.051. Br J Nutr. 2020 Jun 14;123(11):1312-1320. doi: 10.1017/S0007114520000173. Consequently, menses may remain irregular even with good control of the adrenal axis. In children, several groups have found empirically that administration of the largest dose at bedtime is associated with tightest control of adrenal steroidogenesis.