Congenital Adrenal Hyperplasia Management Across the Lifespan

With the introduction of hormone replacement therapy in the 1950s and the advent of neonatal screening programs, now universal in the US, survival rates among neonates born with congenital adrenal hyperplasia have radically improved.^1-4 CAH requires lifelong complex therapeutic management, however, made more challenging by the multiple long-term complications related to the disease itself and to the primary medications (ie, glucocorticoids [GCs]) that affect growth and development, metabolic and cardiovascular health, fertility, and mental health.^1-4

The central defect in CAH does not change – the body cannot synthesize cortisol, which, through loss of negative feedback to the hypothalamic-pituitary-adrenal axis, results in overstimulation of the adrenals and excess androgen production. For the last 60 years, the standard of care has not changed – exogenous GC are administered daily in a cycle that has yet to replicate the circadian rhythm of cortisol’s diurnal peaks and troughs. Nor has the challenge of balancing GC replacement to effectively quell androgen production while avoiding the short- and long-term adverse effects changed either. What consistently does change are the physiologic, hormonal, and enzymatic milieus of the body as it matures to adulthood, a process similar in all humans but with unique challenges in persons treated for CAH.

The primary goals of ongoing treatment shift over time and include optimizing linear growth and bone maturation in infants and children, avoiding central precocious puberty in adolescence, supporting the transition from pediatric to adult care, preventing virilization in females, and optimizing fertility in young adults.² Lifelong treatment goals include preventing life-threatening adrenal crises from cradle to grave and preventing or at least minimizing long-term clinical sequelae of the disease and the treatment. Support for healthy emotional development and optimal quality of life is recommended during all phases.²

Infancy and childhood

The clinical presentation of excess androgen exposure at birth differs by sex. Female newborns may present with abnormal and ambiguous development of the external genitalia with the extent of virilization variable. Male genitalia at birth may appear typical but enlargement is also common.^2,5

Adequate suppression of androgen production during early life is critical to allow normal growth and development including achievement of average adult height.^2,5,6 Short stature in adults with CAH is a combined result of hyperandrogenism and persistent GC treatment, the former responsible for accelerated skeletal maturation and early onset of central puberty and the latter for growth suppression.⁵ GC-related suppression of growth is particularly noticeable during infancy and puberty, making careful monitoring of drug dose, dosing, and subsequent adjustment essential.^2,4,6 Higher than average doses during these developmental periods are associated with decreased final adult height.^2,6 Further, long-acting GCs, although effective adrenal androgen suppressants, are not recommended for prolonged treatment in children given their greater ability to slow growth velocity compared with short-acting formulations, the primary choice being hydrocortisone.¹ Although onset of puberty may trigger an acceleration in height, final adult height for people with CAH is typically 1 to 2 standard deviations below their contemporaries.⁵

A neonate diagnosed with CAH is treated immediately with hydrocortisone at a dose sufficient for replacement but without suppressing 17-hydroxyprogesterone (17OH).⁷ For infants with stable disease, oral hydrocortisone is initiated at a dose of 10-15 mg/m² per day, divided into 3 doses.^2,7 Stress dosing of up to 25 mg/m² per day may be required for initial reduction of elevated adrenal hormones but the dose should be rapidly decreased as soon as target hormone levels are reached.² Linear growth rate during childhood is typically maintained with a dose of 10-12 mg/m² per day.^2,7 Evidence suggests that hydrocortisone doses greater than 20 mg/m² daily in infants (15 to 17 mg/m² in adolescents) are associated with growth suppression during prepubertal growth acceleration and reduced adult height.^2,7

Subclinical aldosterone is seen in all forms of CAH. Guidelines recommend fludrocortisone therapy and adequate dietary sodium begin in infancy.²

Clinical guidelines recommend that infants up to 18 months of age be closely monitored during the first 3 months and then every 3 months after that. The frequency can extend to every 4 months after the age of 18 months.² The efficacy of treatment in children should be monitored with regular assessments of growth velocity, weight, blood pressure in addition to physical examinations.² Signs of hyperandrogenism may appear during childhood and include development of adult apocrine odor, oily skin, or the appearance of pubic hair, although not typically before the age of 18 months.^2,7 Accelerated bone age is also not likely to be apparent before this time.⁷ Notably, according to guidelines, bone age is a “lagging indicator of past poor adrenal suppression, and “should therefore be used judiciously.” X-rays to assess bone age are not useful before the age of 2 years.²

Regular biomarker assessments, however, should indicate the need for dose adjustment before changes in growth, bone age, and physical features are visible, with 17OHP and androstenedione currently the 2 used most frequently to evaluate treatment efficacy.²

Adolescence

Duration of GC effect and dosage should be reevaluated during the transition from childhood to adolescence and again in emerging adulthood when full height is reached.^1,2,6

Priorities shift in managing CAH during adolescence, from supporting physical growth and development to a focus on preserving long-term adult health, optimizing fertility and sexual function, and supporting healthy emotional development.^2,6,8 This period represents a critical opportunity as young individuals assume greater responsibility for their own care, making education for youth and their families paramount.^2,6,8-10

At the same time, puberty drives hormonal changes that can complicate CAH management. Insulin resistance, increased androgen production, and enhanced cortisol clearance often make disease control more challenging.^9-11 Additionally, as adolescents and young adults become more active, they may struggle with the 3-times daily hydrocortisone regimen potentially adding medication adherence to complications in CAH disease management as a transition to adult care grows closer.^2,7,9-11

Higher doses and for some youth more frequent doses of hydrocortisone are required during pubertal development. The balance sought at this stage is to dose without compromising growth; clinical guidelines recommend avoiding doses higher than 17 mg/ m² per day.²

As adolescents become more active, and particularly those who engage in high-intensity sports, it may be important to consider extra dosing of hydrocortisone, typically 2.5 mg, to help support reduced production of catecholamines and dysfunctional glycemic control.⁷ More broadly, during the period between late childhood and early adolescence, suppressing morning elevations in 17OHP can become more difficult.¹² Strategies to overcome the resulting androgen exposure include administering the first GC dose earlier in the morning and increasing either the morning or evening dose. Increasing the nighttime dose may lead to sleep disturbances, however.¹²

A host of other factors may converge to make treatment adherence problematic during adolescence. Young men may misunderstand the consequences of discontinuing treatment, given their fully virilized appearance.^6,13 Young women may be concerned about disease- and medication-related weight gain, hyperandrogenism, hirsutism, or menstrual irregularities, each presenting barriers to prescribed treatment.^6,10,13

Transition to adult care

The transition period from CAH pediatric to adult care can be a time of significant anxiety and confusion, a passage made more complex as it occurs before full emotional maturity. Research focused on this young population has found that between 25%¹⁴ and 50%¹³ who reach the transition do not attend follow-up care after transfer to an adult setting. While there are no controlled studies of strategies for successful transfer of pediatric to adult CAH care, clinical guidelines² and several investigators^11-14 recommend that the transition begin “several years prior to dismissal from pediatric endocrinology.² In an ideal scenario, a gradual shift in care locus would foster consolidation of a relationship with an adult clinician before termination with a pediatric endocrinologist, which typically occurs after age 18 years.²

“At this juncture, patients should be reminded of the importance of continued GC treatment,” guidelines from the Endocrine Society state.² A more urgent call to action comes from a widely published researcher: “The transition period affords the young adult an opportunity for an educational review of CAH that may never arise again so conveniently and will be beneficial for optimising their well-being as adults.”¹⁵ A phased approach should be structured and include psychological support as well as ongoing education about the disease itself as the young person appears receptive and on the essentials of self-care.^2,11-14

A summary of the most critical elements around transition cited in the literature includes^{2, 13-18}:

Multidisciplinary transition clinics involving pediatric and adult endocrinologists, gynecologists, urologists, and psychologists to support good medical adherence among adults with CAH

• Reassessment of treatment regimens that ensures uninterrupted glucocorticoid and mineralocorticoid administration as well as that regimens are adapted to recommendations for adult CAH
• Gynecologic evaluation for all adolescent females, particularly where menstrual flow is blocked and in anticipation of penetrative vaginal intercourse or desired pregnancy
• Testicular ultrasound for young men upon completion of puberty followed by regular examination for testicular adrenal rest tumors (TARTS)
• Counseling on the role of continued adherence to medication in supporting fertility for both men and women
• Psychosexual and genetic counseling

Adults

Preeminent steroid biologist Richard Auchus, MD, PhD, emphasizes the 3 primary goals in care for the adult CAH as: “(1) the prevention of adrenal and gonadal hyperplasia and neoplasia; (2) the prevention [and mitigation] of long-term consequences of adrenal replacement therapies, and (3) the restoration of fertility in those who desire to have children.” ¹⁹ As adult life progresses and priorities shift, both the intensity and complexity of the treatment regimen will require individualization in order to meet each person's present need and to optimize the risk/benefit ratio, Auchus notes.¹⁹

Gonadal dysfunction in both men and women with CAH, including secondary hypogonadism and infertility, is one of the most important long-term complications of the disorder and a focal issue for many adults.²

Men with CAH often experience impaired fertility. The most common contributing factors include the presence of testicular adrenal rest tumors (TARTs)—a primary cause of gonadal failure—and gonadotropin suppression.^5,10 Estimates are that TARTS develop in between 30% and 50% of adolescent boys and are a primary reason for disrupted sperm production.⁶ Vulnerability to the growths increases after periods of poor disease control and has been observed to parallel nonadherence to treatment. The tumors often regress with intensification of GC therapy if they are detected early.^5,10

Given the potential for irreversible testicular damage by TARTs, however, experts, including authors of the 2018 Endocrine Society guidelines on CAH suggest men with CAH considering fatherhood could explore semen cryopreservation.^2,20

Women with CAH face challenges to conception that may include anatomical impediments, ongoing hormonal disturbance, and psychological effects of the disorder.⁶ Vaginal intercourse may not be possible unless there has been reconstructive surgery, adverse effects of which may also be restrictive.⁶ Elevated adrenal androgens in women with CAH, sequelae of poor disease control, can lead to amenorrhea, irregular menses, and infertility.^2,5,8 Between 30% and 60% of women with CAH do experience menstrual disturbance if they are not on contraceptive therapy.¹ When CAH is well controlled, menarche is typically normal.³

In addition to excess adrenal androgens, elevated production of adrenal-derived progesterone is one of the most significant hormonal obstacles to fertility in women. Controlling hormonal imbalance to support conception will often require increased GC dosages to adequately restore the ovulatory cycle.^1,6

Long-term health

There is variable evidence for elevated cardiovascular (CV) risk and metabolic morbidity in the CAH population, which calls for regular follow-up as well as lifestyle counseling and interventions to limit weight gain, prevent obesity and to screen for diabetes, particularly gestational diabetes, and for dyslipidemia.³ Although the findings from contemporary research on CV risk factors in people with CAH is inconsistent, however, a study from the UK found more than half of female participants were obese and one third had insulin resistance.³ A widely cited study from Sweden found a higher proportion of study participants had hypertension, hyperlipidemia, diabetes, and venous thromboembolism compared with controls.³ Higher BMI and poor body composition have been reported with prevalence ranging from 20% to 45%, regardless of type of GC therapy.³

Ongoing exposure to GCs, and particularly to higher doses often needed for effective androgen suppression, is a key risk factor for poor bone health and some studies have found an increased risk of fracture among adults with CAH.³ Data from research over the past 20 years suggests lower bone mass density, ie, osteoporosis or osteopenia, in individuals with CAH of 37% to 81% compared with control populations.³

Psychological health, quality of life

The 2018 Endocrine Society guidelines urge clinicians who care for individuals with CAH to retain a high level of suspicion for mental health issues and a low threshold for referral for treatment, citing the “multiple emotional stressors and coping challenges for the patients and their families with variable consequences for mental health and QOL.”² The guidelines stress that the transition from teenage to adult clinical care is a particularly difficult time for many individuals who may be coping with impaired body image and issues of sexuality related to disordered sexual development and potentially the adverse effects of surgeries.^2,8

A recent retrospective cohort study found that a diagnosis of a depressive or anxiety disorder and prescriptions for antidepressants were more likely among children, adolescents, and young adults with classic CAH compared to their age- and sex-matched peers.²¹ The likelihood of both disorders as well as receiving medication to treat them increased with age with the distribution skewed over time toward men. The study authors concluded that if additional research confirms their findings, enhanced screening for mental health disorders in these young populations is warranted.²¹

Care for individuals with CAH across the lifespan includes instruction and remedial instruction from a young age in use of increased GC dosage, or stress dosing (2-3 times usual dose), during periods of fever, gastroenteritis with dehydration, major surgery accompanied by general anesthesia, and major trauma.² Although the frequency of adrenal crises has decreased over time, perhaps as a result of greater awareness, guidelines and researchers in the field of CAH stress that parents and children require repeated education on the stress dosing regimen and the situations that require medical attention. Parents, older children, adolescents, and adults should have an emergency kit available with injectable hydrocortisone and wear medical identification jewelry.²

Above all...

Researcher Auchus says “Above all, the management of the patient with [CAH] should recognize that these patients are vulnerable to all the other diseases that people without this condition suffer, and they require the same general healthcare as any adult. Women should receive cervical smears, breast exams, and/or mammograms at the standard ages, and men require screening for prostate disease. 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.”

References

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2. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. doi:10.1210/jc.2018-01865

3. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91-159. doi:10.1210/endrev/bnab016

4. Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol. 2022;18(6):337-352. doi: 10.1038/s41574-022-00655-w

5. Pofi R, Ji X, Krone NP, Tomlinson JW. Long‐term health consequences of congenital adrenal hyperplasia. Clin Endocrinol. 2023;1–15. doi:10.1111/cen.14967

6. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020;383(13):1248-1261. doi:10.1056/NEJMra1909786

7. Nordenström A, Falhammar H, Lajic S. Current and novel treatment strategies in children with congenital adrenal hyperplasia. Horm Res Paediatr. 2023;96:560-572. doi: 10.1159/000522260

8. Auchus RJ, Arlt W. Approach to the patient: the adult with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2013;98:2645-2655. doi:10.1210/jc.2013-1440

9. Choi J-H, Yoo H-W. Management issues of congenital adrenal hyperplasia during the transition from pediatric to adult care. Korean J Pediatr. 2017;60(2):31-37 doi:10.3345/kjp.2017.60.2.31

10. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91-159. doi:10.1210/endrev/bnab016

11. Dennis J, Pitts L, Matalka L, Mays L. Comprehensive adolescent healthcare transition program for congenital adrenal hyperplasia: A quality improvement initiative. Health Care Transit. 2024;2:100057. doi:10.1016/j.hctj.2024.100057

12. Merke DP, Poppas DP. Management of adolescents with congenital adrenal hyperplasia. Lancet Diabetes Endocrinol. 2013;1(4):341-352. doi:10.1016/S2213-8587(13)70138-4

13. Gleeson H, Davis J, Jones J, O'Shea E, Clayton PE. 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. Clin Endocrinol. 2012;78(1):23-28. doi:10.1111/cen.12053

14. Davidse K, van Staa A, Geilvoet W, et al. We mind your step: understanding and preventing drop-out in the transfer from paediatric to adult tertiary endocrine healthcare. Endocr Connect. 2022;11(5). https://doi.org/10.1530/EC-22-0025
15. Conway GS. Congenital adrenal hyperplasia: adolescence and transition. Horm Res. 2007;68( Suppl 5):155-7. doi:10.1159/000110614

16. Bachelot A, Vialon M, Baptiste A. Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood. Endocr Connect. 2017;6(7):422-429. doi:10.1530/EC-17-0094
17. Ekbom K, Lajic S, Falhammar H, Nordenstrom A. Transition readiness in adolescents and young adults living with congenital adrenal hyperplasia. Endocr Pract. 2023;29: 266e271. do:10.1016/j.eprac.2023.01.010

18. Twito O, Shatzman-Steuerman R, Dror N, Nabriski D, Eliakim A. The “combined team” transition clinic model in endocrinology results in high adherence rates and patient satisfaction. J Ped Endocrinol Metab. 2019;32(5). doi:10.1515/jpem-2019-0056

19. Auchus RJ. Management of the adult with congenital adrenal hyperplasia. Int J Ped Endocrinol. 2010;2010:614107. doi:10.1155/2010/614107

20. Engels M, Span PN, van Herwaarden AE, Sweep FCGJ, Stikkelbroeck NMML, Claahsen-van der Grinten HL. Testicular adrenal rest tumors: current insights on prevalence, characteristics, origin, and treatment. Endocr Rev. 2019;40(4):973-987. doi:10.1210/er.2018-00258

21. Narasymiw LA, Grosse SC, Cullen KR, Bitsko RN, Perou R, Sarafoglou K. Depressive and anxiety disorders and antidepressant prescriptions among insured children and young adults with congenital adrenal hyperplasia in the United States. Front Endocrinol. 2023;14. doi: 10.3389/fendo.2023.1129584