Androgen Management in Congenital Adrenal Hyperplasia: A Primer

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Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency requires medical treatment from birth to replace cortisol and potentially aldosterone to reduce elevated levels of adrenal androgens. In individuals with CAH, the persistent exposure to excessive androgen levels and frequently required supraphysiologic dosage of glucocorticoids (GCs) lead to long-term complications that include gonadal dysfunction, infertility, cardiovascular and metabolic comorbidity, psychological and interpersonal distress, and poor quality of life.^1,2

21OH activity catalyzes glucocorticoid and mineralocorticoid production in the adrenal cortex. Deficiency in or absence of the enzymatic process results in reduced cortisol levels that in turn allow overproduction of pituitary corticotropin.^1-4 Elevated corticotropin stimulates unchecked adrenal androgen production as a result of elevated levels of precursor steroids that are diverted through unaffected androgen pathways. Whether an infant is born completely 21OH deficient (salt-wasting CAH) or with residual enzymatic activity of 1% to 5% (simple virilizing CAH) the exposure to markedly elevated adrenal androgen production remains.^1-4

In individuals with CAH, the persistent exposure to excessive androgen levels and frequently required supraphysiologic dosage of glucocorticoids (GCs) lead to long-term complications that include gonadal dysfunction, infertility, cardiovascular and metabolic comorbidity, psychological and interpersonal distress, and poor quality of life.^1,2

The benefits of GC plus adjunctive mineralocorticoid treatment at least within the first year in neonates with either form of CAH are well recognized. The ongoing challenge for clinicians who care for individuals with 21OH deficiency CAH over a lifetime lies in the effort to consistently replace GCs at a level to adequately suppress adrenocorticotropin hormone (ACTH)-driven androgen excess while also avoiding excess GC exposure and consequent morbidity.^1-4 The majority of poor health and quality of life outcomes over an individual life lived with CAH are directly attributable to the wide range of hormonal imbalances created by the disease and its treatment.⁵

Impact of androgen exposure

The introduction of GC therapy in the 1960s followed by steadily improving methods for newborn screening together have allowed the majority of children with 21OH deficiency CAH to reach adulthood, shifting perception of the disorder from a pediatric condition to a chronic one, affecting people of all age groups.^1,6 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.^1,6

Adequate suppression of androgen production during early life is critical to allow normal growth and development including achievement of average adult height.^1,5,6 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.⁶ GC-related suppression of growth is particularly noticeable during infancy and puberty, making careful monitoring of drug dose, dosing, and subsequent adjustment essential.^1,5,7 Higher than average doses during these developmental periods are associated with decreased final adult height.^1,5 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.³ Although onset of puberty may trigger an acceleration in height, final adult height among is typically 1 to 2 standard deviations below their contemporaries.⁶

The introduction of GC therapy in the 1960s followed by steadily improving methods for newborn screening together have allowed the majority of children with 21OH deficiency CAH to reach adulthood, shifting perception of the disorder from a pediatric condition to a chronic one, affecting people of all age groups.^1,6

Among the wide range of effects, androgen excess in childhood and teen-age years typically manifests in oily skin, acne, and pubarche; in young women poor hormonal control can lead to female hirsutism, male-pattern baldness, altered body habitus, and irregular menses.^1,3,4

Duration of GC effect and dose should be reevaluated during the transition from childhood to adolescence and adolescence to adulthood. Pubertal hormone changes may require increasing dose, but the decision will need to balance the greater potential for growth suppression during this period.⁷ It should be noted that GC treatment is not always completely effective and for some children fails to normalize growth and development. ⁷

Adult Complications

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.

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.^4,6 As a young adult, a man with classic 21OH that is not well controlled may appear normally virilized and otherwise healthy. But if examination reveals testicular atrophy and gonadotropin suppression, it is possible that adrenal androgen excess has left the individual paradoxically prepubertal.⁸

The suppression of gonadotropin secretion and testosterone synthesis from Leydig cells caused by excess adrenal androgen prevents spermatogenesis, leading to oligospermia or azoospermia.⁶ Sperm production also can be disrupted by TARTs which are estimated to develop in between 30% and 50% of adolescent boys and men with 21OH deficiency CAH.⁵ Vulnerability to the growths increases after periods of poor disease control and coincides with nonadherence to treatment. The tumors often regress with intensification of GC therapy if they are detected early.^1,5

Originally TARTs were believed to originate from aberrant adrenal cells, but recent research has found the tumors exhibit testicular characteristics, suggesting the origin may be in pluripotent cells.⁹ One hypothesis is that elevated ACTH concentrations lead to hyperplasia of such cells, thinking in line with the observation that their appearance is often associated with poor hormonal control with concomitant high concentrations of ACTH.⁹ Treatment that directly suppresses ACTH-release could greatly reduce the risk of TARTS as well as lead to more physiologic doses of GC.⁹

Treatment that directly suppresses ACTH-release could greatly reduce the risk of TARTS as well as lead to more physiologic doses of GC.⁹

Currently there is no evidence to suggest that TARTs have malignant features (eg, high mitotic rate, atypical mitoses) nor have there been reports of cases of malignancy.⁹ Given the potential for irreversible testicular damage by TARTs, however, experts, including authors of the 2018 Endocrine Society guidelines on CAH,¹ suggest men with CAH considering fatherhood could explore semen cryopreservation.^1,9

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

Other contributors to female gonadal dysfunction include secondary polycystic ovaries, hypogonadotropic hypogonadism and, far less frequently than TARTs seen in men, ovarian adrenal rest tumors (OARTs).^6,8 According to some investigators, the low recorded prevalence of OARTs may be related in part to the inability to detect the growths on ultrasound scans whereas in men, TARTS are easily discerned.^6,8

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 may require increased GC dosages to adequately restore the ovulatory cycle.^3,5

Psychological impact

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.”¹ 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.^1,8

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.¹⁰ 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.¹⁰

Clinicians who care for individuals with CAH [must] retain a high level of suspicion for mental health issues and a low threshold for referral for treatment, [given] the “multiple emotional stressors and coping challenges for the patients and their families with variable consequences for mental health and QOL.”¹

Overall, the data on the brain effects and psychological impact of CAH are still limited. Both fetal and postnatal exposure to excess adrenal androgens and GCs are believed to influence the developing brain and could potentially affect mental health.⁵ Findings of the retrospective cohort study just described are mirrored by similar research and registry studies that show “a higher prevalence of anxiety, depression, alcohol misuse, personality disorders, and suicidality among male patients and adjustment disorders among female patients with classic CAH than among controls.”⁵ In addition, it is common for women with CAH to avoid romantic relationships.⁵

Impaired quality of life among adults with CAH is common and although the challenges differ among men and women, the emotional stress of living with a chronic disease including managing complex and potentially harmful GC medication regimens is common to both.

GC Therapy Limitations, Potential Solutions

Although the evolution of GC therapy has proven lifesaving, the paradigm has changed little over the 70 years it has been available. The challenge of managing excess adrenal androgens effectively remains, with evidence to show that androgen levels are still poorly managed in approximately two-thirds of individuals with CAH.^4,11,12 Inadequate androgen suppression despite the high-dose GCs often required puts these people at risk of drug side effects including weight gain, type 2 diabetes, and osteoporosis/osteopenia while leaving them vulnerable to the effects of excess androgen exposure discussed above.^1,4,5

The supraphysiologic doses of GCs used today reflect the absence of a mechanism to directly manage androgen overproduction. Therapies now in development are evaluating ways to reduce the daily required GC dose by optimizing the pharmacokinetics of GC replacement and investigating pathways that separate management of androgen excess from GC treatment of cortisol deficiency.⁷ One research effort is exploring blocking corticotropin releasing factor 1 (CRF1) or other receptors in the hypothalamic pituitary adrenal axis (HPA), a potential strategy to reduce adrenocorticotropic hormone (ACTH) release and so attenuate adrenal androgen production.^2,4,7 Other novel pathways being explored that work via suppression of the HPA axis include a monoclonal antibody to ACTH and a melanocortin type 2 receptor antagonist.^2,3,7

One research effort is exploring blocking CRF1 or other receptors in the HPA axis, a potential strategy to reduce ACTH release and so attenuate adrenal androgen production.^2,4,7

Research to replace GCs more efficiently is focusing on ways to better mimic the physiologic circadian rhythm of cortisol which peaks in the morning and declines gradually over the balance of the day. Current treatments are associated with peak concentrations that decline rapidly to nearly nondetectable levels, leaving individuals exposed to intermittent androgen overproduction and consequently requiring higher GC doses for continuous effect. Dual- and modified-release release oral GCs as well as a continuous subcutaneous hydrocortisone formulation are all being evaluated in clinical trial settings. Gene- and cell-based therapies are also being explored, with several in preclinical and phase 1-2 testing.^2,3,7

References

1 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

2 Schröder MAM, Claahsen ‑ van der Grinten HL. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disor. 2022; 23:631–645. doi:10.1007/s11154-022-09717-w

3 Auer MK, Nordenström A, Lajic S, Reisch N. Congenital adrenal hyperplasia. Lancet. 2022;401(10374): 1-18. doi:10.1016/S0140-6736(22)01330-7

4 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

5 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

6 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

7 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

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. 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

10 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

11 Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121. doi:10.1210/jc.2010-0917

12 Finkielstain GP, Kim MS, Sinaii N, et al. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012;97(12):4429-4438. doi:10.1210/jc.2012-2102