Medical and social challenges awaiting adolescents with congenital adrenal hyperplasia

Introduction

Congenital adrenal hyperplasia (CAH) comprises a group of inherited adrenal disorders characterized by impaired cortisol biosynthesis with variable deficiencies in aldosterone production and excess adrenal androgen secretion. CAH secondary to 21-hydroxylase deficiency (21-OHD) is the commonest genetic cause of primary adrenal insufficiency and is the focus of this review. It is caused by mutations in the CYP21A2 gene and affects up 1 in 20,000 births (1). Classic CAH [salt-wasting (SW) and simple virilising (SV)] usually present at a younger age than the phenotypically milder non-classic CAH (NCCAH) which may present during adolescence, reflecting differing impairment of 21-hydroxylase activity. Advances in neonatal screening and early diagnosis have improved survival and early disease control. The management of CAH during adolescence poses a particularly complex and vulnerable period in the life-long management of CAH, as a range of physiological, psychological, and social factors converge to challenge optimal care. Achieving excellent care is critical during this time (2, 3).

Clinicians are faced with the difficult task of balancing adequate suppression of adrenal androgen excess against the risks associated with supraphysiological glucocorticoid dosing. The endocrine changes of puberty, including activation of the hypothalamic–pituitary–gonadal (HPG) axis, significantly influence adrenal steroid dynamics and glucocorticoid requirements. Poorly controlled hyperandrogenism may result in accelerated skeletal maturation, compromised final adult height, and virilization, while overtreatment is associated with adverse metabolic outcomes such as obesity, insulin resistance, hypertension, and reduced bone mineral density (4).

Adherence to treatment regimens frequently declines during adolescence, as individuals assume greater responsibility for their own care. Factors such as evolving autonomy, psychosocial pressures, and variable health literacy can contribute to inconsistent medication use and clinic attendance. Inadequate medicine adherence compromises disease control and increases the risk of adrenal crises. Supporting adolescents in developing effective self-management skills is a key component of care.

Psychosexual development and issues related to body image are highly relevant in this age group. Individuals with CAH, particularly those with atypical genitalia at birth, may face complex challenges related to gender identity, sexual function, and fertility. The long-term outcomes of early surgical interventions, as well as evolving perspectives on timing and necessity of such procedures, add further complexity to management. Sensitive, developmentally appropriate communication and access to multidisciplinary care are essential to address such concerns comprehensively.

Another crucial aspect of adolescent CAH care is the transition from paediatric to adult health services. This process is often associated with gaps in care continuity, reduced clinic engagement, and increased risk of suboptimal disease management. Structured transition programs that emphasise patient education, autonomy, and coordination between services are vital to ensure sustained engagement and improved long-term outcomes.

Adolescents living with CAH therefore have unique challenges that extend beyond hormonal control. The interplay of endocrine, developmental, and psychosocial factors requires holistic, individualized, and multidisciplinary care. Recognising and proactively managing these challenges is essential to optimise both clinical outcomes and quality of life for affected individuals. In this review, we focus on the commonest form of CAH, 21-OHD, and consider the diagnostic, therapeutic and psychosocial challenges for adolescents living with CAH (Figure 1).

Diagnostic challenges in adolescents presenting with CAH

The endocrine changes of puberty introduce challenges to the diagnosis and ongoing assessment of CAH, particularly in differentiating physiological pubertal maturation from pathological hyperandrogenism and in interpreting standard biochemical markers. Activation of the HPG axis, together with adrenarche, results in increased secretion of adrenal and gonadal androgens, including dehydroepiandrosterone (DHEA), DHEA sulphate (DHEA-S), androstenedione, and testosterone. These changes may complicate diagnosis by phenotypically and biochemically mimicking features of CAH. Unlike SW and SV CAH, non-classic CAH (NCCAH) may present during adolescence.

Non-classic CAH

The extent to which 21-hydroxylase activity is deficient influences the age at presentation of CAH: < 1% enzymatic activity causes SW CAH and presents in infancy, and 1%–2% enzymatic activity causes SV CAH and presents during childhood (5). Individuals with NCCAH have much greater residual 21-hydroxylase activity (∼20%–50%) and often present later and during adolescence. The prevalence of NCCAH is 1 in 200–1,000, with higher prevalences in some ethnic groups e.g., Ashkenazi Jews (4, 6). Many patients with NCCAH are asymptomatic, especially males, as testicular androgen synthesis is much greater that adrenal androgen synthesis (7). If clinical features manifest these include acne, hirsutism, accelerated linear growth, and menstrual irregularities. Such features are common in healthy adolescents, reducing their specificity as indicators of disease. Similarly, advanced bone age may be associated with normal pubertal progression or chronic androgen excess.

The biochemical profile of untreated NCCAH includes normal basal cortisol and aldosterone with mildly elevated androgens and 17-OHP levels. Sub-optimal cortisol levels following an ACTH stimulation test are observed in up to 60% of untreated NCCAH patients. In untreated NCCAH, features of cortisol deficiency are rare, with over 90% demonstrating no signs of hypocortisolism, with fatigue as the predominant feature in the few manifesting symptoms (7). Symptomatic adrenal insufficiency in NCCAH during episodes of intercurrent illness is also rare even in those with a sub-optimal cortisol response to an ACTH stimulation test. Signs of adrenal insufficiency were not observed in a cohort of paediatric NCCAH; and in larger series of older patients, potential features of adrenal insufficiency were observed in only ∼1% (8–10). In a series of patients with NCCAH with a sub-optimal cortisol response to an ACTH stimulation test, no signs of adrenal insufficiency were reported during their life or during surgery (11). The absence of symptomatic hypocortisolism in NCCAH may be due to the protective effects of intermediary cortisol metabolites binding to the glucocorticoid receptor, the free cortisol levels may be elevated, and polymorphisms of the glucocorticoid receptor might increase sensitivity to cortisol (7).

Other causes of hyperandrogenism during adolescence

A key diagnostic challenge is distinguishing CAH from normal pubertal variants and other causes of hyperandrogenism in adolescence (Tables 1, 2). Overlapping clinical and biochemical features increase the risk of overdiagnosis of CAH in adolescents presenting with mild or borderline biochemical abnormalities. Hirsutism may be idiopathic or a feature of an underlying disorder e.g., polycystic ovary syndrome (PCOS). Virilisation in the adolescent girl, which includes additional features of hyperandrogenism such as clitoromegaly, breast atrophy, deepening of voice, may be a manifestation of other gonadal or adrenal disorders including differences of sex development (12). Importantly, for those presenting with rapid onset hyperandrogenism, adrenal and gonadal tumours may be causal and require detailed biochemical, genetic, and radiological investigation (Table 2).

Table 1. Causes of hyperandrogenism in adolescence.

Table 2. Investigation for hyperandrogenism in adolescence.

Therapeutic challenges for CAH management in adolescence

The therapeutic management of SW, SV and NCCAH CAH during adolescence is a complex interplay between dynamic physiological changes of puberty, evolving psychosocial factors, and prevention of long-term consequences of chronic glucocorticoid and mineralocorticoid therapy. Achieving optimal disease control in this period requires balancing adequate suppression of excess adrenal androgen production with avoidance of glucocorticoid overtreatment, while simultaneously addressing broader developmental and reproductive health considerations.

Endocrine changes at puberty and glucocorticoid therapy

The biosynthetic block in 21-OHD results in increases in 17OHP and androstenedione levels. These precursors can be converted to testosterone, 11-keto-testosterone, 11-keto-DHT or dihydrotestoserone (DHT), the latter via the backdoor pathway (5, 13). DHT is more potent than testosterone in binding to the androgen receptor to cause virilisation. Decreased insulin sensitivity usually occurs during puberty and individuals with CAH have increased insulin resistance compared to BMI-match controls (14, 15). Hyperinsulinaemia suppresses hepatic sex hormone binding globulin (SHBG) synthesis leading to increased free testosterone and worsening symptoms. In adolescent girls, hyperinsulinaemia may also stimulate ovarian testosterone production.

A key challenge is the impact of pubertal physiological changes on pharmacokinetics and pharmacodynamics of glucocorticoid therapy. During puberty, cortisol metabolism and clearance is influenced by the increase in sex hormones, growth hormone (GH) and IGF-1 (16). Renal cortisol clearance increases during puberty (17). Increases in GH and IGF-1 at this time may cause reduced activity of 11β-hydroxysteroid dehydrogenase, resulting in impaired inactivation of cortisol into the inactive cortisone. Cortisol half-life is also reduced in girls compared to boys and potentially exacerbated in pubertal girls with CAH (17). These changes contribute to the increased or variable hydrocortisone dose requirement during puberty.

Non-classic CAH management during adolescence

Many patients with NCCAH do not require treatment. The rationale for initiating daily hydrocortisone is debated (4). The decision to intervene with daily hydrocortisone is individualised as the risk-benefit trade-off is different to classic CAH. Most NCCAH patients have adequate cortisol levels for basal conditions and daily hydrocortisone treatment can cause adverse cardiovascular, adrenal, metabolic and bone outcomes. Use of daily hydrocortisone is not usually recommended to compensate for mild cortisol deficiency nor as a first line treatment for hyperandrogenism or menstrual irregularity (7). In those with a sub-optimal ACTH test, stress dosing of hydrocortisone is advised. Daily hydrocortisone may have been commenced during childhood because of concerns regarding reduced final height from accelerated skeletal maturation. Treatment initiated for this reason can be discontinued once final height has been attained.

The main reason to offer treatment to adolescents with NCCAH is to minimise features of hyperandrogenism, and alternative therapies to glucocorticoids are available. Treatment options for hirsutism include cosmetic treatments (e.g., shaving, laser therapy), topical eflornithin, spironolactone and flutamide; and for acne include benzoyl peroxide, antibiotics and retinoids. The anti-androgen contraceptive can be offered for menstrual irregularity.

Classic CAH management during adolescence

The aim of treatment in adolescence is to optimise linear growth, reduce features of hyperandrogenism, address psychosocial challenges, and preserve fertility, cardiovascular and bone health outcomes. Treatment is with hydrocortisone (10 – 15 mg/m2/day), and when indicated, fludrocortisone (50–200 mcg/day) (4). Hydrocortisone is the treatment of choice as longer-acting glucocorticoids (prednisolone, dexamethasone) have more growth suppression. Giving the highest dose consistently early in the morning and mimicking the circadian rhythm has been advocated to prevent elevated androgens (18).

Adequacy of glucocorticoid treatment can be assessed clinically by assessment of growth (including annual bone age), features of hyperandrogenism and pubertal staging; and biochemically by measuring morning pre-hydrocortisone dose 17-OHP, androstenedione and testosterone. Fludrocortisone replacement is assessed by measurement of blood pressure and biochemically by measurement of sodium, potassium and renin. Patients require close monitoring for side effects from overtreatment (poor growth, weight gain, reduced bone mass, hypertension) or under treatment (reduced adult height, fatigue, hyperandrogenism, hypotension, salt-craving). The specific treatment doses required must be individualised as response to therapy is highly variable, underlining the requirement for 3–6 monthly clinical and biochemical evaluation.

Alternative therapeutic options

The use of modified-release hydrocortisone (MR-HC) formulations may have a role for adolescent CAH management by imitating physiological cortisol secretion. MR-HC may improve disease control by reducing daily hydrocortisone requirement, potentially restoring menses, improved fertility and reduced likelihood of adrenal crises (19, 20). Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, shows promise as a novel therapy with the potential to reduce glucocorticoid dose from supraphysiological to physiological levels (21). Long-term health outcomes for adolescents started on either therapy remain limited.

Medicine adherence and self-care

The transition toward patient autonomy, coupled with psychosocial challenges and treatment fatigue, frequently results in inconsistent medicine adherence causing hyperandrogenism, menstrual irregularity, and increased risk of adrenal crisis. Strategies to improve adherence include structured education programs that promote self-management skills, young adult clinics, simplified dosing regimens, use of MR-HC in selected cases and digital reminders (2, 22). The advice should include avoidance of over-sleeping and to give the morning dose on time then go back to sleep. Motivational interviewing and shared decision-making may enhance engagement and autonomy. Engagement with multidisciplinary teams, including specialist nurses and psychologists, is often beneficial.

Adrenal crisis is a significant and potentially life-threatening complication, particularly in adolescents with suboptimal adherence or inadequate stress dosing. Education regarding “sick day rules,” recognition of early symptoms (e.g., pyrexia, fatigue, vomiting), and prompt administration of parenteral hydrocortisone is critical. Adolescents should be equipped with emergency hydrocortisone kits and trained, along with caregivers and school personnel, in their use. Promoting patient confidence in self-administration and decision-making with directed staged education, is a key component of care.

Surgical considerations during adolescence

Clinicians should be alert to the impact of childhood feminising genitoplasty on the adolescent girl with CAH. The decision whether to intervene, age at surgery and optimal procedure remain controversial, and there is currently no consensus view from research, clinicians or patients (23–25). The decision to intervene with surgery therefore remains individualised. Some advocate delaying the option of surgery until adolescence when informed consent from the individual is possible and strengthening support for families (26). Complications of childhood surgery include fistulae, vaginal stenosis, reduced clitoral sensitivity, poor aesthetic outcome and adverse psychosexual problems. Clarifying the specific surgical procedure undertaken (labioplasty, vaginoplasty, clitoroplasty) is helpful to understand the likelihood of complications (27). Outcomes of childhood genital surgery vary, with some individuals experiencing reduced sensitivity, dyspareunia, or need for revision procedures, underscoring the importance of ongoing gynaecological and psychosexual support during adolescence. In those who had childhood genital surgery, an examination under anaesthetic in early adolescence, and prior to menarche, may help inform discussions about future sexual function, likelihood of obstruction to menstrual flow and whether further surgery should be offered.

Fertility

Fertility preservation and reproductive health require early discussion. In males with classic CAH, testicular adrenal rest tumours (TARTs) may occur. TARTs are speculated to develop in utero from totipotent embryonic cells and respond to chronic ACTH stimulation, potentially impairing spermatogenesis. Regular testicular ultrasound screening starting prior to puberty and optimization of glucocorticoid therapy mitigate this risk (28). In females, hyperandrogenism and menstrual irregularities may impact ovulatory function, and prior genital surgery may influence sexual function and satisfaction.

Transition of care to adult services

Poorly structured transition is associated with loss to follow-up, reduced adherence, and poor health outcomes. Transition should begin early (around ages 12–14 years) with gradual preparation, including education on CAH self-management, medication adherence, and health literacy. Assessment of transition readiness should include evaluation of disease knowledge, medication management, management of sick day episodes, and understanding of reproductive and genetic implications. Gradual transfer of responsibility, joint paediatric–adult clinics, and individualized transition plans may improve continuity of care. Dedicated transition coordinators and the use of a structured framework (e.g., ready, steady go) may further support successful transition (22, 29).

Psychosocial challenges for the adolescent living with CAH

The adolescent living with CAH is confronted with challenges from chronic illness burden, atypical hormonal exposure, medical and surgical interventions, and the developmental tasks of autonomy, identity formation, and social integration. Understanding of these domains is essential for healthcare professionals aiming to provide holistic, developmentally appropriate care.

Quality of life and lived experience

Studies on health-related quality of life (HRQoL) in adolescents living with CAH indicate variable and modest impaired outcomes, influenced by disease control, treatment burden, and psychosocial factors. A recent case–control study reported largely comparable overall HRQoL to healthy peers, although adolescents exhibited reduced school functioning (30). Systematic review and meta-analysis data indicate inconsistent findings across domains, with some studies showing preserved physical health but impairments in emotional and social functioning (31). NCCAH may have minimal HRQoL impact, whereas classic CAH is more frequently associated with psychosocial burden (32). Importantly, treatment-related factors, including glucocorticoid exposure and quality of care, height and weight appear to significantly modulate HRQoL outcomes (33, 34). Chronic disease burden, treatment fatigue, concerns regarding body image and fertility, and challenges with disclosure and stigma contribute to adverse lived experience (35, 36). Adolescents may report a discrepancy between clinical indicators of disease control and subjective well-being. To address unmet psychosocial needs, supportive family dynamics, access to multidisciplinary care, and effective patient education may be associated with improved psychosocial outcomes.

Psychosexual development

Adolescents living with CAH may experience altered psychosexual development, potentially influenced by prenatal androgen exposure and medical interventions (37). Most individuals with CAH assigned female at birth identify with the female gender, despite increased rates of gender-atypical behaviour. However, a small but increased prevalence of gender dysphoria has been reported compared to the general population (5). The influence of CAH on sexual orientation is not established (38). Sexual function in females may be affected, particularly in those undergoing early genital surgery, with reports of reduced sensitivity and dyspareunia. Concerns regarding body image, disclosure, fertility and sexual relationships may occur. Fertility-related anxiety may further impact psychosexual well-being (5). Developmentally appropriate, open discussions regarding gender, sexuality, fertility, and reproductive health should be integrated into routine care to address such issues.

Mental health

Individuals living with CAH are at increased risk of psychiatric morbidity, particularly anxiety and depressive disorders (39, 40). Population-based cohort studies have demonstrated higher rates of hospital-treated psychiatric conditions compared with matched controls, suggesting clinically significant mental health vulnerability across the lifespan (41). The aetiology is multifactorial, involving chronic disease burden, glucocorticoid exposure with potential central neuropsychiatric effects, and psychosocial stressors including body image concerns and stigma related to DSD (5). Importantly, severity of disease and treatment adequacy appear to modulate risk, with poorly controlled CAH associated with worse psychological outcomes (4). Integrated multidisciplinary care, including psychological support, is recommended to mitigate adverse mental health outcomes.

Summary

Adolescents living with CAH face a broad spectrum of medical and psychosocial challenges that may significantly influence overall well-being, treatment adherence, and long-term outcomes. A multidisciplinary, patient-centred approach that integrates endocrine management with psychological and social support is essential to address these complex needs during this formative stage of life.

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Footnotes

Edited by: Tulay Guran, Marmara University, Türkiye

Reviewed by: Vera M. Zdravkovic, University Children's Hospital, Serbia