The core clinical problem is a delicate biochemical balancing act. In 21-hydroxylase deficiency, impaired cortisol synthesis causes the adrenal glands to accumulate precursor steroids, including 17-hydroxyprogesterone and androstenedione, which are shunted into androgen production. Some of these precursors are converted into potent androgens such as dihydrotestosterone, including via the so-called backdoor pathway, driving virilisation. Treatment therefore aims to suppress excess adrenal androgens with glucocorticoids, but overtreatment carries its own toll: obesity, insulin resistance, hypertension and reduced bone mineral density. Undertreatment, by contrast, risks accelerated skeletal maturation, compromised adult height and progressive virilisation. During puberty, this tightrope becomes harder to walk because rising sex hormones, growth hormone and IGF-1 alter cortisol metabolism and clearance, and renal cortisol clearance itself increases, producing higher and more variable hydrocortisone requirements.

Diagnosis is its own puzzle during adolescence. Activation of the hypothalamic-pituitary-gonadal axis, together with adrenarche, floods the circulation with adrenal and gonadal androgens such as DHEA, DHEA sulphate, androstenedione and testosterone, which can mimic CAH both clinically and biochemically. This is particularly relevant for non-classic CAH, the milder form in which roughly 20 to 50 percent of enzyme activity is preserved. Unlike salt-wasting CAH, which presents in infancy with less than one percent residual activity, or simple virilising CAH, which emerges in childhood, non-classic CAH often first announces itself in adolescence with acne, hirsutism, accelerated growth or menstrual irregularity, all features that are common in healthy teenagers and therefore poorly specific. Prevalence estimates range from one in 200 to one in 1,000, with higher rates in some groups such as Ashkenazi Jews, and many affected individuals, especially males, remain asymptomatic because gonadal androgen production dwarfs the adrenal contribution.

The biochemical picture of untreated non-classic CAH adds further nuance. Basal cortisol and aldosterone are typically normal, with only mildly elevated androgens and 17-hydroxyprogesterone, and sub-optimal cortisol responses to ACTH stimulation testing appear in up to 60 percent of untreated patients. Yet symptomatic cortisol deficiency is strikingly rare: more than 90 percent show no signs of hypocortisolism, and in larger series potential features of adrenal insufficiency were observed in only about one percent. The review notes that this apparent protection may reflect intermediary cortisol metabolites binding the glucocorticoid receptor, elevated free cortisol levels, or receptor polymorphisms that heighten cortisol sensitivity. Distinguishing non-classic CAH from polycystic ovary syndrome, idiopathic hirsutism, differences of sex development and, in cases of rapid-onset hyperandrogenism, adrenal or gonadal tumours requires a layered workup spanning androgens, gonadotrophins, imaging, dexamethasone suppression testing and genetic studies, and the authors caution that mild borderline biochemistry risks overdiagnosis.

For adolescents with classic CAH, therapy revolves around hydrocortisone at 10 to 15 milligrams per square metre per day, supplemented with fludrocortisone where mineralocorticoid replacement is needed. Hydrocortisone is preferred because longer-acting glucocorticoids such as prednisolone and dexamethasone suppress growth more strongly. Monitoring blends clinical assessment of growth, bone age, pubertal stage and features of hyperandrogenism with biochemical markers including morning pre-dose 17-hydroxyprogesterone, androstenedione and testosterone, while blood pressure, sodium, potassium and renin track fludrocortisone adequacy. Because responses vary widely, the authors stress the need for clinical and biochemical review every three to six months. Puberty compounds the difficulty: falling insulin sensitivity, which is already increased in CAH compared with BMI-matched controls, drives hyperinsulinaemia that suppresses sex hormone binding globulin, raising free testosterone and, in girls, potentially stimulating ovarian testosterone production.

Non-classic CAH demands a different calculus. Many patients need no treatment at all, and daily hydrocortisone is generally not recommended either to correct mild biochemical cortisol deficiency or as first-line therapy for hyperandrogenism or menstrual irregularity, since the cardiovascular, metabolic and bone risks of daily glucocorticoids can outweigh the benefits. Where treatment is sought, alternatives exist: cosmetic measures, topical eflornithine, spironolactone and flutamide for hirsutism; benzoyl peroxide, antibiotics and retinoids for acne; and anti-androgenic contraceptives for menstrual disturbance. Hydrocortisone started in childhood to protect final height can often be discontinued once adult height is achieved, with stress dosing reserved for those with sub-optimal ACTH responses.

Novel therapies are reshaping the landscape. Modified-release hydrocortisone formulations, which more closely imitate physiological cortisol secretion, may reduce daily dose requirements, restore menstrual cycles, improve fertility prospects and lower the likelihood of adrenal crises. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, has shown in phase 3 paediatric trials the potential to bring glucocorticoid dosing down from supraphysiological to physiological levels by dampening the drive to the adrenal axis. Long-term outcome data in adolescents started on either approach remain limited, however, and adherence remains the Achilles heel of every regimen. Autonomy, psychosocial pressure and treatment fatigue frequently produce inconsistent medication use, risking hyperandrogenism, menstrual irregularity and life-threatening adrenal crises. Structured education, simplified dosing, digital reminders, motivational interviewing and shared decision-making all help, as does practical advice such as taking the morning dose on time before going back to sleep. Every adolescent should carry an emergency hydrocortisone kit and be trained, alongside caregivers and school staff, in sick day rules and early symptom recognition.

Surgical and reproductive issues add a deeply personal dimension. Many adolescent girls with CAH have undergone feminising genitoplasty in infancy, and the review emphasises that clinicians must understand which procedures were performed, since complications can include fistulae, vaginal stenosis, reduced clitoral sensitivity, poor aesthetic outcomes and adverse psychosexual consequences. Whether to operate, and when, remains controversial, with no consensus among researchers, clinicians or patients, and some experts now advocate delaying surgery until adolescence when the individual can give informed consent. An examination under anaesthetic in early adolescence, before menarche, can inform discussions about future sexual function and possible obstruction to menstrual flow. Fertility deserves early conversation too: in males, testicular adrenal rest tumours, thought to arise from embryonic cells and driven by chronic ACTH stimulation, can impair spermatogenesis, making regular testicular ultrasound screening from before puberty and optimised glucocorticoid therapy important protective measures, while in females hyperandrogenism and prior genital surgery may affect ovulation and sexual wellbeing.

Finally, the psychosocial toll is substantial and increasingly well documented. Health-related quality of life is often broadly preserved, but studies report impairments in emotional, social and school functioning, with treatment burden, body image concerns, fertility anxiety, disclosure difficulties and stigma all contributing, and non-classic disease generally carrying a lighter load than classic CAH. Most individuals assigned female at birth identify as female, though gender-atypical behaviour is more common and a small but increased prevalence of gender dysphoria has been reported, while the effect on sexual orientation remains unresolved. Population-based studies show elevated rates of anxiety, depression and hospital-treated psychiatric conditions compared with matched controls, with poorly controlled disease associated with worse psychological outcomes. Transition to adult services emerges as a decisive intervention point: poorly structured handover leads to loss to follow-up and deteriorating health, whereas early preparation from around age 12 to 14, staged education, joint paediatric-adult clinics and structured frameworks such as Ready, Steady, Go can sustain engagement. The authors conclude that only multidisciplinary, patient-centred care, integrating endocrine expertise with psychological and social support, can optimise both clinical outcomes and quality of life for this often overlooked group.

Subject of Research: Diagnostic, therapeutic and psychosocial challenges facing adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Article Title: Medical and social challenges awaiting adolescents with congenital adrenal hyperplasia

Article References: Nixon, M., & Davies, J. H. (2026). Medical and social challenges awaiting adolescents with congenital adrenal hyperplasia. Frontiers in Adolescent Medicine, 4, Article 1870467. https://doi.org/10.3389/fradm.2026.1870467

Image Credits: AI Generated

DOI: 10.3389/fradm.2026.1870467

Keywords: congenital adrenal hyperplasia, 21-hydroxylase deficiency, adolescence, puberty, glucocorticoids, hyperandrogenism, non-classic CAH, adrenal crisis, transition care, fertility, mental health, genitoplasty