Congenital adrenal hyperplasia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Loss of 21-hydroxylase activity reduces cortisol synthesis. ACTH rises through loss of feedback, enlarging adrenal tissue and diverting precursors toward androgen. Severe enzyme deficiency also impairs aldosterone, producing renal sodium loss, volume depletion and hyperkalaemia. Simple virilising and non-classic phenotypes retain more mineralocorticoid function and present differently.

Monitoring is a balance between under-treatment and over-treatment. Excess androgen may accelerate childhood growth and bone age, disturb cycles, cause hirsutism or reduce fertility; too much glucocorticoid promotes weight gain, hypertension, diabetes, osteoporosis and impaired growth. Hormone samples must be interpreted relative to dose timing, adherence, life stage and the exact assay.

CAH care extends beyond prescriptions. Differences of sex development require respectful multidisciplinary support and shared decisions. Genetic counselling, partner carrier testing where appropriate, puberty and fertility review, pregnancy planning, psychological wellbeing and a structured paediatric-to-adult transition are core components rather than optional additions.

Key points

Congenital adrenal hyperplasia is a group of inherited steroid-synthesis disorders; 21-hydroxylase deficiency causes most cases and produces cortisol deficiency with excess adrenal androgen, plus aldosterone deficiency in salt-wasting disease.
Classic salt-wasting CAH can present in infancy with vomiting, weight loss, dehydration, hyponatraemia, hyperkalaemia and shock; newborn screening and genital appearance do not identify every affected child.
Treatment replaces glucocorticoid and, when deficient, mineralocorticoid while restraining excess ACTH and androgen; complete biochemical suppression at the cost of iatrogenic Cushing syndrome is not the goal.
Adults need reliable daily medication, sick-day dosing, emergency injection training, two or more kits under NICE guidance, and an NHS Steroid Emergency Card.
Hydrocortisone is first-choice routine adult replacement at a total 15 to 25 mg daily in divided doses, with any higher CAH dose determined by specialist biochemical and clinical goals.
Fludrocortisone need is judged from blood pressure, postural symptoms, potassium, sodium and renin; excessive dosing causes hypertension, oedema and renin suppression.
Male fertility can be impaired by testicular adrenal rest tumours and gonadotrophin suppression, while women may have androgen-related anovulation, genital or sexual-health concerns and complex pregnancy planning.
Never stop replacement abruptly, and treat suspected adrenal crisis immediately with parenteral hydrocortisone and isotonic saline while the precipitating illness is managed.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Severe 21-hydroxylase deficiency

Marked inherited enzyme loss reduces both cortisol and aldosterone synthesis, creating androgen excess alongside renal salt wasting and crisis vulnerability.

Partial 21-hydroxylase deficiency

Residual enzyme activity preserves more mineralocorticoid function, producing simple virilising or non-classic phenotypes with later androgen-related presentation.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Cortisol synthesis falls
The enzymatic block limits adrenal cortisol production, weakening negative feedback to the hypothalamus and pituitary as the process continues.
2
ACTH stimulation increases
Loss of feedback raises ACTH, enlarges adrenal tissue and increases production of steroid precursors upstream of the block.
3
Precursors enter androgen pathways
Accumulated precursors are diverted toward adrenal androgens, affecting genital development, growth, bone age, menstrual function, hair growth and fertility.
4
Mineralocorticoid loss may coexist
In severe disease, reduced aldosterone causes renal sodium loss, volume depletion and potassium retention, particularly dangerous during illness or poor replacement.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Neonatal salt loss

Poor feeding, vomiting, weight loss, dehydration, hyponatraemia and hyperkalaemia in the first weeks of life can progress quickly to shock.

Androgen excess

Prenatal virilisation, early pubic hair, rapid childhood growth, advanced bone age, acne, hirsutism or cycle disturbance reflects increased adrenal androgen exposure.

Non-classic presentation

Later hirsutism, acne, irregular ovulation or subfertility may resemble polycystic ovary syndrome and requires appropriate early-morning follicular 17-hydroxyprogesterone testing.

Under-replacement

Fatigue, weight loss, nausea, salt craving, postural symptoms, recurrent crisis or rising androgen markers can result from inadequate dosing, poor absorption or missed treatment.

Over-replacement

Central weight gain, bruising, proximal weakness, hypertension, dysglycaemia, low bone density or growth suppression indicates excessive glucocorticoid exposure.

Testicular adrenal rests

Testicular nodularity, pain, abnormal semen analysis or infertility can reflect ACTH-responsive adrenal rest tissue, sometimes present before symptoms.

Red flags requiring action

Vomiting, diarrhoea, hypotension, confusion, hypoglycaemia or collapse in steroid-dependent CAH is adrenal crisis until assessed and needs immediate emergency hydrocortisone.
An infant with dehydration, hyperkalaemia and hyponatraemia requires urgent paediatric endocrine treatment even when external genital appearance is typically male.
Failure to retain oral glucocorticoid during illness demands injected replacement and emergency hospital assessment rather than repeated tablets at home.
Severe headache, hypertension or neurological symptoms during pregnancy require obstetric assessment; steroid changes and delivery cover belong with a specialist endocrine-obstetric team.
A new testicular mass must not be assumed to be benign adrenal rest tissue without ultrasound and specialist evaluation for competing diagnoses.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serum 17-hydroxyprogesteroneFirst step
Why
Identify the characteristic precursor elevation and follow biochemical control in 21-hydroxylase deficiency.
Interpretation and limitations
Obtain at a standard relation to treatment and time of day; a very low value can indicate over-treatment, while isolated elevation should not prompt dose escalation without clinical context.
02
Androstenedione and testosterone
Why
Assess downstream androgen exposure alongside symptoms, growth, cycles and fertility.
Interpretation and limitations
Age, sex, treatment timing and assay ranges matter; discordant results require adherence and sampling review rather than reflex glucocorticoid increase.
03
Electrolytes and plasma renin
Why
Evaluate salt balance and adequacy of mineralocorticoid replacement.
Interpretation and limitations
High renin with postural symptoms or hyperkalaemia can support under-replacement, whereas hypertension, oedema and suppressed renin suggest excess; interpret medicines and salt intake.
04
ACTH stimulation and genetic testing
Why
Clarify equivocal non-classic disease or define the causal steroidogenic variant.
Interpretation and limitations
Specialist stimulated steroid profiles distinguish enzyme defects, while CYP21A2 results support counselling but must be reconciled with phenotype and complex gene structure.
05
Testicular ultrasound
Why
Detect and follow adrenal rest tumours in males at risk of gonadal dysfunction.
Interpretation and limitations
Bilateral rete-testis lesions fit adrenal rests, but atypical or unilateral masses require urological and radiological review before treatment assumptions.
06
Growth bone and metabolic assessment
Why
Identify cumulative androgen excess and glucocorticoid toxicity across life stages.
Interpretation and limitations
In children use height velocity, pubertal stage and bone age; in adults integrate weight, blood pressure, HbA1c, lipids, fractures and bone density.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Polycystic ovary syndrome

Chronic irregular cycles and hirsutism commonly suggest PCOS, whereas childhood features, marked precursor elevation or family history support congenital adrenal disease.

Androgen-secreting tumour

Rapid virilisation or abrupt biochemical change is more concerning for an ovarian or adrenal tumour than a stable inherited enzyme disorder.

Primary adrenal insufficiency

Autoimmune adrenal failure causes cortisol and aldosterone deficiency but does not produce the characteristic ACTH-driven adrenal androgen excess of congenital hyperplasia.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01CRISISSuspected adrenal crisis in CAHFirst stepA steroid-dependent person is haemodynamically unwell, hypoglycaemic or unable to absorb oral replacement.

1Give intramuscular or intravenous hydrocortisone immediately; obtaining cortisol or ACTH must never delay treatment.
2Call emergency services, establish monitoring and restore circulation with 0.9% sodium chloride while checking glucose and electrolytes.
3Continue stress-dose hydrocortisone by infusion or divided parenteral doses according to NICE and seek endocrine advice.
4Identify infection, gastroenteritis, missed treatment or another precipitant, then return to oral sick-day dosing only after absorption and stability recover.

02ROUTINEStable adult replacementClassic CAH is established and the patient is clinically stable on oral therapy.

1Use the lowest glucocorticoid regimen that preserves wellbeing and acceptable androgen control without Cushingoid toxicity.
2Adjust fludrocortisone from clinical volume status, blood pressure, electrolytes and renin rather than a fixed lifelong dose.
3Standardise hormone sampling to dose timing and review adherence, shift work, exercise and interacting medicines before changing treatment.
4Rehearse sick-day rules, injection technique, emergency kit expiry and card carriage at every meaningful review.

03FERTILITYReproductive planningA person with CAH seeks contraception, pregnancy, paternity or fertility assessment.

1Clarify hormone control, cycles, sexual function, semen history, genital concerns and current glucocorticoid formulation sensitively.
2Arrange testicular ultrasound and semen analysis when male subfertility is suspected, or ovulatory and androgen assessment for women.
3Provide genetic counselling and discuss partner testing, inheritance and reproductive options without assuming a desired outcome.
4Manage conception, pregnancy and delivery in endocrine-obstetric or andrology services, avoiding dexamethasone as routine maternal replacement because it crosses the placenta.

04TRANSITIONTransfer to adult servicesAn adolescent is assuming responsibility for lifelong CAH care.

1Confirm the young person understands diagnosis, daily dosing, crisis symptoms, injection use, prescriptions and confidential access to care.
2Summarise genotype, surgeries, growth, puberty, fertility, previous crises and current laboratory targets in a shared record.
3Address body image, sexual wellbeing, mental health, alcohol, travel, work and sport with developmentally appropriate autonomy.
4Complete a named handover to an adult endocrine team before paediatric follow-up ends, with no gap in emergency medication.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Replace cortisol and moderate ACTH-driven androgen excess while approximating physiological daytime exposure.

Immediate-release hydrocortisone

NICE recommends 15 to 25 mg orally each day in two to four divided doses, using higher CAH dosing only with specialist advice.

Avoid late excessive dosing, abrupt cessation and biochemical over-suppression; review growth, weight, blood pressure, glucose, bone health, infection and individual sick-day requirements.

Replace mineralocorticoid activity in salt-wasting CAH and maintain sodium balance and circulating volume.

Fludrocortisone

Use the specialist-selected daily dose, commonly initiated within the NICE 50 to 300 microgram range and adjusted to clinical and renin response.

Monitor lying and standing pressure, oedema, sodium, potassium and renin; heat, exercise, pregnancy, infancy and interacting medicines can alter salt requirement.

Provide life-saving cortisol exposure when shock or vomiting makes routine oral treatment inadequate.

Emergency hydrocortisone injection

Give 100 mg intramuscularly or intravenously at once for suspected adult adrenal crisis, followed by the NICE hospital stress regimen.

There is no meaningful overdose concern in this emergency; do not wait for laboratory confirmation, and replace expired kits after use with repeat training.

Offer an alternative cortisol exposure profile for selected patients whose androgen control or treatment burden remains problematic.

Modified-release hydrocortisone

Use only the specialist CAH regimen licensed for the patient's age and agreed through the local formulary or commissioning pathway.

It does not remove sick-day or injection requirements; monitor total steroid exposure, adherence, cost or supply pathway and current SmPC restrictions.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Adrenal crisis

Insufficient stress glucocorticoid or mineralocorticoid replacement during illness can cause vomiting, shock, hypoglycaemia, hyponatraemia and hyperkalaemia.

Growth and skeletal harm

Under-treatment accelerates growth and bone maturation through androgen excess, while chronic glucocorticoid excess impairs growth and contributes to osteoporosis.

Reproductive and psychological burden

Androgen excess, gonadal dysfunction, fertility concerns and differences of sex development can affect relationships, wellbeing and reproductive planning across the lifespan.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Review symptoms, crisis frequency, adherence and steroid technique alongside timed 17-hydroxyprogesterone and androstenedione rather than targeting a single normal result.
Track blood pressure, postural change, sodium, potassium and renin to detect both salt loss and fludrocortisone excess.
In growing patients, record height velocity, weight, puberty and bone age; adult follow-up should include metabolic and fracture risk from cumulative glucocorticoid exposure.
Assess cycles, fertility goals, sexual health and testicular findings proactively because patients may not volunteer sensitive or gradually developing problems.
Inspect emergency kit contents and expiry, confirm practical injection competence and ensure the current NHS Steroid Emergency Card is carried.
During pregnancy or major surgery, document stress-dose ownership and postpartum or postoperative step-down with the relevant specialist team.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Male appearance can delay diagnosis

A salt-wasting newborn with typically male external genitalia may lack an obvious genital clue, so electrolyte collapse must trigger CAH consideration.

A normal precursor is not always success

Driving 17-hydroxyprogesterone fully into the normal range can require harmful glucocorticoid excess; clinical balance and downstream androgens are more informative.

Renin is contextual

Position, salt intake, medicines and hydration affect renin, so mineralocorticoid dosing combines the result with pressure, potassium and symptoms.

Adrenal rests are ACTH responsive

Improved hormonal control may reduce early testicular lesions, but fibrotic advanced disease can continue to impair fertility despite biochemical improvement.

Fertility may return quickly

Optimising androgen and gonadotrophin physiology can restore ovulation or spermatogenesis, making contraception and preconception counselling relevant during treatment changes.

11Common pitfallsFrequent interpretation and management errors.

01
Do not normalise every adrenal precursor by escalating glucocorticoid regardless of weight, blood pressure, growth, glucose or bone harm.
02
Do not omit mineralocorticoid review because an adult has tolerated a stable dose for years; renal, dietary, pregnancy and climate factors change balance.
03
Do not reassure a vomiting steroid-dependent patient after one repeated oral dose when absorption is failing; use emergency injection and hospital care.
04
Do not diagnose non-classic CAH from a random borderline 17-hydroxyprogesterone without timed sampling and specialist confirmatory testing.
05
Do not assume a testicular lesion is definitely an adrenal rest or definitely cancer; imaging pattern and urological-endocrine review are required.
06
Do not allow transition, pregnancy or surgery to proceed without named responsibility for daily replacement, stress cover and emergency access.