Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia can present in childhood, adolescence or adulthood. CAH is an autosomal recessive genetic condition, the most common form being due to 21 hydroxylase deficiency. The diagnosis is confirmed biochemically with elevated 17 hydroxyprogesterone (17OHP) and androgens.

Neonatal patients 

Gender assignation

In girls who present with ambiguous genitalia there may be a delay in assignment of gender at birth while urgent assessment of karyotype, anatomy and biochemistry is made. 

A multidisciplinary team (including a paediatric endocrinologist, gynaecologist or urologist, a geneticist and a counsellor or psychologist) should be involved in the assessment of these children and to provide information and support for the parents.

Genital surgery may also be required although there are possible advantages to delaying this to an older age, this needs to be carefully discussed between the parents and the multidisciplinary team.

Salt loosing crises  

Boys and girls not diagnosed at birth may present with a salt wasting crisis within the first three weeks of life. These infants require immediate resuscitation with parenteral glucocorticoid replacement, intravenous fluids and correction of hyooglycaemia as for any hypoadrenal crisis.

This should be followed by enteral circadian glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) therapy. Weight based dosing is recommended for paediatric patients - as for Addison's disease

Glucocorticoid and mineralocorticoid replacement therapy

Emergency treatment should be followed by enteral circadian glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) therapy.

Weight based dosing is recommended for paediatric patients - as for Addison's disease

Paediatric patients

Glucocorticoid and mineralocorticoid replacement therapy 

Management should by a paediatric endocrinologist. Emergency treatment should be followed by enteral circadian glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) therapy.

Weight based dosing is recommended for paediatric patients, with hydrocortisone and fludrocortisone doses then optimised to maintain biochemical control, normal growth and appropriately timed puberty and prevention of adrenal crises. 

Regular clinical monitoring  

Children with CAH require regular monitoring for concordance with medication, symptoms of dizziness, and signs of low blood pressure may indicate subootimal replacement.

Assessment of bone age as well at plotting height and weight is useful, as accelerated bone age may be a clue to under treatment or poor compliance.

Changes in growth velocity and pubertal development are also useful indicators of control.

If precocious puberty is suspected, additional investigations may be required to confirm this (LH, FSH, estradiol or testosterone, LHRH test, US of uterus in girls).

Regular biochemical monitoring

Monitoring of  urea and electrolytes are required on a regular basis.

Monitor 17OHP, androstenedione, testosterone and renin levels to ensure that doses of hydrocortisone and fludrocortisone are adequate as children grow.

Precocious puberty

If gonadoptrophin dependent precocious puberty is diagnosed, consider starting GnRH analogues to suppress this to an appropriate time, and to maximise growth potential.

Adolescence

Regular clinical monitoring  

Management should by a paediatric endocrinologist and in mid to late adolescence joint with an adult endocrinologist.

Hydrocortisone and fludrocortisone doses should be optimised to maintain biochemical control, if it is felt that biochemical control would be improved by longer acting glucocorticoids this should be considered in late adolescence after the completion of growth. The focus should be towards normal progression of puberty, menarche, menstrual cycle and reduction of the development of TARTS and prevention of adrenal crises.

Children and adolescents with CAH require regular monitoring for concordance with medication, symptoms of dizziness, and signs of low blood pressure may indicate suboptimal replacement. 

Assessment of bone age as well at plotting height and weight is useful, as accelerated nine age may be a clue to under treatment or poor compliance. Changes in growth velocity and pubertal development are also useful indicators of control.

Regular biochemical monitoring

Monitoring of urea and electrolytes is required on a regular basis.

Monitor 17OHP, androstenedione, testosterone and renin levels to ensure that doses of hydrocortisone and fludrocortisone are adequate and concordance is still satisfactory as the patient assumes responsibility for their own medications.

Delayed or absent puberty  

If puberty and/or menarche/menstrual cycle is affected additional investigations may be required (LH, FSH, estradiol or testosterone, US of uterus in girls). 

Suppressed LH and FSH levels suggest that androgen production secondary to poorly controlled CAH may be affecting gonadotrophin production interfering with puberty.

Arrange gynaecological assessment
   

Girls who have had previous surgery should have an examination by a gynaecologist to review the need for further surgery or vaginal dilatation, this should occur in late adolescence.

Assess boys for testicular rest tissue. Boys particularly those with poor biochemical control should be considered for testicular ultrasound to examine for TARTS.

Cardiovascular risk assessment

In patients with elevated BMI general screening for diabetes and dyslipidaemia should be recommended.

Adult patients with CAH with glucocorticoid and mineralocorticoid deficiency

Continue circadian glucocorticoid and mineralocorticoid replacement therapy

Management should by an adult endocrinologist. Hydrocortisone and fludrocortisone doses should be optimised to maintain biochemical control, if it is felt that biochemical control would be improved by longer acting glucocorticoids this should be considered.

The focus should be towards maintaining sexual health and fertility and cardiovascular health and prevention of adrenal crises.

Monitor for signs of glucocorticoid/mineralocorticoid excess or deficiency, including BMI, stretch marks,  bruising, and elevated  blood pressure.

Typical adult dosing would be with hydrocortisone 10-15mg on waking, 5mg 5 hours after rising, and 5mg at 9 hours after rising. Doses should be adjusted down to the minimal that controls symptoms and virilisation to minimise adverse metabolic and body composition effects.

Typical mineralocorticoid replacement would be with fludrocortisone 100mg on waking though the dose should be adjusted and may be given in divided doses to achieve optimum control of blood pressure, with normal urea and eledtrolytes and renin.

Cardiovascular risk assessment  

In patients requiring life-long glucocorticoid replacement therapy, screening for diabetes and dyslipidaemia should be recommended.

Women with virilisation  

Women with ongoing or poorly controlled virilisation may require larger doses of glucocorticoids to suppress their hypothalamo-pituitary-adrenal axis to reduce adrenal androgen production.

This may be achieved by switching to a more potent agent such as prednisolone or dexamethasone (typical doses would be 7.5mg and 0.75mg respectively total daily dose) and or switching to reverse circadian replacement therapy e.g. 5mg prednisolone on retiring with 2.5mg on waking.

Conventional treatments for acne and hirsuitism may also be used as below for simple virilising CAH (as for PCOS management).

Adults seeking fertility

If female patients have oligomenorrhoea or amenorrhoea despite optimising biochemical control of CAH referral to a fertility expert may be necessary.Increased doses of glucocorticoids may be indicated to restore ovulation and suppress progesterone in patients who have failed to conceive on standard replacement therapy.

If male patients have reduced sperm count testicular ultrasound should be perfomed to examine for TARTS. Genotyping of partners is recommended to identify whether future babies are at risk of CAH and consideration whether the mother requires glucocorticoids that pass the placenta during the pregnancy (that is a switch to dexamethasone during pregnancy) to prevent potential  virilsation of female foetuses.

Possible simple virilising or non classic CAH (now known as CAH with intact glucocorticoid and mineralocorticoid reserve)

Polycystic ovarian syndrome, idiopathic hirsuitism, hirsuitism and hyperandrogenism, Cushing’s syndrome, virilising tumours, prolactinoma, thyroid dysfunction or the HAIRAN syndrome may all present with similar features to CAH in adult women. 

If the clinical picture is consistent with PCOS but the testosterone is elevated, the simplest way to exclude a virilising tumour is to perform a low dose dexamethasone suppression test. If there is a strong suspicion of CAH, and the patient is seeking fertility, a 17OH progesterone should be performed with a synacthen test if the result is elevated, though this is not mandatory in all patients with hirsuitism.

Confirmed CAH with intact glucocorticoid and mineralocorticoid reserve (previously known as simple virilising CAH)

Similarities with PCOS

These patients can often be treated in the same way as women with PCOS with treatment tailored to the individual's primary complaint e.g. with a combined oral contraceptive pill and or anti-androgens. These patients do not typically experience fertility problems.

For patients with severe or unresponsive virilisation, or with fertility problems, reverse circadian glucocorticoid therapy as for classic CAH above, can be used. However, this puts this otherwise low risk group of patients at risk of hypoadrenal crises, as well as the long-term adverse effects of long-term glucocorticoid therapy.

Weight  

Diet and lifestyle advice are essential for all patients presenting with a clinical picture indistinguishable from  PCOS.

Management of other cardiovascular risk factors should also be undertaken when indicated.

Suggest patient support groups, for example Verity.

Consider metformin with slow dose titration, to minimise gastrointestinal side effects, or controlled release metformin if this is poorly tolerated.

Consider further management of obesity, for example with orlistat if indicated.

Acne  

Diet and lifestyle advice are essential for all patients presenting with a clinical picture indistinguishable from  PCOS.

A combined oral contraceptive pill should be considered as any will reduce free androgen levels. For severe androgenic acne, a combined pill containing the anti-androgen cyproterone such as cocyprindiol is more effective.

Where acne is the primary clinical concern, non hormonal measures may be more appropriate, for example antibiotics or retinoic acid, and so specialist dermatology advice should be sought.

Hirsuitism

Diet and lifestyle advice are essential for all patients presenting with a clinical picture indistinguishable from  PCOS.

Warn patients that all treatments for hirsuitism tend to take at least six months and none are 100% effective.

Topical eflornithine or other topical measures may be considered first line, and are usually given in addition to metformin given for other indications.

A combined oral contraceptive pill (COCP) should also be considered and for severe hirsuitism, one containing an anti-androgen is most effective such as cocyprindiol or dianette. An anti-androgen, for example spironolactone (dose titrate from 25 to 200mg), may be added to the COCP if no effects have been observed after at least six months. Cyproterone acetate has also been widely used although this is not licenced and requires close monitoring of liver function. Finasteride is another alternative anti-androgen for exceptional use only.

Where the COCP is contraindicated - for example in patients over 35 years, smokers, those with a history of thromboembolism, or is not tolerated with mood disturbance - anti-androgens may still be prescribed in the presence of robust contraception.

If hirstuitism is severe, for example requiring daily shaving, and there has been no response to topical and medical therapies, consider pulsed light therapy or laser hair removal.

If the hirsuitism has not responded to these conventional treatments, and in particular if the patient has another indication eg seeking fertility, reverse circadian glucocorticoid (typically prednisolone 5mg on retiring, 2.5mg on waking) is effective. However due to the potential adverse effects of glucocorticoids, in particular the weight gain and the need for robust patient education, this is not generally recommended as first line therapy.

Oligomenorrhoea

Diet and lifestyle advice are essential for all patients presenting with a clinical picture indistinguishable from  PCOS.

Metformin should also be considered to improve menstrual regularity.

The COCP will almost always restore regular withdrawal bleeds, and is generally well tolerated. Where this is contra-indicated, or not well tolerated, consider intermittent progesterone (norethisterone acetate 5mg tds 5/7) to induce endometrial shedding every three months in amenorrhoeic patients.

If menses have not been restored by these conventional treatments, and in particular if the patient is seeking fertility, reverse circadian glucocorticoid (typically prednisolone 5mg on retiring, 2.5mg on waking) is effective. However due to the potential adverse effects of glucocorticoids, in particular the weight gain and the need for robust patient education, this is not generally recommended as first line therapy.

Fertility

Diet and lifestyle advice are essential for all patients presenting with a clinical picture indistinguishable from  PCOS.

Many patients with simple virilising CAH will have normal fertility and so require no specific treatment.

If the patient has been seeking fertility for more than a year, if they are oligomenorrhoeic, or if they are confirmed as having anovulatory cycles, reverse circadian glucocorticoid (typically prednisolone 5mg on retiring, 2.5mg on waking) is effective at restoring regular ovulation.

Patients should also be referred for genetic counselling and to consider testing of their partner.

Patients should also be reviewed in a formal fertility clinic for fertility and preconception counselling, and to investigate both partners for other causes.

Genetic counselling

All affected families should be offered genetic counselling and screening where appropriate. This should be offered again at transition to adult services, and again when before a patient chooses to start a family to arrange prenatal counselling and partner testing.

Patient education

All patients with CAH treated with glucocorticoids are at risk of adrenal crises if they miss doses or become unwell.

Careful counselling is required about sick day rules and carrying identification that states they are taking glucocorticoids. The Addison's Society has produced excellent materials to assist this.

Adrenal crises

As with any condition where the patient is dependent on glucocorticoids, all patients are at risk of adrenal crises if they miss doses of glucocorticoids or become unwell.

Immediate treatment is the same for any hypo-adrenal crisis with 100mg intramuscular hydrocortisone which patients and their families should be taught to administer at home.

Careful counselling is required about sick day rules and carrying identification that states they are taking glucocorticoids.

Glucocorticoid replacement therapy

The mainstay of management is replacing glucocorticoid and mineralocorticoid deficiency.

Glucocorticoid doses should adequately control elevated androgen levels (testosterone) while trying to prevent the consequences of glucocorticoid excess. Complete suprression of 17OHP and androstenedione is no longer considered worthwhile in most cases (except when seeking fertility), as this probably reflects over treatment and us likely to lead to adverse glucocorticoid effects.

In neonates, children and adolescents hydrocortisone is used as other glucocorticoids have been associated with poor growth. In late adolescence and adulthood, these may be insufficient to control virilisation and longer acting glucocorticoids such as prednisolone and dexamethasone could be considered.

Mineralocorticoid replacement  

The mainstay of management is replacing glucocorticoid and mineralocorticoid deficiency.

Fludrocortisone doses should maintain normal electrolytes and blood pressure and the renin level should be within the normal range.