Congenital Adrenal Hyperplasia

What is congenital adrenal hyperplasia (CAH)?

Congenital adrenal hyperplasia (CAH) is the commonest inherited (congenital) endocrine (hormone) disorder caused by mutations in genes coding for enzymes in the adrenal gland that synthesis steroid hormones. Patients with CAH have adrenal insufficiency, that is a deficiency in the stress hormone cortisol. Their body’s response to this is to try and push the adrenal glands harder and they therefore enlarge in size (hyperplasia).

What does the adrenal gland do?

The body has two adrenal glands one sitting above each kidney. The adrenal gland consists of a central portion (the medulla) responsible for the release of adrenaline and the outside layer (the cortex) which is responsible for generating the steroid hormones. There are three classes of steroid hormones secreted by the adrenal cortex and they are: glucocorticoids, important for sugar metabolism, mineralocorticoids important for salt balance, and androgens which are male sex hormones. The main glucocorticoid secreted by the adrenal gland is the stress hormone cortisol, the main mineralocorticoid is aldosterone and the main androgen is testosterone.

What causes congenital adrenal hyperplasia?

CAH results from mutations in the genes that code for enzymes that make steroid hormones in the adrenal gland. The most common enzyme affected is 21- hydroxylase and this enzyme is essential for the generation of cortisol and aldosterone. Depending on the severity of the enzyme deficiency, patients with CAH may either have just a deficiency of cortisol or a combined deficiency of cortisol and aldosterone.

When there is deficiency in cortisol the brain recognises this and through a gland called the pituitary at the base of the brain releases a hormone called ACTH to try and stimulate the adrenal gland to produce cortisol. However, as there is an enzyme block pre-cursor hormones build up behind the block and these pre-cursor hormones are then converted into androgen such as testosterone. An analogy is that of a motorway, where the steroids driving down the motorway normally come off at junction 21 to produce cortisol, however there is a jam at junction 21 resulting in a build-up of steroid traffic which travels on down the motorway to the next junction and comes off as androgens like testosterone.

Thus, patients with CAH essentially have two problems; a deficiency of cortisol with or without aldosterone deficiency and an excess of adrenal androgens such as testosterone. The excess of male hormone such as testosterone leads to many of the problems experienced by patients with CAH such as virilisation of the female infant, early (precocious) puberty in both boys and girls and infertility problems in men and women.

Are there different forms of congenital adrenal hyperplasia?

Yes, depending on the severity of the enzyme defect in the adrenal there are different forms of congenital adrenal hyperplasia. In the commonest form of CAH 21 hydroxylase deficiency these are classified as follows:

Classic: this is when there is a severe enzyme defect resulting in cortisol deficiency usually presenting early in life. The classic form is sub categorised into salt – wasting and non- salt wasting depending on whether or not the enzyme defect is so severe as to result in a deficiency of the mineralocorticoid aldosterone. Patients who are not salt wasting are also known as simple virilising because they suffer from the excess androgens but not the deficiency in aldosterone.

Non- classic: is a milder form of enzyme defect where patients often don’t present until the time of puberty where they might have signs of excess androgen. It is often not diagnosed in men but maybe diagnosed in women presenting with problems such as facial hair and irregular periods.

Who does CAH affect and how common is it?
CAH is a recessive disorder meaning you inherit a mutation in the gene from both your mother and father and you need to have mutation in both genes to develop the disease. It occurs approximately in one in every 12,000 live births and affects boys and girls equally. Approximately 7 in 10 affected patients have classic salt wasting CAH.

What are the signs and symptoms of CAH?

Classic CAH usually present’s at birth or shortly after birth. Female infants exposed in utero (the womb) to excess male hormones have masculinisation (virilisation) of their external genitalia which may give some ambiguity as to the diagnosis of gender. Therefore, female infants may be diagnosed at birth.

Both boys and girls with classic salt - wasting CAH may present within the first few days of birth with an adrenal salt wasting crisis. In many countries now there is neonatal screening that will pick up the diagnosis within the first few days of birth if the baby has not already presented. 

In the classic simple virilising form of CAH, which is not picked up on neonatal screening, patients may present within the first couple of years of life with pseudo-precocious puberty, the young child showing excessive growth and development of pubic and axillary hair. Girls with late onset congenital adrenal hyperplasia tend to present around the time of puberty with evidence of virilisation such as hair in a male pattern distribution on the body and irregular periods.

The problems patients with CAH face depends on their age. In childhood the main challenge is controlling excessive growth and precocious puberty and if this is not well controlled then patients will have an early puberty and ultimately short stature. During early adult life both men and women may have problems with infertility if the excess androgens are not controlled. Throughout life patients with CAH are prone to adrenal crisis due to their cortisol deficiency.

What current treatments are available for CAH?

The aim of treatment in CAH is to replace the deficient steroid hormone cortisol and to normalise the excessive androgen secretion. This is achieved by replacing the steroid hormone cortisol with hydrocortisone which is the pharmacological name for cortisol. In children hydrocortisone is almost always the treatment of choice for replacing cortisol, however, in adults longer acting and more potent glucocorticoid hormones are used such as prednisolone and dexamethasone. Hydrocortisone is usually given three times daily, sometimes with a dose last thing at night and some patients may take it twice daily and some even four times daily. Prednisolone is usually given twice daily and dexamethasone used as a last thing at night treatment. Patients deficient in aldosterone are also required to take replacement with fludrocortisone to achieve normal salt balance.

What are the side effects of treatment?

The major challenge in the treatment of CAH is balancing between giving too little and too much steroid hormone replacement. Too little steroid hormone replacement results in high androgen levels with all its complications in addition to which patients have the symptoms of adrenal insufficiency such as fatigue and a risk of adrenal crisis. Too much steroid hormone results in suppression of growth in children, weight gain, abdominal obesity, hypertension, thin skin, and later in life the risk of cardiovascular disease and osteoporosis. High doses of steroid are needed at times of stress for example when patients have infections but long term excessive steroid exposure results in the above complications.

What are the limitations for current treatment of CAH?

 In healthy individuals the cortisol levels show a distinct circadian (around the day) rhythm. Cortisol levels start to rise from around 3am in the morning and peak shortly after waking. They gradually decline over the day to low levels from about 7pm in the evening through to 3am in the morning. This pattern of cortisol secretion is important for health with the rise in the early morning cortisol preparing you for the day.

Loss of the circadian rhythm of cortisol is associated with fatigue, depression and metabolic abnormalities. The challenge in treatment of CAH is that no currently available formulation can replace the normal circadian rhythm of cortisol. Hydrocortisone has a short half-life in the blood such that it is cleared quickly from the body. Currently patients with CAH usually wake with low cortisol and have to take a hydrocortisone tablet on waking to rapidly build up their cortisol levels. They then have to take medication usually three times a day to maintain the cortisol levels. Despite this, and even when they take medication last thing at night, cortisol levels are low on waking.

In CAH this results in a build-up of androgens before the morning dose and androgens are rarely fully controlled throughout the 24 hours. Attempts to control the overnight release of androgens include giving longer acting steroids such as prednisolone and dexamethasone last thing at night. The difficulty with these regimens is they require giving a steroid at a time when cortisol levels are normally low and there is a risk of over treating patients with steroids and some patients find it difficult to sleep when they take steroids last thing at night.

What is the Diurnal approach to treating CAH?

Diurnal’s approach to the treatment of CAH is to generate a formulation of hydrocortisone designed to mimic the body’s diurnal rhythm. This formulation would allow administration last thing at night, but not release hydrocortisone until 2 or 3am in the morning. It would then allow gradual absorption of hydrocortisone such that cortisol levels build up to peak on waking. A second dose in the morning could then provide the daytime levels steroid needed for normal functioning.

Further support for people affected by CAH

CAH LogoThe CAH Support Group, Living with CAH exists to provide support to people and families affected by CAH, as well as to increase awareness of the condition to the public and medical profession.

Visit the Living with CAH website for further information and to view their short 3-minute explanatory animation of CAH.