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Treatment of Addison’s disease

In patients with Addison’s disease the adrenals have been destroyed, most commonly by an autoimmune reaction. The treatment of Addison’s disease is to replenish the hormones that the adrenal cortex normally produces; these are mineralocorticoids and glucocorticoids, given as tablets. Furthermore, the adrenal cortex normally secretes adrenal androgens, or more precisely steroids that can be converted to androgens elsewhere in the body. Particularly women with Addison’s disease have low levels of androgens, and some may benefit from replacement therapy with dehydroepiandrosterone (DHEA). Provided optimal replacement therapy most patient lead normal lives, with normal life expectancy.

Mineralocorticoid replacement

Aldosterone, the main mineralocorticoid, plays a key role in the water and electrolyte balance. Without aldosterone the body loses sodium (NaCl, table salt) and water, and the blood pressure drops. Hence, the symptoms of mineralocorticoid deficiency are salt craving and dizziness/lightheadedness when rising from the lying or sitting to erect position.

In clinical practice fludrocortisone (Florinef ®) is used for mineralocorticoid replacement. When the intake and loss of electrolytes is normal, the daily dose of fludro cortisone is typically 0.05 – 0.20 mg, taken in the morning. In warmer climate, it may be necessary to increase the dose to compensate for the increased salt and water loss.

Patients with Addison’s disease who develop high blood pressure should be reassessed to make sure their mineralcocorticoid dose is not too high. If there is no sign of over-replacement the patient should receive conventional antihypertensive therapy and continue with fludrocortisone.

Glucocorticoid replacement

The glucocorticoids have numerous physiological effects; the most important are regulation of energy metabolism, bone metabolism, and modulation of the immune system, as well as neuropsychological effects. Cortisol levels vary with time of the day; the levels are highest at awakening and lowest at bedtime.

The conventional glucocorticoid replacement doses have been hydrocortisone (i.e. cortisol) 20 mg + 10 mg or cortisone acetate 25 mg + 12,5; the latter drug is converted into cortisol with loss of about 1/5 of the dose. Such dosages are higher than the amount of cortisol that the adrenals normally produce, and the treatment does not restore the normal cortisol biorhythm. Recent recommendations are 10 mg hydrocortisone on awakening, 5 mg at lunchtime and 5 mg in the early evening (or 12,5 mg + 6.25 + 6.25 mg cortisone acetate). Some patients prefer twice daily treatment and find it difficult to remember the lunch time dose; others prefer to divide the daily dose into four portions, which mimic more closely the normal biorhythm.

Some experts oppose the use of cortisone acetate, since this is a pro-drug that has to be converted to the active hormone (cortisol) in the body, but this has not been demonstrated as a clinical problem. Others prescribe synthetic glucocorticoids such as prednisolone or dexamethasone in adrenal failure, which give a stable glucocorticoid effect throughout the day and night. In our experience, these drugs frequently give side-effects (i.e. cushingoid side effects such as overweight), and the surveillance of the therapy is even more difficult than for cortisone acetate and hydrocortisone.

Recently, new strategies for physiological glucocorticoid replacement have been suggested, such as modified-release hydrocortisone tablets and continuous subcutaneous hydrocortisone infusion (CSHI), and these treatments may become clinical routine in the future.

The means for assessing the glucocorticoid replacement therapy is crude and difficult to apply to the individual patient. Essentially, the physician relies on clinical signs of low cortisol levels (fatigue, abdominal or muscular pain, weight loss, hyperpigmentation) and high cortisol levels (weight gain, muscle weakness, psychiatric symptoms) for assessment of the dose.

Androgen replacement

The adrenal glands normally secrete high amounts of DHEA, which is converted to the sex steroids in other organs or tissues. A daily dose of 25-50 mg DHEA or less is usually sufficient to restore normal levels of DHEA, DHEA(S), androstenedione and testosterone in patients with Addison’s disease, but controlled trails have failed to show that such treatment significantly improves wellbeing.

Replacement in acute adrenal failure

A common advice is to increase the dose two to three-fold during minor illnesses, tapering down to normal dose over two to three days when the illness subsides. The thumb rule is to double the dose in fever above 38.5 ° C, and to triple the dose when the temperature exceeds 39.5 ° C. In severe illness and when the uptake of tablets is reduced (i.e. vomiting and diarrhoea), glucocorticoids should be administered intravenously, either in frequent boluses or as continuous infusion, depending on the severity of the illness. Do not delay contact with your physician, as many patients do require hospitalisation.

It is of utmost importance patients be equipped with a medical alert card that give instruction about treatment of adrenal crises and an emergency kit including hydrocortisone for intramuscular administration. Furthermore, it is advisable that they are offered vaccination against influenza and pneumococcal infection, as well as travel vaccinations. However, neither of these recommendations is based on strict evidence, and the requirements are likely to vary between individuals and type of infection.

Possibly, slightly increased dosage may be beneficial during psychological strain and strenuous physical activity, since cortisol normally increases in these situations. Patients commonly self-medicate in stressful situations, indicating subjective benefit of glucocorticoids. However, short-term glucocorticoid excess is well known to boost wellbeing, and such use is usually not recommended of fear of over-dosage.

Pregnancy and labour

It is generally recommended to continue with unchanged doses of glucocorticoids throughout the pregnancy, and give hydrocortisone intravenously during labour. Since lower glucocorticoid replacement dose is now recommended in adrenal insufficiency, the risk of under-replacement during pregnancy requires special attention. Symptoms of adrenal insufficiency such as nausea, vomiting, dizziness and hyperpigmentation may easily be misinterpreted as common symptoms of pregnancy, rendering the assessment of the replacement therapy difficult.

The fludrocortisone doses often need to be increased in the course of the pregnancy. The fludrocortisone dosage can be guided by evaluation of blood pressure, oedema and serum electrolytes. Androgen replacement in pregnancy is not likely to be hazardous, but has not been studied and cannot be recommended.