What is adrenal insufficiency?

Adrenal insufficiency occurs when the adrenal gland fails to provide adequate levels of the stress hormone cortisol.  This may occur through failure of the adrenal gland itself (primary adrenal failure commonly called Addison’s disease) or failure of the pituitary gland to stimulate normal cortisol levels from the adrenal gland (secondary adrenal insufficiency).  In addition, adrenal insufficiency may occur in patients treated with steroids, which suppresses cortisol secretion and results in a temporary and occasionally permanent adrenal insufficiency, called tertiary adrenal insufficiency.  

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 androgen is testosterone.  The pituitary gland stimulates the release of cortisol but doesn’t affect the release of the other adrenal hormones.  Thus, in secondary adrenal insufficiency due to a pituitary failure, there is only loss of the hormone cortisol where as in primary adrenal insufficiency there may be a deficiency of cortisol, aldosterone and testosterone.  

What causes adrenal insufficiency?

Secondary adrenal insufficiency due to pituitary failure may occasionally be congenital (inherited) and present at birth but more commonly presents in childhood or adult life through damage due to usually a benign pituitary tumour.  Primary adrenal insufficiency may also be congenital, as in congenital adrenal hyperplasia, but is most commonly acquired occasionally in childhood but usually in adult life.  Primary adrenal insufficiency was originally reported by Addison. He described failure of the adrenal glands due to tuberculosis. Nowadays primary adrenal insufficiency acquired during life is usually autoimmune in nature.

What are the signs and symptoms of adrenal insufficiency?

The onset of adrenal insufficiency is often slow and the signs and symptoms can be nonspecific.  Fatigue, weight loss, and aches and pains are common signs of adrenal insufficiency. Primary adrenal insufficiency was originally reported by Addison. He described failure of the adrenal glands due to tuberculosis. Most commonly, patients present with an adrenal crisis when they have a stress, such as an infection, which precipitates a crisis because of adrenal insufficiency.  The diagnosis is then made on the basis of the history and also blood tests, which may show low salt levels and deficient cortisol. In patients with primary adrenal insufficiency the pituitary reacts to try and stimulate the adrenal gland by releasing the hormone ACTH to stimulate the adrenal.  ACTH increases pigmentation in the skin as well as stimulating the adrenal. Thus, patients with primary adrenal insufficiency may also present with increased pigmentation and is commonly seen on pressure points such as the elbows and knuckles as well as the gums and creases in the hands.

How common is adrenal insufficiency?

Primary adrenal insufficiency or Addison’s disease occurs in approximately 1 in 10,000 to 1 in 15,000 people and is more commonly found in women as autoimmunity is more common in women.  Secondary adrenal insufficiency due to pituitary failure is twice as common as Addison’s disease and can affect both sexes equally.

How is adrenal insufficiency treated?

The treatment of adrenal insufficiency involves the replacement of the stress hormone cortisol usually with hydrocortisone tablets taken 2 to 3 times daily.  In some patients longer acting steroids such as prednisolone and dexamethasone are used.  In patients with primary adrenal insufficiency if there is loss of the hormone aldosterone this is replaced with fludrocortisone tablets usually taken once daily but maybe taken twice daily.  Treatment is usually life-long once the diagnosis has been made.  Importantly patients need to be aware if they are unwell or stressed they need to increased their steroid dose and if they are vomiting to take intramuscular injections of hydrocortisones.  This is described usually as “the sick day rules”.  

What are the limitations for current treatment of adrenal insufficiency?

When properly monitored and controlled there are usually no side effects of treatment, however many patients with adrenal insufficiency complain of fatigue and lack of energy.  This may be due to a failure of current hydrocortisone treatment to replace the normal cortisol rhythm.  In healthy individuals cortisol levels rise from around 3am in the morning and peak shortly after waking.  They gradually decline over the day to low levels to about 7pm in the evening through to 3 am in morning.  It is thought that the rise in cortisol levels in the early morning prepare you for the day and it is known that the loss of the circadian rhythm of cortisol is associated with fatigue, depression and metabolic abnormalities.  

What is the Diurnal approach to treating Adrenal Insufficiency?

Diurnal’s approach to the treatment of AI 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.