Cushing's disease

Cushing’s disease (also known as Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease)^[1][2] is a cause of Cushing’s syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing’s syndrome,^[3] when excluding Cushing’s syndrome from exogenously administered corticosteroids.

This should not be confused with ectopic Cushing syndrome or exogenous steroid use.^[4]

Cushing’s disease (also known as Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease)^[1][2] is a cause of Cushing’s syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing’s syndrome,^[3] when excluding Cushing’s syndrome from exogenously administered corticosteroids.

This should not be confused with ectopic Cushing syndrome or exogenous steroid use.^[4]

In 1924, the Soviet neurologist Nikolai Mikhailovich Itsenko reported two patients with pituitary adenoma. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of cortisol by the adrenal glands. The disease associated with this increased secretion of cortisol was described by Harvey Cushing in 1932, after Cushing was presented with a unique case of the disease^[5] In 1910, the American neurosurgeon Harvey Cushing (1869-1939) was presented with a case of a 23-year-old woman called Minnie G.. Minnie’s symptoms included painful obesity, amenorrhea, hypertrichosis (abnormal hair growth), underdevelopment of secondary sexual characteristics, hydrocephalus and cerebral tension.^[3] This combination of symptoms was not yet described by any medical disorder at the time.^[3] However, Cushing was confident that Minnie’s symptoms were due to dysfunction of the pituitary gland, and resembled those associated with an adrenal tumor. Given this conviction, and his knowledge of the three anterior pituitary cell types, Cushing hypothesized that if acidophil hyperpituitarism (excess secretion from the acidophil cells) caused acromegaly, then an excess of basophil cells must be involved in another pituitary disorder that involves sexual dysfunction (amenorrhea in females and erectile dysfunction in males) and could explain Minnie’s symptoms.^[3] Experimental evidence and case reports by Cushing led to his publication in 1932 on pituitary basophilism as the cause of Cushing’s disease. In this publication, the clinical symptoms of the disease, named after Harvey Cushing, were described.^[6][7] Out of the 12 cases with hypercortisolism described in Cushing’s monograph on the pituitary body, 67% died within a few years after symptom presentation, whereas Minnie G. survived for more than 40 years after symptom presentation, despite the fact that she did not receive any treatments for a pituitary tumor.^[3] The prolonged survival led to the uniqueness of Minnie’s case. The reason behind this survival remains a mystery, since an autopsy of Minnie was refused after her death.^[3] However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the basophil adenoma Minnie might have harbored underwent partial infarction, leading to symptom regression.^[3] The other hypothesis was that Minnie might have suffered from Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing’s syndrome (Carney complex) can infrequently cause spontaneous symptom regression of the latter.^[3]

Cushing’s disease (also known as Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease)^[1][2] is a cause of Cushing’s syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing’s syndrome,^[3] when excluding Cushing’s syndrome from exogenously administered corticosteroids. This should not be confused with ectopic Cushing syndrome or exogenous steroid use.^[4]

Cases of Cushing’s disease are rare, and few epidemiological data is available on the disease. An 18 year study conducted on the population of Vizcaya, Spain reported a 0.004% prevalence of Cushing’s disease.^[5] The average incidence of newly diagnosed cases was 2.4 cases per million inhabitants per year. The disease is often diagnosed 3–6 years after the onset of illness.^[5] Several studies have shown that Cushing’s disease is more prevalent in women than men at a ratio of 3-6:1, respectively.^[6][7] Moreover, most women affected were between the ages of 50 and 60 years. The prevalence of hypertension, and abnormalities in glucose metabolism are major predictors of mortality and morbidity in untreated cases of the disease.^[5] The mortality rate of Cushing’s disease was reported to be 10-11%,^[5][8] with the majority of deaths due to vascular disease ^[9][5] Women aged 45–70 years have a significantly higher mortality rate than men.^[5] Moreover, the disease shows a progressive increase with time. Reasons for the trend are unknown, but better diagnostic tools, and a higher incidence rate are two possible explanations.^[5]

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