Cushing's syndrome: from physiological principles to diagnosis and clinical care

Abstract

The physiological control of cortisol synthesis in the adrenal cortex involves stimulation of adrenocorticotrophic hormone (ACTH) by hypothalamic corticotrophin-releasing hormone (CRH) and then stimulation of the adrenal by ACTH. The control loop of the hypothalamic-pituitary-adrenal (HPA) axis is closed by negative feedback of cortisol on the hypothalamus and pituitary. Understanding this system is required to master the diagnosis, differential diagnosis and treatment of endogenous hypercortisolism -Cushing's syndrome. Endogenous Cushing's syndrome is caused either by excess ACTH secretion or by autonomous cortisol release from the adrenal cortex. Diagnosis of cortisol excess exploits three physiological principles: failure to achieve the normal nadir in the cortisol diurnal rhythm, loss of sensitivity of ACTH-secreting tumours to cortisol negative feedback, and increased excretion of free cortisol in the urine. Differentiating a pituitary source of excess ACTH (Cushing's disease) from an ectopic source is accomplished by imaging the pituitary and sampling for ACTH in the venous drainage of the pituitary. With surgical removal of ACTH or cortisol-secreting tumours, secondary adrenal insufficiency ensues because of the prior suppression of the HPA axis by glucocorticoid negative feedback. Medical therapy is targeted to the anatomical location of the dysregulated component of the HPA axis. Future research will focus on new diagnostics and treatments of Cushing's syndrome. These are elegant examples of translational research: understanding basic physiology informs the development of new approaches to diagnosis and treatment. Appreciating pathophysiology generates new areas for inquiry of basic physiological and biochemical mechanisms.

Secondary Hypertension: Differential Diagnosis and Basic Principles of Treatment

“…Cushing's syndrome is characterized by many symptoms and signs, which have been caused by increased concentrations of cortisol in the body tissue (purple stretch marks, plethoric appearance of the face, weakness of the proximal muscles, spontaneous bruising, unexplained osteoporosis, hypertension) (32)(33)(34)(35). Depending on the aetiology, Cushing's syndrome can be distinguished into several types: one dependent of the adrenocorticotropic hormone (ACTH) (pituitary adenoma that secretes ACTH (Cushing's disease)) and the syndrome of ectopic secretion of ACTH (neuroendocrine tumours (bronchial carcinoids)), and Cushing's syndrome independent of ACTH (adenoma or cancer of the adrenal gland, adrenal hyperplasia) (32)(33)(34)(35).…”

“…Depending on the aetiology, Cushing's syndrome can be distinguished into several types: one dependent of the adrenocorticotropic hormone (ACTH) (pituitary adenoma that secretes ACTH (Cushing's disease)) and the syndrome of ectopic secretion of ACTH (neuroendocrine tumours (bronchial carcinoids)), and Cushing's syndrome independent of ACTH (adenoma or cancer of the adrenal gland, adrenal hyperplasia) (32)(33)(34)(35). The prevalence of Cushing's syndrome in patients with hypertension is 0.5-1.0%.…”

“…The prevalence of Cushing's syndrome in patients with hypertension is 0.5-1.0%. The mechanisms for hypertension in patients with Cushing's syndrome are multiple and include the following: mineralocorticosteroid activity of cortisol, activation of the renin-angiotensin-aldosterone system, increased reactivity to the vasoconstrictor effect (angiotensin 2, catecholamines, vasopressin), and reduced activity of the vasodilatory system (NO synthase, prostacyclin, kallikrein-kinin system) (32)(33)(34)(35).…”

“…Treatment for the iatrogenic Cushing's syndrome and medicines that affect the metabolism of dexamethasone and cortisol (phenytoin, phenobarbital, carbamazepine, rifampin, pioglitazone, diltiazem and cimetidine, fenofibrate, synthetic glucocorticoids) should be discontinued before the screening test (33)(34)(35).…”

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

“…Of course, this biologic phenomenon contributes to the death of the salmon and probably should not be characterized as 'piscine pseudoCushing's syndrome'. In humans, chronic or intermittent increases in hypothalamic-pituitary-adrenal (HPA) axis activity has been observed in many medical disorders associated with psychological, inflammatory, chemical and physical stressors (10,11,12). Laboratory findings in these patients can overlap with states of pathologic hypercortisolism and cause significant diagnostic confusion.…”