Hypertension in Cushing’s Syndrome: From Pathogenesis to Treatment

Abstract

Hypertension is one of the most distinguishing features of endogenous Cushing’s syndrome (CS), as it is present in about 80% of adult patients whereas in children its prevalence is about 47%. Hypertension in CS is significantly correlated with the duration of hypercortisolism and results from the interplay between several pathophysiological mechanisms regulating plasma volume, peripheral vascular resistance and cardiac output, all of which are increased in this state. Glucocorticoids cause hypertension through several mechanisms: their intrinsic mineralocorticoid activity; through activation of the renin-angiotensin system; by enhancement of vasoactive substances, and by causing suppression of the vasodilatory systems. In addition, glucocorticoids may exert some hypertensive effects on cardiovascular regulation through the CNS via both glucocorticoid and mineralocorticoid receptors. Hypertension in CS usually resolves with surgical removal of the tumor, but some patients require pharmacological antihypertensive treatment both pre- and postoperatively. Thiazides and furosemide should be avoided, while adrenergic blockade and calcium channel antagonists are usually ineffective. Mineralocorticoid receptor antagonists, Ang II blockers and ACE inhibitors are good anti-hypertensive options; PPAR-γ agonists may help in many aspects of the insulin resistance syndrome. The relatively selective glucocorticoid receptor antagonist Mifepristone (RU 486) could reduce blood pressure in patients with CS. Neuromodulatory agents such as the serotonin inhibitors cyproheptadine and ritanserin, valproid acid, dopamine agonists, somatostatin analogs may occasionally be effective, as well as drugs acting directly at the adrenal levels, such as Ketoconazole and aminoglutetimide or even opDDD. Treating hypertension in CS remains a difficult task and a big challenge, in order to decrease the morbidity and mortality associated with the disease.

Metabolic comorbidities in Cushing's syndrome

“…renovascular resistance; insulin resistance; and sleep apnoea (159,160). GCs can induce hepatic synthesis of angiotensinogen, increase angiotensin II receptor type 1 concentration in the brain and peripheral tissue and enhance both angiotensin II-stimulated inositol phosphate-3 production in vascular smooth muscle cells and its central actions (159,161).…”

“…CS patients have been shown to have a blunted vascular and renal response to pharmacological doses of atrial natriuretic peptide compared to normal controls and hypertensive subjects (165). Impaired production of vasodilators including prostaglandins, prostacyclins and compounds of the kallikrein-kinin system might also contribute to CS hypertension (160). Moreover, cortisol-induced hypertension is characterised by reduced activity of the nitric oxide pathway (166).…”

PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

“…The factors that are thought to contribute to the hypertensive effects of cortisol excess include the mineralocorticoid activity of cortisol, activation of the renin-angiotensin system, enhanced vasoconstriction and blunted vasodilatation (13,14). In rare cases, secretion of aldosterone is the main cause of hypertension and optional hypokalemia, and co-secretion of cortisol may play a minor role.…”

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).…”