Glucocorticoid Hypertension

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What are glucocorticoids?

The adrenal cortex secretes three major types of steroid hormones, each produced in one of three concentric cortical layers, also known as zones. Glucocorticoids are steroid hormones produced by the zona fasciculata of the adrenal cortex ( Fig. 9.1 ). Cortisol is the major glucocorticoid in humans, and it is a pivotal regulator for a wide variety of functions, such as metabolic homeostasis, immune responses, and hemodynamic stability. The physiological synthesis of cortisol is regulated by the pituitary adrenocorticotropic hormone (ACTH), and it follows a typical circadian pattern with the largest peak in early morning and nadir around midnight.

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What are mineralocorticoids?

The outermost zone of the adrenal cortex, zona glomerulosa, produces mineralocorticoids (see Fig. 9.1 ). Aldosterone is the prototype human mineralocorticoid and its main function is salt and water regulation. These effects are mediated primarily via mineralocorticoid receptors (MRs) located in the distal convoluted tubule and cortical collecting duct of the kidneys. MRs are also found in the colon, eccrine glands, and other tissues. In the kidneys, activating MR ligands promote the expression of epithelial sodium channels (ENaCs), which, in turn, facilitate sodium and water reabsorption with compensatory potassium and H ⁺ urinary excretion. Physiological aldosterone synthesis is regulated via the renin-angiotensin-aldosterone system, which is triggered by low renal perfusion and hyperkalemia. Excessive activation of the MRs leads to intravascular volume expansion and, subsequently, to hypertension with or without hypokalemia and metabolic alkalosis.

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How do glucocorticoids influence blood pressure?

The affinity of MRs for cortisol is similar to that for aldosterone. Although circulating concentrations of cortisol normally exceed those of aldosterone by roughly 1000 times, peripheral tissues inactivate cortisol to cortisone via the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2; see Fig. 9.1 ).

Activation of MRs by glucocorticoids occurs when these hormones circulate in excessive amounts due to either endogenous overproduction or pharmacologic administration. Such supraphysiological concentrations of glucocorticoids result in saturation of HSD11B2 and subsequent activation of MR by active glucocorticoids. Other mechanisms by which glucocorticoids contribute to hypertension include suppression of vasodilators, such as nitric oxide and prostaglandins; enhancing the effects of vasoconstrictors, including angiotensin II receptor; and alterations of the sensitivity of the sympathetic nervous system. In addition, patients with chronic glucocorticoid excess often develop central obesity and sleep apnea, which further contributes to hypertension. Indirectly, numerous endogenous and exogenous inhibitors of HSD11B2 facilitate MR activation by physiological cortisol levels, leading to hypertension. Causes of glucocorticoid-induced hypertension are listed in Box 9.1 .

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What is Cushing syndrome?

Cushing syndrome refers to a clinical phenotype associated with chronic glucocorticoid excess. This syndrome can be caused by either excessive cortisol synthesis or by exogenous glucocorticoids administered at supraphysiological doses. Endogenous Cushing Syndrome can be ACTH-dependent (either from a pituitary adenoma producing ACTH, or, rarely, from an ectopic ACTH or corticotropin-releasing hormone [CRH] source), or ACTH-independent (autonomous adrenal cortisol excess from a benign adenoma or a cortical carcinoma).

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Is Cushing syndrome common?

Although exogenous or iatrogenic Cushing Syndrome is relatively common, endogenous Cushing Syndrome is a rare disease with an incidence of 1 to 2 per million per year. Endogenous Cushing Syndrome is most commonly caused by an ACTH-producing pituitary adenoma, and this form is also known as Cushing disease.

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