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Hypertension affects approximately 20% of Americans (1). "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure defines hypertension as a blood pressure exceeding 139/89 mm Hg for adults aged 18 years or older based on the mean of 2 or more properly measured seated BP readings on each of 2 or more office visits. A new category designated prehypertension has been added to these guidelines. Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent cardivoascular disease. The prevalence of hypertension increases with age and most individuals with hypertension are diagnosed with primary (essential) hypertension. Hypertension is a major risk factor for stroke, ischemic heart disease, and cardiac failure. It is the second most common reason for office visits to physicians in the United States. Despite the increasing understanding of the pathophyisology of hypertension, control of the disease is often difficult and far from optimal. Idiopathic (primary or essential) hypertension accounts for approximately 85 % of the diagnosed cases. It is estimated that approximately 15 % of hypertensive patients have identifiable conditions that result in blood pressure elevation (secondary hypertension) such as primary renal disease, oral contraceptive use, sleep apnea syndrome, congenital or acquired cardiovascular disease (i.e. coarctation of the aorta) and excess hormonal secretion.

Endocrine Hypertension is a term assigned to states in which hormonal derangements result in clinically significant hypertension. The most common causes of endocrine hypertension are excess production of mineralocorticoids (i.e. primary hyperaldosteronism), catecholamines (pheochromocytoma), and glucocorticoids (Cushing's syndrome). One important question in this regard is when to screen for secondary causes. The clinician should carefully screen for other cardinal signs and symptoms of Cushing's syndrome, hyperthyroidism, acromegaly, or pheochromocytoma. Hypertension in young patients and refractory hypertension (characterized by the use of > 3 antihypertensive drugs) should alert the physician to pursue screening for secondary causes. The importance of endocrine mediated hypertension resides in the fact that in most cases, the cause is clear and can be traced to the actions of a hormone, often produced in excess by a tumor, i.e. removing an aldosteronoma in a patient with hypertension due to primary aldosteronism. More importantly, once the diagnosis is made, a disease-specific targeted antihypertensive therapy can be implemented, and in some cases, surgical intevention may result in complete cure, obviating the need of a life-long antihypertensive treatment.

Clinical Diagnosis of Endocrine Hypertension

The first step when evaluating a patient with suspected endocrine-related hypertension is to exclude other causes of secondary hypertension, particularly renal disorders. A detailed medical history should be obtained. The onset of hypertension and the response to previous anti-hypertensive treatment should be determined, not forgetting that most hypertensive patients have poor compliance. The extent of target organ damage (i.e. retinopahy, nephropathy, claudication, abdominal or carotid bruits) and the overall cardiovascular risk status should also be explored in detail.

As in other causes of hypertension, the clinician should question the patient about dietary habits, weight fluctuations, use of over the counter drugs and health supplements, recreational drugs, and oral contraceptives. Moreover, a detailed family history may provide valuable insights into familiar forms of endocrine hypertension. The review of systems should include disease-specific questions. Most patients harboring a pheochromocytoma are symptomatic. Symptoms may include headaches, palpitations, anxiety-like attacks and profuse sweating. The absence of these symptoms renders the diagnosis unlikely, although cases of normotensive and/or asymptomatic pheochromocytomas have been reported. Patients with Cushing's syndrome often complain of weight gain, insomnia, depression, easy bruising and fatigue. Acne and hirsutism can also be observed. Primary hyperaldosteronism is manifested by mild to severe hypertension. Hyopkalemia is frequently present but it is not a universal finding. Polyuria, myopathy and cardiac dysrhythmias may occur in cases of severe hypokalemia. To better understand the sequelae of disturbed adrenal hormone synthesis, please refer to Figure 1 and also to the following chapters in endotext.com: Endocrine Testing Protocols - Endocrine hypertension, chapter 7, by Helmy Siragy; Endocrine Hypertension in Childhood, chapter 9, by Ian Marshall and Maria New, and Adrenal Physiology and Diseases, Chapter 34, Karel Pacak, Pheochromocytoma; Chapter 35, Christian A. Koch, von Hippel-Lindau Syndrome.

Figure 1. Adrenal steroidogenesis. Z Glom = zona glomerulosa; Z Fas = zona fasciculata; Z Ret = zona reticularis; 19-H = 19-Hydroxylase; HSD = Hydroxysteroid dehydrogenase; P450aro = aromatase; 5alpha-Red = 5alpha-Reductase. The 3 adrenal cortex zones Z Glom, Z Fas, and Z Ret stand above the "column" of hormones that are produced in the respective zone. The steroidogenic enzymes on the left starting with P450scc (Desmolase) are listed in order for "vertical and horizontal reading", i.e. Desmolase converts cholesterol to pregnenolone, 3beta-OH-Steroid Dehydrogenase I/II convert pregnenolone to progesterone, 17-OH-Pregnenolone to 17-OH-Progesterone, and P450c11 converts deoxycorticosterone to 18-OH-Corticosterone and 11-Deoxycortisol to cortisol, etc.

PRIMARY ALDOSTERONISM

Previous studies have reported a prevalence of primary aldosteronism (PA) of 1-2 %. Newer data suggest a prevalence of approximately 4-10 % among the hypertensive population (2,3). Many patients with PA (up to 50%) may not present with hypokalemia but are rather normokalemic (4,5). PA can be a sporadic or familial condition. Most cases of sporadic PA are caused by a aldosterone-producing adrenal adenoma. Bilateral zona glomerulosa hyperplasia is much more common in sporadic primary hyperaldosteronism than previously thought and is an important differential diagnosis, since it is treated medically, i.e. by spironolactone, rather than by adrenalectomy (6). Very rarely PA can be caused by an adrenal carcinoma, or unilateral adrenal cortex hyperplasia (also called primary adrenal hyperplasia). Familial aldosteronism is estimated to affect 2% of all patients with primary hyperaldosteronism and is classified as type 1 and 2. (7). In familial hyperaldosteronism type 1, an autosomal dominantly inherited chimeric gene defect in CYP11B1/CYPB2 (coding for 11beta-hydroxylase/aldosterone synthase) causes ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata, making mineralocorticoid production regulated by corticotropin (8,9). The hybrid gene has been identified on chromosome 8. Under normal conditions, aldosterone secretion is mainly stimulated by hyperkalemia and angiotensin II. An increase of serum potassium of 0.1 mmol/L increases aldosterone by 35%. In familial hyperaldosteronism type 1 or glucocorticoid-remediable aldosteronism, urinary hybrid steroids 18-oxocortisol and18-hydroxycortisol are 30-fold higher than in sporadic aldosteronomas. Intracranial aneurysms and hemorrhagic stroke are clinical features frequently associated with familial hyperaldosteronism type 1 (10). The diagnosis is made by documenting dexamethasone suppression of serum aldosterone using the Liddle's Test (dexamethasone 0.5 mg q 6h for 48 h should reduce plasma aldosterone to nearly undetectable levels (below 4 ng/dl) (11,12) ) or by genetic testing (Southern Blot or PCR). In contrast, familial hyperaldosteronism type 2 is not glucocorticoid remediable. The responsible gene has been linked to chromosome 7p22 but has not yet been identified (13). Primary aldosteronism is screened for by measuring plasma aldosterone (PA) and renin activity (PRA). A PA/PRA-ratio > 30 with a concomitant PA > 20 ng/dl has a sensitivity of 90% and specificity of 91% for primary aldosteronism (14). Confirmatory testing can be done by different techniques (see Endocrine Testing Protocols, Endocrine Hypertension, Chapter 7, Helmy Siragy). To clinically distinguish hyperplasia from unilateral adenoma, imaging with computed tomography and magnetic resonance imaging are helpful but adrenal venous sampling with cosyntropin infusion is often essential: cutoff for unilateral adenoma > 4 "cortisol-corrected" aldosterone ratio (adenoma side aldosterone/cortisol : normal adrenal gland aldosterone/cortisol); cutoff for bilateral hyperplasia < 3 "cortisol-corrected" aldosterone ratio (high-side aldosterone/cortisol : low-side aldosterone/cortisol).

Adrenal adenomas producing aldosterone should be removed. Nearly all patients with such endocrine hypertension are then improved and up to 60% are cured (normotensive) from hypertension (15). Bilateral hyperplasia is treated with spironolactone and/or amiloride. In cases of familial hyperaldosteronism type 1, dexamethasone is also effective.

PHEOCHROMOCYTOMA

These rare neuroendocrine tumors are composed of chromaffin tissue containing neurosecretory granules (16). Most pheochromocytomas are sporadic but some occur in an inherited form. Recent studies suggest a percentage of up to 24% of hereditary pheochromocytomas (17). Patients with multiple endocrine neoplasia type 1 or type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and those with germline mutations in the SDHB/C/D genes can develop hereditary pheochromocytomas (18). The biochemical profile of pheochromocytomas associated with the aforementioned hereditary syndromes varies (19). Especially in patients with MEN 2 and VHL syndrome, pheochromocytomas may be "silent". Blood pressure does not correlate with circulating catecholamines (20). Hypertension is paroxysmal in approximately 50% of patients with pheochromocytoma. The diagnosis can be established by measuring fractionated plasma or urinary metanephrines and normetanephrines. Measurement of plasma free metanephrines is considered the best test for diagnosing pheochromocytoma (21). For further information please refer to Adrenal Physiology and Diseases, Chapter 34, Karel Pacak, Pheochromocytoma; Chapter 35, Christian A. Koch, von Hippel-Lindau Syndrome, and Endocrine Testing Protocols, Endocrine Hypertension, Chapter 7, Helmy Siragy).

CONGENITAL ADRENAL HYPERPLASIA: 11BETA-HYDROXYLASE DEFICIENCY

11beta-hydroxylase is responsible for the conversion of deoxycorticosterone (DOC) to corticosterone and 11-deoxycortisol to cortisol. In approximately 2/3 of individuals affected by a deficiency of this enzyme, hypertension ensues (22). The inheritance mode is autosomal recessive. The responsible gene CYP11B1 is located on chromosome 8 and mutated. Since corticotropin is chronically elevated and precursors such as 17-OH progesterone and androstendione accumulate, androgen production is increased and may lead to prenatal virilization (see Chapter 9, Endocrine Hypertension in Children, Ian Marshall and Maria I New).

CONGENITAL ADRENAL HYPERPLASIA: 17ALPHA- HYDROXYLASE DEFICIENCY

This enzyme deficiency is rare and leads to diminished production of cortisol and sex steroids. Chronic elevation of ACTH causes an increased production of DOC and corticosterone with subsequent hypertension and hypokalemia. The responsible gene for cytochrome P450C17 is located on chromosome 10q24 (see Chapter 9, Endocrine Hypertension in Children, Ian Marshall and Maria I New).

APPARENT MINERALOCORTICOID EXCESS

Low-renin hypertension can present in various forms, one of them is apparent mineralocorticoid excess (AME), an autosomal recessive disorder caused by deficiency of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) enzyme. In 1977, New et al. (23) first described this syndrome and in 1995 Wilson et al. (24) first reported mutations in the 11beta-HSD2 gene cause AME. The 11beta-HSD2 enzyme is co-expressed with the mineralocorticoid receptor in renal tubular cells and leads to conversion of cortisol to cortisone (25). Cortisone does not bind to the mineralocorticoid receptor. Cortisol and aldosterone bind with equal affinity to the mineralocorticoid receptor but normal circulating concentrations of cortisol are 100 to 1000 fold higher than those of aldosterone (26). If 11beta-HSD2 is oversaturated or defective, more cortisol will be available to bind to the mineralocorticoid receptor (27). A diminished 11beta-HSD2 activity may be hereditary or acquired, i.e. by inhibition of the enzyme by glycyrrhhetinic acid (licorice, chewing tobacco, carbenoloxone). 11beta-HSD2 is located on chromosome 16q22. In childhood, AME often causes growth retardation, hypokalemia, diabetes insipidus renalis, and nephrocalcinosis. Diminished 11beta-HSD2 activity may play a role in the pathogenesis of preeclampsia (28). The diagnosis of AME can be established by measuring free unconjugated steroids in urine (free cortisol/free cortisone ratio), and/or steroid metabolites (tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone) (29). Affected individuals have low renin and aldosterone levels, normal plasma cortisol levels, and hypokalemia. Treatment of AME consists of spironolactone, triamterene, or amiloride. Renal transplant is an option for patients with advanced renal insufficiency.

CONSTITUTIVE ACTIVATION OF THE MINERALOCORTICOID RECEPTOR (GELLER SYNDROME)

The MC receptor can be mutated leading to the onset of hypertension before age 20 (30). In vitro experiments demonstrate that progesterone and spironolactone, usually antagonists of the mineralocorticoid receptor, become agonists in Geller syndrome, suggesting "gain of function" mutations in the MC gene on chromosome 4q31. The inheritance pattern is autosomal-dominant.

LIDDLE SYNDROME

In 1963, Liddle (31) described patients with severe hypertension, hypokalemia, and metabolic alkalosis, who had low plasma aldosterone levels and plasma renin activity. An improvement of the hypertension occurred after salt restriction and triamterene therapy. Spironolactone is ineffective in this autosomal-dominant inherited syndrome. So-called "gain of function" mutations in the genes coding for the beta- or gamma-subunit of the renal epithelial sodium channel, located at chromosome 16p13, lead to constitutive activation of renal sodium resorption and subsequent volume expansion.

PSEUDOHYPALDOSTERONISM TYPE 2

Pseudohypoaldosteronism type 2 or Gordon's syndrome (32) belongs to low renin hypertension and has an unknown prevalence, since many patients remain undiagnosed. Published families with this condition are predominantly from Australia (Gordon et al.) or the United States (Lifton et al.). Hypertension in these patients may develop as a consequence of increased renal salt reabsorption, and hyperkalemia ensues as a result of reduced renal K excretion despite normal glomerular filtration and aldosterone secretion (33). The reduced renal secretion of potassium makes this condition look like an aldosterone-deficient state ("Pseudohypoaldosteronism").

These features are chloride-dependent. Infusion of sodium chloride instead of sodium bicarbonate corrects the abnormalities as does the administration of thiazide diuretics which inhibit salt reabsorption in the distal nephron. Gordon and coworkers found that all features could be reversed by very strict dietary salt restriction (32). Gordon syndrome is an autosomal dominantly inherited disorder with genes mapping to chromosomes 1, 12, and 17 (34,35). Recently, mutations have been identified in WNK kinases WNK1 and WNK4 on chromosomes 12 and 17, respectively (34). Abnormalities such as (activating) mutations in the amiloride-sensitive sodium channel of the distal renal tubule are responsible for the clinical phenotype. Severe dietary salt restriction, antihypertensives with preferably use of thiazide diuretics can control the hypertension in this syndrome.

INSULIN RESISTANCE

Hypertension, obesity, and diabetes mellitus type 2 are frequently cardinal features of the metabolic syndrome. Patients with essential hypertension often are insulin resistant (36). Interestingly, not all insulin resistant patients are obese. In insulin-sensitive tissues, insulin can directly stimulate the calcium pump leading to calcium loss from the cell (37). In an adipocyte, elevated cytosolic calcium concentrations can induce insulin resistance. In a cell resistant to insulin, the insulin-induced calcium loss from cells would be decreased. With the subsequent increase in intracellular calcium, vascular smooth muscle cells respond more eagerly to vasoconstrictors and thus lead to rising blood pressure. Other mechanisms possibly explaining the association of insulin resistance and hypertension are increased sodium retention and increased activity of the adrenergic nervous system (reviewed in 38).

HYPERPARATHYROIDISM

Parathyroid hormone levels in hypertensive patients usually are in the normal range and appropriate for the serum calcium concentration. When infused, PTH is a vasodilator (39). High-calcium intake may lower blood pressure (40,41). However, hypercalcemia is associated with an increased incidence of hypertension (1). In patients with primary hyperparathyroidism, hypertension is observed in approximately 40% of cases. The mechanisms of these observations/associations are unclear. In MEN syndromes, hypertension in patients with hyperparathyroidism may be related to an underlying pheochromocytoma or primary aldosteronism.

CUSHING'S SYNDROME

Hypercortisolemia is associated with hypertension in approximately 80% of cases (42,43). In Cushing's disease, renin and DOC levels are usually normal, whereas in ectopic corticotropin syndrome, hypokalemia is common and related to an increased mineralocorticoid activity with suppressed renin and elevated DOC levels. There are several mechanisms of blood pressure elevation in Cushing's syndrome: increased hepatic production of angiotensinogen and cardiac output by glucocorticoids, reduced production of prostaglandins via inhibition of phospholipase A, increased insulin resistance, and oversaturation of 11beta-HSD activity with increased mineralocorticoid effect (44-46).

GLUCOCORTICOID RESISTANCE

This autosomal recessive or dominant inherited disorder is rare and caused by inactivating mutations of the glucocorticoid receptor gene (47,48). Cortisol and ACTH are elevated but there are no clinical features of Cushing's syndrome. Permanent elevation of ACTH can lead to stimulation of adrenal compounds with mineralocorticoid activity, and elevation of cortisol may lead to stimulation of the mineralocorticoid receptor, resulting in hypertension. In women, hirsutism and oligomenorrhea may develop through stimulation of androgens.

HYPERTHYROIDISM

In thyrotoxicosis, patients usually are tachycardic and have high cardiac output with an increased stroke volume and elevated systolic blood pressure (49,50).

HYPOTHYROIDISM

Diastolic hypertension may result from extracellular volume expansion and increased systemic vascular resistance. In 32% of hypertensive hypothyroid patients, replacement therapy with thyroxine leads to a fall in diastolic blood pressure to 90 mm Hg or less (51).

ACROMEGALY

One third of patients with growth hormone excess suffer from hypertension. Growth hormone has antinatriuretic actions and may lead to sodium retention and volume expansion (52).