Hypertension affects approximately 20% of Americans (1). The assignment of a diagnosis of hypertension is dependent on the appropriate measurement of blood pressure, the level of the blood pressure elevation, and the duration of follow-up (2). "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 cardiovascular 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 pathophysiology 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), thyroid hormone, 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, hyper- or hypothyroidism, acromegaly, or pheochromocytoma. Hypertension in young patients and refractory hypertension (characterized by poorly controlled blood pressure on > 3 antihypertensive drugs) should alert the physician to screen 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 such as 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 intervention may result in complete cure, obviating the need for life-long antihypertensive treatment.

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 and review of systems should be obtained. The onset of hypertension and the response to previous anti-hypertensive treatment should be determined. Consideration of adherence to prescribed antihypertensive regimen should be given (? poor compliance). A history of target organ damage (i.e. retinopathy, nephropathy, claudication, heart disease, abdominal or carotid artery disease) 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 (salt intake etc.), 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 familial 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, similar to symptoms of hyperthyroidism. The absence of these symptoms renders the diagnosis of pheochromocytoma 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 (in women) 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. A thorough physical exam with attention to evidence of target organ injury and features of secondary hypertension should be conducted.

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, Saroj Nimkarn, and Maria New, and Adrenal Physiology and Diseases, Chapter 34, Karel Pacak, Pheochromocytoma; Chapter 35, Christian A. Koch, McClellan M. Walther, and Marston Linehan, 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.

In a community-based study (Framingham Offspring) comprising 1688 nonhypertensive participants, increased plasma aldosterone concentrations within the physiologic range predisposed persons to the development of hypertension (3). 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 (4-6). In patients with mild to moderate hypertension without hypokalemia, the prevalence of PA has been reported to be 3% (7). Many patients with PA (up to 60%) may not present with hypokalemia but are rather normokalemic (8-11). Low renin hypertension is not always easy to differentiate from PA (12). PA can be a sporadic or familial condition. Most cases of sporadic PA are caused by an aldosterone-producing adrenal adenoma. However, 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 with aldosterone antagonists, rather than by adrenalectomy (13). Selective use of adrenal venous sampling is helpful in this setting (14-16). 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. (17, 18). 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 (19,20). 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 and 18-hydroxycortisol are 30-fold higher than in sporadic aldosteronomas. Intracranial aneurysms and hemorrhagic stroke are clinical features frequently associated with familial hyperaldosteronism type 1 (21). The diagnosis is made by documenting dexamethasone suppression of serum aldosterone using the Liddle’s Test (dexamethasone 0.5 mg q 6h for 48h should reduce plasma aldosterone to nearly undetectable levels (below 4 ng/dl) (22,23) 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 (24).

Primary aldosteronism is screened for by measuring plasma aldosterone (PA) and plasma renin activity (PRA). There are various assays for measuring aldosterone which can prove to be problematic (25-27). A PA/PRA-ratio > 30 with a concomitant PA > 20 ng/dl has a sensitivity of 90% and specificity of 91% for primary aldosteronism (28). Because low renin hypertension can be difficult to distinguish from PA, an upright plasma aldosterone of at least 15 ng/dl may be helpful (12). 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). If a “young” patient with hypertension and PA presents with an at least 1 cm sized hypodense adrenal lesion with a normal-appearing contralateral adrenal gland, adrenal venous sampling is likely not necessary (14).

Adrenal adenomas producing aldosterone should be removed. Nearly all patients with such endocrine hypertension have improved blood pressure control and up to 60% are cured (normotensive without antihypertensive therapy) from hypertension (29-31). Bilateral adrenal hyperplasia is treated with spironolactone, epleronone, and/or amiloride (32-34). In cases of familial hyperaldosteronism type 1, dexamethasone is also effective. Parameters of insulin sensitivity can be restored to normal with treatment of PA (35).

These rare neuroendocrine tumors are composed of chromaffin tissue containing neurosecretory granules (36). Most pheochromocytomas are sporadic but some occur in an inherited form. Recent studies suggest up to 24% of pheochromocytomas are hereditary (37). 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 (38-40). The biochemical profile of pheochromocytomas associated with the aforementioned hereditary syndromes varies (41). Patients with MEN 2 and VHL syndrome may have clinically “silent” pheochromocytomas. Normotensive patients may also have sporadic pheochromocytomas (42). Blood pressure does not correlate with circulating catecholamines (43). Hypertension is paroxysmal in approximately 50% of patients with pheochromocytoma. The diagnosis can be established by measuring free plasma or fractionated urinary metanephrines and normetanephrines. Measurement of plasma free metanephrines by HPLC is considered the best test for diagnosing pheochromocytoma (39,44). When this test cannot be performed, measuring plasma free metanephrines by RIA or measuring plasma chromogranin A may represent good markers for pheochromocytoma (45-48). Combining the results of plasma chromogranin A and urinary catecholamines may yield a sensitivity for diagnosis of pheochromocytoma of almost 100% (47). In rare circumstances, pheochromocytomas release large amounts of dopamine (49). Approximately 35% of extra-adrenal pheochromocytomas are malignant (metastasizing) as opposed to approximately 10% of those arising in the adrenal gland. The risk for malignancy increases when the tumor exceeds 5 cm in size (40). Therefore, for such tumors, open adrenalectomy is the suggested procedure for tumor removal rather than laparoscopic or retroperitoneoscopic minimally invasive tumor removal (Koch, unpublished observation in a patient with MEN2-related bilateral pheochromocytomas). CT or MR imaging can localize the tumor in approx. 90 % of cases. For malignant pheochromocytomas, 123MIBG or 131MIBG scintigraphy may be helpful. Approx. 50% of patients with malignant pheochromocytomas respond to 131MIBG therapy by partial remission. Chemotherapy is usually administered according to the so-called Averbuch protocol from 1988. For further information please refer to Adrenal Physiology and Diseases, Chapter 34, Karel Pacak, Pheochromocytoma; Chapter 35, Christian A. Koch, MM Walther, and Marston Linehan, Von Hippel-Lindau Syndrome, and Endocrine Testing Protocols, Endocrine Hypertension, Chapter 7, Helmy Siragy).

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, monogenic low renin hypertension ensues (50-51). 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, Saroj Nimkarn, and Maria I New).

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 as well as pseudohermaphroditism in males, and sexual infantilism in females (52,53). The responsible gene for cytochrome P450C17 is located on chromosome 10q24 (see Chapter 9, Endocrine Hypertension in Children, Ian Marshall, Saroj Nimkarn, and Maria I New).

Low-renin hypertension (undetectable aldosterone, hypokalemia) 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 (54-57). In 1977, New et al. (58) first described this syndrome and in 1995 Wilson et al. (59) first reported mutations in the 11beta-HSD2 gene located on chromosome 16q22 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 (60). 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 (61). If 11beta-HSD2 is oversaturated or defective, more cortisol will be available to bind to the mineralocorticoid receptor (62). Diminished 11beta-HSD2 activity may be hereditary or acquired. Acquired deficiency of this enzyme may result from inhibition by glycyrrhhetinic acid which may occur with use of licorice, chewing tobacco, and carbenoloxone. 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 (63). 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) (64). Affected individuals have low renin and aldosterone levels, normal plasma cortisol levels, and hypokalemia. Treatment of AME consists of spironolactone, eplerenone, triamterene, or amiloride. Renal transplant is an option for patients with advanced renal insufficiency.

The MC receptor can be mutated leading to the onset of hypertension before age 20 (65). 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.

In 1963, Liddle (66) 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.

Pseudohypoaldosteronism type 2 or Gordon’s syndrome (67) is a rare Mendelian disorder, transmitted in an autosomal dominant fashion, and can cause low renin hypertension (68). It has an unknown prevalence, since many patients remain undiagnosed. Published families with this condition (hypertension, hyperkalemia, metabolic acidosis, normal renal function, low/normal aldosterone levels) 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 (69). The reduced renal secretion of potassium makes this condition look like an aldosterone-deficient state, thus the term “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 (67). Gordon syndrome is an autosomal dominantly inherited disorder with genes mapping to chromosomes 1, 12, and 17 (70,71). Mutations have been identified in WNK kinases WNK1 and WNK4 on chromosomes 12 and 17, respectively (70). Abnormalities such as activating mutations in the amiloride-sensitive sodium channel of the distal renal tubule are responsible for the clinical phenotype (72,73). Severe dietary salt restriction, antihypertensives with preferably use of thiazide diuretics can control the hypertension in this syndrome. Interestingly, common variants in WNK1 contribute to blood pressure variation in the general population (74).

The metabolic syndrome is characterized by hypertension, abdominal obesity, dyslipidemia, and insulin resistance. At least 24% of adults in the United States meet the criteria for the diagnosis of metabolic syndrome, and this number may even be higher for individuals over the age of 50 years (75,76). Insulin resistance is significantly associated with hypertension in Hispanics (77). Patients with essential hypertension often are insulin resistant (78). Interestingly, not all insulin resistant patients are obese. Excess weight gain, however, accounts for as much as 70% of the risk for essential hypertension and also increases the risk for end stage renal disease (79). In insulin-sensitive tissues, insulin can directly stimulate the calcium pump leading to calcium loss from the cell (80). 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 (81). In obesity, increased production of most adipokines (bioactive peptides secreted by adipose tissue) impacts on multiple functions including insulin sensitivity, blood pressure, lipid metabolism, and others (82).

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 (83). High-calcium intake may lower blood pressure (84,85). 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. Hypertension is not cured or better controlled after parathyroidectomy (86). Arterial stiffness measured in the radial artery seems to be increased in patients with mild primary hyperparathyroidism (87). In MEN syndromes, hypertension in patients with hyperparathyroidism may be related to an underlying pheochromocytoma or primary aldosteronism.

Hypercortisolemia is associated with hypertension in approximately 80% of cases (88,89). In patients with Cushing’s disease, night-time blood pressure decline is significantly lower than that in patients with essential hypertension (90). After cure of Cushing’s syndrome, approximately 30% of patients have persistent hypertension (91). In patients with 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 (92-95).

This autosomal recessive or dominant inherited disorder is rare and caused by inactivating mutations of the glucocorticoid receptor gene (96,97). 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 increases systolic blood pressure by increasing heart rate, decreasing systemic vascular resistance, and raising cardiac output (98,99). In thyrotoxicosis, patients usually are tachycardic and have high cardiac output with an increased stroke volume and elevated systolic blood pressure (100,101). Subclinical hyperthyroidism may contribute to left ventricular hypertrophy and thereby lead to hypertension (102), although it has not yet been found to be associated with hypertension (103).

Hypothyroid patients have impaired endothelial function, increased systemic vascular resistance, extracellular volume expansion, and an increased diastolic blood pressure (104). In 32% of hypertensive hypothyroid patients, replacement therapy with thyroxine leads to a fall in diastolic blood pressure to 90 mm Hg or less (105). There is a positive association between serum TSH and blood pressure within the normal serum TSH range, statistically significant for diastolic hypertension (106). Subclinical hypothyroidism seems not to be associated with hypertension (107).

The prevalence of hypertension in patients with growth hormone excess is approximately 46% and more frequent than in the general population (108-110). Growth hormone has antinatriuretic actions and may lead to sodium retention and volume expansion (111). Increased systolic output and high heart rate as manifestations of a hyperkinetic syndrome may lead to congestive heart failure (112). Blood pressure values are increased in patients with acromegaly associated with reduced glucose tolerance or diabetes compared to those with normal glucose tolerance (110). The RAAS system appears to be implicated in the pathogenesis of hypertension in patients with growth hormone excess (113).