ABSTRACT

Endocrine hypertension typically is referred to disorders of the adrenal gland including primary aldosteronism, glucocorticoid excess, and the pheochromocytoma-paraganglioma syndromes. Rare conditions in patients with congenital adrenal hyperplasia and glucocorticoid resistance (Chrousos syndrome) can also lead to hypertension. Nonadrenal endocrine disorders, such as growth hormone excess or deficiency, thyroid dysfunction, primary hyperparathyroidism, testosterone deficiency, vitamin D deficiency, obesity-associated hypertension, insulin resistance and metabolic syndrome are also linked to hypertension. In this chapter, we provide an overview of endocrine hypertension including rare syndromes of mineralocorticoid excess. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Hypertension is the most common diagnosis in USA as it affects approximately 31% of Americans (1,2) and approx. 33% of the Mozambican population using a blood pressure cutoff of 139/89 mm Hg (3). The assignment of a diagnosis of hypertension is dependent on the appropriate measurement of blood pressure, the level of blood pressure (BP) elevation, and the duration of follow-up (4). The secondary causes of hypertension include mostly renal as well as endocrine diseases. An accurate diagnosis of endocrine hypertension offers clinicians the chance to achieve an optimal treatment with either specific pharmacologic or surgical therapy (5). Herein, the different causes of endocrine hypertension with a focus on prevalence, clinical presentation, and currently diagnostic tools.

Classification of BP

Based on recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)(8), the classification of BP for adults aged 18 years or older has been as follows:

• Normal: Systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg
• Prehypertension: Systolic 120-139 mm Hg, diastolic 80-89 mm Hg
• Stage 1: Systolic 140-159 mm Hg, diastolic 90-99 mm Hg
• Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater

The 2017 ACC/AHA guidelines eliminate the classification of prehypertension and divides it into two levels (9):

• Elevated blood pressure with a systolic pressure between 120- and 129-mm Hg and diastolic pressure less than 80 mm Hg
• Stage 1 hypertension, with a systolic pressure of 130 to 139 mm Hg or a diastolic pressure of 80 to 89 mm Hg

Figure 1 provides an overview of classification of BP for adults 18 years and older.

Figure 1.

Classification of Hypertension. AHA, American Heart Association; ACC, American College of Cardiology; ESC, European Society of Cardiology; ESH, European Society of Hypertension; DHL, German Hypertension League; NICE, National Institute for Health and Care Excellence of the United Kingdom. DBP, diastolic blood pressure; SBP, systolic blood pressure. Modified from: Jordan J, Kurschat C, Reuter H. Arterial hypertension. Dtsch Arztebl Int. 2018 Aug 20;115(33-34):557-568(10)

Prevalence of Resistant Hypertension and Typical Causes

The prevalence of resistant hypertension is high: 53% of patients in NHANES had a BP < 140/90 mm Hg vs. 48% in the Framingham Heart Study. In NHANES participants with chronic kidney disease, 37% had a BP < 130/80 mm Hg. In ALLHAT, 34% of patients remained uncontrolled after 5-year follow-up on at least 2 antihypertensive drugs (5).

One important question in this regard is when to screen for secondary causes. Some patients with hypertension, but without primary aldosteronism, demonstrate ACTH-dependent aldosterone hypersecretion by stress (18). The clinician should carefully screen for cardinal signs and symptoms of Cushing syndrome, hyper- or hypothyroidism, acromegaly, insulin resistance (acanthosis nigricans), or pheochromocytoma (flushing and excessive sweating). 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 (14). 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.

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 including teas and herbal preparations, 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. Many patients harboring a pheochromocytoma are symptomatic. Symptoms may include headaches, palpitations, anxiety-like attacks and profuse sweating, similar to symptoms of hyperthyroidism. The triad headache, palpitations, and sweating in a hypertensive patient was initially found to have a sensitivity of 91% and specificity of 94% for pheochromocytoma (19). More recent studies suggest that this typical triad of symptoms is found much less frequently, for instance, in only 10% of cases (20). Ten or more percent of patients with pheochromocytoma may not have any clinical symptoms and may be normotensive (19,21,22).

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. The challenge these days is to recognize patients with evolving Cushing’s syndrome amongst the many obese and often poorly controlled diabetic individuals. An Endocrine Society Clinical Practice Guideline can assist in this task (23). Primary hyperaldosteronism is manifested by mild to severe hypertension. Hypokalemia can be present, but it is not a universal finding and there is normokalemic and normotensive primary aldosteronism (24,25). 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.

Low renin is often associated with several causes of hypertension. Figure 2 lists conditions with low renin levels.

Figure 2.

Low Renin Conditions

Despite the increasing understanding of the pathophysiology of hypertension, control of the disease is often difficult and far from optimal. Recent large meta-analyses and genotype studies have identified some “risk genes” for hypertension (15). Surendran and colleagues found a low frequency nonsense variant in the gene ENPEP, which codes for the enzyme aminopeptidase A that converts angiotensin II into angiotensin III and therefore being part of the regulation of the renin-angiotensin-aldosterone system (26). Liu and colleagues observed associations for the aggregation of rare and low frequency missense variants in the genes NPR1, DBH, and PTPMT1 (27). The gene DBH codes for the enzyme dopamine beta-hydroxylase, which catalyzes the conversion of dopamine into noradrenaline and, thereby, influences the autonomic nervous system. The gene PTPMT1 codes for the mitochondrial protein tyrosine phosphatase 1, which influences insulin production (27).

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 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. 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 (28).

The prevalence of resistant hypertension is high: 53% of patients in NHANES had a BP < 140/90 mm Hg vs. 48% in the Framingham Heart Study. In NHANES participants with chronic kidney disease, 37% had a BP < 130/80 mm Hg. In ALLHAT, 34% of patients remained uncontrolled after 5-year follow-up on at least 2 antihypertensive drugs (16). Table 2 presents clinical history, physical exam findings, and routine labs that suggest specific endocrine causes of hypertension.

PRIMARY ALDOSTERONISM

Surgical Treatment

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 (56–59). This outcome is influenced by various factors including age, duration of hypertension, coexistence of renal insufficiency, use of more than 2 antihypertensive drugs preoperatively, family history of hypertension, and others. Parameters of insulin sensitivity can be restored to normal with treatment of PA (60). A cross-sectional study including 460 pts with primary aldosteronism and 1363 controls with essential hypertension found no significant difference between pre- and postoperative levels of fasting plasma glucose and serum lipids (61). This topic has been extensively reviewed from a pro and contra perspective. If a patient does not desire surgery/adrenalectomy for a unilateral aldosteronoma/hyperplasia (Figure 3), medical therapy should be initiated (54). AVS and CT/MRI of the adrenal glands show a unilateral abnormality in 60.5% and 56%, respectively, but were congruent on the involved side in the same patient in only 37% in a recent systematic review (62). If a patient is older than age 40 years, the risk for an adrenal incidentaloma increases (62). Unilateral adrenalectomy can be helpful in some patients with primary aldosteronism and bilateral adrenal hyperplasia (56).

Figure 3.

Conn adenoma. Appearance of a 1 cm right-sided adrenal nodule (arrow) on contrast-enhanced computed tomography in a middle-aged man with hypertension treated for 20 years, initially only with a betablocker before becoming medically refractory and hypokalemic with inappropriate kaliuresis. After laparoscopic right adrenalectomy, the patient required only one antihypertensive drug to control his blood pressure.

PHEOCHROMOCYTOMA (PPGLS)

Surgical Treatment

For tumors exceeding 5 cm in size, open adrenalectomy has long been considered the suggested procedure for tumor removal rather than laparoscopic or retroperitoneoscopic minimally invasive tumor removal, to ensure complete tumor resection, prevent tumor (capsule) rupture, and avoid local recurrence (22) (Figure 4 and 5)

Figure 4.

Computed tomography showing recurrence of a right adrenal pheochromocytoma. unpublished observation in a patient with MEN2-related bilateral pheochromocytomas and unilateral tumor recurrence 11 years after bilateral adrenalectomy, photo: courtesy of Prof. Andrea Tannapfel).

Figure 5.

Macroscopic photo of a right adrenal pheochromocytoma removed from the above patient with multiple endocrine neoplasia type 2.

For pheochromocytomas less than 6 cm, a recent cohort study from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018 compared patients undergoing total vs. cortical-sparing adrenalectomy and found that patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. The authors recommend cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma (91). A retrospective, multicenter, international study in patients carrying the Met918Thr RET variant with no age restrictions who were followed from 1970 to 2016 based on registry data from 48 centers globally, found that adrenal-sparing surgery in multiple endocrine neoplasia type 2B can preserve normal adrenal function. In that study, three (10%) of the 31 patients in whom adrenal-sparing surgery had been performed, developed long-term recurrence, while normal adrenal function was maintained in 16 (62%) of patients (92). Apparently one third of one functioning adrenal gland is sufficient for normal glucocorticoid and mineralocorticoid secretion (93).

CUSHING’S SYNDROME

Hypercortisolemia is associated with hypertension in approximately 80% of adult cases and half of children (94,95). A workshop consensus paper attempted to rationalize the treatment of hypertension in patients with Cushing’s syndrome (95). In patients with Cushing’s disease, night-time blood pressure decline is significantly lower than that in patients with essential hypertension (96). After cure of Cushing’s syndrome, approximately 30% of patients have persistent hypertension (97). In children and adolescents, blood pressure normalization occurs in most patients within a year and seems to be dependent on the degree and duration of presurgical hypercortisolemia (94). 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 (98).

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-Hydroxysteroid dehydrogenase activity with increased mineralocorticoid effect through stimulation of the mineralocorticoid receptor (99). Screening studies for Cushing’s syndrome include measuring 24-h urinary free cortisol excretion on at least 2 occasions, performing a 1 mg dexamethasone suppression test, checking a midnight salivary cortisol and diurnal rhythm of cortisol secretion, and others listed in the recent Endocrine Society Clinical Practice Guideline (100). Therapy should be directed at removing glucocorticoid excess (101). Hypokalemia (especially in patients with ectopic ACTH production) can be treated with mineralocorticoid receptor antagonists such as spironolactone or eplerenone. Thiazide diuretics may also be helpful.

Given the increasing improvement in imaging and laboratory (assays etc.) techniques/modalities, one can expect an increasing number of incidentally discovered tumors and nodules in various organs including the adrenal glands. The future challenge will be when and to which extent to test individuals for disease conditions (102,103). For those individuals with adrenal incidentalomas but clearly lack of clinical features of Cushing’s syndrome, subclinical hypercortisolism may be detected biochemically depending upon which cutoff values and assays will be used (104). For the latter population, the American Association of Clinical Endocrinologists recommend using a cutoff for (8 AM) serum cortisol of 5 mcg/dl after 1 mg overnight (11 PM) dexamethasone which reveals approx. 58% sensitivity at a 100% specificity (105). A lower cutoff for serum cortisol suppression, i.e. 1.8 mcg/dl, usually rules out Cushing’s syndrome (102). A prospective, randomized study including 45 patients with subclinical hypercortisolism and adrenal incidentalomas was divided into 23 pts who underwent adrenalectomy and 22 pts under surveillance. Monitoring included glycemic control, blood pressure, lipid profile, obesity, and bone mineral density. In the surgical group, diabetes mellitus improved in 62% and hypertension in 67% of pts, whereas the conservative group showed worsening of glycemic control, blood pressure and lipid profiles (37).

To better understand the sequelae of disturbed adrenal hormone synthesis, please refer to Figure 6 and related Endotext chapters (106,107).

Figure 6.

Adrenal Steroid Synthesis. 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. (modified from ref. 35: Koch CA. Encyclopedia of Endocrine Disease, 2004)

GLUCOCORTICOID RESISTANCE (CHROUSOS SYNDROME)

This autosomal recessive or dominant inherited disorder is rare and caused by inactivating mutations of the glucocorticoid receptor gene (108,109). Cortisol and ACTH are elevated but there are no clinical features of Cushing syndrome. Permanent elevation of ACTH can lead to stimulation of adrenal compounds with mineralocorticoid activity (corticosterone, DOC), along with elevated cortisol secretion may lead to stimulation of the mineralocorticoid receptor, resulting in hypertension. In women, hirsutism and oligo-amenorrhea may develop through stimulation of androgens (androstenedione, DHEA, 5-androstendiol). Clinically, children may present with ambiguous genitalia and precocious puberty. Men may be infertile and/or oligospermic. Women may have acne, excessive hair, menstrual irregularities with oligo- anovulation, as well as infertility (108–110).

Treatment entails suppression of ACTH secretion with high doses of dexamethasone (1-3 mg/day). Mineralocorticoid receptor-dependent hypertension may be treated with blockade of the receptor, with spironolactone or eplerenone.

CONGENITAL ADRENAL HYPERPLASIA

DEOXYCORTICOSTERONE-PRODUCING TUMOR

Deoxycorticosterone-producing tumors are rare adrenal tumors presented mostly large and malignant (125). Along with deoxycortisone, androgens and estrogens may be co-secreted. Women may present virilization and men feminization. Hypertension and hypokalemia may manifest with rapid onset. Renin and aldosterone are often low.

APPARENT MINERALOCORTICOID EXCESS

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 (49,126,127). This enzyme converts cortisol to the inactive cortisone in renal tubular cells.

In 1977, New et al. (128) first described this syndrome and in 1995 Wilson et al. (129) first reported that 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 (130,131). 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 (132). If 11beta-HSD2 is oversaturated or defective, more cortisol will be available to bind to the mineralocorticoid receptor (133). Diminished 11beta-HSD2 activity may be hereditary or acquired. Acquired deficiency of this enzyme may result from inhibition by glycyrrhizin acid which may occur with use of licorice, chewing tobacco, and carbenoxolone. In childhood, AME often causes growth retardation/short stature, hypertension, hypokalemia, diabetes insipidus renalis, and nephrocalcinosis. Diminished 11beta-HSD2 activity may play a role in the pathogenesis of preeclampsia (134). 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) (135). 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.

CONSTITUTIVE ACTIVATION OF THE MINERALOCORTICOID RECEPTOR (GELLER SYNDROME)

The Mineralocorticoid (MC) receptor can be mutated leading to the onset of hypertension before age 20 (136). In vitro experiments demonstrate that progesterone and spironolactone, usually antagonists of the (MC) 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 (137) 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 reabsorption and subsequent volume expansion. The 24-h urine cortisone/cortisol ratio is normal.

PSEUDOHYPALDOSTERONISM TYPE 2

Pseudohypoaldosteronism type 2 or Gordon’s syndrome (138) is a rare Mendelian disorder, transmitted in an autosomal dominant fashion, and can cause low renin hypertension (139). 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 or the United States (138). 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 (140). 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 (138). Gordon syndrome is an autosomal, dominantly inherited disorder with genes mapping to chromosomes 1, 12, and 17 (141,142). Mutations have been identified in WNK kinases WNK1 and WNK4 on chromosomes 12 and 17, respectively (141,143). Abnormalities such as activating mutations in the amiloride-sensitive sodium channel of the distal renal tubule are responsible for the clinical phenotype (144,145). 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 (146).

INSULIN RESISTANCE

The metabolic syndrome is characterized by hypertension, abdominal/visceral obesity, dyslipidemia, and insulin resistance (147). 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 (148). Insulin resistance is significantly associated with hypertension in Hispanics and can cause vascular dysfunction (16,149). Patients with essential hypertension often are insulin resistant (150). 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 (16). In insulin-sensitive tissues, insulin can directly stimulate the calcium pump leading to calcium loss from the cell (151). 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. 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 (152,153).

PRIMARY HYPERPARATHYROIDISM

Parathyroid hormone levels in hypertensive patients usually are in the normal range and appropriate for the serum calcium concentration. However, patients with essential hypertension excrete more calcium compared to normotensive people, suggesting an enhanced parathyroid gland function (154). When infused, PTH is a vasodilator, although chronic infusion of PTH raises blood pressure in healthy subjects (155,156). High-calcium intake may lower blood pressure (157,158). 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 usually not cured or better controlled after parathyroidectomy (159). In patients with asymptomatic primary hyperparathyroidism, surgery/parathyroidectomy did not show any benefit regarding blood pressure or quality of life when compared to medical management (160). On the other hand, severe hypertension may improve in patients with primary hyperparathyroidism who undergo parathyroidectomy. Arterial stiffness measured in the radial artery seems to be increased in patients with mild primary hyperparathyroidism (161). Patients with primary hyperparathyroidism have carotid vascular abnormalities (162). In normotensive patients with primary hyperparathyroidism, SBP variability is increased and is reduced by parathyroidectomy (163,164). Furthermore, parathyroidectomy in patients with primary hyperparathyroidism may decrease risk of cardiovascular diseases by lowering total cholesterol levels, although ambulatory diastolic BP increases in response to surgery (165). Another contributory factor to hypertension in patients with primary HPT may be endothelial dysfunction (166). In MEN syndromes, hypertension in patients with hyperparathyroidism may be related to an underlying pheochromocytoma or primary aldosteronism. Criteria for parathyroidectomy have recently been revisited at the Fourth International Workshop on the management of asymptomatic primary hyperparathyroidism, including now skeletal and/or renal involvement (nephrocalcinosis on imaging) (167).

HYPERTHYROIDISM

Hyperthyroidism increases systolic blood pressure by increasing heart rate, decreasing systemic vascular resistance, and raising cardiac output (168–171). In thyrotoxicosis, patients usually are tachycardic and have high cardiac output with an increased stroke volume and elevated systolic blood pressure (172,173). Approx. one third of patients with hyperthyroidism have hypertension which often resolves after achieving euthyroidism (174). Subclinical hyperthyroidism may contribute to left ventricular hypertrophy and thereby lead to hypertension , although it has not yet been found to be associated with hypertension (174).

HYPOTHYROIDISM

Hypothyroid patients have impaired endothelial function, increased systemic vascular resistance, extracellular volume expansion, and an increased diastolic blood pressure (89,171,175). Hypothyroid patients have higher mean 24-h systolic blood pressure and BP variability on 24-h ambulatory BP monitoring (176). In 32% of hypertensive hypothyroid patients, replacement therapy with thyroxine leads to a fall in diastolic blood pressure to 90 mm Hg or less (177). There is a positive association between serum TSH and blood pressure within the normal serum TSH range, statistically significant for diastolic hypertension (177). Subclinical hypothyroidism may or may not to be associated with hypertension. Hypothyroidism can lead to volume-dependent blood pressure elevation with low plasma renin concentrations (178–180).

ACROMEGALY

The prevalence of hypertension in patients with growth hormone excess is approximately 46% and more frequent than in the general population (181,182). Growth hormone has antinatriuretic actions and may lead to sodium retention and volume expansion (181,182). Increased systolic output and high heart rate as manifestations of a hyperkinetic syndrome may lead to congestive heart failure (181,183). Blood pressure values are increased in patients with acromegaly associated with reduced glucose tolerance or diabetes compared to those with normal glucose tolerance (181). The RAAS system appears to be implicated in the pathogenesis of hypertension in patients with growth hormone excess (181,183–185). Comorbidities in acromegalics, such as hypertension, hyperlipidemia, diabetes mellitus, and cardiomyopathy, all may improve even with partial biochemical control of growth hormone excess (184,186). However, in some patients, hypertension and diabetes mellitus may persist after attempting biochemical cure/remission (187).

OTHER POTENTIAL ENDOCRINE CONDITIONS CAUSING ENDOCRINE HYPERTENSION

There is accumulating evidence that vitamin D deficiency may be linked to an increased cardiovascular risk and hypertension (188). Potential mechanisms in this setting are concurrent insulin resistance and direct vitamin D action through the renin-angiotensin-aldosterone system (Figure 7).

Figure 7.

Pathway of vitamin D metabolism and its relationship with PTH and the renin-angiotensin-aldosterone system (modified from Ullah et al., 2009)(188)

Testosterone deficiency is frequently identified in obese individuals and those with diabetes mellitus and/or metabolic syndrome including hypertension. Replacement therapy in selected patients may be beneficial not only related to their symptomatology of androgen deficiency such as low libido, poor erections, fatigue, and others, but also in regards to their metabolic profile and blood pressure (189,190).

Similarly, individuals with growth hormone deficiency may be at risk for developing hypertension, mostly because of their body composition being more “fat” and “inflamed” when compared to subjects with growth hormone sufficiency, as assessed by serum IFG-1 levels matched to gender and age. The key in such patients will be to replace them with growth hormone individually to an IGF-1 level at which no features of growth hormone excess develop and to increase physical activity. In obese subjects who are willing to take on major lifestyle changes with the goal to lose weight, eat and live healthier, temporary medication assistance (phentermine, topiramate, liraglutide, lorcaserin, orlistat, naltrexone-bupropion) including administration of growth hormone may be acceptable (191–193).

Individual tissue-dependent sensitivity of the glucocorticoid receptor and actions of endogenous glucocorticoids may play a major role in the development of hypertension, obesity, and diabetes mellitus (119,194,195).

Similarly, individuals with growth hormone deficiency may be at risk for developing hypertension, mostly because of their body composition being more “fat” and “inflamed” when compared to subjects with growth hormone sufficiency, as assessed by serum IFG-1 levels matched to gender and age. The key in such patients will be to replace them with growth hormone individually to an IGF-1 level at which no features of growth hormone excess develop and to increase physical activity. In obese subjects who are willing to take on major lifestyle changes with the goal to lose weight, eat and live healthier, temporary medication assistance (phentermine, topiramate, liraglutide, lorcaserin, orlistat, naltrexone-bupropion) including administration of growth hormone may be acceptable (191–193).

Individual tissue-dependent sensitivity of the glucocorticoid receptor and actions of endogenous glucocorticoids may play a major role in the development of hypertension, obesity, and diabetes mellitus (119,194,195).

REFERENCES

1.

Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: A rising tide. Hypertension. 2004;44(4):398–404. [PubMed: 15326093]

2.

Cutler JA, Sorlie PD, Wolz M, Thom T, Fields LE, Roccella EJ. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988-1994 and 1999-2004. Hypertension. 2008;52(5):818–827. [PubMed: 18852389]

3.

Damasceno A, Azevedo A, Silva-Matos C, Prista A, Diogo D, Lunet N. Hypertension prevalence, awareness, treatment, and control in mozambique: Urban/rural gap during epidemiological transition. Hypertension. 2009;54(1):77–83. [PubMed: 19470872]

4.

Hemmelgarn BR, McAllister FA, Myers MG, McKay DW, Bolli P, Abbott C, Schiffrin EL, Grover S, Honos G, Lebel M, Mann K, Wilson T, Penner B, Tremblay G, Tobe SW, Feldman RD., Canadian Hypertension Education Program. The 2005 Canadian Hypertension Education Program recommendations for the management of hypertension: part 1- blood pressure measurement, diagnosis and assessment of risk. Can. J. Cardiol. 2005;21(8):645–56. [PubMed: 16003448]

5.

O’Shea PM, Griffin TP, Fitzgibbon M. Hypertension: The role of biochemistry in the diagnosis and management. Clin. Chim. Acta. 2017;465:131–143. [PubMed: 28007614]

6.

Vischer AS, Burkard T. Principles of blood pressure measurement – current techniques, office vs ambulatory blood pressure measurement. In: Advances in Experimental Medicine and Biology.Vol 956. Springer New York LLC; 2017:85–96. [PubMed: 27417699]

7.

Muntner P, Shimbo D, Carey RM, Charleston JB, Gaillard T, Misra S, Myers MG, Ogedegbe G, Schwartz JE, Townsend RR, Urbina EM, Viera AJ, White WB, Wright JT. Measurement of blood pressure in humans: A scientific statement from the american heart association. Hypertension. 2019;73(5):E35–E66. [PubMed: 30827125]

8.

National High Blood Pressure Education Program B. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.; 2004. Available at: http://www​.ncbi.nlm.nih​.gov/pubmed/20821851. Accessed December 22, 2019.

9.

Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Himmelfarb CD, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the American college of cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71(6):1269–1324. [PubMed: 29133354]

10.

Jordan J, Kurschat C, Reuter H. Arterial hypertension-diagnosis and treatment. Dtsch. Arztebl. Int. 2018;115(33–34):557–558. [PMC free article: PMC6156553] [PubMed: 30189978]

11.

Nwankwo T, Yoon SS. Burt V, Gu Q. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief. 2013;(133):1–8. u. [PubMed: 24171916]

12.

Camelli S, Bobrie G, Postel-Vinay N, Azizi M, Plouin PF, Amar L. LB01.11. J. Hypertens. 2015;33:e47.

13.

Gupta-Malhotra M, Banker A, Shete S, Hashmi SS, Tyson JE, Barratt MS, Hecht JT, Milewicz DM, Boerwinkle E. Essential hypertension vs. secondary hypertension among children. Am. J. Hypertens. 2015;28(1):73–80. [PMC free article: PMC4318949] [PubMed: 24842390]

14.

Young WF, Calhoun DA, Lenders JWM, Stowasser M, Textor SC. Screening for endocrine hypertension: An endocrine society scientific statement. Endocr. Rev. 2017;38(2):103–122.

15.

Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F. A Prospective Study of the Prevalence of Primary Aldosteronism in 1,125 Hypertensive Patients. J. Am. Coll. Cardiol. 2006;48(11):2293–2300. [PubMed: 17161262]

16.

Koch CA, Chrousos GP. Endocrine hypertension : underlying mechanisms and therapy. Humana Press; 2013.

17.

Plouin PF, Degoulet P, Tugayé A, Ducrocq MB, Ménard J. Nouv. Presse Med. 1981;10(11):869–72. [Screening for phaeochromocytoma : in which hypertensive patients? A semiological study of 2585 patients, including 11 with phaeochromocytoma (author’s transl)] [PubMed: 7208288]

18.

Markou A, Sertedaki A, Kaltsas G, Androulakis II, Marakaki C, Pappa T, Gouli A, Papanastasiou L, Fountoulakis S, Zacharoulis A, Karavidas A, Ragkou D, Charmandari E, Chrousos GP, Piaditis GP. Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension. J. Clin. Endocrinol. Metab. 2015;100(8):2857–64. [PubMed: 25974737]

19.

Agarwal A, Gupta S, Mishra AK, Singh N, Mishra SK. Normotensive pheochromocytoma: Institutional experience. World J. Surg. 2005;29(9):1185–1188. [PubMed: 16091986]

20.

Bhansali A, Rajput R, Behra A, Rao KLN, Khandelwal N, Radotra BD. Childhood sporadic pheochromocytoma: Clinical profile and outcome in 19 patients. J. Pediatr. Endocrinol. Metab. 2006;19(5):749–756. [PubMed: 16789642]

21.

Otsuka F, Ogura T, Nakagawa M, Hayakawa N, Kataoka H, Oishi T, Makino H. Normotensive bilateral pheochromocytoma with Lindau disease: case report. Endocr. J. 1996;43(6):719–23. [PubMed: 9075613]

22.

Lenders JWM, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SKG, Murad MH, Naruse M, Pacak K, Young WF. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2014;99(6):1915–1942. [PubMed: 24893135]

23.

Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM, Edwards H. The diagnosis of Cushing’s syndrome: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2008;93(5):1526–1540. [PMC free article: PMC2386281] [PubMed: 18334580]

24.

Fardella CE, Mosso L, Gómez-Sánchez C, Cortés P, Soto J, Gómez L, Pinto M, Huete A, Oestreicher E, Foradori A, Montero J. Primary Hyperaldosteronism in Essential Hypertensives: Prevalence, Biochemical Profile, and Molecular Biology 1 . J. Clin. Endocrinol. Metab. 2000;85(5):1863–1867. [PubMed: 10843166]

25.

Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, Papadopoulos N, Vogiatzis K, Zamboulis C. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet (London, England). 2008;371(9628):1921–6. [PubMed: 18539224]

26.

Surendran P, Drenos F, Young R, Warren H, Cook JP, Manning AK, Grarup N, Sim X, Barnes DR, Witkowska K, Staley JR, Tragante V, Tukiainen T, Yaghootkar H, Masca N, Freitag DF, Ferreira T, Giannakopoulou O, Tinker A, Harakalova M, Mihailov E, Liu C, Kraja AT, Fallgaard Nielsen S, Rasheed A, Samuel M, Zhao W, Bonnycastle LL, Jackson AU, Narisu N, Swift AJ, Southam L, Marten J, Huyghe JR, Stančáková A, Fava C, Ohlsson T, Matchan A, Stirrups KE, Bork-Jensen J, Gjesing AP, Kontto J, Perola M, Shaw-Hawkins S, Havulinna AS, Zhang H, Donnelly LA, Groves CJ, Rayner NW, Neville MJ, Robertson NR, Yiorkas AM, Herzig K-H, Kajantie E, Zhang W, Willems SM, Lannfelt L, Malerba G, Soranzo N, Trabetti E, Verweij N, Evangelou E, Moayyeri A, Vergnaud A-C, Nelson CP, Poveda A, Varga T V, Caslake M, de Craen AJ, Trompet S, Luan J, Scott RA, Harris SE, Liewald DC, Marioni R, Menni C, Farmaki A-E, Hallmans G, Renström F, Huffman JE, Hassinen M, Burgess S, Vasan RS, Felix JF., CHARGE-Heart Failure Consortium. Uria-Nickelsen M, Malarstig A, Reily DF, Hoek M, Vogt T, Lin H, Lieb W, EchoGen Consortium, Traylor M, Markus HF, METASTROKE Consortium, Highland HM, Justice AE, Marouli E, GIANT Consortium, Lindström J, Uusitupa M, Komulainen P, Lakka TA, Rauramaa R, Polasek O, Rudan I, Rolandsson O, Franks PW, Dedoussis G, Spector TD, EPIC-InterAct Consortium, Jousilahti P, Männistö S, Deary IJ, Starr JM, Langenberg C, Wareham NJ, Brown MJ, Dominiczak AF, Connell JM, Jukema JW, Sattar N, Ford I, Packard CJ, Esko T, Mägi R, Metspalu A, de Boer RA, van der Meer P, van der Harst P, Lifelines Cohort Study, Gambaro G, Ingelsson E, Lind L, de Bakker PI, Numans ME, Brandslund I, Christensen C, Petersen ER, Korpi-Hyövälti E, Oksa H, Chambers JC, Kooner JS, Blakemore AI, Franks S, Jarvelin M-R, Husemoen LL, Linneberg A, Skaaby T, Thuesen B, Karpe F, Tuomilehto J, Doney AS, Morris AD, Palmer CN, Holmen OL, Hveem K, Willer CJ, Tuomi T, Groop L, Käräjämäki A, Palotie A, Ripatti S, Salomaa V, Alam DS, Shafi Majumder A Al, Di Angelantonio E, Chowdhury R, McCarthy MI, Poulter N, Stanton A V, Sever P, Amouyel P, Arveiler D, Blankenberg S, Ferrières J, Kee F, Kuulasmaa K, Müller-Nurasyid M, Veronesi G, Virtamo J, Deloukas P, Wellcome Trust Case Control Consortium, Elliott P, Understanding Society Scientific Group, Zeggini E, Kathiresan S, Melander O, Kuusisto J, Laakso M, Padmanabhan S, Porteous D, Hayward C, Scotland G, Collins FS, Mohlke KL, Hansen T, Pedersen O, Boehnke M, Stringham HM, EPIC-CVD Consortium, Frossard P, Newton-Cheh C, CHARGE+ Exome Chip Blood Pressure Consortium, Tobin MD, Nordestgaard BG, T2D-GENES Consortium, GoT2DGenes Consortium, ExomeBP Consortium, CHD Exome+ Consortium, Caulfield MJ, Mahajan A, Morris AP, Tomaszewski M, Samani NJ, Saleheen D, Asselbergs FW, Lindgren CM, Danesh J, Wain L V, Butterworth AS, Howson JM, Munroe PB. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat. Genet. 2016;48(10):1151–1161. [PMC free article: PMC5056636] [PubMed: 27618447]

27.

Liu C, Kraja AT, Smith JA, Brody JA, Franceschini N, Bis JC, Rice K, Morrison AC, Lu Y, Weiss S, Guo X, Palmas W, Martin LW, Chen YDI, Surendran P, Drenos F, Cook JP, Auer PL, Chu AY, Giri A, Zhao W, Jakobsdottir J, Lin LA, Stafford JM, Amin N, Mei H, Yao J, Voorman A, Larson MG, Grove ML, Smith A V., Hwang SJ, Chen H, Huan T, Kosova G, Stitziel NO, Kathiresan S, Samani N, Schunkert H, Deloukas P, Li M, Fuchsberger C, Pattaro C, Gorski M, Kooperberg C, Papanicolaou GJ, Rossouw JE, Faul JD, Kardia SLR, Bouchard C, Raffel LJ, Uitterlinden AG, Franco OH, Vasan RS, O’Donnell CJ, Taylor KD, Liu K, Bottinger EP, Gottesman O, Daw EW, Giulianini F, Ganesh S, Salfati E, Harris TB, Launer LJ, Dörr M, Felix SB, Rettig R, Völzke H, Kim E, Lee WJ, Lee I, Te, Sheu WHH, Tsosie KS, Edwards DRV, Liu Y, Correa A, Weir DR, Völker U, Ridker PM, Boerwinkle E, Gudnason V, Reiner AP, Van Duijn CM, Borecki IB, Edwards TL, Chakravarti A, Rotter JI, Psaty BM, Loos RJF, Fornage M, Ehret GB, Newton-Cheh C, Levy D, Chasman DI. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat. Genet. 2016;48(10):1162–1170. [PMC free article: PMC5320952] [PubMed: 27618448]

28.

Melcescu E, Koch CA. Endocrine Hypertension.; 2000. Available at: http://www​.ncbi.nlm.nih​.gov/pubmed/25905183. Accessed December 21, 2019.

29.

Vasan RS, Evans JC, Larson MG, Wilson PWF, Meigs JB, Rifai N, Benjamin EJ, Levy D. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N. Engl. J. Med. 2004;351(1):33-41+111. [PubMed: 15229305]

30.

Seiler L, Rump LC, Schulte-Mönting J, Slawik M, Borm K, Pavenstädt H, Beuschlein F, Reincke M. Diagnosis of primary aldosteronism: value of different screening parameters and influence of antihypertensive medication. Eur. J. Endocrinol. 2004;150(3):329–37. [PubMed: 15012618]

31.

Streeten DHP, Tomycz N, Anderson GH. Reliability of screening methods for the diagnosis of primary aldosteronism. Am. J. Med. 1979;67(3):403–413. [PubMed: 474586]

32.

Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R, Allolio B, Seufert J, Schirpenbach C, Beuschlein F, Bidlingmaier M, Endres S, Quinkler M. Participants of the German Conn’s Registry. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J. Clin. Endocrinol. Metab. 2009;94(4):1125–30. [PubMed: 19190103]

33.

Ulick S, Blumenfeld JD, Atlas SA, Wang JZ, Vaughan ED. The unique steroidogenesis of the aldosteronoma in the differential diagnosis of primary aldosteronism. J. Clin. Endocrinol. Metab. 1993;76(4):873–8. [PubMed: 8473399]

34.

Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, Van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004;136(6):1227–1235. [PubMed: 15657580]

35.

Asbach E, Williams TA, Reincke M. Recent Developments in Primary Aldosteronism. Exp. Clin. Endocrinol. Diabetes. 2016;124(6):335–41. [PubMed: 27219889]

36.

Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF. The management of primary aldosteronism: Case detection, diagnosis, and treatment: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2016;101(5):1889–1916. [PubMed: 26934393]

37.

Toniato A, Bernante P, Rossi GP, Pelizzo MR. The role of adrenal venous sampling in the surgical management of primary aldosteronism. World J. Surg. 2006;30(4):624–627. [PubMed: 16568223]

38.

Gordon RD, Stowasser M. Familial forms broaden the horizons for primary aldosteronism. Trends Endocrinol. Metab. 1998;9(6):220–227. [PubMed: 18406272]

39.

Stowasser M, Gordon RD. Primary aldosteronism: From genesis to genetics. Trends Endocrinol. Metab. 2003;14(7):310–317. [PubMed: 12946873]

40.

Melcescu E, Phillips J, Moll G, Subauste JS, Koch CA. 11Beta-hydroxylase deficiency and other syndromes of mineralocorticoid excess as a rare cause of endocrine hypertension. Horm. Metab. Res. 2012;44(12):867–78. [PubMed: 22932914]

41.

Grim CE, Weinberger MH. Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism. Pediatrics. 1980;65(3):597–604. [PubMed: 6987607]

42.

Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, Lin JP, Huggard P, Gordon RD, Stratakis CA. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J. Med. Genet. 2000;37(11):831–5. [PMC free article: PMC1734468] [PubMed: 11073536]

43.

Charmandari E, Sertedaki A, Kino T, Merakou C, Hoffman DA, Hatch MM, Hurt DE, Lin L, Xekouki P, Stratakis CA, Chrousos GP. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. J. Clin. Endocrinol. Metab. 2012;97(8):E1532–9. [PMC free article: PMC3410272] [PubMed: 22628607]

44.

Weinberger MH, Fineberg NS. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch. Intern. Med. 1993;153(18):2125–9. [PubMed: 8379804]

45.

Wulczyn K, Perez-Reyes E, Nussbaum RL, Park M. Primary aldosteronism associated with a germline variant in CACNA1H. BMJ Case Rep. 2019;12(5) [PMC free article: PMC6536178] [PubMed: 31126930] [CrossRef]

46.

Seidel E, Schewe J, Scholl UI. Genetic causes of primary aldosteronism. Exp. Mol. Med. 2019;51(11) [PMC free article: PMC6834635] [PubMed: 31695023] [CrossRef]

47.

Schirpenbach C, Seiler L, Maser-Gluth C, Beuschlein F, Reincke M, Bidlingmaier M. Automated chemiluminescence-immunoassay for aldosterone during dynamic testing: comparison to radioimmunoassays with and without extraction steps. Clin. Chem. 2006;52(9):1749–55. [PubMed: 16858077]

48.

Stowasser M, Gordon RD. Aldosterone assays: an urgent need for improvement. Clin. Chem. 2006;52(9):1640–2. [PubMed: 16940462]

49.

Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess syndrome: an overview. Arq. Bras. Endocrinol. Metabol. 2004;48(5):687–96. [PubMed: 15761540]

50.

Vaidya A, Dluhy R. Hyperaldosteronism. MDText.com, Inc; 2000.

51.

Tsiavos V, Markou A, Papanastasiou L, Kounadi T, Androulakis II, Voulgaris N, Zachaki A, Kassi E, Kaltsas G, Chrousos GP, Piaditis GP. A new highly sensitive and specific overnight combined screening and diagnostic test for primary aldosteronism. Eur. J. Endocrinol. 2016;175(1):21–8. [PubMed: 27072145]

52.

Stowasser M, Gordon RD. Primary aldosteronism - Careful investigation is essential and rewarding. Molecular and Cellular Endocrinology. 2004;217:33–39. In. Vol. [PubMed: 15134798]

53.

Fourkiotis V, Vonend O, Diederich S, Fischer E, Lang K, Endres S, Beuschlein F, Willenberg HS, Rump LC, Allolio B, Reincke M, Quinkler M. Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism. Eur. J. Endocrinol. 2013;168(1):75–81. [PubMed: 23033260]

54.

Jansen PM, van den Meiracker AH, Jan Danser AH. Aldosterone synthase inhibitors: pharmacological and clinical aspects. Curr. Opin. Investig. Drugs. 2009;10(4):319–26. [PubMed: 19337952]

55.

Stowasser M, Gordon RD. Primary aldosteronism: Learning from the study of familial varieties. J. Hypertens. 2000;18(9):1165–1176. [PubMed: 10994747]

56.

Sukor N, Gordon RD, Yee KK, Jones M, Stowasser M. Role of unilateral adrenalectomy in bilateral primary aldosteronism: A 22-year single center experience. J. Clin. Endocrinol. Metab. 2009;94(7):2437–2445. [PubMed: 19401369]

57.

Letavernier E, Peyrard S, Amar L, Zinzindohoué F, Fiquet B, Plouin P-F. Blood pressure outcome of adrenalectomy in patients with primary hyperaldosteronism with or without unilateral adenoma. J. Hypertens. 2008;26(9):1816–23. [PubMed: 18698217]

58.

Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J. Surg. 2005;29(2):155–9. [PubMed: 15650803]

59.

Rossi GP. Surgically correctable hypertension caused by primary aldosteronism. Best Pract. Res. Clin. Endocrinol. Metab. 2006;20(3):385–400. [PubMed: 16980201]

60.

Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi GL, Novello M, Favret G, Melis A, Cavarape A, Sechi LA. Insulin sensitivity in patients with primary aldosteronism: A follow-up study. J. Clin. Endocrinol. Metab. 2006;91(9):3457–3463. [PubMed: 16822818]

61.

Matrozova J, Steichen O, Amar L, Zacharieva S, Jeunemaitre X, Plouin PF. Fasting plasma glucose and serum lipids in patients with primary aldosteronism a controlled cross-sectional study. Hypertension. 2009;53(4):605–610. [PubMed: 19221213]

62.

Kempers MJE, Lenders JWM, Van Outheusden L, Van Der Wilt GJ, Kool LJS, Hermus ARMM, Deinum J. Systematic review: Diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann. Intern. Med. 2009;151(5):329–337. [PubMed: 19721021]

63.

Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin. Proc. 1983;58(12):802–804. [PubMed: 6645626]

64.

Guerrero MA, Schreinemakers JMJ, Vriens MR, Suh I, Hwang J, Shen WT, Gosnell J, Clark OH, Duh Q-Y. Clinical spectrum of pheochromocytoma. J. Am. Coll. Surg. 2009;209(6):727–32. [PubMed: 19959041]

65.

Erlic Z, Rybicki L, Peczkowska M, Golcher H, Kann PH, Brauckhoff M, Müssig K, Muresan M, Schäffler A, Reisch N, Schott M, Fassnacht M, Opocher G, Klose S, Fottner C, Forrer F, Plöckinger U, Petersenn S, Zabolotny D, Kollukch O, Yaremchuk S, Januszewicz A, Walz MK, Eng C, Neumann HPH., European-American Pheochromocytoma Study Group. Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin. Cancer Res. 2009;15(20):6378–85. [PubMed: 19825962]

66.

Jiménez C, Cote G, Arnold A, Gagel RF. Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J. Clin. Endocrinol. Metab. 2006;91(8):2851–8. [PubMed: 16735498]

67.

Eisenhofer G, Lenders JWM, Goldstein DS, Mannelli M, Csako G, Walther MM, Brouwers FM, Pacak K. Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin. Chem. 2005;51(4):735–744. [PubMed: 15718487]

68.

Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JWM, Pacak K. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J. Clin. Endocrinol. Metab. 2001;86(5):1999–2008. [PubMed: 11344198]

69.

Neumann HPH, Vortmeyer A, Schmidt D, Werner M, Erlic Z, Cascon A, Bausch B, Januszewicz A, Eng C. Evidence of MEN-2 in the original description of classic pheochromocytoma. N. Engl. J. Med. 2007;357(13):1311–5. [PubMed: 17898100]

70.

Bravo EL, Tagle R. Pheochromocytoma: State-of-the-art and future prospects. Endocr. Rev. 2003;24(4):539–553. [PubMed: 12920154]

71.

Lu Y, Li P, Gan W, Zhao X, Shen S, Feng W, Xu Q, Bi Y, Guo H, Zhu D. Clinical and Pathological Characteristics of Hypertensive and Normotensive Adrenal Pheochromocytomas. Exp. Clin. Endocrinol. Diabetes. 2016;124(6):372–379. [PubMed: 27219882]

72.

Prejbisz A, Lenders JWM, Eisenhofer G, Januszewicz A. Cardiovascular manifestations of phaeochromocytoma. J. Hypertens. 2011;29(11):2049–2060. [PubMed: 21826022]

73.

Giavarini A, Chedid A, Bobrie G, Plouin PF, Hagège A, Amar L. Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma. Heart. 2013;99(19):1438–1444. [PubMed: 23837998]

74.

Y-Hassan S. Clinical Features and Outcome of Pheochromocytoma-Induced Takotsubo Syndrome. Analysis of 80 Published Cases. Am. J. Cardiol. 2016;117(11):1836–1844. [PubMed: 27103159]

75.

Gagnon N, Mansour S, Bitton Y, Bourdeau I. TAKOTSUBO-LIKE CARDIOMYOPATHY in A LARGE COHORT of PATIENTS with PHEOCHROMOCYTOMA and PARAGANGLIOMA. Endocr. Pract. 2017;23(10):1178–1192. [PubMed: 28704094]

76.

Miehle K, Kratzsch J, Lenders JWM, Kluge R, Paschke R, Koch CA. Adrenal incidentaloma diagnosed as pheochromocytoma by plasma chromogranin A and plasma metanephrines. J. Endocrinol. Invest. 2005;28(11):1040–2. [PubMed: 16483187]

77.

Bausch B, Tischler AS, Schmid KW, Leijon H, Eng C, Neumann HPH. Max Schottelius: Pioneer in Pheochromocytoma. J. Endocr. Soc. 2017;1(7):957–964. [PMC free article: PMC5689150] [PubMed: 29264546]

78.

Eisenhofer G, Lenders JWM, Siegert G, Bornstein SR, Friberg P, Milosevic D, Mannelli M, Linehan WM, Adams K, Timmers HJ, Pacak K. Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur. J. Cancer. 2012;48(11):1739–1749. [PMC free article: PMC3372624] [PubMed: 22036874]

79.

Niculescu DA, Ismail G, Poiana C. Plasma free metanephrine and normetanephrine levels are increased in patients with chronic kidney disease. Endocr. Pract. 2014;20(2):139–44. [PubMed: 24014007]

80.

Eisenhofer G, Lattke P, Herberg M, Siegert G, Qin N, Därr R, Hoyer J, Villringer A, Prejbisz A, Januszewicz A, Remaley A, Martucci V, Pacak K, Ross HA, Sweep FCGJ, Lenders JWM. Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma. Ann. Clin. Biochem. 2013;50(1):62–69. [PMC free article: PMC4714582] [PubMed: 23065528]

81.

De Jong WHA, Eisenhofer G, Post WJ, Muskiet FAJ, De Vries EGE, Kema IP. Dietary influences on plasma and urinary metanephrines: Implications for diagnosis of catecholamine-producing tumors. J. Clin. Endocrinol. Metab. 2009;94(8):2841–2849. [PubMed: 19567530]

82.

Neumann HPH, Young WF, Eng C. Pheochromocytoma and Paraganglioma. N. Engl. J. Med. 2019;381(6):552–565. [PubMed: 31390501]

83.

Majumdar S, Friedrich CA, Koch CA, Megason GC, Fratkin JD, Moll GW. Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma. Pediatr. Blood Cancer. 2010;54(3):473–5. [PubMed: 19927285]

84.

Timmers HJLM, Gimenez-Roqueplo A-P, Mannelli M, Pacak K. Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr. Relat. Cancer. 2009;16(2):391–400. [PMC free article: PMC4711350] [PubMed: 19190077]

85.

Bhatia KSS, Ismail MM, Sahdev A, Rockall AG, Hogarth K, Canizales A, Avril N, Monson JP, Grossman AB, Reznek RH. 123I-metaiodobenzylguanidine (MIBG) scintigraphy for the detection of adrenal and extra-adrenal phaeochromocytomas: CT and MRI correlation. Clin. Endocrinol. (Oxf). 2008;69(2):181–8. [PubMed: 18394016]

86.

Lenders JWM, Pacak K, Walther MM, Marston Linehan W, Mannelli M, Friberg P, Keiser HR, Goldstein DS, Eisenhofer G. Biochemical diagnosis of pheochromocytoma: Which test is best? J. Am. Med. Assoc. 2002;287(11):1427–1434. [PubMed: 11903030]

87.

Koch CA. Should 123I-MIBG scintigraphy be part of the workup for pheochromocytomas? Nat. Clin. Pract. Endocrinol. Metab. 2009;5(2):76–7. [PubMed: 19165218]

88.

Koopmans KP, Jager PL, Kema IP, Kerstens MN, Albers F, Dullaart RPF. 111In-octreotide is superior to 123I-metaiodobenzylguanidine for scintigraphic detection of head and neck paragangliomas. J. Nucl. Med. 2008;49(8):1232–7. [PubMed: 18632829]

89.

Mazza A, Beltramello G, Armigliato M, Montemurro D, Zorzan S, Zuin M, Rampin L, Marzola MC, Grassetto G, Al-Nahhas A, Rubello D. Arterial hypertension and thyroid disorders: What is important to know in clinical practice? Ann. Endocrinol. (Paris). 2011;72(4):296–303. [PubMed: 21777903]

90.

Jimenez C, Cabanillas ME, Santarpia L, Jonasch E, Kyle KL, Lano EA, Matin SF, Nunez RF, Perrier ND, Phan A, Rich TA, Shah B, Williams MD, Waguespack SG. Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J. Clin. Endocrinol. Metab. 2009;94(2):386–91. [PubMed: 19017755]

91.

Neumann HPH, Tsoy U, Bancos I, Amodru V, Walz MK, Tirosh A, Kaur RJ, McKenzie T, Qi X, Bandgar T, Petrov R, Yukina MY, Roslyakova A, Van Der Horst-Schrivers ANA, Berends AMA, Hoff AO, Castroneves LA, Ferrara AM, Rizzati S, Mian C, Dvorakova S, Hasse-Lazar K, Kvachenyuk A, Peczkowska M, Loli P, Erenler F, Krauss T, Almeida MQ, Liu L, Zhu F, Recasens M, Wohllk N, Corssmit EPM, Shafigullina Z, Calissendorff J, Grozinsky-Glasberg S, Kunavisarut T, Schalin-Jäntti C, Castinetti F, Vlček P, Beltsevich D, Egorov VI, Schiavi F, Links TP, Lechan RM, Bausch B, Young WF, Eng C. Comparison of Pheochromocytoma-Specific Morbidity and Mortality among Adults with Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy. JAMA Netw. Open. 2019. [PMC free article: PMC6692838] [PubMed: 31397861] [CrossRef]

92.

Castinetti F, Waguespack SG, Machens A, Uchino S, Hasse-Lazar K, Sanso G, Else T, Dvorakova S, Qi XP, Elisei R, Maia AL, Glod J, Lourenço DM, Valdes N, Mathiesen J, Wohllk N, Bandgar TR, Drui D, Korbonits M, Druce MR, Brain C, Kurzawinski T, Patocs A, Bugalho MJ, Lacroix A, Caron P, Fainstein-Day P, Borson Chazot F, Klein M, Links TP, Letizia C, Fugazzola L, Chabre O, Canu L, Cohen R, Tabarin A, Spehar Uroic A, Maiter D, Laboureau S, Mian C, Peczkowska M, Sebag F, Brue T, Mirebeau-Prunier D, Leclerc L, Bausch B, Berdelou A, Sukurai A, Vlcek P, Krajewska J, Barontini M, Vaz Ferreira Vargas C, Valerio L, Ceolin L, Akshintala S, Hoff A, Godballe C, Jarzab B, Jimenez C, Eng C, Imai T, Schlumberger M, Grubbs E, Dralle H, Neumann HP, Baudin E. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. lancet. Diabetes Endocrinol. 2019;7(3):213–220. [PMC free article: PMC8132299] [PubMed: 30660595]

93.

Brauckhoff M, Gimm O, Thanh PN, Bär A, Ukkat J, Brauckhoff K, Bönsch T, Dralle H, McHenry CR, Thompson GB, Duh QY. Critical size of residual adrenal tissue and recovery from impaired early postoperative adrenocortical function after subtotal bilateral adrenalectomy. In: Surgery.Vol 134. Mosby Inc.; 2003:1020–1027. [PubMed: 14668736]

94.

Lodish MB, Sinaii N, Patronas N, Batista DL, Keil M, Samuel J, Moran J, Verma S, Popovic J, Stratakis CA. Blood pressure in pediatric patients with Cushing syndrome. J. Clin. Endocrinol. Metab. 2009;94(6):2002–8. [PMC free article: PMC2690429] [PubMed: 19293264]

95.

Isidori AM, Graziadio C, Paragliola RM, Cozzolino A, Ambrogio AG, Colao A, Corsello SM, Pivonello R., ABC Study Group. The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on cardiovascular complications. J. Hypertens. 2015;33(1):44–60. [PMC free article: PMC4342316] [PubMed: 25415766]

96.

Zacharieva S, Orbetzova M, Stoynev A, Shigarminova R, Yaneva M, Kalinov K, Nachev E, Elenkova A. Circadian blood pressure profile in patients with Cushing’s syndrome before and after treatment. J. Endocrinol. Invest. 2004;27(10):924–30. [PubMed: 15762039]

97.

Baid S, Nieman LK. Glucocorticoid excess and hypertension. Curr. Hypertens. Rep. 2004;6(6):493–499. [PubMed: 15527696]

98.

Juszczak A, Sulentic P, Grossman A. Cushing’s Syndrome.; 2000. Available at: http://www​.ncbi.nlm.nih​.gov/pubmed/25905314. Accessed January 16, 2020.

99.

Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann. N. Y. Acad. Sci. 2002;970:134–44. [PubMed: 12381548]

100.

Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. Endo Soc Cushing’s. J. Clin. Endocrinol. Metab. 2008;93(5):1526–40. [PMC free article: PMC2386281] [PubMed: 18334580]

101.

Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Endocrine Society. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2015;100(8):2807–31. [PMC free article: PMC4525003] [PubMed: 26222757]

102.

Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. ESEC 2016 Guideline incidentaloma adrenal. Eur. J. Endocrinol. 2016. [PubMed: 27390021] [CrossRef]

103.

Lopez D, Luque-Fernandez MA, Steele A, Adler GK, Turchin A, Vaidya A. “Nonfunctional” adrenal Tumors and the risk for incident diabetes and cardiovascular outcomes: A cohort study. Ann. Intern. Med. 2016;165(8):533–542. [PMC free article: PMC5453639] [PubMed: 27479926]

104.

Chatzellis E, Kaltsas G. Adrenal Incidentalomas.; 2000. Available at: http://www​.ncbi.nlm.nih​.gov/pubmed/25905250. Accessed January 16, 2020.

105.

Zeiger MA, Thompson GB, Duh Q-Y, Hamrahian AH, Angelos P, Elaraj D, Fishman E, Kharlip J., American Association of Clinical Endocrinologists, American Association of Endocrine Surgeons. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executive summary of recommendations. Endocr. Pract. 15(5):450–3. [PubMed: 19632968]

106.

Hannah-Shmouni F, Melcescu E, Koch CA. Testing for Endocrine Hypertension.; 2000. Available at: http://www​.ncbi.nlm.nih​.gov/pubmed/25905199. Accessed December 21, 2019.

107.

Gläsker S, Neumann HPH, Koch CA, Vortmeyer A. Von Hippel-Lindau Disease.; 2000. Available at: http://www​.ncbi.nlm.nih​.gov/pubmed/25905347. Accessed January 16, 2020.

108.

Kino T, Vottero A, Charmandari E, Chrousos GP. Familial/sporadic glucocorticoid resistance syndrome and hypertension. Ann. N. Y. Acad. Sci. 2002;970:101–11. [PubMed: 12381545]

109.

Chrousos GP, Vingerhoeds A, Brandon D, Eil C, Pugeat M, DeVroede M, Loriaux DL, Lipsett MB. Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J. Clin. Invest. 1982;69(6):1261–1269. [PMC free article: PMC370198] [PubMed: 6282933]

110.

Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: Clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J. Clin. Endocrinol. Metab. 2008;93(5):1563–1572. [PMC free article: PMC2386273] [PubMed: 18319312]

111.

Nebesio TD, Eugster EA. Observation of hypertension in children with 21-hydroxylase deficiency: a preliminary report. Endocrine. 2006;30(3):279–82. [PubMed: 17526939]

112.

Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, Reynolds JC, Hanna RM, Merke DP. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 2012;97(12):4429–38. [PMC free article: PMC3513542] [PubMed: 22990093]

113.

Kim MS, Merke DP. Cardiovascular disease risk in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Semin. Reprod. Med. 2009;27(4):316–21. [PMC free article: PMC4830727] [PubMed: 19530065]

114.

Zachmann M, Tassinari D, Prader A. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients. J. Clin. Endocrinol. Metab. 1983;56(2):222–9. [PubMed: 6296182]

115.

New MI, Geller DS, Fallo F, Wilson RC. Monogenic low renin hypertension. Trends Endocrinol. Metab. 2005;16(3):92–97. [PubMed: 15808805]

116.

Mimouni M, Kaufman H, Roitman A, Morag C, Sadan N. Hypertension in a neonate with 11 β-hydroxylase deficiency. Eur. J. Pediatr. 1985;143(3):231–233. [PubMed: 3872797]

117.

Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HFL, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2010;95(9):4133–4160. [PMC free article: PMC2936060] [PubMed: 20823466]

118.

Speiser PW, White PC. Congenital adrenal hyperplasia. N. Engl. J. Med. 2003;349(8):776–88. [PubMed: 12930931]

119.

Melcescu E, Griswold M, Xiang L, Belk S, Montgomery D, Bray M, Del Ben KS, Uwaifo GI, Marshall GD, Koch CA. Prevalence and cardiometabolic associations of the glucocorticoid receptor gene polymorphisms N363S and BclI in obese and non-obese black and white Mississippians. Hormones (Athens). 11(2):166–77. [PubMed: 22801563]

120.

Hochberg Z, Even L, Zadik Z. Mineralocorticoids in the mechanism of gynecomastia in adrenal hyperplasia caused by 11β-hydroxylase deficiency. J. Pediatr. 1991;118(2):258–260. [PubMed: 1993958]

121.

Kacem M, Moussa A, Khochtali I, Nabouli R, Morel Y, Zakhama A. Bilateral adrenalectomy for severe hypertension in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: Long term follow-up. Ann. Endocrinol. (Paris). 2009;70(2):113–118. [PubMed: 19195642]

122.

New MI. Male pseudohermaphroditism due to 17 alpha-hydroxylase deficiency. J. Clin. Invest. 1970;49(10):1930–41. [PMC free article: PMC322683] [PubMed: 5456802]

123.

Wong S-L, Shu S-G, Tsai C-R. Seventeen alpha-hydroxylase deficiency. J. Formos. Med. Assoc. 2006;105(2):177–81. [PubMed: 16477341]

124.

Costa-Santos M, Kater CE, Auchus RJ., Brazilian Congenital Adrenal Hyperplasia Multicenter Study Group. Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 2004;89(1):49–60. [PubMed: 14715827]

125.

Müssig K, Wehrmann M, Horger M, Maser-Gluth C, Häring HU, Overkamp D. Adrenocortical carcinoma producing 11-deoxycorticosterone: A rare cause of mineralocorticoid hypertension. J. Endocrinol. Invest. 2005;28(1):61–65. [PubMed: 15816373]

126.

Carvajal CA, Gonzalez AA, Romero DG, González A, Mosso LM, Lagos ET, Hevia M del P, Rosati MP, Perez-Acle TO, Gomez-Sanchez CE, Montero JA, Fardella CE. Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 2003;88(6):2501–7. [PubMed: 12788846]

127.

Lin-Su K, Zhou P, Arora N, Betensky BP, New MI, Wilson RC. In vitro expression studies of a novel mutation delta299 in a patient affected with apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 2004;89(5):2024–7. [PubMed: 15126515]

128.

New MI, Levine LS, Biglieri EG, Pareira J, Ulick S. Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension. J. Clin. Endocrinol. Metab. 1977;44(5):924–33. [PubMed: 870517]

129.

Wilson RC, Krozowski ZS, Li K, Obeyesekere VR, Razzaghy-Azar M, Harbison MD, Wei JQ, Shackleton CH, Funder JW, New MI. A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 1995;80(7):2263–2266. [PubMed: 7608290]

130.

Stewart PM, Krozowski ZS, Gupta A, Milford D V., Howie AJ, Sheppard MC, Whorwood CB. Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11β-hydroxysteroid dehydrogenase type 2 gene. Lancet. 1996;347(8994):88–91. [PubMed: 8538347]

131.

Stewart PM, Corrie JE, Shackleton CH, Edwards CR. Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle. J. Clin. Invest. 1988;82(1):340–9. [PMC free article: PMC303514] [PubMed: 3164727]

132.

Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM. Cloning of human mineralocorticoid receptor complementary DNA: Structural and functional kinship with the glucocorticoid receptor. Science (80-.) . 1987;237(4812):268–275. [PubMed: 3037703]

133.

Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: Target tissue specificity is enzyme, not receptor, mediated. Science (80-.) . 1988;242(4878):583–585. [PubMed: 2845584]

134.

Heilmann P, Buchheim E, Wacker J, Ziegler R. Alteration of the activity of the 11beta-hydroxysteroid dehydrogenase in pregnancy: relevance for the development of pregnancy-induced hypertension? J. Clin. Endocrinol. Metab. 2001;86(11):5222–6. [PubMed: 11701681]

135.

Quinkler M, Oelkers W, Diederich S. In Vivo Measurement of Renal 11β-Hydroxysteroid Dehydrogenase Type 2 Activity . J. Clin. Endocrinol. Metab. 2000;85(12):4921–4922. [PubMed: 11134165]

136.

Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FTF, Sigler PB, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science (80-.) . 2000;289(5476):119–123. [PubMed: 10884226]

137.

Liddle GW, Bledsoe T, Coppage WS. Hypertension reviews. J. Tenn. Med. Assoc. 1974;67(8):669. [PubMed: 4852328]

138.

Gordon RD, Geddes RA, Pawsey CG, O’Halloran MW. Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction. Australas. Ann. Med. 1970;19(4):287–94. [PubMed: 5490655]

139.

Geller DS. Mineralocorticoid resistance. Clin. Endocrinol. (Oxf). 2005;62(5):513–520. [PubMed: 15853818]

140.

Klemm SA, Gordon RD, Tunny TJ, Thompson RE. The syndrome of hypertension and hyperkalemia with normal GFR (Gordon’s syndrome): is there increased proximal sodium reabsorption? Clin. Invest. Med. 1991;14(6):551–8. [PubMed: 1838973]

141.

Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford D V, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. Human hypertension caused by mutations in WNK kinases. Science. 2001;293(5532):1107–12. [PubMed: 11498583]

142.

Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr. Rev. 2004;25(2):309–340. [PubMed: 15082524]

143.

Sakoh T, Sekine A, Mori T, Mizuno H, Kawada M, Hiramatsu R, Hasegawa E, Hayami N, Yamanouchi M, Suwabe T, Sawa N, Ubara Y, Fujimaru T, Sohara E, Shinichi U, Hoshino J, Takaichi K. A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4. Mol. Genet. genomic Med. 2019;7(6):e705. [PMC free article: PMC6565545] [PubMed: 31044551]

144.

Xie J, Craig L, Cobb MH, Huang C-L. Role of with-no-lysine [K] kinases in the pathogenesis of Gordon’s syndrome. Pediatr. Nephrol. 2006;21(9):1231–6. [PubMed: 16683163]

145.

Kahle KT, Wilson FH, Leng Q, Lalioti MD, O’Connell AD, Dong K, Rapson AK, MacGregor GG, Giebisch G, Hebert SC, Lifton RP. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat. Genet. 2003;35(4):372–6. [PubMed: 14608358]

146.

Tobin MD, Raleigh SM, Newhouse S, Braund P, Bodycote C, Ogleby J, Cross D, Gracey J, Hayes S, Smith T, Ridge C, Caulfield M, Sheehan NA, Munroe PB, Burton PR, Samani NJ. Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population. Circulation. 2005;112(22):3423–9. [PubMed: 16301342]

147.

Koch CA, Bornstein SR, Birkenfeld AL. Introduction to Hanefeld Symposium: 40+ years of metabolic syndrome. Rev. Endocr. Metab. Disord. 2016;17(1):1–4. [PubMed: 27165257]

148.

Haffner SM, Ruilope L, Dahlöf B, Abadie E, Kupfer S, Zannad F. Metabolic syndrome, new onset diabetes, and new end points in cardiovascular trials. J. Cardiovasc. Pharmacol. 2006;47(3):469–75. [PubMed: 16633092]

149.

Saad MF, Rewers M, Selby J, Howard G, Jinagouda S, Fahmi S, Zaccaro D, Bergman RN, Savage PJ, Haffner SM. Insulin resistance and hypertension: The insulin resistance atherosclerosis study. Hypertension. 2004;43(6):1324–1331. [PubMed: 15123571]

150.

Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N. Engl. J. Med. 1987;317(6):350–7. [PubMed: 3299096]

151.

Levy J, Gavin JR, Hammerman MR, Avioli L V. Ca2+-Mg2+-ATPase Activity in Kidney Basolateral Membrane in Non-Insulin-Dependent Diabetic Rats: Effect of Insulin. Diabetes. 1986;35(8):899–905. [PubMed: 2942433]

152.

Bogaert YE, Linas S. The role of obesity in the pathogenesis of hypertension. Nat. Clin. Pract. Nephrol. 2009;5(2):101–11. [PubMed: 19107106]

153.

Graessler J, Schwudke D, Schwarz PEH, Herzog R, Shevchenko A, Bornstein SR. Top-down lipidomics reveals ether lipid deficiency in blood plasma of hypertensive patients. PLoS One. 2009;4(7):e6261. [PMC free article: PMC2705678] [PubMed: 19603071]

154.

McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S. Enhanced parathyroid function in essential hypertension: A homeostatic response to a urinary calcium leak. Hypertension. 1980;2(2):162–168. [PubMed: 7380520]

155.

Bukoski RD, Ishibashi K, Bian K. Vascular actions of the calcium-regulating hormones. Semin. Nephrol. 1995;15(6):536–49. [PubMed: 8588114]

156.

Hulter HN, Melby JC, Peterson JC, Cooke CR. Chronic continuous PTH infusion results in hypertension in normal subjects. J. Clin. Hypertens. 1986;2(4):360–70. [PubMed: 3543230]

157.

Bucher HC, Cook RJ, Guyatt GH, Lang JD, Cook DJ, Hatala R, Hunt DL. Effects of dietary calcium supplementation on blood pressure. A meta-analysis of randomized controlled trials. JAMA. 1996;275(13):1016–22. [PubMed: 8596234]

158.

Allender PS, Cutler JA, Follmann D, Cappuccio FP, Pryer J, Elliott P. Dietary calcium and blood pressure: A meta-analysis of randomized clinical trials. Ann. Intern. Med. 1996;124(9):825–831. [PubMed: 8610952]

159.

Bollerslev J, Rosen T, Mollerup CL, Nordenström J, Baranowski M, Franco C, Pernow Y, Isaksen GA, Godang K, Ueland T, Jansson S. Effect of surgery on cardiovascular risk factors in mild primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 2009;94(7):2255–2261. [PubMed: 19351725]

160.

Bollerslev J, Jansson S, Mollerup CL, Nordenström J, Lundgren E, Tørring O, Varhaug J-E, Baranowski M, Aanderud S, Franco C, Freyschuss B, Isaksen GA, Ueland T, Rosen T. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J. Clin. Endocrinol. Metab. 2007;92(5):1687–92. [PubMed: 17284629]

161.

Rubin MR, Maurer MS, McMahon DJ, Bilezikian JP, Silverberg SJ. Arterial stiffness in mild primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 2005;90(6):3326–30. [PubMed: 15769995]

162.

Walker MD, Fleischer J, Rundek T, McMahon DJ, Homma S, Sacco R, Silverberg SJ. Carotid vascular abnormalities in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 2009;94(10):3849–56. [PMC free article: PMC2758727] [PubMed: 19755478]

163.

Concistrè A, Grillo A, La Torre G, Carretta R, Fabris B, Petramala L, Marinelli C, Rebellato A, Fallo F, Letizia C. Ambulatory blood pressure monitoring-derived short-term blood pressure variability in primary hyperparathyroidism. Endocrine. 2018;60(1):129–137. [PubMed: 28702887]

164.

Storvall S, Ryhänen EM, Heiskanen I, Sintonen H, Roine RP, Schalin-Jäntti C. Surgery Significantly Improves Neurocognition, Sleep, and Blood Pressure in Primary Hyperparathyroidism: A 3-Year Prospective Follow-Up Study. Horm. Metab. Res. 2017;49(10):772–777. [PubMed: 28922677]

165.

Ejlsmark-Svensson H, Rolighed L, Rejnmark L. Effect of Parathyroidectomy on Cardiovascular Risk Factors in Primary Hyperparathyroidism: A Randomized Clinical Trial. J. Clin. Endocrinol. Metab. 2019;104(8):3223–3232. [PubMed: 30860588]

166.

Ekmekci A, Abaci N, Colak Ozbey N, Agayev A, Aksakal N, Oflaz H, Erginel-Unaltuna N, Erbil Y. Endothelial function and endothelial nitric oxide synthase intron 4a/b polymorphism in primary hyperparathyroidism. J. Endocrinol. Invest. 2009;32(7):611–6. [PubMed: 19574729]

167.

Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the fourth international workshop. In: Journal of Clinical Endocrinology and Metabolism.Vol 99. Endocrine Society; 2014:3561–3569. [PMC free article: PMC5393490] [PubMed: 25162665]

168.

Danzi S, Klein I. Thyroid hormone and blood pressure regulation. Curr. Hypertens. Rep. 2003;5(6):513–520. [PubMed: 14594573]

169.

Prisant LM, Gujral JS, Mulloy AL. Hyperthyroidism: a secondary cause of isolated systolic hypertension. J. Clin. Hypertens. (Greenwich). 2006;8(8):596–599. [PMC free article: PMC8109671] [PubMed: 16896276]

170.

Kempf T, Wollert KC. Risk stratification in critically ill patients: GDF-15 scores in adult respiratory distress syndrome. Crit. Care. 2013;17(4):173. [PMC free article: PMC4057454] [PubMed: 23905849]

171.

Berta E, Lengyel I, Halmi S, Zrínyi M, Erdei A, Harangi M, Páll D, Nagy E V, Bodor M. Hypertension in Thyroid Disorders. Front. Endocrinol. (Lausanne). 2019;10:482. [PMC free article: PMC6652798] [PubMed: 31379748]

172.

Fountoulakis S, Tsatsoulis A. Molecular genetic aspects and pathophysiology of endocrine hypertension. Hormones (Athens). 5(2):90–106. [PubMed: 16807222]

173.

Iglesias P, Acosta M, Sánchez R, Fernández-Reyes MJ, Mon C, Díez JJ. Ambulatory blood pressure monitoring in patients with hyperthyroidism before and after control of thyroid function. Clin. Endocrinol. (Oxf). 2005;63(1):66–72. [PubMed: 15963064]

174.

Völzke H, Alte D, Dörr M, Wallaschofski H, John U, Felix SB, Rettig R. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J. Hypertens. 2006;24(10):1947–53. [PubMed: 16957553]

175.

Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr. Rev. 2008;29(1):76–131. [PubMed: 17991805]

176.

Streeten DHP, Anderson GH, Howland T, Chiang R, Smulyan H. Effects of thyroid function on blood pressure. Recognition of hypothyroid hypertension. Hypertension. 1988;11(1):78–83. [PubMed: 3338842]

177.

Iqbal A, Schirmer H, Lunde P, Figenschau Y, Rasmussen K, Jorde R. Thyroid stimulating hormone and left ventricular function. J. Clin. Endocrinol. Metab. 2007;92(9):3504–3510. [PubMed: 17566088]

178.

Stabouli S, Papakatsika S, Kotsis V. Hypothyroidism and hypertension. Expert Rev. Cardiovasc. Ther. 2010;8(11):1559–65. [PubMed: 21090931]

179.

Ittermann T, Thamm M, Wallaschofski H, Rettig R, Völzke H. Serum thyroid-stimulating hormone levels are associated with blood pressure in children and adolescents. J. Clin. Endocrinol. Metab. 2012;97(3):828–34. [PubMed: 22205713]

180.

Cai Y, Ren Y, Shi J. Blood pressure levels in patients with subclinical thyroid dysfunction: a meta-analysis of cross-sectional data. Hypertens. Res. 2011;34(10):1098–105. [PubMed: 21796125]

181.

Colao A, Ferone D, Marzullo P, Lombardi G. Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management. Endocr. Rev. 2004;25(1):102–152. [PubMed: 14769829]

182.

Rizzoni D, Porteri E, Giustina A, De Ciuceis C, Sleiman I, Boari GEM, Castellano M, Muiesan ML, Bonadonna S, Burattin A, Cerudelli B, Agabiti-Rosei E. Acromegalic patients show the presence of hypertrophic remodeling of subcutaneous small resistance arteries. Hypertens. (Dallas, Tex. 1979) 2004;43(3):561–5. [PubMed: 14988391]

183.

Lombardi G, Galdiero M, Auriemma RS, Pivonello R, Colao A. Acromegaly and the cardiovascular system. Neuroendocrinology. 2006;83(3–4):211–7. [PubMed: 17047385]

184.

Colao A, Terzolo M, Bondanelli M, Galderisi M, Vitale G, Reimondo G, Ambrosio MR, Pivonello R, Lombardi G, Angeli A. degli Uberti EC. GH and IGF-I excess control contributes to blood pressure control: results of an observational, retrospective, multicentre study in 105 hypertensive acromegalic patients on hypertensive treatment. Clin. Endocrinol. (Oxf). 2008;69(4):613–20. [PubMed: 18410555]

185.

Bielohuby M, Roemmler J, Manolopoulou J, Johnsen I, Sawitzky M, Schopohl J, Reincke M, Wolf E, Hoeflich A, Bidlingmaier M. Chronic growth hormone excess is associated with increased aldosterone: a study in patients with acromegaly and in growth hormone transgenic mice. Exp. Biol. Med. (Maywood). 2009;234(8):1002–9. [PubMed: 19491373]

186.

Sardella C, Urbani C, Lombardi M, Nuzzo A, Manetti L, Lupi I, Rossi G, Del Sarto S, Scattina I, Di Bello V, Martino E, Bogazzi F. The beneficial effect of acromegaly control on blood pressure values in normotensive patients. Clin. Endocrinol. (Oxf). 2014;81(4):573–81. [PubMed: 24661019]

187.

González B, Vargas G, de Los Monteros ALE, Mendoza V, Mercado M. Persistence of Diabetes and Hypertension After Multimodal Treatment of Acromegaly. J. Clin. Endocrinol. Metab. 2018;103(6):2369–2375. [PubMed: 29618021]

188.

Ullah MI, Uwaifo GI, Nicholas WC, Koch CA. Does vitamin d deficiency cause hypertension? Current evidence from clinical studies and potential mechanisms. Int. J. Endocrinol. 2010;2010:579640. [PMC free article: PMC2798112] [PubMed: 20049157]

189.

Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men. Am. J. Med. 2007;120(10):835–40. [PubMed: 17904450]

190.

Shabsigh R, Arver S, Channer KS, Eardley I, Fabbri A, Gooren L, Heufelder A, Jones H, Meryn S, Zitzmann M. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome. Int. J. Clin. Pract. 2008;62(5):791–8. [PMC free article: PMC2327081] [PubMed: 18266714]

191.

Sattler FR, Castaneda-Sceppa C, Binder EF, Schroeder ET, Wang Y, Bhasin S, Kawakubo M, Stewart Y, Yarasheski KE, Ulloor J, Colletti P, Roubenoff R, Azen SP. Testosterone and growth hormone improve body composition and muscle performance in older men. J. Clin. Endocrinol. Metab. 2009;94(6):1991–2001. [PMC free article: PMC2690426] [PubMed: 19293261]

192.

Widdowson WM, Gibney J. The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: a metaanalysis. J. Clin. Endocrinol. Metab. 2008;93(11):4413–7. [PubMed: 18697875]

193.

Mekala KC, Tritos NA. Effects of recombinant human growth hormone therapy in obesity in adults: a meta analysis. J. Clin. Endocrinol. Metab. 2009;94(1):130–7. [PubMed: 18940879]

194.

Zhang J, Ge R, Matte-Martone C, Goodwin J, Shlomchik WD, Mamula MJ, Kooshkabadi A, Hardy MP, Geller D. Characterization of a novel gain of function glucocorticoid receptor knock-in mouse. J. Biol. Chem. 2009;284(10):6249–59. [PMC free article: PMC2649105] [PubMed: 19017639]

195.

Michailidou Z, Carter RN, Marshall E, Sutherland HG, Brownstein DG, Owen E, Cockett K, Kelly V, Ramage L, Al-Dujaili EAS, Ross M, Maraki I, Newton K, Holmes MC, Seckl JR, Morton NM, Kenyon CJ, Chapman KE. Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet. FASEB J. 2008;22(11):3896–907. [PMC free article: PMC2749453] [PubMed: 18697839]