Overview of Endocrine Hypertension - Tahoma Clinic · Overview of Endocrine Hypertension Christian...

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

Overview of Endocrine HypertensionChristian A Koch, MD, PhD, FACP, MACEProf. Koch is presently the Head of the Medicover MVZ Oldenburg and affiliated with the Carl von Ossietzky University as well as theTechnical University of Dresden. He also isAdjunct Professor at the University of Louisville, KY. Before June 2017, Koch had served as a tenured professor at the University of Mississippi Medical Center in Jackson, MS,

George P Chrousos, MD, MACE, MACP, FRCPDivision of Endocrinology, Metabolism and Diabetes (N.C.N., G.P.C., E.C.), First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘AghiaSophia’ Children's Hospital, Athens, 11527, Greece; Division of Endocrinology and Metabolism (N.C.N., G.P.C., E.C.), Center of Clinical, Experimental Surgery and TranslationalResearch, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece

Last Update: October 26, 2016.

ABSTRACTEndocrine 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 andglucocorticoid resistance (Chrousos syndrome) can also lead to hypertension. Nonadrenal endocrine disorders, such as growth hormoneexcess or deficiency, thyroid dysfunction, testosterone deficiency, vitamin D deficiency, obesity-associated hypertension, insulinresistance and metabolic syndrome are also linked to hypertension. In this chapter, we provide an overview of endocrine hypertensionincluding rare syndromes of mineralocorticoid excess. For complete coverage of all related areas of endocrinology, we invite you to visitour FREE web-book, WWW.ENDOTEXT.ORG.

INTRODUCTIONHypertension affects approximately 31% of Americans (1, 2) and approx. 33% of the Mozambican population (3). The prevalence ofhypertension is even higher than 33% in Germany, England, Spain, and Scandinavian countries. The assignment of a diagnosis ofhypertension is dependent on the appropriate measurement of blood pressure, the level of the blood pressure elevation, and the durationof follow-up (4). Data from the National Health and Nutrition Examination Survey 2011-2012 showed an increase in the prevalence ofhypertension in all age groups compared to 1991 (5). Among adults with hypertension in that survey, 52% achieved a BP of less than140/90 mm Hg with 76% taking antihypertensives, and with 83% being aware of their hypertension.

The Eight Report of the Joint National Committee for the management of high blood pressure (BP) in adults provides different BPtargets for various groups, therefore defines hypertension more broadly and individually (6). BP cutoff / treatment targets are now beingcontroversially discussed after publication of the results of the Systolic Blood Pressure Intervention Trial (SPRINT) (7,8). BPassessment should be based on the mean of 2 or more properly measured seated BP readings on each of 2 or more office visits. Based onexpert opinion, the 8 Joint National Committee panel recommends treating a blood pressure exceeding 139/89 mm Hg for adults fromage 18 years to 60 and in all patients with diabetes or nondiabetic chronic kidney disease. For individuals aged 60 years or older, the BPgoal should be less than 150/90 mm Hg and hypertensive people age 30 through 59 y should have a diastolic goal of less than 90 mmHg (6). The SPRINT study included 9361 hypertensive patients with a high risk cardiovascular profile who were nondiabetic and olderthan age 50 y. Randomization was aimed to a target systolic BP of 130 to 140 mm Hg vs. less than 120 mm Hg, identical to the targetsin the 2010 Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (9). Exclusion criteria of the SPRINT study were ahistory of diabetes or prior cerebrovascular accident. 31% of the study individuals were African American and 28% had chronic kidneydisease. The group with a SBP less than 120 mm Hg had a 24% reduction in events such as myocardial infarction, nonmyocardialinfarction acute coronary syndrome, acute decompensated heart failure, or death from cardiovascular disease. There was an increasednumber of visits to the emergency room for hypotension in the intensive treatment group. Both SPRINT and ACCORD studies showedan adverse effect of intensive BP treatment regarding glomerular filtration rate in people with initial normal renal function, but there wasno increase in the incidence of end-stage renal disease in either study in the intensive treatment arm. The ACCORD study showed areduction in the rate of total stroke by 40%. Summarizing the results of 17,114 participants enrolled in recent BP trials, Krakoffconcludes that a SBP in the range of 125-135 mm Hg range is likely to be optimal on treatment for most hypertensive patients (10).

For children, hypertension is defined as an average systolic blood pressure (BP) and/or diastolic BP that is greater than the 95thpercentile for age, gender, and height on more than 3 occasions. Normal BP in children is defined as a SBP and DBP smaller than the90th percentile for age, gender, and height (11,12). Cuff size and arm circumference play a very important role in measuring correctblood pressures. In children and adolescents, BP is classified as normal (<90 percentile for SBP or DBP), prehypertensive, stage 1hypertensive (95 to the 99 percentile plus 5 mm Hg), and stage 2 hypertensive (>99 percentile plus 5 m Hg).

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

th

th

th th th

Overview of Endocrine Hypertension - Endotext - NCBI Boo... https://www.ncbi.nlm.nih.gov/books/NBK278980/?report=...

1 of 24 2/11/19, 8:44 AM

reason for office visits to physicians in the United States. Analysis of the Framingham study data suggested that individuals from age 40to 69 years have a increasing risk of stroke or coronary artery disease mortality with every 20 mm Hg increment in SBP.

Despite the increasing understanding of the pathophysiology of hypertension, control of the disease is often difficult and far fromoptimal. Recent large meta-analyses and genotype studies have identified some “risk genes” for hypertension. Surendran and colleagues(13) found a low frequency nonsense variant in the gene ENPEP, which codes for the enzyme aminopeptidase A that convertsangiotensin II into angiotensin III and therefore being part of the regulation of the renin-angiotensin-aldosterone system. Liu andcolleagues (14) observed associations for the aggregation of rare and low frequency missense variants in the genes NPR1, DBH, andPTPMT1. The gene DBH codes for the enzyme dopamine beta-hydroxylase, which catalyzes the conversion of dopamine intonoradrenaline and, thereby, influences the autonomic nervous system. The gene PTPMT1 codes for the mitochondrial protein tyrosinephosphatase 1, which influences insulin production.

Idiopathic (primary or essential) hypertension accounts for approximately 85 % of the diagnosed cases. It is estimated thatapproximately 15 % of hypertensive patients have identifiable conditions that result in blood pressure elevation (secondaryhypertension), such as primary renal disease, oral contraceptive use, sleep apnea syndrome, congenital or acquired cardiovasculardisease (i.e. coarctation of the aorta) and excess hormonal secretion.

Endocrine Hypertension accounts for approx. 3% of the secondary forms of hypertension and is a term assigned to states in whichhormonal derangements result in clinically significant hypertension (15,16). The most common causes of endocrine hypertension areexcess production of mineralocorticoids (i.e. primary hyperaldosteronism), catecholamines (pheochromocytoma), thyroid hormone, andglucocorticoids (Cushing syndrome) (17). One important question in this regard is when to screen for secondary causes. Some patientswith hypertension, but without primary aldosteronism, demonstrate ACTH-dependent aldosterone hypersecretion by stress (18). Theclinician should carefully screen for cardinal signs and symptoms of Cushing syndrome, hyper- or hypo-thyroidism, acromegaly, insulinresistance (acanthosis nigricans), or pheochromocytoma. Hypertension in young patients and refractory hypertension (characterized bypoorly controlled blood pressure on > 3 antihypertensive drugs) should alert the physician to screen for secondary causes. Theimportance of endocrine-mediated hypertension resides in the fact that in most cases, the cause is clear and can be traced to the actionsof a hormone, often produced in excess by a tumor, such as an aldosteronoma, in a patient with hypertension due to primaryaldosteronism. 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.

CLINICAL DIAGNOSIS OF ENDOCRINE HYPERTENSIONThe first step when evaluating a patient with suspected endocrine-related hypertension is to exclude other causes of secondaryhypertension, particularly renal disorders. A detailed medical history and review of systems should be obtained. The onset ofhypertension and the response to previous anti-hypertensive treatment should be determined. Consideration of adherence to prescribedantihypertensive 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 indetail.

The prevalence of resistant hypertension is high: 53% of patients in NHANES had a blood pressure < 140/90 mm Hg vs. 48% in theFramingham Heart Study. In NHANES participants with chronic kidney disease, 37% had a BP < 130/80 mm Hg. In ALLHAT, 34% ofpatients remained uncontrolled after 5 year follow-up on at least 2 antihypertensive drugs (19).

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 systemsshould include disease-specific questions. Most patients harboring a pheochromocytoma are symptomatic. Symptoms may includeheadaches, 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% forpheochromocytoma (20). More recent studies suggest that this typical triad of symptoms is found much less frequently, for instance, inonly 10% of cases (21). Ten or more percent of patients with pheochromocytoma may not have any clinical symptoms and may benormotensive (21-28).

Patients with Cushing syndrome often complain of weight gain, insomnia, depression, easy bruising and fatigue. Acne and hirsutism (inwomen) can also be observed. The challenge these days is to recognize patients with evolving Cushing’s syndrome amongst the manyobese and often poorly controlled diabetic individuals. An Endocrine Society Clinical Practice Guideline can assist in this task (29).Primary hyperaldosteronism is manifested by mild to severe hypertension. Hypokalemia can be present, but it is not a universal findingand there is normokalemic and normotensive primary aldosteronism (30). Polyuria, myopathy and cardiac dysrhythmias may occur incases of severe hypokalemia. A thorough physical exam with attention to evidence of target organ injury and features of secondary


2 of 24 2/11/19, 8:44 AM

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 inendotext.com: Section Endocrine Testing Protocols – Chapter 7. Testing for Endocrine hypertension, Melcescu & Koch; SectionAdrenal Disease and Function - Chapter 35, Von Hippel-Lindau Disease. Gläsker S, Neumann HPH, Koch CA, Vortmeyer AO.

Figure 1 Adrenal Steroid Synthesis.

Z Glom = zona glomerulosa; Z Fas = zona fasciculata; Z Ret = zona reticularis; 19-H = 19-Hydroxylase; HSD = Hydroxysteroiddehydrogenase; P450aro = aromatase; 5alpha-Red = 5alpha-Reductase. The 3 adrenal cortex zones Z Glom, Z Fas, and Z Ret standabove 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 convertsdeoxycorticosterone to 18-OH-Corticosterone and 11-Deoxycortisol to cortisol, etc. (modified from ref. 31: Koch CA. Encyclopedia ofEndocrine Disease, 2004)

PRIMARY ALDOSTERONISMIn a community-based study (Framingham Offspring) comprising 1688 nonhypertensive participants, increased plasma aldosteroneconcentrations within the physiologic range predisposed persons to the development of hypertension (32). Previous studies havereported a prevalence of primary aldosteronism (PA) of 1-2 %. Newer data suggest an overall prevalence of >5% and possibly > 10%among the hypertensive population (33-36). In patients with mild to moderate hypertension without hypokalemia, the prevalence of PAhas been reported to be 3% (37). In patients with resistant hypertension, the prevalence ranges between 17 and 23 % (36). In a studyinvolving 1616 patients with resistant hypertension, 21% (338 pts) had an Aldosterone/Renin Ratio of > 65 with concomitant plasmaaldosterone concentrations of > 416 pmol/L (15 ng). After salt suppression testing, only 11% (182 pts) of these patients had primaryaldosteronism (38). In patients with adrenal incidentaloma and hypertension, the prevalence of aldosteronism is low at 2% (36). Many(up to 63%) patients with PA may not present with hypokalemia but are rather normokalemic (36,39-42). Low renin hypertension is notalways easy to differentiate from PA (43). Born-Frontsberg and colleagues found that 56% of 553 patients with primary aldosteronismhad hypokalemia and 16% had cardio-and cerebrovascular comorbidities (44). In addition to the patient group with resistanthypertension, screening for primary aldosteronism is recommended for those patients with diuretic-induced or spontaneoushypokalemia, those with hypertension and a family history of early-onset hypertension or cerebrovascular accident at young age, andthose with hypertension and an adrenal incidentaloma (12,36,45). Recently, a study including 148 hypertensive patients found that a newovernight diagnostic test using pharmaceutical renin-angiotensin-aldosterone system blockade with dexamethasone, captopril andvalsartan, has low cost, is rapid, safe and easy to perform with an estimated sensitivity of 98% and specificity of 100% (46).


3 of 24 2/11/19, 8:44 AM

The 2016 Endocrine Society clinical practice guideline for the management of primary aldosteronism suggest that patients withhypertension, spontaneous hypokalemia, undetectable renin, and a plasma aldosterone concentration above 20 ng/dl (550 pmol/L) maynot need to undergo further confirmatory testing but instead proceed with further imaging and/or adrenal vein sampling or (if unable orunwilling to undergo surgery/adrenalectomy) treatment with a mineralocorticoid antagonist (36).

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 previouslythought and is an important differential diagnosis, since it is treated medically with aldosterone antagonists, rather than byadrenalectomy (47,48). Selective use of adrenal venous sampling is helpful in this setting (48-50). Very rarely, PA can be caused by anadrenal 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, type 2, andtype 3 (51-53). Patients with familial aldosteronism type 3 produce amounts of 18-OHF and 18-oxoF 10-1,000 times higher thanpatients with familial aldosteronism type 1 (approx. 20 times normal) or patients with familial aldosteronism type 2 or sporadicaldosteronism (54). Patients with familial aldosteronism type 3 have a paradoxical rise of aldosterone after dexamethasone, atrophy ofthe zona glomerulosa, diffuse hyperplasia of the zona fasciculata, and severe hypertension in early childhood (around age 7 years) that isresistant to drug therapy but curable by bilateral adrenalectomy (55).

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 (56,57). The hybrid gene has been identified on chromosome 8. Undernormal conditions, aldosterone secretion is mainly stimulated by hyperkalemia and angiotensin II. An increase of serum potassium of0.1 mmol/L increases aldosterone by 35%. In familial hyperaldosteronism type 1 or glucocorticoid-remediable aldosteronism, urinaryhybrid steroids 18-oxocortisol and 18-hydroxycortisol are approx. 20-fold higher than in sporadic aldosteronomas. Intracranialaneurysms and hemorrhagic stroke are clinical features frequently associated with familial hyperaldosteronism type 1 (58). Thediagnosis is made by documenting dexamethasone suppression of serum aldosterone using the Liddle’s Test (dexamethasone 0.5 mg q6h for 48h should reduce plasma aldosterone to nearly undetectable levels (below 4 ng/dl) (59,60) or by genetic testing (Southern Blotor PCR). In contrast, familial hyperaldosteronism type 2 is not glucocorticoid-remediable. The responsible gene has been linked tochromosome 7p22 but has not yet been identified (61). Familial aldosteronism type 3 is caused by heterozygous gain-of-functionmutation in the potassium channel GIRK4 (encoded by KCNJ5) leading to an increase in aldosterone synthase expression andproduction of aldosterone (51,62).

Another evolving familial form of primary aldosteronism appears to be linked to germline mutations in CACNA1D and CACNA1H,genes that encode voltage-gated calcium channels (51).

Primary aldosteronism is screened for by measuring plasma aldosterone (PA) and plasma renin activity (PRA) or direct reninconcentration. There are various assays for measuring aldosterone, which can prove to be problematic (63-65). Measuring PRA iscomplicated and includes generating angiotensin from endogenous angiotensinogen. Quantification of renin’s conversion ofangiotensinogen to angiotensin is performed utilizing radioimmunoassays for PRA, which are not standardized among laboratories.Measuring plasma renin molecules directly by an automated chemiluminescence immnoassay as direct renin concentration also isfeasible. A PA/PRA-ratio > 30 with a concomitant PA > 20 ng/dl has a sensitivity of 90% and specificity of 91% for primaryaldosteronism (66). Because low renin hypertension can be difficult to distinguish from PA, an upright plasma aldosterone of at least 15ng/dl may be helpful (43).

As hypokalemia can reduce aldosterone secretion, it should be corrected before further diagnostic work-up. Also, if a patient withhypertension treated with an ACE inhibitor or ARB, calcium channel blocker, and a diuretic (all of which should increase PRA, therebylower the PA/PRA-ratio or ARR), still has a suppressed renin and 2-digit plasma aldosterone level, primary aldosteronism is likely.Because of medication interference, it is commonly recommended to withdraw betablockers, ACE inhibitors, ARBs (angiotensinreceptor blockers), renin inhibitors, dihydropyridine calcium channel blockers, nonsteroidal anti-inflammatory drugs, and centralalpha2-agonists approx. 2 weeks before PA/PRA-ratio or ARR testing, and to hold spironolactone, eplerenone, amiloride, andtriamterene, and loop diuretics approx. 4 weeks before ARR testing. Licorice root products should also be withheld 4 weeks prior totesting (36). Confirmatory testing can be done by different techniques (36).

To clinically distinguish hyperplasia from unilateral adenoma, imaging with computed tomography and magnetic resonance imaging arehelpful but adrenal venous sampling (AVS) with cosyntropin (ACTH) infusion is often essential if the patient desires surgery in case ofa unilateral adenoma: 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-sidealdosterone/cortisol: low-side aldosterone/cortisol).

If a patient does not desire surgery/adrenalectomy for a unilateral aldosteronoma/hyperplasia (Figure 2), medical therapy should be


4 of 24 2/11/19, 8:44 AM

initiated. AVS and CT/MRI of the adrenal glands show a unilateral abnormality in 60.5% and 56%, respectively, but were congruent onthe involved side in the same patient in only 37% in a recent systematic review (67). If a patient is older than age 40 years, the risk foran adrenal incidentaloma increases (68). Unilateral adrenalectomy can be helpful in some patients with primary aldosteronism andbilateral adrenal hyperplasia (69).

Figure 2 Conn adenoma.

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

Adrenal adenomas producing aldosterone should be removed. Nearly all patients with such endocrine hypertension have improvedblood pressure control and up to 60% are cured (normotensive without antihypertensive therapy) from hypertension (70-72). Thisoutcome is influenced by various factors including age, duration of hypertension, coexistence of renal insufficiency, use of more than 2antihypertensive drugs preoperatively, family history of hypertension, and others. Bilateral adrenal hyperplasia is treated withspironolactone, eplerenone, and/or amiloride (36,73). Currently under investigation are aldosterone synthase inhibitors, which may nothave any nongenomic/non-mineralocorticoid receptor-mediated adverse effects (74). In cases of familial hyperaldosteronism type 1,dexamethasone is also effective by suppressing ACTH and subsequently aldosterone overproduction. Parameters of insulin sensitivitycan be restored to normal with treatment of PA (75). A cross-sectional study including 460 pts with primary aldosteronism and 1363controls with essential hypertension found no significant difference between pre- and postoperative levels of fasting plasma glucose andserum lipids (76). This topic has been extensively reviewed from a pro and contra perspective (77).

PHEOCHROMOCYTOMAThese rare neuroendocrine tumors are composed of chromaffin tissue containing neurosecretory granules (78). Mostpheochromocytomas are sporadic but some occur in an inherited form. Recent studies suggest up to 24% of pheochromocytomas are


5 of 24 2/11/19, 8:44 AM

hereditary (79). 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 (28,80,81). There iscontroversy when genetic testing should be obtained in patients with pheochromocytoma, especially considering cost effectiveness(81,82). Erlic and coworkers (81) used six predictors to develop a screening algorithm in order to find out which patients should begenetically tested for germline mutations. If any of these 6 predictors is present, the patient should be tested, according to these authors(Figure 3).

Figure 3

Proposed Algorithm for Genetic Testing in pheochromocytoma. Modified from Erlic et al., 2009 (ref. 81)

The 2014 Endocrine Society clinical practice guideline recommends that all patients with pheochromocytoma-paraganglioma shouldbe engaged in shared decision making for genetic testing (28). All patients with paraganglioma should undergo testing for succinatedehydrogenase (SDH) mutations and those patients with metastatic disease should be tested for SDHB mutations. Recognizing thedistinct genotype-phenotype presentations of patients with hereditary tumors, the guideline recommends a personalized approach topatient management.

The biochemical profile of pheochromocytomas associated with the aforementioned hereditary syndromes varies (83). Patients withMEN 2 and VHL syndrome may have clinically “silent” pheochromocytomas. Normotensive patients may also have sporadicpheochromocytomas (24). It appears that approx. 15% of patients with pheochromocytoma are normotensive (22-27). Blood pressuredoes not correlate with circulating catecholamines in patients with pheochromocytoma (84).

Although in older textbooks one finds still the term Sipple syndrome for multiple endocrine neoplasia type 2, it now appears that theoriginal description of classic MEN-2 was made by Felix Fraenkel in 1886 (85).

Hypertension is paroxysmal in approximately 50% of patients with pheochromocytoma. The diagnosis can be established by measuringfree plasma or fractionated urinary metanephrines and normetanephrines (28). When plasma free metanephrines cannot be measured by


6 of 24 2/11/19, 8:44 AM

HPLC with electrochemical detection or high-throughput automated liquid–chromatography-tandem mass spectrometry (LC-MS/MS),measuring plasma free metanephrines by RIA or measuring plasma chromogranin A may represent good markers forpheochromocytoma (86-89). In rare circumstances, pheochromocytomas release large amounts of dopamine (90). In patients with renalfailure, plasma concentrations of free metanephrines can be increased several fold (91-93).

Approximately 35% of extra-adrenal pheochromocytomas are malignant (metastasizing) as opposed to approximately 10% of thosearising in the adrenal gland. The risk for malignancy increases when the tumor exceeds 5 cm in size and when there is a germlinemutation in the SDHB gene (94-96). Therefore, for such tumors exceeding 6 cm in size, open adrenalectomy is the suggested procedurefor tumor removal rather than laparoscopic or retroperitoneoscopic minimally invasive tumor removal, to ensure complete tumorresection, prevent tumor rupture, and avoid local recurrence (page 1931 in ref. 28; Koch, Figure 4a,b, unpublished observation in apatient with MEN2-related bilateral pheochromocytomas and unilateral tumor recurrence 11 years after bilateral adrenalectomy, photo:courtesy of Prof. Andrea Tannapfel).

Figure 4a Computed tomography showing recurrence of a right adrenal pheochromocytoma.


7 of 24 2/11/19, 8:44 AM

Figure 4b Macroscopic photo of a right adrenal pheochromocytoma removed from the above patient withmultiple endocrine neoplasia type 2

CT or MR imaging can localize the tumor in approx. 95 % of cases. For malignant pheochromocytomas, 18F-Fluorodopamine and 18F-FDG PET appears to be more helfpul than 123I-MIBG or 131I-MIBG scintigraphy (28,97). In fact, MIBG scintigraphy shouldnowadays only been used in selected patients (98,99). Many medications can interfere with 123I-MIBG or 131I-MIBG uptake (forinstance, calcium channel blockers, antipsychotics) and should be discontinued before the scan/imaging. The 2014 Endocrine Societyguideline (28) recommends the use of 123I-MIBG in patients with metastatic pheochromocytoma-paraganglioma when radiotherapywith 131I-MIBG is planned and occasionally in some patients with an increased risk for metastatic disease (large tumor size, extra-adrenal tumor, multifocal or recurrent disease).

For patients with head and neck paragangliomas, 111In-octreotide has a very good sensitivity (100). Approx. 50% of patients withmalignant pheochromocytomas respond to 131I-MIBG therapy by partial remission or at least stable disease (94). Chemotherapy isusually administered according to the so-called Averbuch protocol from 1988. New therapies may include tyrosine kinase inhibitors inselected patients (101-103).

CONGENITAL ADRENAL HYPERPLASIA: 11BETA-HYDROXYLASE DEFICIENCYThe most common cause of congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency. Hypertension per se has not beenregarded as a component of this syndrome. Recent data have suggested that hypertension may be more prevalent in this patientpopulation than previously thought (104-106).

Approx. 5% of all cases of CAH care caused by 11beta-hydroxylase deficiency. 11beta-hydroxylase is responsible for the conversion ofdeoxycorticosterone (DOC) to corticosterone (precursor of aldosterone) and 11-deoxycortisol to cortisol. In approximately 2/3 ofindividuals affected by a deficiency of this enzyme, monogenic low renin hypertension with low aldosterone levels ensues caused byaccumulation of 11-deoxycortisol and DOC (107,108). The earliest age of onset of hypertension was reported at birth (109). Theinheritance mode is autosomal recessive. The responsible gene CYP11B1 is located on chromosome 8 and mutated (110). Sincecorticotropin (ACTH) is chronically elevated and precursors such as 17-OH progesterone and androstendione accumulate, androgenproduction is increased and may lead to prenatal virilization with resulting pseudohermaphroditism in females. Males may develop


8 of 24 2/11/19, 8:44 AM

pseudoprecocious puberty, short stature, and sometimes prepubertal gynecomastia (111,112). Usually, glucocorticoid replacementreduces hypertension in these patients. In selected patients, bilateral adrenalectomy may be safe and effective in managing bloodpressure (113).

CONGENITAL ADRENAL HYPERPLASIA: 17ALPHA-HYDROXYLASE DEFICIENCYThis enzyme deficiency is rare and leads to diminished production of cortisol and sex steroids. Chronic elevation of ACTH causes anincreased production of DOC and corticosterone with subsequent hypertension, hypokalemia, low aldosterone concentrations withsuppressed renin as well as pseudohermaphroditism in XY males (114), and sexual infantilism and primary amenorrhea in females(115,116). Diagnosis may be delayed until puberty. Plasma adrenal androgen levels are low as are cortisol, aldosterone, plasma reninactivity, and 17alpha-hydroxyprogesterone. DOC, corticosterone, and 18-hydroxycorticosterone are elevated. Blood pressure is reducedby glucocorticoid replacement. The responsible gene for cytochrome P450C17 is located on chromosome 10q24.

APPARENT MINERALOCORTICOID EXCESSLow-renin hypertension (undetectable aldosterone, hypokalemia) can present in various forms, one of them is apparentmineralocorticoid excess (AME), an autosomal recessive disorder caused by deficiency of the 11beta-hydroxysteroid dehydrogenasetype 2 (11beta-HSD2) enzyme (117-120). This enzyme converts cortisol to the inactive cortisone in renal tubular cells.

In 1977, New et al. (121) first described this syndrome and in 1995 Wilson et al. (122) first reported mutations in the 11beta-HSD2 genelocated on chromosome 16q22 cause AME. The 11beta-HSD2 enzyme is co-expressed with the mineralocorticoid receptor in renaltubular cells and leads to conversion of cortisol to cortisone (123). Cortisone does not bind to the mineralocorticoid receptor. Cortisoland aldosterone bind with equal affinity to the mineralocorticoid receptor but normal circulating concentrations of cortisol are 100 to1000 fold higher than those of aldosterone (124). If 11beta-HSD2 is oversaturated or defective, more cortisol will be available to bind tothe mineralocorticoid receptor (125). Diminished 11beta-HSD2 activity may be hereditary or acquired. Acquired deficiency of thisenzyme 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/short stature, hypertension, hypokalemia, diabetes insipidus renalis, andnephrocalcinosis. Diminished 11beta-HSD2 activity may play a role in the pathogenesis of preeclampsia (126). The diagnosis of AMEcan be established by measuring free unconjugated steroids in urine (free cortisol/free cortisone ratio), and/or steroid metabolites(tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone) (127). 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 MC receptor can be mutated leading to the onset of hypertension before age 20 (128). In vitro experiments demonstrate thatprogesterone and spironolactone, usually antagonists of the mineralocorticoid receptor, become agonists in Geller syndrome, suggesting“gain of function” mutations in the MC gene on chromosome 4q31. The inheritance pattern is autosomal-dominant.

LIDDLE SYNDROMEIn 1963, Liddle (129) described patients with severe hypertension, hypokalemia, and metabolic alkalosis, who had low plasmaaldosterone 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 codingfor the beta- or gamma-subunit of the renal epithelial sodium channel, located at chromosome 16p13, lead to constitutive activation ofrenal sodium reabsorption and subsequent volume expansion. The 24-h urine cortisone/cortisol ratio is normal.

PSEUDOHYPALDOSTERONISM TYPE 2Pseudohypoaldosteronism type 2 or Gordon’s syndrome (130) is a rare Mendelian disorder, transmitted in an autosomal dominantfashion, and can cause low renin hypertension (131). It has an unknown prevalence, since many patients remain undiagnosed. Publishedfamilies with this condition (hypertension, hyperkalemia, metabolic acidosis, normal renal function, low/normal aldosterone levels) arepredominantly from Australia (Gordon et al.) or the United States (Lifton et al.). Hypertension in these patients may develop as aconsequence of increased renal salt reabsorption, and hyperkalemia ensues as a result of reduced renal K excretion despite normalglomerular filtration and aldosterone secretion (132). The reduced renal secretion of potassium makes this condition look like analdosterone-deficient state, thus the term “pseudohypoaldosteronism”.

These features are chloride-dependent. Infusion of sodium chloride instead of sodium bicarbonate corrects the abnormalities, as does theadministration of thiazide diuretics, which inhibit salt reabsorption in the distal nephron. Gordon and coworkers found that all featurescould be reversed by very strict dietary salt restriction (130). Gordon syndrome is an autosomal, dominantly inherited disorder with


9 of 24 2/11/19, 8:44 AM

genes mapping to chromosomes 1, 12, and 17 (133,134). Mutations have been identified in WNK kinases WNK1 and WNK4 onchromosomes 12 and 17, respectively (133). Abnormalities such as activating mutations in the amiloride-sensitive sodium channel ofthe distal renal tubule are responsible for the clinical phenotype (135,136). Severe dietary salt restriction, antihypertensives, withpreferably use of thiazide diuretics, can control the hypertension in this syndrome. Interestingly, common variants in WNK1 contributeto blood pressure variation in the general population (137). Figure 5 lists conditions with low renin levels.

Figure 5 Low renin conditions

Insulin Resistance

The metabolic syndrome is characterized by hypertension, abdominal/visceral obesity, dyslipidemia, and insulin resistance (138). Atleast 24% of adults in the United States meet the criteria for the diagnosis of metabolic syndrome, and this number may even be higherfor individuals over the age of 50 years (139). Insulin resistance is significantly associated with hypertension in Hispanics and can causevascular dysfunction (140,141). Patients with essential hypertension often are insulin resistant (142). Interestingly, not all insulinresistant patients are obese. Excess weight gain, however, accounts for as much as 70% of the risk for essential hypertension and alsoincreases the risk for end stage renal disease (143). In insulin-sensitive tissues, insulin can directly stimulate the calcium pump leadingto calcium loss from the cell (144). In an adipocyte, elevated cytosolic calcium concentrations can induce insulin resistance. In a cellresistant to insulin, the insulin-induced calcium loss from cells would be decreased. With the subsequent increase in intracellularcalcium, vascular smooth muscle cells respond more eagerly to vasoconstrictors and thus lead to rising blood pressure. Othermechanisms possibly explaining the association of insulin resistance and hypertension are increased sodium retention and increasedactivity of the adrenergic nervous system (145). In obesity, increased production of most adipokines (bioactive peptides secreted byadipose tissue) impacts on multiple functions including insulin sensitivity, blood pressure, lipid metabolism, and others (146-148).

Hyperparathyroidism

Parathyroid hormone levels in hypertensive patients usually are in the normal range and appropriate for the serum calcium


10 of 24 2/11/19, 8:44 AM

concentration. However, patients with essential hypertension excrete more calcium compared to normotensive people, suggesting anenhanced parathyroid gland function (149). When infused, PTH is a vasodilator, although chronic infusion of PTH raises blood pressurein healthy subjects (150,151). High-calcium intake may lower blood pressure (152,153). However, hypercalcemia is associated with anincreased 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 afterparathyroidectomy (154,155). In patients with asymptomatic primary hyperparathyroidism, surgery/parathyroidectomy did not show anybenefit regarding blood pressure or quality of life when compared to medical management (156). On the other hand, severe hypertensionmay improve in patients with primary HPT who undergo parathyroidectomy (157). Arterial stiffness measured in the radial artery seemsto be increased in patients with mild primary hyperparathyroidism (158). Patients with primary hyperparathryoidism have carotidvascular abnormalities (159). Another contributory factor to hypertension in patients with primary HPT may be endothelial dysfunction(160). In MEN syndromes, hypertension in patients with hyperparathyroidism may be related to an underlying pheochromocytoma orprimary aldosteronism. Criteria for parathyroidectomy have recently been revisited at the Fourth International Workshop on themanagement of asymptomatic primary hyperparathyroidism, including now skeletal and/or renal involvement (nephrocalcinosis onimaging) (161).

Cushing Syndrome

Hypercortisolemia is associated with hypertension in approximately 80% of adult cases and half of children (162-166). A recentworkshop consensus paper attempts to rationalize the treatment of hypertension in patients with Cushing syndrome (167). In patientswith Cushing disease, night-time blood pressure decline is significantly lower than that in patients with essential hypertension (168).After cure of Cushing syndrome, approximately 30% of patients have persistent hypertension (169). In children and adolescents, bloodpressure normalization occurs in most patients within a year and seems to be dependent on the degree and duration of presurgicalhypercortisolemia (164,165). In patients with Cushing disease, renin and DOC levels are usually normal, whereas in ectopiccorticotropin syndrome, hypokalemia is common and related to an increased mineralocorticoid activity with suppressed renin andelevated DOC levels.

There are several mechanisms of blood pressure elevation in Cushing syndrome: increased hepatic production of angiotensinogen andcardiac 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 through stimulation of the mineralocorticoid receptor(170,171). 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, andothers listed in the recent Endocrine Society Clinical Practice Guideline (29). Therapy should be directed at removing glucocorticoidexcess (172). Hypokalemia (especially in patients with ectopic ACTH production) can be treated with mineralocorticoid receptorantagonists 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 numberof incidentally discovered tumors and nodules in various organs including the adrenal glands. The future challenge will be when and towhich extent to test individuals for disease conditions (173,174). For those individuals with adrenal incidentalomas but clearly lack ofclinical features of Cushing syndrome, subclinical hypercortisolism may be detected biochemically depending upon which cutoff valuesand assays will be used. 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 (175). A lower cutoff for serum cortisol suppression, i.e. 1.8 mcg/dl, usually rules out Cushing syndrome (173). Aprospective, randomized study including 45 patients with subclinical hypercortisolism and adrenal incidentalomas was divided into 23pts 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 theconservative group showed worsening of glycemic control, blood pressure and lipid profiles (176).

Glucocorticoid Resistance (Chrousos syndrome)

This autosomal recessive or dominant inherited disorder is rare and caused by inactivating mutations of the glucocorticoid receptor gene(177,178). Cortisol and ACTH are elevated but there are no clinical features of Cushing syndrome. Permanent elevation of ACTH canlead to stimulation of adrenal compounds with mineralocorticoid activity (corticosterone, DOC), along with elevated cortisol secretionmay lead to stimulation of the mineralocorticoid receptor, resulting in hypertension. In women, hirsutism and oligo-amenorrhea maydevelop through stimulation of androgens (androstendione, DHEA 5-androstendiol,). Clinically, children may present with ambiguousgenitalia and precocious puberty. Men may be infertile and/or oligospermic. Women may have acne, excessive hair, menstrualirregularities with oligo- anovulation, as well as infertility (177,179).

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, for instance spironolactone or eplerenone.


11 of 24 2/11/19, 8:44 AM

Hyperthyroidism

Hyperthyroidism increases systolic blood pressure by increasing heart rate, decreasing systemic vascular resistance, and raising cardiacoutput (180,181). In thyrotoxicosis, patients usually are tachycardic and have high cardiac output with an increased stroke volume andelevated systolic blood pressure (182,183). Approx. one third of patients with hyperthyroidism have hypertension which often resolvesafter achieving euthyroidism (184,185). Subclinical hyperthyroidism may contribute to left ventricular hypertrophy and thereby lead tohypertension (186), although it has not yet been found to be associated with hypertension (187).

Hypothyroidism

Hypothyroid patients have impaired endothelial function, increased systemic vascular resistance, extracellular volume expansion, and anincreased diastolic blood pressure (188,189). Hypothyroid patients have higher mean 24-h systolic blood pressure and BP variability on24-h ambulatory BP monitoring (190). In 32% of hypertensive hypothyroid patients, replacement therapy with thyroxine leads to a fallin diastolic blood pressure to 90 mm Hg or less (191). There is a positive association between serum TSH and blood pressure within thenormal serum TSH range, statistically significant for diastolic hypertension (192). Subclinical hypothyroidism may or may not to beassociated with hypertension (193-195). Hypothyroidism can lead to volume-dependent blood pressure elevation with low plasma reninconcentrations (196-198).

Acromegaly

The prevalence of hypertension in patients with growth hormone excess is approximately 46% and more frequent than in the generalpopulation (199-201). Growth hormone has antinatriuretic actions and may lead to sodium retention and volume expansion (201-203).Increased systolic output and high heart rate as manifestations of a hyperkinetic syndrome may lead to congestive heart failure(201,204). Blood pressure values are increased in patients with acromegaly associated with reduced glucose tolerance or diabetescompared to those with normal glucose tolerance (201). The RAAS system appears to be implicated in the pathogenesis of hypertensionin patients with growth hormone excess (200-206). Comorbidities in acromegalics, such as hypertension, hyperlipidemia, diabetesmellitus, and cardiomyopathy, all may improve even with partial biochemical control of growth hormone excess (207-210).

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 (reviewedin ref. 211,212). Potential mechanisms in this setting are concurrent insulin resistance and direct vitamin D action through the renin-angiotensin-aldosterone system (Figure 6).


12 of 24 2/11/19, 8:44 AM

Figure 6

Pathway of vitamin D metabolism and its relationship with PTH and the renin-angiotensin-aldosterone system (modified from Ullahet al., 2009, ref. 211)

Testosterone deficiency is frequently identified in obese individuals and those with diabetes mellitus and/or metabolic syndromeincluding hypertension. Replacement therapy in selected patients may be beneficial not only related to their symptomatology ofandrogen deficiency such as low libido, poor erections, fatigue, and others, but also in regards to their metabolic profile and bloodpressure (213-220).

Similarly, individuals with growth hormone deficiency may be at risk for developing hypertension, mostly because of their bodycomposition being more “fat” and “inflamed” when compared to subjects with growth hormone sufficiency, as assessed by serum IFG-1levels matched to gender and age. The key in such patients will be to replace them with growth hormone individually to an IGF-1 levelat which no features of growth hormone excess develop and to increase physical activity. In obese subjects who are willing to take onmajor 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 (221-228).

Individual tissue-dependent sensitivity of the glucocorticoid receptor and actions of endogenous glucocorticoids may play a major rolein the development of hypertension, obesity, and diabetes mellitus (229-231).

References

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

1.

Cutler JA, Sorlie PD, Wolz M, Thom T, Fields LE, Roccella EJ. Trends in hypertension prevalence, awareness, treatment, andcontrol rates in United States adults between 1988-1994 and 1999-2004. Hypertension. 2008 Nov;52(5):818-27

2.


13 of 24 2/11/19, 8:44 AM

16.

17.

18.

19.

20.

21.

22.

Damasceno A, Azevedo A, Silva-Matos C, Prista A, Diogo D, Lunet N. Hypertension prevalence, awareness, treatment, andcontrol in Mozambique: urban/rural gap during epidemiological transition. Hypertension. 2009 Jul;54(1):77-83

3.

Hemmelgarn BR, McAllister FA, Myers MG, et al. 2005 The 2005 Canadian Hypertension Education Program recommendationsfor the management of hypertension: part 1-blood pressure measurement, diagnosis, and assessment of risk. Can J Cardiol21:645-656

4.

Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: National Health and NutritionExamination Survey, 2011-2012. NCHS Data Brief. 2013 Oct;(133):1-8.

5.

James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for themanagement of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee(JNC 8). JAMA. 2014 Feb 5;311(5):507-20. doi: 10.1001/jama.2013.284427. Erratum in: JAMA. 2014 May 7;311(17):1809.

6.

SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, RahmanM, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT.A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16.

7.

Verdecchia P, Angeli F, Reboldi G. The SPRINT trial. J Am Soc Hypertens. 2015 Oct;9(10):750-38.

ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, Simons-Morton DG,Basile JN, Corson MA, Probstfield JL, Katz L, Peterson KA, Friedewald WT, Buse JB, Bigger JT, Gerstein HC, Ismail-Beigi F.Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85.

9.

Krakoff LR. A Tale of 3 Trials: ACCORD, SPRINT, and SPS3. What Happened? Am J Hypertens. 2016 Sep;29(9):1020-310.

Xi B, Zhang M, Zhang T, Li S, Steffen LM. Simplification of childhood hypertension definition using blood pressure to heightratio among US youths aged 8-17years, NHANES 1999-2012. Int J Cardiol. 2015 Feb 1;180:210-3.

11.

Brady TM & Feld LG 2009 Pediatric approach to hypertension. Semin Nephrol 29379-388.12.

Surendran P, Drenos F, Young R, Warren H, Cook JP, Manning AK, et al. Trans-ancestry meta-analyses identify rare andcommon variants associated with blood pressure and hypertension. Nat Genet. 2016 Oct;48(10):1151-61.

13.

Liu C, Kraja AT, Smith JA, Brody JA, Franceschini N, Bis JC, Rice K, et al. Meta-analysis identifies common and rare variantsinfluencing blood pressure and overlapping with metabolic trait loci. Nat Genet. 2016 Oct;48(10):1162-70.

14.

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; PAPY Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. JAm Coll Cardiol. 2006 Dec 5;48(11):2293-300

Koch CA. Endocrine hypertension: What is new? Rev Port Endocrinol Diabetes Metab. 2012;7(2):52-61

Koch CA, Chrousos GP (eds). Endocrine Hypertension. Contemporary Endocrinology Series. Springer, New York, 2013, ISBN:978-1-60761-547-7 (Print), ISBN-10: 978-1-60761-548-4 (online)

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

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, GilesTD, Falkner B, Carey RM. American Heart Association Professional Education Committee 2008 Resistant hypertension:diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional EducationCommittee of the Council for High Blood Pressure Research. Hypertension. 2008 Jun;51(6):1403-19

Plouin PF, Degoulet P, Tugayé A, Ducrocq MB, Ménard J. Screening for pheochromocytoma: in which hypertensive patients ? Asemiological study of 2,585 patients including 11 with pheochromocytoma. Nouv Presse Med. 1981 Mar 7;10(11):869-72.

Kopetschke R, Slisko M, Kilisli A, Tuschy U, Wallaschofski H, Fassnacht M, Ventz M, Beuschlein F, Reincke M, Reisch N,Quinkler M. Frequent incidental discovery of pheochromocytoma: data from a German cohort of 201 pheochromocytomas. Eur JEndocrinol. 2009 Aug;161(2):355-61.

Walther MM et al., Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison withsporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 162: 659-664


14 of 24 2/11/19, 8:44 AM

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

Otsuka F, Ogura T, Nakagawa M, Hayakawa N, Kataoka H, Oishi T, Makino H. Normotensive bilateral pheochromocytoma withLindau disease. Endocr J. 1996 Dec;43(6):719-23

Agarwal A, Gupta S, Mishra AK, Singh N, Mishra SK. Normotensive pheochromocytoma: institutional experience. World J Surg.2005 Sep;29(9):1185-8.

Bhansali A, Rajput R, Behra A, Rao KL, Khandelwal N, Radotra BD. Childhood sporadic pheochromocytoma: clinical profile andoutcome in 19 patients. J Pediatr Endocrinol Metab. 2006 May;19(5):749-56.

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 Hypertensiveand Normotensive Adrenal Pheochromocytomas. Exp Clin Endocrinol Diabetes. 2016 Jun;124(6):372-9.

Eren E, Saglam H, Caliskan Y, Kiristioglu I, Tarim O. Pediatric patients with pheochromocytoma: Experience of a tertiary healthcenter. Pediatr Int. 2015 Oct;57(5):875-9

Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; EndocrineSociety. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014Jun;99(6):1915-42

Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM & Montori VM. The diagnosis of Cushing’ssyndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93,1526-1540.

Markou A, Pappa T, Kaltsas G, Gouli A, Mitsakis K, Tsounas P, Prevoli A, Tsiavos V, Papanastasiou L, Zografos G, Chrousos GP,Piaditis GP. Evidence of primary aldosteronism in a predominantly female cohort of normotensive individuals: a very high oddsratio for progression into arterial hypertension. J Clin Endocrinol Metab. 2013 Apr;98(4):1409-16

Koch CA. Adrenal cortex, physiology. In: Martini L (ed.): Encyclopedia of Endocrinology and Endocrine Diseases. AcademicPress, San Diego, CA, 2004

Vasan RS, Evans JC, Larson MG, et al. 2004 Serum aldosterone and the incidence of hypertension in nonhypertensive persons. NEngl J Med 351:33-41

Gordon RD, Stowasser M, Tunny TJ, et al. 1994 High incidence of primary hyperaldosteronism in 199 patients referred withhypertension. Clin Exp Pharmacol Physiol 21:315-318

Fardella CE, Mosso L, Gomez-Sanchez CE, et al. 2000 Primary hyperaldosteronism in essential hypertensives: prevalence,biochemical profile, and molecular biology. J Clin Endocrinol Metab 85:1863-1867

Mulatero P, Milan A, Fallo F, et al. 2006 Comparison of confirmatory tests for the diagnosis of primary aldosteronism. J ClinEndocrinol Metab 91(7):2618-23

Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr. The Management of PrimaryAldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin EndocrinolMetab. 2016 May;101(5):1889-916

Williams JS, Williams GH, Raji A, et al. 2006 Prevalence of primary hyperaldosteronism in mild to moderate hypertension withouthypokalemia. J Hum Hypertens 20:129-136

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. Lancet2008;371:1921-1926

Stowasser M, Gordon RD. 2000 Primary aldosteronism: learning from the study of familial varieties. J Hypertension 18:1165-1176

Streeten DH, Tomycz N, Anderson GH. 1979 Reliability of screening methods for the diagnosis of primary aldosteronism. Am JMed 67:403-413

Seiler L, Rump LC, Schulte-Monting J, et al. 2004 Diagnosis of primary aldosteronism: value of different screening parametersand influence of antihypertensive medication. Eur J Endocrinol 150:329-337

Mattson C, Young WF Jr. 2006 Primary aldosteronism: diagnostic and treatment strategies. Nat Clin Pract Nephrol 2:198-208

Giacchetti G, Ronconi V, Lucarelli G, et al. 2006 Analysis of screening and confirmatory tests in the diagnosis of primaryaldosteronism: need for a standardized protocol. J Hypertens 24:737-745

Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R, Allolio B, Seufert J, Schirpenbach C, Beuschlein F,


15 of 24 2/11/19, 8:44 AM

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

Bidlingmaier M, Endres S, Quinkler M; Participants of the German Conn's Registry. Cardiovascular and cerebrovascularcomorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s registry. J Clin EndocrinolMetab 2009;94:1125-1130

Stowasser M 2009 Update in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 94 3623-3630.

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 JEndocrinol. 2016 Jul;175(1):21-8

Ulick S, Blumenfeld JD, Atlas SA, et al. 1992 The unique steroidogenesis of the aldosteronoma in the differential diagnosis ofprimary aldosteronism. J Clin Endocrinol Metab 76:873-878

Thompson GB, Young WF Jr. 2006 Selective use of adrenal venous sampling in the lateralization of aldosterone-producingadenomas. World J Surg 886-887

Young WF, Stanson AW, Thompson GB, et al. 2004 Role of adrenal venous sampling in primary aldosteronism. Surgery136:1227-1235

Toniato A, Bernante P, Rossi GP, Pelizzo MR. 2006 The role of adrenal venous sampling in the surgical management of primaryaldosteronism. World J Surg 30:624-627

Asbach E, Williams TA, Reincke M. Recent Developments in Primary Aldosteronism. Exp Clin Endocrinol Diabetes. 2016Jun;124(6):335-41

Gordon RD, Stowasser M. 1998 Familial forms broaden the horizons for primary aldosteronism. Trends Endocrinol Metab9:220-223

Stowasser M, Gordon RD. 2006 Monogenic mineralocorticoid hypertension. Best Pract Res Clin Endocrinol Metab 20:401-420

Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertensionfeaturing nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008 Aug;93(8):3117-23

Mulatero P. A new form of hereditary primary aldosteronism: familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2008Aug;93(8):2972-4.

Sutherland DJ, Ruse JL, Laidlaw JC. 1966 Hypertension, increased aldosterone secretion and low plasma renin activity relieved bydexamethasone. Can Med Assoc J 95:1109-1119

Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel JM. 1992 A chimeric 11 beta-hydroxylase/aldosteronesynthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355:262-265

Litchfield WR, Anderson BF, Weiss RJ, et al. 1998 Intracranial aneurysms and hemorrhagic stroke in glucocorticoid-remediablealdosteronism. Hypertension 31:445-450

Litchfield WR, New MI, Coolidge C, et al. 1997 Evaluation of the dexamethasone suppression test for the diagnosis ofglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 82:3570-3573

Grim CE, Weinberger MH. 1980 Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism. Pediatrics 65:597-604

Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, Lin JP, Huggard P, Gordon RD, Stratakis CA. 2000 A novel genetic locus forlow renin hypertension: familial hyperaldosteronism type II maps to chromosome 7p22. J Med Genet 37:831-835

Charmandari E, Sertedaki A, Kino T, Merakou C, Hoffman DA, Hatch MM, Hurt DE, Lin L, Xekouki P, Stratakis CA, ChrousosGP. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominanthypertension. J Clin Endocrinol Metab. 2012 Aug;97(8):E1532-9

Stowasser M, Gordon RD. 2006 Aldosterone assays: an urgent need for improvement. Clin Chem 52:1640-1642

Schirpenbach C, Seiler L, Maser-Gluth C, et al. 2006 Automated chemiluminescence-immunoassay for aldosterone duringdynamic testing: comparison to radioimmunoassay with and without extraction steps. Clin Chem 52:1749-1755

Kratzsch J, Wende D, Thiery J, Koch CA. Basal aldosterone-renin-ratio and aldosterone levels in healthy adults during the salineload test. Clin Chem Lab Med 2007;45-9:A114-A115 (German dissertation, D. Wende, 2008)

Weinberger MH, Fineberg NS. 1993 The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Int Med153:2125-2129


16 of 24 2/11/19, 8:44 AM

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR, Deinum J. Systematic review:diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009Sep 1;151(5):329-37

Hedeland H, Ostberg G, Hokfelt B. On the prevalence of adrenocortical adenomas in an autopsy material in relation tohypertension and diabetes. Acta Med Scand 1968;184:211-214

Sukor N, Gordon RD, Ku YK, Jones M & Stowasser M 2009 Role of Unilateral adrenalectomy in bilateral primary aldosteronism:a 22-year single center experience. Journal of Clinical Endocrinology and Metabolism 94 2437-2445.

Letavernier E, Peyrard S, Amar L, Zinzindohoue F, Fiquet B & Plouin PF 2009 Blood pressure outcome of adrenalectomy inpatients with primary hyperaldosteronism with or without unilateral adenoma. Journal of Hypertension 26 1816-1823.

Meyer A, Brabant G, Behrend M. 2005 Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg29:155-159

Rossi GP. 2006 Surgically correctable hypertension caused by primary aldosteronism. Best Pract Res Clin Endocrinol Metab20:385-400

Karagiannis A, Tziomalos K, Kakafika A, et al. 2007 Eplerenone relieves spironolactone-induced painful gynecomastia in a patientwith primary aldosteronism. Nephrol Dial Transplant 22(1):293

Jansen PM, van den Meiracker AH & Jan Danswer AH 2009 Aldosterone synthase inhibitors: pharmacological and clinicalaspects. Curr Opin Investig Drugs 10 319-326.

Catena C, Lapenna R, Baroselli S, et al. 2006 Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J ClinEndocrinol Metab 91:3457-3463

Matrozova J, Streichen O, Amar L, Zacharieva S, Jeunemaitre , Plouin PF. Fasting plasma glucose and serum lipids in patients withprimary aldosteronism: a controlled cross-sectional study. Hypertension 2009; 53:601-610

Remde H, Hanslik G, Rayes N, Quinkler M. Glucose Metabolism in Primary Aldosteronism. Horm Metab Res. 2015Dec;47(13):987-93

Koch CA, Vortmeyer AO, Zhuang Z, Brouwers FM, Pacak K. 2002 New insights into the genetics of familial chromaffin celltumors. Ann NY Acad Sci 970:11-28

Neumann HPH, et al. 2002 Germline mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1486-1488

Koch CA, Pacak K, Chrousos GP. 2002 The molecular pathogenesis of hereditary and sporadic adrenocortical andadrenomedullary tumors. J Clin Endocrinol Metab 87(12):5367-84

Erlic Z, Rybicki L, Peczkowska M, Golcher H, Kann P, Brauckhoff M, Mussig K, Muresan M, Schaffler A, Reisch N, Schott M,Fassnacht M, Opocher G, Klose S, Fottner C, Forrer F, Plockinger U, Petersenn S, Zabolotny D, Kollukch O, Yaremchuk S,Januszewicz A, Walz M, Eng C & Neumann HPH 2009 Clinical predictors and algorithm for the genetic diagnosis ofpheochromocytoma patients. Clinical Cancer Res 15 6378-6385.

Jiménez C, Cote G, Arnold A, Gagel RF. Should patients with apparently sporadic pheochromocytoma or paragangliomas bescreened for hereditary syndromes ? J Clin Endocrinol Metab. 2006 Aug;91(8):2851-8.

Eisenhofer G, Walther MM, Huynh TT, et al. 2001 Pheochromoytomas in von Hippel-Lindau syndrome and multiple endocrineneoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86:1999-2008

Bravo EL, Tagle R. 2003 Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 24:539-553

Neumann HP, Vortmeyer A, Schmidt D, Werner M, Erlic Z, Cascon A, Bausch B, Januszewicz A, Eng C. Evidence of MEN-2 inthe original description of classic pheochromocytoma. N Engl J Med. 2007 Sep 27;357(13):1311-5

Unger N, Pitt C, Schmidt IL, et al. 2006 Diagnostic value of various biochemical parameters for the diagnosis ofpheochromocytoma in patients with adrenal mass. Eur J Endocrinol 154:409-417

Miehle K, Kratzsch J, Lenders JW, Kluge R, Paschke R, Koch CA. 2005 Adrenal incidentaloma diagnosed as pheochromocytomaby plasma chromogranin A and plasma metanephrines. J Endocrinol Invest 28:1040-1042

Grossrubatscher E, Dalino P, Vignati F, et al. 2006 The role of chromogranin A in the management of patients withpheochromocytoma. Clin Endocrinol 65:287-293


17 of 24 2/11/19, 8:44 AM

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

106.

107.

Giovanella L, Squin N, Ghelfo A, Ceriani L. 2006 Chromogranin A immunoradiometric assay in diagnosis of pheochromocytoma:comparison with plasma metanephrines and 123I-MIBG scan. Q J Nucl Med Mol Imaging 50:344-347

Koch CA, Rodbard JS, Brouwers FM, Eisenhofer G, Pacak K. 2003 Hypotension in a woman with a metastatic dopamine-secretingcarotid body tumor. Endocr Pract 9:310-314

Eisenhofer G, Huysmans F, Pacak K, Walther MM, Sweep FC, Lenders JW. Plasma metanephrines in renal failure. Kidney Int.2005 Feb;67(2):668-77

Niculescu DA, Ismail G, Poiana C. Plasma free metanephrine and normetanephrine levels are increased in patients with chronickidney disease. Endocr Pract. 2014 Feb;20(2):139-44

Koch CA, Pamporaki C, Kantorovich V. Endocrine hypertension and chronic kidney disease (chap.16). in: Chronic kidney diseaseand hypertension. Weir MR, Lerma EV (editors). Springer, New York, 2015

Majumdar S, Friedrich CA, Koch CA, Megason GC, Fraktin JD, Moll GW. Compound heterozygous mutation with a novel splicedonor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma. Pediatr BloodCancer. 2010 Mar;54(3):473-5

Singer J, Koch CA, Kassahun W, Lamesch P, Eisenhofer G, Kluge R, Lincke T, Seiwerts M, Borte G, Schierle K, Paschke R. Apatient with a large recurrent pheochromocytoma demonstrating the pitfalls of diagnosis. Nat Rev Endocrinol. 2011 Sep6;7(12):749-55.

Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, Pacak K. Clinical aspects of SHDx-related pheochromocytoma andparaganglioma. Endocr Relat Cancer. 2009 Jun;16(2):391-400

Timmers HJ, Eisenhofer G, Carrasquillo JA, Chen CC, Whatley M, Ling A, Adams KT, Pacak K. Use of 6-18F-fluorodopaminepositron emission tomography as first-line investigation for the diagnosis and localization of non-metastatic and metataticpheochromocytoma. Clin Endocrinol (Oxf). 2009 Jul;71(1):11-7

Bhatia KS, 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 pheochromocytoma: CT and MRIcorrelation. Clin Endocrinol (Oxf). 2008 Aug;69(2):181-8.

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

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

Joshua AM, Ezzat S, Asa SL, Evans A, Broom R, Freeman M, Knox JJ. Rationale and evidence for sunitinib in the treatment ofmalignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 2009;94:5-9

Jimenez C, Cabanillas ME, Santarpia L, Jonasch E, Kyle KL, Lano EA, Matin SF, Nunez RF, Perrier NDm, Phan A, Rich TA,Shah B, Williams MD, Waguespack SG. Use of 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 Metab2009;94:386-391

Matro J, Giubellino A, Pacak K. Current and future therapeutic approaches for metastatic pheochromocytoma and paraganglioma:focus on SDHB tumors.

Horm Metab Res. 2013 Feb;45(2):147-53

Nebesio TD, Eugster EA 2006 Observation of hypertension in children with 21-hydroxylase deficiency: a preliminary report.Endocrine 30 279-282.

105.Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, Reynolds JC, Hanna RM, Merke DP. Clinical characteristicsof a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012 Dec;97(12):4429-38

Kim MS, Merke DP. Cardiovascular disease risk in adult women with congenital adrenal hyperplasia due to 21-hydroxylasedeficiency. Semin Reprod Med. 2009 Jul;27(4):316-21.

Zachmann M, Tassinari D, Prader A. 1983 Clinical and biochemical variabilitiy of congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency. J Endocrinol Metab 56:222-229


18 of 24 2/11/19, 8:44 AM

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

New MI, Geller DS, Fallo F, Wilson RC. 2005 Monogenic low renin hypertension. Trends Endocrinol Metab 16:92-97

Mimouni M, Kaufman H, Roitman A, Morag C, Sadan N. Hypertension in a neonate with 11 beta-hydroxylase deficiency. Eur JPediatr. 1985 Jan;143(3):231-3.

Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003;349:776-788

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

Hochberg Z, Even L, Zadik Z. Mineralocorticoids in the mechanism of gynecomastia in adrenal hyperplasia caused by 11 beta-hydroxylase deficiency. J Pediatr. 1991 Feb;118(2):258-60

Kacem M, Moussa A, Khochtali I, Nabouli R, Morel Y & Zakhama A 2009 Bilateral Adrenalectomy for severe hypertension incongenital adrenal hyperplasia due to 11beta Hydroxylase deficiency: long term follow-up. Annals of Endocrinology 70 113-118.

New MI. Male pseudohermaphroditism due to 17 alpha-hydroxylase deficiency. J Clin Invest. 1970 Oct;49(10):1930-41.

Wong SL, Shu SG, Tsai CR. 2006 Seventeen alpha-hydroxylase deficiency. J Formos Med Assoc 105:177-181

Costa-Santos M, Kater CE, Auchus RJ, et al. 2004 Two prevalent CYP17 mutations and genotype-phenotype correlations in 24Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab 89:49-60

Lavery GG, Ronconi V, Draper N, et al. 2003 Late-onset apparent mineralocorticoid excess caused by novel compoundheterozygous mutations in the HSD11B2 gene. Hypertension 42:123-129

Carvajal CA, Gonzales AA, Romero DG, Gonzales A, et al. 2003 Two homozygous mutations in the 11 beta-hydroxysteroiddehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. J Clin Endocrinol Metab 88:2501-2507

Palermo M, Quinkler M, Stewart PM. 2004 Apparent mineralocorticoid excess syndrome: an overview. Arq Bras EndocrinolMetab 48:687-696

Lin-Su K, Zhou P, Arora N, et al. 2004 In vitro expression studies of a novel mutation delta299 in a patient affected with apparentmineralocorticoid excess. J Clin Endocrinol Metab 89:2024-2027

New MI, Levine LS, Biglieri EG, Paeira J, Ulick S. 1977 Evidence for an unidentified ACTH-induced steroid hormone causinghypertension. J Clin Endocrinol Metab 44:924-933

Wilson RC, Krozowski ZS, Li K, et al. 1995 A mutation in the HSD11B2 gene in a family with apparent mineralocorticoidexcess. J Clin Endocrinol Metab 80:2263-2266

Stewart PM, Corrie JE, Shackleton CH, Edwards CR. 1988 Syndrome of apparent mineralocorticoid excess. A defect in thecortisol-cortisone shuttle. J Clin Invest 82:340-349

Arriza JL, Weinberger C, Cerelli G, Glaser TM, et al. 1987 Cloning of the human mineralocorticoid receptor complementaryDNA: structural and functional kinship with the glucocorticoid receptor. Science 237:268-275

Funder JW, Pearce PT, Smith R, Smith AI. 1988 Mineralocorticoid action: target tissue specificity is enzyme, not receptormediated. Science 242:583-585

Heilmann P, Buchheim E, Wacker J, Ziegler R. 2001 Alteration of the activity of the 11beta-hydroxysteroid dehydrogenase inpregnancy: relevance for the development of pregnancy-induced hypertension ? J Clin Endocrinol Metab 276:5222-5226

Quinkler M, Oelkers W, Diederich S. 2000 In vivo measurement of renal 11beta-hydroxysteroid dehydrogenase type 2 activity. JClin Endocrinol Metab 85:4921-4922

Geller DS, Farhi A, Pinkerton N, et al. 2000 Activating mineralocorticoid receptor mutation in hypertension exacerbated bypregnancy. Science 289:119-123

Liddle GW, Bledsoe T, Coppage WS Jr. 1963 A familial renal disorder simulating primary aldosteronism but with negligiblealdosterone secretion. Trans Assoc Am Physicians 76:199-213

Gordon RD, Geddes RA, Pawsey CG, Oâ€™Halloran MW. 1970 Hypertension and severe hyperkalemia associated withsuppression of renin and aldosterone and completely reversed by dietary sodium restriction. Australas Ann Med 19:287-294

Geller DS. 2005 Mineralocorticoid resistance. Clin Endocrinol 62:513-520

Klemm SA, Gordon RD, Tunny TJ, Thompson RE 1991 The syndrome of hypertension and hyperkalemia with normal GFR


19 of 24 2/11/19, 8:44 AM

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

(Gordonâ€™s syndrome): is there increased proximal sodium reabsorption ? Clin Invest Med 14:551-558

Wilson FH, Disse-Nicodeme S, Choate KA, et al. 2001 Human hypertension caused by mutations in WNK kinases. Science293:11-14

Mansfield TA, Simon DB, Farfel Z, et al. 1997 Multilocus linkage of familial hyperkalemia and hypertension,pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p-q21. Nat Genet 16:202-205

Kahle KT, Wilson FH, Leng Q, et al. 2003 WNK4 regulates the balance between renal NaCl reabsorption and K secretion. NatGenet 35:372-376

Xie J, Craig L, Cobb MH, Huang CL. 2006 Role of with-no-lysine (K) kinases in the pathogenesis of Gordonâ€™s syndrome.Pediatr Nephrol 21(9):1231-6

Tobin MD, Raleigh SM, Newhouse S, et al. 2005 Association of WNK1 gene polymorphisms and haplotypes with ambulatoryblood pressure in the general population. Circulation 112:3423-3429

Koch CA, Bornstein SR, Birkenfeld AL. Introduction to Hanefeld Symposium: 40+ years of metabolic syndrome. Rev EndocrMetab Disord. 2016 Mar;17(1):1-4

Haffner SM, Ruilope L, Dahlof B, et al. 2006 Metabolic syndrome, new onset diabetes, and new end points in cardiovasculartrials. J Cardiovasc Pharmacol 47:469-475

Saad MF, Rewers M, Selby J, et al. Insulin resistance and hypertension: the insulin resistance atherosclerosis study. Hypertension43:1324-1331

Shankar SS, Steinberg HO. Insulin resistance and hypertension. In: Endocrine Hypertension (eds. Koch CA, Chrousos GP).Springer, New York 2013; pp.239-250

Ferrannini E, Buzzigoli G, Bonadonna R, et al. 1987 Insulin resistance in essential hypertension. N Engl J Med 317:350-357

Uwaifo GI. Obesity-associated hypertension. In: Endocrine Hypertension (eds. Koch CA, Chrousos GP). Springer, New York,2013; pp. 251-288

Levy J, Gavin JR III, Hammermann MR, et al. 1986 Ca- and Mg-ATPase activity in kidney basolateral membrane in non insulindependent diabetic rats: effect of insulin. Diabetes 35:899-905

Dluhy RG, Lawrence JE, Williams GH. Endocrine Hypertension. In: Williams Textbook of Endocrinology, 10th edition,Saunders, 2002, pages 552-585

Ronti T, Lupattelli G, Mannarino E. 2006 The endocrine function of adipose tissue:an update. Clin Endocrinol 64:355-365

Bogaert YE & Linas S 2009 The role of obesity in the pathogenesis of hypertension. Nat Clin Pract Nephrol 5 101-111.

Graessler J, Schwudke D, Schwarz PE, Herzog R, Shevchenko A, Bornstein SR. Top-down lipidomics reveals ether lipiddeficiency in blood plasma of hypertensive patients. PLoS One. 2009 Jul 15;4(7):e6261

McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S. Enhanced parathyroid function in essentialhypertension: a homeostatic response to a urinary calcium leak. Hypertension. 1980 Mar-Apr;2(2):162-8.

Bukoski RD, Ishibashi K, Bian K. 1995 Vascular actions of the calcium regulating hormones. Semin Nephrol 15:536-549

Hulter HN, Melby JC, Peterson JC & Cooke CR 1986 Chronic continuous PTH infusion results in hypertension in normalsubjects. Journal of Clinical Hypertension 2 360-370.

Bucher HC, Cook RJ, Guyatt GH, et al. 1996 Effects of dietary calcium supplementation in blood pressure: a metaanalysis ofrandomized controlled trials. JAMA 275:1016-1022

Allender PS, Cutler JA, Follmann D, et al. 1996 Dietary calcium and blood pressure: a metaanalysis of randomized clinical trials.Ann Intern Med 124:825-831

Carrelli AL, Silverberg SJ. Primary hyperparathyroidism and hypertension. In: Endocrine Hypertension (eds. Koch CA, ChrousosGP). Springer, New York, 2013, pp.181-194

Bollerslev J, Rosen T, Mollerup CL, Nordenstrom J, Baranowski M, Franco C, Pernow Y, Isaksen GA, Godang K, Ueland T et al;SIPH Study Group 2009 Effect of surgery on cardiovascular risk factors in mild primary hyperparathyroidism. Journal of ClinicalEndocrinology and Metabolism 94 2255-2261.


20 of 24 2/11/19, 8:44 AM

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

Bollerslev J, Jansson S, Mollerup CL, Nordenström J, Lundgren E, Tørring O, Varhaug JE, Baranowski M, Aanderud S, FrancoC, Freyschuss B, Isaksen GA, Ueland T, Rosen T. Medical observation, compared with parathyroidectomy for asymptomatichyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab. 2007 May;92(5):1687-92.

Puepet FH, Agaba EI, Chuhwak EK & Ugoya SO 2008 Primary hyperparathyroidism presenting with severe hypertension in amiddle aged Nigerian—a case report. Nigerian Postgraduate Medical Journal 15 58-60.

Rubin MR, Maurer MS, McMahon DJ, et al. 2005 Arterial stiffness in mild primary hyperparathyroidism. J Clin EndocrinolMetab 90:3326-3330

Walker MD, Fleischer J, Rundek T, McMahon DJ, Homma S, Sacco R, Silverberg SJ. Carotid vascular abnormalities in primaryhyperparathyroidism. J Clin Endocrinol Metab. 2009 Oct;94(10):3849-56

Ekmekci A, Abaci N, Ozbey NC, Agayev A, Aksakal N, Oflaz H, Erginel-Unaltuna N & Erbil Y 2009 Endothelial Function andEndothelial Nitric Oxide Synthase Intron 4a/b Polymorphism in Primary Hyperparathyroidism. Journal of EndocrinologicalInvestigation

Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT Jr. Guidelines for the management ofasymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin EndocrinolMetab. 2014 Oct;99(10):3561-9

Savage M, Lienhardt A, Lebrethon M, et al. 2001 Cushing’s disease in childhood : presentation, investigation, treatment and long-term outcome. Horm Res 55:24-30

Magiakou M, Mastorakos G, Oldfield EH, et al. 1994 Cushing’s syndrome in children and adolescents. Presentation, diagnosis,and therapy. N Engl J Med 331:629-636

Lodish MB, Sinaii N, Patronas N, Batista DL, Keil M, Samuel J, Moran J, Verma S, Popovic J, Stratakis CA. Blood pressure inpediatric patients with Cushing syndrome. J Clin Endocrinol Metab. 2009 Jun;94(6):2002-8.

Magiakou MA, Mastorakos G, Zachman K, Chrousos GP. Blood pressure in children and adolescents with Cushing’s syndromebefore and after surgical care. J Clin Endocrinol Metab. 1997 Jun;82(6):1734-8.

Robyn JA, Koch CA, Montalto J, Yong A, Warne GL, Batch JA. Cushing's syndrome in childhood and adolescence. J PaediatrChild Health. 1997 Dec;33(6):522-7.

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 Jan;33(1):44-60

Zacharieva S, Orbetzova M, Stoynev A, et al. 2004 Circadian blood pressure profile in patients with Cushingâ€™s syndromebefore and after treatment. J Endocrinol Invest 27:924-930

Baid S, Nieman LK. 2004 Glucocorticoid excess and hypertension. Curr Hypertens Rep 6:493-499

Torpy DJ, Mullen N, Ilias I, Nieman LK. 2002 Association of hypertension and hypokalemia with Cushingâ€™s syndromecaused by ectopic ACTH secretion. Ann NY Acad Sci 970:134-144

Pirpiris M, Yeung S, Dewar E, et al. 1993 Hydrocortisone-induced hypertension in men. The role of cardiac output. Am JHypertension 6:287-294

Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A; Endocrine Society. Treatment ofCushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Aug;100(8):2807-31

Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM.Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with theEuropean Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175(2):G1-G34

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 Aug 2. doi: 10.7326/M16-0547


21 of 24 2/11/19, 8:44 AM

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

Zeiger MA, Thompson GB, Duh QY, Hamrahian AH, Angelos P, Elaraj D, Fishman E, Kharlip J; American Association ofClinical Endocrinologists; American Association of Endocrine Surgeons. American Association of Clinical Endocrinologists andAmerican Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executivesummary of recommendations. Endocr Pract. 2009 Jul-Aug;15(5):450-3.

Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F & Ballotta E 2009 Surgical versus conservative managementfor subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Annals of Surgery 249 388-391.

Kino T, Vottero A, Charmandari E, Chrousos GP. 2002 Familial/sporadic glucocorticoid resistance syndrome and hypertension.Ann NY Acad Sci 970:101-111

Chrousos GP, Vingerhoeds A, Brandon D, et al. 1982 Primary cortisol resistance. J Clin Invest 69:1261-1269

Charmandari E, Kino T, Ichijo T & Chrousos GP 2008 Generalized glucocorticoid resistance: clinical aspects, molecularmechanisms, and implications of a rare genetic disorder. Journal of Clinical Endocrinology and Metabolism 93 1563-1572.

Danzi S, Klein I. 2003 Thyroid hormone and blood pressure regulation. Curr Hypertens Rep 5:513-520

Prisant LM, Gujral JS, Mulloy AL. 2006 Hyperthyroidism: a secondary cause of isolated systolic hypertension. J Clin Hypertens8:596-599

Klein I. 1990 Thyroid hormone and the cardiovascular system. Am J Med 88:631-637

Woeber KA. 1992 Thyrotoxicosis and the heart. N Engl J Med 327:94-98

Fountoulakis S, Tsatsoulis A. Molecular genetic aspects and pathophysiology of endocrine hypertension. Hormones (Athens).2006 Apr-Jun;5(2):90-106

Iglesias P, Acosta M, Sanchez R, Fernandez-Reyes MJ, Mon C & Diez JJ 2005 Ambulatory blood pressure monitoring in patientswith hyperthyroidism before and after control of thyroid function. Clinical Endocrinology 63 66-72.

Tamer I, Sargin M, Sargin H, et al. 2005 The evaluation of left ventricular hypertrophy in hypertensive patients with subclinicalhyperthyroidism. Endocr J 52:421-425

Volzke H, Alte D, Dorr M, et al. 2006 The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertens 24:1947-1953

Biondi B, Klein I. 2004 Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 24:1-13

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 Sep;72(4):296-303

Kotsis V, Alevizaki M, Stabouli S, Pitiriga V, Rizos Z, Sion M & Zakopoulos N 2007 Hypertension and hypothyroidism: resultsfrom an ambulatory blood pressure monitoring study. Journal of Hypertension 25 993-999.

Streeten DHP, Anderson GH Jr, Howland T, et al. 1988 Effects of thyroid function on blood pressure: recognition of hypothyroidhypertension. Hypertension 11:78-83

Iqbal A, Figenschau Y, Jorde R. 2006 Blood pressure in relation to serum thyrotropin : the Tromso study. J Hum Hypertens20(12):932-6

Walsh JP, Bremner AP, Bulsara MK, et al. 2006 Subclinical thyroid dysfunction and blood pressure: a community-based study.Clin Endocrinol 65:486-491

Biondi B & Cooper DS 2008 The clinical significance of subclinical thyroid dysfunction. Endocrine Reviews 29 76-131.

Duan Y, Wang X, Peng W, Feng Y, Tang W, Wu X, Mao X, Bo R, Li W, Chen J, Qin Y, Liu C & Liu C 2009 Gender-specificassociations between subclinical hypothyroidism and blood pressure in Chinese adults. Endocrine 2009

Stabouli S, Papakatsika S, Kotsis V. Hypothyroidism and hypertension. Expert Rev Cardiovasc Ther. 2010 Nov;8(11):1559-65

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

Cai Y, Ren Y, Shi J. Blood pressure levels in patients with subclinical thyroid dysfunction: a meta-analysis of cross-sectional data.


22 of 24 2/11/19, 8:44 AM

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

Hypertens Res. 2011 Oct;34(10):1098-105

Vitale G, Pivonello R, Auriemma RS, et al. 2005 Hypertension in acromegaly and in the normal population: prevalence anddeterminants. Clin Endocrinol 63:470-476

Bondanelli M, Amrosio MR, Degliuberti EC. 2001 Pathogenesis and prevalence of hypertension in acromegaly. Pituitary4:239-249

Colao A, Ferone D, Marzullo P, et al. 2004 Systemic complications of acromegaly: epidemiology, pathogenesis, and management.Endocr Rev 25:102-152

Rizzoni D, Porteri E, Giustina A, De Ciuceis C, Sleiman I, Boari GE, Castellano M, Muiesan ML, Bonadonna S, Burattin A,Cerudelli B, Agabiti-Rosei E. Acromegalic patients show the presence of hypertrophic remodeling of subcutaneous smallresistance arteries. Hypertension. 2004 Mar;43(3):561-5.

Falkheden T, SjÃgren B. 1964 Extracellular fluid volume and renal function in pituitary insufficiency and acromegaly. ActaEndocrinol 46:80-88

Lombardi G, Galdiero M, Auriemma RS, et al. 2006 Acromegaly and the cardiovascular system. Neuroendocrinology 83:211-217

Mulatero P, Veglio F, Maffei P, Bondanelli M, Bovio S, Daffara F, Leotta G, Angeli A, Calvo C, Martini C, degli Uberti EC,Terzolo M. CYP11B2-344T/C gene polymorphism and blood pressure in patients with acromegaly. J Clin Endocrinol Metab.2006 Dec;91(12):5008-12

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

Delaroudis SP, Efstathiadou ZA, Koukoulis GN, Kita MD, Farmakiotis D, Dara OG, Goulis DG, Makedou A, Makris P, SlavakisA et al. 2008 Amelioration of cardiovascular risk factors with partial biochemical control of acromegaly. Clinical Endocrinology69 279-284.

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-1 excess control contributes to blood pressure control: results of an observational, retrospective,multicenter study in 105 hypertensive acromegalic patients on hypertensive treatment. Clin Endocrinol (Oxf). 2008Oct;69(4):613-20.

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

East HE, Subauste JS, Gandhi A, Koch CA. About secondary causes of diabetes mellitus. J Miss State Med Assoc. 2012Nov;53(11):380-3

Ullah MI, Uwaifo GI, Nicholas WC, Koch CA. Does vitamin D deficiency cause hypertension ? Current evidence from clinicalstudies and potential mechanisms. Int J Endocrinol. 2010;2010:579640.

Judd SE, Tangpricha V. Vitamin D deficiency and risk for cardiovascular disease. Am J Med Sci. 2009 Jul;338(1):40-4

Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men. Am JMed. 2007 Oct;120(10):835-40.

Shabsigh R, Arver S, Channer KS, Eardley I, Fabbri A, Gooren L, Heufelder A, Jones H, Meryn S, Zitzmann M. The triad oferectile dysfunction, hypogonadism, and the metabolic syndrome. Int J Clin Pract. 2008 May;62(5):791-8.

Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. JClin Endocrinol Metab. 2006 Nov;91(11):4335-43.

Zitzmann M. Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism. Asian JAndrol. 2008 May;10(3):364-72.

Morgentaler A, Zitzmann M, Traish AM, Fox AW, Jones TH, Maggi M, Arver S, Aversa A, Chan JC, Dobs AS, Hackett GI,Hellstrom WJ, Lim P, Lunenfeld B, Mskhalaya G, Schulman CC, Torres LO. Fundamental Concepts Regarding TestosteroneDeficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc. 2016 Jul;91(7):881-96


23 of 24 2/11/19, 8:44 AM

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA. Testosterone deficiency as a risk factor for cardiovascular disease. HormMetab Res. 2011 Mar;43(3):153-64

Haring R, Völzke H, Felix SB, Schipf S, Dörr M, Rosskopf D, Nauck M, Schöfl C, Wallaschofski H. Prediction of metabolicsyndrome by low serum testosterone levels in men: results from the study of health in Pomerania. Diabetes. 2009Sep;58(9):2027-31

Heufelder AE, Saad F, Bunck MC, Gooren LJ. 52-week treatment with diet and exercise plus transdermal testosterone reversesthe metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasmatestosterone. J Androl. 2009

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 oldermen. J Clin Endocrinol Metab. 2009 Jun;94(6):1991-2001

Widdowson WM, Gibney J. The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: ametaanalysis. J Clin Endocrinol Metab. 2008 Nov;93(11):4413-7

Mekala KC, Tritos NA. Effects of recombinant human growth hormone therapy in obesity in adults: a metaanalysis. J ClinEndocrinol Metab. 2009 Jan;94(1):130-7

Bannink EM, van der Palen RL, Mulder PG, de Muinck Keizer-Schrama SM. Long-term follow-up of GH-treated girls withTurner syndrome: metabolic consequences. Horm Res. 2009;71(6):343-9.

Di Somma C, Pivonello R, Pizza G, De Rosa A, Lombardi G, Colao A, Savastano S. Prevalence of the metabolic syndrome inmoderately severely obese subjects with and without growth hormone deficiency. J Endocrinol Invest. 2009

Russell M, Bredella M, Tsai P, Mendes N, Miller KK, Klibanski A, Misra M. Relative growth hormone deficiency and cortisolexcess are associated with increased cardiovascular risk markers in obese adolescent girls. J Clin Endocrinol Metab. 2009Aug;94(8):2864-71

Uwaifo GI, Melcescu E, McDonald A, Koch CA. A case of profound weight loss secondary to use of phentermine. J Miss StateMed Assoc. 2009 Dec;50(12):407-15

Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, Loomba R, Camilleri M, Singh S. Association ofPharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. JAMA.2016 Jun 14;315(22):2424-34

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 receptorhaploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet. FASEB J. 2008 Nov;22(11):3896-907.

Zhang J, Ge R, Matte-Martone C, Goodwin J, Shlomchik WD, Mamula MJ, Kooshkabadi A, Hardy MP & Geller D 2009Characterization of a novel gain of function glucocorticoid receptor knock-in mouse. J Biol Chem 284 6249-6259.

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 andnon-obese black and white Mississippians. Hormones (Athens). 2012 Apr-Jun;11(2):166-77

Copyright © 2000-2019, MDText.com, Inc.

This electronic version has been made freely available under a Creative Commons (CC-BY-NC-ND) license. A copy of the license can be viewed at http://creativecommons.org/licenses/by-nc-nd/2.0/.

Bookshelf ID: NBK278980 PMID: 25905214


24 of 24 2/11/19, 8:44 AM

Overview of Endocrine Hypertension - Tahoma Clinic · Overview of Endocrine Hypertension Christian...

Documents

Transcript of Overview of Endocrine Hypertension - Tahoma Clinic · Overview of Endocrine Hypertension Christian...