The hypertension of Cushing's syndrome: controversies in the pathophysiology and focus on cardiovascular complications : Journal of Hypertension

Journal Logo

REVIEWS

The hypertension of Cushing's syndrome

controversies in the pathophysiology and focus on cardiovascular complications

Isidori, Andrea M.a; Graziadio, Chiaraa; Paragliola, Rosa Mariab; Cozzolino, Alessiac; Ambrogio, Alberto G.d; Colao, Annamariac; Corsello, Salvatore M.b; Pivonello, Rosarioc on behalf of the ABC Study Group

Author Information
Journal of Hypertension 33(1):p 44-60, January 2015. | DOI: 10.1097/HJH.0000000000000415

Abstract

INTRODUCTION

Cushing's syndrome, or chronic hypercortisolism, is a severe endocrine disease due to the prolonged exposure to glucocorticoid excess [1–3]. The endogenous Cushing's syndrome, caused by the endogenous overproduction of cortisol by the adrenal glands, is secondary to an adrenocorticotrophin (ACTH)-secreting pituitary tumor [pituitary-dependent Cushing's syndrome (CS) or Cushing's disease (CD)] in around 70%, a cortisol-secreting adrenal lesion (adrenal-dependent Cushing's syndrome) in 15–20%, and an ACTH-secreting extra-pituitary tumor [ectopic Cushing's syndrome (ECS)] in 10–15% of the cases [1–3]. The chronic administration of exogenous corticosteroids for different clinical conditions may induce the development of an exogenous CS [1–3]. CS is associated with a 2–5-fold increase in mortality compared to the general population, mainly due to cardiovascular complications [1–3]. CS is indeed characterized by a peculiar clinical picture complicated by several comorbidities, mainly including systemic arterial hypertension, together with visceral obesity, impairment of glucose tolerance and dyslipidemia, configuring a metabolic syndrome [4–6]. However, the hypertension related to CS is not simply a component of the CS-related metabolic syndrome. Indeed, CS-related hypertension displays several peculiarities, develops early and can persist several years after clinical and hormonal remission of the disease [4–6].

The hypothalamus–pituitary–adrenal axis (HPA), which is responsible for the circadian rhythm of endogenous cortisol secretion, contributes to the circadian rhythm of blood pressure (BP) [7,8], and HPA dysregulation has been suggested as one of the factors involved in the pathogenesis of essential hypertension (EH) [9,10]. Exogenous corticosteroids, which are prescribed to approximately 1% of the adult population for various clinical conditions [11], significantly affect this equilibrium [12,13], and are associated with an increased risk of cardiovascular and cerebrovascular diseases [14].

The ‘Altogether to Beat Cushing's syndrome’ (ABC) study group produced a systematic analysis of the peculiarities of hypertension associated with endogenous and exogenous CS, focusing on its controversial pathophysiology and long-term clinical consequences. This novel pathophysiology-oriented therapeutic approach enabled a treatment-algorithm to be proposed during the first ABC workshop held in Capri in 2012.

EPIDEMIOLOGY OF HYPERTENSION IN CUSHING'S SYNDROME

Epidemiological data on hypertension associated with CS are largely retrospective. However, the available data suggested that 70–85% of adult patients [15,16] and 50–78% of pediatric patients [17–20] with endogenous CS suffer from hypertension, compared to approximately 20% of patients long-term treated with exogenous corticosteroids [21,22]. A specific feature of hypertension associated with endogenous CS is the lack of a significant difference in gender or among the different etiologies of endogenous CS [15,16,23], as well as in the degree of hypercortisolism, as BP values were found to be not correlated with circulating cortisol levels [15,24,25]. Nevertheless, one study on pediatric patients with CS showed a difference in the prevalence of systolic hypertension in ACTH-independent (74%) and ACTH-dependent CS (44%), despite an apparently similar degree of hypercortisolism, and demonstrated a positive correlation between BP values and circulating cortisol levels [18]. Anyway, although the prevalence of hypertension is similar among various forms of endogenous CS, a tendency towards higher BP is seen in adrenal compared to pituitary tumors. Figure 1 shows the BP values reported in the largest studies, according to the different etiologies of CS. The duration of hypercortisolism seems to be correlated with the development of hypertension [15]; however, half of the pediatric patients with CS, whose time to diagnosis is short, still develop hypertension within a limited period of time [26,27].

F1-6
FIGURE 1:
The SBP (black) and DBP (white) values (mean ±SEM) are reported for some of the largest studies, according to the different causes of Cushing's syndrome. The gray boxes summarize the mean weighted pressure value for each group of studies; the black boxes summarize the overall effect for all groups.

PATHOGENESIS OF HYPERTENSION IN CUSHING'S SYNDROME

The mechanisms involved in the development of hypertension are complex and only partially understood. This review summarizes the major data regarding the renin–angiotensin system (RAS), the mineralocorticoid activity, the sympathetic nervous system, and the vasoregulatory system, together with indirect mechanisms, which contribute to the development of CS-related hypertension (Table 1). The mechanisms through which hypercortisolism induces hypertension directly or indirectly, as well as the mechanisms by which specific treatments, which could counteract directly or indirectly the hypercortisolism-induced changes that contribute to the CS-related hypertension and consequent cardiovascular damage, are discussed in this review, and reviewed in Fig. 2. The pleiotropic effects of glucocorticoids and the several regulatory mechanisms controlling BP show significant overlap, suggesting that a rigorous comparison of in-vivo and in-vitro models is necessary to identify the relative contribution of each component and draw reliable conclusions. In addition, in most experimental settings, the acute effects of glucocorticoids differ in many aspects from chronic effects of either endogenous glucocorticoids or exogenous corticosteroids. A systematic review of the mechanisms involved in the pathogenesis of hypertension induced by glucocorticoid excess in humans (Table 1) and animals (Table 1S, https://links.lww.com/HJH/A423) is described in this section of the review. This approach allowed the appraisal of both the new pathways and the old paradigms. Specific following sections of the review focus on the clinical features and cardiovascular damage associated with CS-related hypertension, and on the effect of treatment for CS on hypertension. The review terminate with statements on the pharmacological treatment of the hypertension associated with CS, driven by the available knowledge. These statements were the basis for the development of a treatment algorithm for CS-related hypertension; this proposed algorithm is displayed in Fig. 3.

T1-6
TABLE 1:
Mechanisms involved in the pathogenesis of hypertension induced by glucocorticoid excess in human studies
F2-6
FIGURE 2:
The pathophysiological mechanisms involved in the development of glucocorticoid-related hypertension. The symbols ↑, ↓ and ↔ represent, respectively, an increase, decrease and null effect for each of the affected pathway, on the basis of the studies listed in Table 1 and Table 1S (https://links.lww.com/HJH/A423). In caps blue are highlighted the drugs that can be used to counteract the pathways altered by glucocorticoid excess. AC, adenylatecyclase; ADP, adenosine diphosphate; AKAP1, A-kinase anchor protein 1; AT, angiotensin; ATI, angiotensin type 1 receptor; AT-R antagonists, angiotensin receptor antagonists; cAMP, cyclic adenosine-monophosphate; CMKII, calcium-calmodulin-dependent protein kinase type 2; CNP, C-type natriuretic peptide; CRH, corticotropin-releasing hormone; eNOS, endothelial nitric oxide synthase; ET, endothelin; ETA, endothelin receptor A; ETB, endothelin receptor B; FOXOs, forkheadhomeobox type O transcription factors; GRE DNA, glucocorticoid response element-DNA; GSK3β, glycogen synthase kinase 3 Beta; GTP, guanosine triphosphate; HDAC, histone deacetylase; isGC, isoform guanylatecyclase; L-Arg, L-arginine; MEF2, myocyte enhancer factor-2; MR, mineralcorticoid receptor; NAD, nicotinamide adenine dinucleotide; NFAT, nuclear factor of activated T cells; NO, nitric oxide; NPA, natriuretic peptide receptor type A; NPB, natriuretic peptide receptor type B; O2, oxygen; O2 -, superoxide anion radical; pGC, particulateguanylate cyclase; PI3K γ, phosphatidyl inositol 3-hydroxy kinase; PKA, protein kinase A; PKG, cGMP-dependent protein kinase; RCAN1, regulator of calcineurin 1 protein; sGC, soluble guanylatecyclase; SRF, serum response factor; Thr, threonine; VCAM-1, vascular cell adhesion molecule 1.
F3-6
FIGURE 3:
Treatment algorithm based on a pathophysiological targets of glucocorticoid excess. ACEi, angiotensin-converting enzyme inhibitor; BP, blood pressure; EH, essential hypertension.

The renin–angiotensin system

The RAS is the most extensively investigated system as a putative contributor to hypertension in CS. Angiotensinogen is almost invariably increased [29], due to stimulation of the hepatic synthesis, whereas renin may be suppressed, as expected [30], or often normal [29], which is inappropriate in view of the enhanced mineralocorticoid activity associated with CS. Circulating angiotensin II levels have been reported to be normal [31], but the number of angiotensin II receptors (type 1A) appears increased, and an enhanced pressor response to angiotensin II infusion has been described in CS [32]. Confirmatory data on the involvement of the angiotensin pathways come from the acute lowering of BP obtained following oral administration of an angiotensin I-converting enzyme inhibitor (ACEi) in CS [29,33]. The fact that exogenous corticosteroids administration is more frequently associated with suppressed renin, due to a compensatory mechanism no longer observed in endogenous CS, where renin is often inappropriately normal, suggests that a long-standing hypercortisolism can induce angiotensin receptor signaling dysregulation. The clear evidence of the angiotensin pathway involvement in the development of hypertension in CS suggests that this should be the first pharmacological target. In fact, ACEi have been successfully used to counteract hypertensive effects of glucocorticoids [29,33], and given the enhanced sensitivity of angiotensin receptors and the cardiovascular remodeling frequently observed in CS, angiotensin receptor blockers (ARBs) also appear a reasonable first choice in the treatment algorithm (Fig. 3).

The mineralocorticoid activity

The mineralocorticoid activity has been traditionally considered a major player of hypertension secondary to glucocorticoid excess. The mineralocorticoid receptor is a nuclear receptor, mainly expressed at a renal level, which is able to bind two different corticosteroids, aldosterone and cortisol, with equal affinity [34]. Binding selectivity in the renal cortex is guaranteed by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2 (11beta-HSD2), which catalyzes the deactivation of cortisol to cortisone [35]. Severe CS is characterized by elevated cortisol levels that overwhelm the ‘protective’ role of 11beta-HSD2, leading to a functional mineralocorticoid excess, due to the binding and activation of the mineralocorticoid receptor by excessive glucocorticoids [36]. The mineralocorticoid receptor hyperactivation at the renal level is known to induce sodium retention and potassium excretion; this mechanism could explain the development in patients with CS of both hypertension, through sodium retention, and hypokalemia. However, although most studies agree that 11beta-HSD2 saturation is the major mechanism for the development of hypokalemia [37], its role in determining hypertension is less evident. Some studies suggest that hypertension induced by chronic hypercortisolism is not primarily mediated through sodium retention [38,39], which is instead a feature of acute glucocorticoid excess [30]. In fact, chronic hypercortisolism is associated with normal circulating sodium and normal sodium excretion [30,40]. It is noteworthy that another isoform of 11beta-HSD, the type-1 (11beta-HSD1), highly expressed in the liver and the adipose tissue, and also in the heart, vascular endothelial and smooth muscle cells, catalyzes the reactivation of cortisone into cortisol, regulating local cortisol bioavailability, and complicating the role of 11beta-HSD and the enhanced mineralcorticoid activity in the development of CS-related hypertension [35]. Moreover, beyond the mineralocorticoid receptor, glucocorticoid receptor also seems to play a role in the renal regulation of sodium balance in patients with CS. Indeed, both mineralocorticoid receptor and glucocorticoid receptor have been thought to be responsible for the enhanced epithelial sodium channel activation (ENaC) and glomerular hyperfiltration, as the selective blockade of mineralocorticoid receptor or glucocorticoid receptor is insufficient to fully restore baseline conditions [40]. This is consistent with clinical observations in CS patients, whose BP improves more under mifepristone, a selective glucocorticoid receptor antagonist [41], than under spironolactone and epleronone, which are mineralocorticoid receptor antagonists [39,42]. In summary, renal mineralocorticoid receptor activation does not appear to be the main determinant of hypertension in most patients with CS, except in those with extremely elevated circulating cortisol levels where renal mineralocorticoid receptor hyperactivation contributes to additional sodium and fluid retention, beyond the increased excretion of potassium and consequent hypokalemia. However, this does not exclude the possibility that inappropriate vascular activation of mineralocorticoid receptor contributes to increased arterial wall tension, even after mild chronic cortisol elevation. In addition, a vascular mineralocorticoid receptor may exhibit different kinetics, for instance, signal transduction might be produced at different ligand concentrations from those working in the kidney [43]. Indeed, mineralocorticoid receptor blockade improves left ventricular hypertrophy and failure in rats with low-aldosterone hypertension, independently of BP-lowering, likely through an attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated mineralocorticoid receptor [44]. In conclusion, renal mineralocorticoid receptor blockade with standard doses of spironolactone or epleronone is a reasonable adjunctive treatment in patients with hypokalemia (Fig. 3). Whether higher doses are required to achieve an efficacious mineralocorticoid receptor blockade in the vasculature wall remains to be established.

The sympathetic nervous system

The sympathetic nervous system, mediated by the catecholaminergic pathway, was traditionally considered an important pathway in the development of CS-related hypertension. However, only limited controlled data support this evidence. In patients with CD, the concentrations of catecholamines, including noradrenaline and adrenaline, and adrenergic receptors seem unaltered [31], as phenylethanolamine N-methyltransferase, the enzyme responsible for noradrenaline to adrenaline methylation [45]. An enhanced pressor response to adrenergic agonists has been reported, but this evidence is controversial. In patients with CD, noradrenaline [46] and the beta-adrenergic agonists isoprenaline and isoproterenol [31] elicited a greater response than in normotensive patients. In contrast, no difference in BP increase between CS patients and control patients has been observed after infusions of the selective alpha1-adrenergic receptor agonist phenylephrine [47]. Cardiac autonomic function was also investigated and found to be impaired in CS. A recent study compared the responses of CS patients and healthy controls to various autonomic tests, finding in the former a reduced sympathetic reactivity [48]. The inconsistent findings and the fact that most CS patients also develop diabetes, requiring treatment with glucose-lowering drugs, suggest that adrenergic blockade should not be a first-line treatment for CS-related hypertension (Fig. 3). In addition, a rare, yet described, contraindication to beta-blockers as a first-line agent is represented by CS secondary to an ECS associated with pheochromocytomas [37].

The vasoregulatory system

Many substances with vasoregulatory properties have been reported to contribute to hypertension secondary to glucocorticoid excess. Endothelin-1 (ET-1), a potent vasoconstrictor, has been implicated in the pathogenesis of early hypertension and premature atherosclerosis due to glucocorticoid excess [49]. To date, only one study has found an increased ET-1 in patients with CS, although it was not correlated with BP or cortisol excretion [50]. Interestingly, in more than half of the patients, circulating ET-1 levels remained elevated even after correction of hypercortisolism [50], a finding attributed to persistent vascular damage. Erythropoietin (EPO) mediates glucocorticoid-induced vasoconstriction in a dose-dependent manner, but this phenomenon has been demonstrated only in healthy individuals acutely treated with exogenous corticosteroids [51], but no proof exists of glucocorticoid regulation of EPO gene expression. No data are presently available in endogenous CS. Enhanced vascular responsiveness to various vasoconstrictors could be explained, at least in experimental studies on murine aortic myocytes, through glucocorticoid-induced down-regulation of the plasma membrane sodium–calcium exchanger [52]. This mechanism has been advocated as a rationale for the use of calcium antagonists in the management of CS-related hypertension (Fig. 3). Most studies on vasodilators have demonstrated the detrimental effects of glucocorticoid excess on the nitric oxide pathway through different mechanisms: inhibition of nitric oxide synthase (NOS) expression [53,54], reduced availability of substrates due to inhibition of the arginine transporter, or impaired cofactor generation due to inhibition of the tetrahydrobiopterin synthesis [55]. This is confirmed by the low urinary nitric oxide metabolites [54] and reduced plasma nitrate/nitrite ratio associated with CS [56]. However, different studies demonstrated an increase in endothelial NOS (eNOS) staining in subcutaneous small-resistance arteries of CS patients; this has been interpreted as a paradoxical increase secondary to enhanced oxidative stress [57]. A beneficial transient activation of cerebral eNOS has been reported to explain the neuroprotective effects of glucocorticoid infusion after stroke. This transient activation, apparently due to a nongenomic glucocorticoid receptor action, is responsible for increased regional cerebral blood flow [58]. The role of cyclic guanosine 3,5-monophosphate (cGMP), a downstream target of nitric oxide signaling, remains unexplored in CS. Its degradation is controlled by phosphodiesterase type 5 (PDE5) and regulated by steroid hormones [59] such as androgens, but data on glucocorticoids are missing. PDE5 inhibition could offer a potential treatment to prevent cardiac remodeling associated with CS [60]. cGMP is a crucial second messenger activated by G-coupled cardiac natriuretic peptide receptors [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)]. ANP, a hormone with natriuretic vasorelaxant and RAS-inhibiting properties, is often reported as increased in CS [61–63]. Nevertheless, there is evidence that ANP action is blunted in CS. Indeed, impaired cGMP generation was described when physiological doses of ANP were infused into patients with CD [64] or given to murine renal vascular smooth muscle cells pretreated with dexamethasone [65]. This further finding, however, was not confirmed in all studies [66]. CS might also be associated with impaired production of other powerful vasodilators including prostaglandins, prostacyclins and compounds of the kallikrein–kinin system [29,67], the latter due to accelerated renal kininase activity [68].

The metabolic factor

A metabolic derangement is a common finding in CS; it is manly characterized by an impairment of glucose and lipid metabolism, together with a catabolic state, represented by a generalized proteolysis. The effects of glucocorticoids on glucose metabolism are complex and include: increase of hepatic glucose production, reduction of glycogen synthesis, decrease of insulin-dependent glucose uptake into peripheral tissues, breakdown of proteins and lipids to provide additional substrates for glucose production, and inhibition of insulin release [69,70]. At hepatic level, glucocorticoids not only antagonize metabolic actions of insulin but also potentiate the effects of different hormones that increase glucose levels, such as glucagon and adrenaline [69,70]. The affected signaling pathways include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) [71], and the nuclear liver X receptor (LXR) [72]. The peripheral effects of glucocorticoids are mainly exerted at the level of skeletal muscle and visceral fat, where glucocorticoids reduce glucose uptake by inhibiting the expression and phosphorylation of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3-K), and protein kinase B (PKB)/Atk [69], all contributing to a decrease in intracellular glucose uptake. A randomized controlled trial in humans revealed that glucocorticoids, even at low doses, can increase fasting plasma glucose and insulin levels, and can decrease the ability of insulin to suppress endogenous glucose production and lipolysis, while increasing whole-body proteolysis [73].

The majority of patients with CS develops an overt metabolic syndrome, where the impairment of glucose tolerance and the dyslipidemia are associated with hypertension, and are strictly dependent on the visceral adiposity and insulin resistance, which are common features of the CS [4]. A study on patients with CD clearly demonstrated that circulating insulin levels were increased, suggesting a state of insulin resistance, and that an increased waist-to-hip ratio, which is a surrogate clinical marker of visceral adiposity, was significantly correlated with insulin levels and the best predictor of the increase in carotid intima–media thickness (IMT), an important preatherosclerotic lesion [74]. These evidences suggested a direct link between visceral adiposity, insulin resistance and premature atherosclerosis in CD [75]. In the long term, glucocorticoid excess can impair insulin release from the pancreatic beta cells, and this phenomenon is probably responsible for the passage from a hyperinsulinemic impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients who develop CS [76,77]. Noteworthy, metabolic syndrome has been also documented in patients long-term cured from CD [78]. It is noteworthy that the metabolic derangements are likely important factors in the long-term cardiovascular outcome, by accelerating atherosclerosis and vasculature remodeling; however, in respect to the etiology of hypertension, they are more likely facilitating conditions.

The vascular factor

Vascular remodeling is a possible consequence of hypertension due to glucocorticoid excess. Hypertrophic changes in the morphology of small-resistance arteries (increased media to lumen ratio, media thickness and wall thickness) have been described in patients with CS [57]. Increased vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to be responsible for vasculature remodeling in various experimental models of glucocorticoid excess [79]. Hyperinsulinemia, impaired insulin signaling and insulin/IGF-I receptors hybrid formation have been claimed to play a role in vasculature smooth muscle cell dysfunction [80,81]. This vascular remodeling and dysfunction may contribute to the aggravation of hypertension associated with CS.

The sleep apnea

The obstructive sleep apnea syndrome (OSAS) is one of the most common secondary conditions associated with resistant hypertension, for which, however, a treatment is available [82]. One-third of the patients with CS develop OSAS [83,84]. The sleep disturbances are strictly correlated with the visceral obesity of patients with CD, making it unclear whether it is primarily due to a direct effect of cortisol excess or secondary to obesity. However, OSAS has been described in lean patients with ECS [85], and CD patients without OSAS exhibit an impaired sleep architecture, with fragmented sleep and an abnormal pattern in rapid eye movements, that resemble the sleep impairment of patients with major depression [84]; these evidences suggest a direct contribution of nocturnal hypercortisolemia. CS and OSAS share the activation of sympathetic nervous system and alterations of cortisol circadian rhythm [86]. Unfortunately, the effects of continuous positive airway pressure (CPAP) in lowering BP in unselected patients with OSAS turned out to be below expectation [82,87]. More recently, it has been shown that CPAP is mainly effective on nocturnal BP [87]. Therefore, a treatment of OSAS with CPAP might be useful in patients with CS, who do not have the physiological decrease of BP during the night, namely the nondipper hypertensive patients with CS.

CLINICAL FEATURES AND CARDIOVASCULAR DAMAGE ASSOCIATED WITH HYPERTENSION IN CUSHING'S SYNDROME

A near–linear relationship between hypertension and cardiovascular, renal and neurological morbid and fatal events has been repeatedly shown [88]. The relationship between hypertension and cardiovascular mortality is modified by the concomitance of other risk factors. Metabolic syndrome and glucocorticoid excess are two recognized important modifiers [89]. Hypertension is an independent predictor of mortality in patients with CD [90–92]. Most studies on CS failed to show a differential elevation between SBP and DBP, while the loss of the physiological nocturnal decrease [12] appears an early feature of both endogenous and exogenous glucocorticoid excess, with a high proportion of patients with nondipper hypertension [7,8].

Hypertension in the different subtypes of Cushing's syndrome

The prevalence of hypertension appears similar among various forms of endogenous CS; however, clinical and pathophysiological differences characterize the subtypes of CS. A tendency towards higher BP is seen in adrenal over pituitary tumors associated with CS. This difference might be related to the specific vasoactive effects of adrenal sex steroids (androgens, estrogen and their metabolites), which are generally suppressed in cortisol-secreting adrenal tumors compared to pituitary tumors responsible for CD [93,94]. Alternatively, it could be due to the retention of some circadian rhythmicity of cortisol secretion in mild CD that is lost in adrenal tumors responsible for adrenal-dependent CS. However, even in CD, over half of the patients do not present nocturnal BP-dipping, showing a lower than 10% fall in SBP and DBP at night and abnormal heart rate values [8]. Zacharieva et al.[95] compared the circadian BP of 100 patients with CS (80 CD and 20 adrenal CS), with 40 patients with EH, and found the blunting of nocturnal decline more severe in patients with adrenal disease. The nocturnal drop in heart rate was preserved in both groups, suggesting that the main effect was on vascular tone. In ECS, more frequently than in other subtypes of CS, patients develop severe hypokalemia, mainly due to saturation of the activity of the 11beta-HSD2. The rapidity and severity of onset of hypercortisolism in this condition is responsible for a severe organ damage [37]. A rarely recognized form of familial CS, with an insidious onset, has been recently identified [96]. Assie et al.[96] described 33 patients with ACTH-independent macronodular hyperplasia, most with ARMC5 mutations. Few studies describing the characteristics of hypertension in this genetic form of CS are available [96,97]; interestingly, whereas hypercortisolism is the most frequent reason for clinical presentation in families with bilateral macronodular adrenal hyperplasia positive for ARMC5 mutations, hyperaldosteronism is unusually prominent in those negative for ARMC5 mutations [97]. Future studies of the genotype–phenotype relationships in familial CS may provide an opportunity to study the very early stages of CS development. Completely different is the hypertension associated with exogenous glucocorticoid that affects about 20% of patients receiving prolonged treatment with corticosteroids. In these cases, the clinical picture is determined by the dose, route of administration, duration and type of steroid used [98].

Cardiac damage

CS is associated with an increased mortality from multisystem risk that is already elevated several years before the diagnosis, confirming that is caused by cortisol excess. Compared to matched controls, patients with active disease have a hazard ratio of 6.0 (2.1–17.1) for heart failure and of 2.1 (0.5–8.6) for acute myocardial infarction (AMI). An increased prevalence of left ventricular hypertrophy and concentric remodeling are consistently found in CS [99]. Muiesan et al.[99] also described important left ventricular functional alterations, such as a decrease in left ventricular systolic performance measured at the mid-wall, and a change in diastolic filling with an abnormal relaxation pattern. Toja et al.[100] found that CS patients presented a more severe change in left ventricular mass index and relative wall thickness than both normotensive and matched hypertensive controls. No clinically relevant diastolic dysfunction was seen in patients or controls with normal BP [100], suggesting that hypertension was involved, albeit not the only factor, in the whole range of cardiac alterations observed in CS. The most important ultrastructural abnormality in CS cardiomyopathy is myocardial fibrosis. This seems directly related to cortisol action rather than to cardiac hypertrophy or BP, exerted through an enhanced responsiveness to angiotensin II [101]. Activation of the mineralocorticoid receptor and glucocorticoid receptor also contributes to its development. It was recently shown that glucocorticoids activate cardiac mineralocorticoid receptor during experimental myocardial infarction [102], supporting the use of mineralocorticoid receptor antagonists. Yiu et al.[103] demonstrated that myocardial fibrosis is significantly increased in untreated CS compared to EH, and partly reversible after successful treatment of CS. On ECG, CD patients show prolonged QT and features of left ventricular hypertrophy, even if the association of CD with a prolonged QT seems to be independent of other risk factors, including hypertension. This suggests a cardiotoxic effect of hypercortisolism per se[104]. Moreover, in comparison with patients matched for similar cardiovascular risk factors, CS patients show a sympathovagal imbalance, characterized by relatively increased parasympathetic activity. It is still unknown whether this acts to counterbalance cortisol-induced effects on BP, and cardiac structure and function or has a different pathophysiological significance [105]. Hypertensive CS patients show impairment in all parasympathetic function parameters. The significantly different expiratory-to-inspiratory ratio might be explained by the effect of hypertension or antihypertensive medications in some patients [48].

Vasculature remodeling: large vessels

The IMT of both the carotid and aortic arteries is significantly increased in CS patients and associated with premature development of carotid atherosclerotic plaques [75,106]. Compared to matched controls, patients with active disease have a hazard ratio of 4.5 (1.8–11.1) of having a stroke [92]. Successful treatment of glucocorticoid excess decreases carotid artery IMT, which, however, remains above matched controls, respectively, 1 [74] and 5 [78] years after the cure. In untreated patients, IMT is closely correlated to central adiposity and insulin resistance, suggesting a causative link that, however, is lost after the cure, claiming into cause additional factors such as persistence of hypertension or inflammation [74,78].

Vasculature remodeling: small vessels

Cushing's syndrome is also associated with endothelial dysfunction, which precedes the development of atherosclerosis [4,74,107]. CS is associated with altered brachial flow-mediated vasodilation [108]. Endothelial dysfunction is associated with impaired microvascular reactivity, which seems to be modulated by hypertension [109], and with vascular smooth cell hypertrophy and wall fibrosis of small arteries [57]. These effects are probably due to mineralocorticoid pro-inflammatory actions. CS patients also show structural abnormalities in the resistance arteries, as indicated by an increased media-to-lumen ratio. These abnormalities are characterized by hypertrophic remodeling rather than the eutrophic remodeling usually observed in patients with EH which seems to be the consequence of cortisol growth-stimulating properties and/or vascular oxidative stress [57]. However, glucocorticoids may also activate the mineralocorticoid receptor in vascular smooth muscle cells, which involves mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK)-dependent pathways [110]. All these data suggest that glucocorticoids contribute to cardiovascular remodeling via mineralocorticoid receptor signaling, independently of sodium retention or circulating aldosterone [111].

Neither renal nor retinal damage induced by hypertension have been adequately investigated in CS patients. It has been found that more than 80% of CS patients have increased urinary albumin excretion. In general, renal proteinuria may be caused by increased glomerular filtration rate, resulting from higher intraglomerular pressure, damage to the glomerular barrier or decreased tubular reabsorption. Urinary albumin excretion is positively correlated with SBP and DBP, and fasting plasma glucose, suggesting that these factors may have contributed to the increased albumin excretion. However, it is also possible that hypercortisolemia itself increases urinary albumin excretion, although the mechanism is not clear yet [112]. An increased excretion rate of some amino acids, including cysteine, has been documented in patients with active CD, but not in cured patients [113], suggesting a specific effect of glucocorticoid excess on renal function. Renal effects of glucocorticoid also includes calcium metabolism that is responsible for hypercalciuria, increased urinary oxalate and ultimately to nephrolithiasis, a common feature of active CS [114]. Further studies are necessary to investigate both renal and retinal damage secondary to hypertension in CS patients.

EFFECT OF TREATMENT OF CUSHING'S SYNDROME ON HYPERTENSION

The definitive therapy of CS-related hypertension is the surgical removal of the tumor responsible for the disease. However, medical therapy is gaining a broader spectrum of applications [115], not only in preparation for surgery or recurrences, due to the recent development of new agents with proven efficacy in lowering ACTH secretion from pituitary tumors and antisteroidal drugs to counteract glucocorticoid excess. Interestingly, mortality data show that adequate control of hypercortisolemia does not always result in a normalization of BP. Some studies reveal a normalization of the increased cardiovascular risk after immediate surgical cure of CD [116,117], whereas others did not [90–92]. Interestingly, studies with longer follow-up tend to show a persistently elevated risk that is specific for AMI and stroke, but not for heart failure [92]. Among all CS patients, men, those with diabetes or hypertension have a significantly higher mortality risk [3].

Effect of surgical treatment

Transsphenoidal resection of pituitary tumor for CD provides a long-term cure in more than 70% of the cases [2,3,19,115]. After 5 years of cortisol normalization, however, hypertension was found in 40% of the patients, notably higher than would be expected in a sex and age-matched population [74,78]. Bilateral adrenalectomy is recommended for inoperable or occult sources of CS. A large Mayo Clinic cohort found that bilateral adrenalectomy resolved hypertension in 64% of the patients, which is a higher improvement rate than seen with parameters such as diabetes and obesity, confirming the strict association of high BP with glucocorticoid excess [118]. Magiakou et al.[25] evaluated 31 children with CS of different etiologies before and 1 year after surgery: 93.5% had preoperative systolic hypertension that persisted after surgical treatment in 30.7, 15.8 and 5.5% of patients at 3, 6 and 12 months, respectively. DBP completely normalized in all patients within 3 months [25]. In contrast, after successful treatment of 23 children with CS, an Italian study found a persistent significant impairment in arterial distensibility and altered 24-h BP monitoring, compared to controls [119]. This suggests that while BP improves faster in young patients, who are somewhat protected from microvascular damage, an increased cardiovascular risk persists despite cortisol and BP normalization. Recent mortality data reveal that increased hypertension can be found after 30 years of follow-up [92], independently of surgical removal of the cause of CS. The risk appears as a consequence of the length of exposure to glucocorticoid excess, with an increased mortality found in patients with symptoms lasting for more than 3 years prior to surgery, compared to those with less than a 3-year history [3].

Effect of medical therapy

Medical therapy of endogenous glucocorticoid excess includes agents that modulate pituitary or ectopic ACTH release (somatostatin analogs, dopamine agonists), inhibit steroidogenesis (ketoconazole, metyrapone, mitotane, etomidate) or block the glucocorticoid receptor (mifepristone) [120]. Several studies which evaluated the effectiveness of these drugs on the control of hypercortisolism in patients with CS also analyzed the effect on clinical feature, including BP and hypertension. Table 2 described the outcome of recent registered clinical trials in patients with CS, detailing the effects of these compounds on BP and hypertension. Ketoconazole, an inhibitor of 17-alpha hydroxilase and 17,20 lyase activity, improved BP in over 80% of the cases [120]. Metyrapone, an inhibitor of 11-beta-hydroxylase activity, with a good response in urinary free cortisol (UFC) levels [122], is, however, associated with a potential rise in intermediates with mineralocorticoid activity, thus potentially worsening hypertension, as well as hypokalemia. Mitotane has been widely used in patients with adrenocortical carcinoma, but also in severe cases of CS, as an alternative to bilateral adrenalectomy. In particular, in ECS, UFC levels were normalized in 91% of the patients, leading to improved BP in 63% of the hypertensive patients, who were able to stop or reduce antihypertensive drugs [123]. Various novel agents have been evaluated for their possible inhibition of ACTH secretion, including the dopamine agonist cabergoline and most recently somatostatin analog pasireotide; both cabergoline and pasireotide have been demonstrated to significantly improve hypertension associated with CD [124,125]. In particular, in two different multicenter prospective clinical trial, pasiretotide was able to improve SBP and DBP by 6 and 4 mmHg, respectively, when administered alone [126], and by 12 and 8 mmHg, respectively, when administered in combination with cabergoline and ketoconazole [127]. The new compound LCI699, an orally active inhibitor of the 11-beta-hydroxylase, is being investigated in CS [128]. However, similar to metyrapone, the inhibition of 11-beta-hydroxylase activity increases cortisol and aldosterone precursors with mineralcorticoid activity, and could induce hypokalemia and worsen hypertension. The experience with mifepristone, a glucocorticoid receptor antagonist, is limited; BP was reduced in about half of the patients, although in some patients, hypertension and hypokaliemia worsened, requiring co-treatment with spironolactone [129]. In a recent multicenter, prospective, open-label study, mifepristone induced improvement in BP in a significant number of patients with CS; in particular, DBP was improved in 38% of the patients displaying only hypertension, whereas DBP and/or antihypertensive treatment was decreased in more 52% of the patients displaying hypertension alone or in association with disturbances of glucose metabolism [130]. However, despite the treatment with mifepristone, in most cases, additional antihypertensive agents were also necessary. In summary, hypertension can be difficult to control without normalization of hypercortisolemia, but this is often insufficient, suggesting the need for an integrated pharmacologic approach [131].

T2-6
TABLE 2:
Recent registered clinical trials on novel treatments for Cushing's syndrome reporting effect on blood pressure and hypertension
T3-6
TABLE 2:
(Continued) Recent registered clinical trials on novel treatments for Cushing's syndrome reporting effect on blood pressure and hypertension

TREATMENT OF HYPERTENSION IN CUSHING'S SYNDROME

Table 2S (https://links.lww.com/HJH/A423) presents a systematic review of studies investigating the pharmacological treatment of hypertension in CS patients, as well as the effects of medical or surgical therapy of CS on hypertension. This enabled a number of clinical considerations to be drawn that have been integrated with the pharmacology statements driven by experimental data to build the treatment algorithm presented in Fig. 3. First, clinical control of hypertension has been considered difficult in the presence of sustained long-standing hypercortisolism. Therefore, it is reasonable that the primary medical goal in most studies has been to control glucocorticoid excess. However, given that treatment is often surgical and the response not always successful at the first attempt, a reasonable position would be to use add-on antihypertensives to prevent cardiovascular complications. Although the prevalence of hypertension is high in CS patients, less than 50% are actually treated for hypertension prior to surgery, especially if they are young patients [19,91]. This discrepancy may be related to the evidence that, unless BP is extremely high, once the etiology of CS is established, most physicians wait for surgical cure or relay on antisteroids rather than commencing early antihypertensive treatment. This approach seems driven by empirical reasoning rather than evidence-based medicine, as the few available studies exploring the effects of antihypertensives showed consistent, reproducible effects. A different scenario is when the syndrome is not yet recognized, and the patients, especially when older, are inadequately treated for an EH. Second, use of add-on antihypertensives is supported by data on end-organ complications that seem to occur earlier and at lower BP values in CS than in EH. Such accelerated vascular remodeling and atherosclerosis should prompt aggressive treatment. Third, studies show that the antihypertensive drug is often selected according to generic guidelines for the management of EH rather than pathophysiological considerations relative to CS. This could also explain the discrepancy in results: some studies found no improvement in BP, whereas in others, even a single antihypertensive drug was effective. The proposed treatment algorithm (Fig. 3) is based on a step-up approach with different drugs specifically targeting the pathways most commonly affected by glucocorticoid excess. Fourth, persistence of hypertension after treatment of CS deserves special attention. An aggressive approach, such as with lipid-lowering drugs following ischemic heart attack, could be advocated for the treatment of residual hypertension following resolution of the glucocorticoid excess. Fifth, little attention has been paid to the impaired endothelial function, in particular, on the nitric oxide pathway, despite solid pathophysiological data and promising preliminary results. On the basis of the recent publications showing both early diastolic impairment and blunted natriuretic peptide signaling in hypercortisolism and the antiremodeling effects of chronic PDE5i in diabetic cardiomyopathy, CS patients may be excellent candidates for a dedicated study on chronic PDE5i to revert cardiovascular remodeling. Similarly, the effect of lifestyle interventions and physical activity on the outcome of CS after treatment has not been studied. Considering that myopathy and obesity both reduce the mobility of these patients, specific guidelines are needed to aid physicians in choosing a suitable rehabilitation program. Finally, the results of the recent multicenter, randomized controlled clinical trials exploring the effects of pasireotide [126] and LCI699 [128] or mifrepistone [130] allow a more precise estimate of how much BP is likely to drop following effective control of hypercortisolemia. However, these drugs have a complex mechanism of action that focuses mainly on the control of hypercortisolism. Hence, it cannot be ruled out that the effects on BP may be due to a combination of many different factors. These recent studies have shown that hypercortisolism control is very effective in lowering both systolic and diastolic pressure. Therefore, whereas the old retrospective, heterogeneous studies reviewed herein suggested that control of hypercortisolemia was insufficient to prevent end-organ disease, this may not necessarily apply to the more recent, well controlled trials, in which stricter remission/cure criteria are applied. However, even in the latest studies, only about 50% of the patients were able to discontinue antihypertensives completely. Given the data on the presence of significant cardiovascular comorbidities even after complete remission, prompt and aggressive control of BP remains desirable.

Proposed algorithm for the treatment of Cushing's syndrome-related hypertension

The European guidelines for the management of hypertension recommend to lower BP with drugs, even when hypertension is in the grade 1 range, if total cardiovascular risk is high because of diabetes, cardiac or kidney disease [89,132]. The data, herein presented, clearly show that CS represents a condition of increased risk deserving pharmacological treatment. Furthermore, although lifestyle modifications are recommended for CS patients, especially dietary control of metabolic syndrome [133], some other interventions, such as physical exercise and weight control, are more difficult in patients with CS, due to myopathy and generalized pain, which often characterize the disease. Recent guidelines indicate that diuretics, beta-blockers, calcium antagonists, ACEis and ARBs are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations [89]. However, given the pathophysiological peculiarities of CS, integrated with the recent recommendations [89], the ABC study group formulated a treatment algorithm that is specifically tailored for the management of CS-related hypertension (Fig. 3). This algorithm includes as a first-line treatment the use of any of the two blockers of the RAS, ACEi or ARB, in light of the many evidences supporting a major alteration of this pathway in CS, and for their cardioprotective effects. Conversely, beta-blockers are not considered a first-line drug, in part, because they are not superior, or even slightly worse, than calcium antagonists in reducing total mortality, cardiovascular events and stroke, but also for the possible contraindications, represented by metabolic syndrome, glucose intolerance and sleep apnea, all very frequent in patients with active CS or after the cure [134]. Calcium antagonists are powerful in lowering BP and do not present specific contraindications in respect to CS; they also have a greater efficacy than diuretics and beta-blockers in delaying atherosclerosis and IMT of the carotid artery [135] and preventing stroke [136]. Among diuretics, spironolactone should be used to control hypokalemia, when present, and has been found to have beneficial effects in heart failure [137], and, although never tested in randomized controlled studies on hypertension, can be used as a third-line drug to lower BP. Eplerenone could be used as an alternative to spironolactone, especially in men [138]; however, it is not available as a subsidized medication in several countries, it is expensive compared to amiloride and spironolactone and, therefore, could suffer compliance in medium to long-term treatment. Thiazides should be used cautiously for the risk of aggravating hypokalemia, which is very common in CS, hyperuricemia, gout and diabetes, which may occur in CS [139,140]. Hydrochlorothiazide has been used for prevention of calcium-containing kidney stones, a frequent complication of CS, because at high dose, it can reduce urinary calcium excretion [139,140]; however, thiazides also reduce free water clearance and recent evidences questioned their use for kidney stone prevention [141,142]. Aliskiren, a direct inhibitor of renin at the site of its activation, has never been tested in CS; it can have possible complications in patients with diabetes and cannot be combined with any other drug acting on RAS. For these reasons it should not be a first choice. The alpha-blocker doxazosin has effectively been used as third-line therapy in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) [143] and does not offer specific contraindications related to CS. Monotherapy is seldom sufficient to control BP in CS; however, no controlled studies on combination therapies are available in this group of patients. In non-CS patients, the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension [414] trial documented the positive synergy an ACEi–calcium antagonist combination. This combination was superior to the combination of beta-blocker and diuretics in reducing cardiovascular events [144] that appeared to elicit more cases of new-onset diabetes in susceptible individuals, compared with other combinations [145]. Agents acting at different levels of the RAS should never be combined. New BP-lowering drugs (nitric oxide donors, vasopressin antagonists, neutral endopeptidase inhibitors, aldosterone synthase inhibitors, etc.) are all undergoing early stages of investigation [128,146].

In summary, the most appropriate approach to treat hypertension and related cardiovascular damage in patients with CS seems to commence with an ACEi or an ARB, if necessary, coupled with calcium-antagonists and/or a mineralocorticoid receptor antagonist, depending on the severity of the condition and the presence of hypokalemia. Use of other diuretics, alpha-blockers and, eventually, beta-blockers should be limited to selected cases after appropriate dose-titration of other agents taking into account the possible contraindications related to the state of hypercortisolemia.

ACKNOWLEDGEMENTS

Conflicts of interest

Disclosure: A.M.I. has been occasional consultant for Bayer, Otsuka and Besins. A.Coz. received a fee for presentation from Novartis. A.Col. has been principal investigator of research studies from Novartis, Ipsen, Pfizer and Lilly, has received research grants from Novartis, Ipsen, Pfizer, Ferring, Lilly, Merck-Serono, Novo-Nordisk, has been occasional consultant for Novartis, Ipsen and Pfizer, and has received fees and honoraria from Ipsen, Novartis, and Pfizer. R.P. has been principal investigator of research studies from Novartis, has received research grants from Novartis, Viropharma, Pfizer and IBSA, has been occasional consultant for Novartis, Ipsen, Pfizer, Viropharma, and Ferring, and received fees and honoraria for presentations from Novartis.

Reviewers’ Summary Evaluations Reviewer 2

This ambitious review of an important subject would have benefitted by addressing each of the various aetiologies of Cushing's separately. They differ widely in clinical and laboratory presentation, natural history, pathophysiology and appropriate treatment. Treatment priorities will also be different for each unique patient, rejecting a formalised approach. Hopefully, this review may assist choices of antihypertensive agents. The exciting recent contributions from genetics to the understanding of familial forms deserve great attention and emphasis, promising early identification of those at risk from this often insidious and late-diagnosed condition, and better understanding of pathophysiology.

Reviewer 3

The different causes of Cushing's syndrome with the attendant diversity of the pathophysiological mechanisms underlying the rise of blood pressure make it difficult to provide definitive guidelines for antihypertensive treatment in these patients. However, a careful and thorough evaluation of the present knowledge has allowed the authors to provide some major therapeutic recommendations, some of which of definite clinical relevance.

REFERENCES

1. Pivonello R, De Martino MC, De LM, Lombardi G, Colao A. Cushing's syndrome. Endocrinol Metab Clin North Am 2008; 37:135–149.ix.
2. Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO. Mortality in Cushing's syndrome: a systematic review and meta-analysis. Eur J Intern Med 2012; 23:278–282.
3. Lambert JK, Goldberg L, Fayngold S, Kostadinov J, Post KD, Geer EB. Predictors of mortality and long-term outcomes in treated Cushing's disease: a study of 346 patients. J Clin Endocrinol Metab 2013; 98:1022–1030.
4. Pivonello R, Faggiano A, Lombardi G, Colao A. The metabolic syndrome and cardiovascular risk in Cushing's syndrome. Endocrinol Metab Clin North Am 2005; 34:327–339.viii.
5. Pivonello R, De Martino MC, De Leo M, Tauchmanovà L, Faggiano A, Lombardi G, Colao A. Cushing's syndrome: aftermath of the cure. Arq Bras Endocrinol Metabol 2007; 51:1381–1391.
6. Bertoia ML, Waring ME, Gupta PS, Roberts MB, Eaton CB. Implications of new hypertension guidelines in the United States. Hypertension 2012; 60:639–644.
7. Imai Y, Abe K, Sasaki S, Minami N, Nihei M, Munakata M, et al. Altered circadian blood pressure rhythm in patients with Cushing's syndrome. Hypertension 1988; 12:11–19.
8. Pecori GF, Toja PM, De Martin M, Maronati A, Scacchi M, Omboni S, et al. Circadian blood pressure profile in patients with active Cushing's disease and after long-term cure. Horm Metab Res 2007; 39:908–914.
9. Walker BR, Stewart PM, Shackleton CH, Padfield PL, Edwards CR. Deficient inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase in essential hypertension. Clin Endocrinol (Oxf) 1993; 39:221–227.
10. Watt GC, Harrap SB, Foy CJ, Holton DW, Edwards HV, Davidson HR, et al. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens 1992; 10:473–482.
11. Van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM 2000; 93:105–111.
12. Imai Y, Abe K, Sasaki S, Minami N, Munakata M, Nihei M, et al. Exogenous glucocorticoid eliminates or reverses circadian blood pressure variations. J Hypertens 1989; 7:113–120.
13. Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004; 141:764–770.
14. Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts AC, Leufkens HG, Walker BR. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart 2004; 90:859–865.
15. Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G. High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines. Clin Endocrinol (Oxf) 2004; 61:768–777.
16. Valassi E, Santos A, Yaneva M, Tóth M, Strasburger CJ, Chanson P, et al. The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol 2011; 165:383–392.
17. Devoe DJ, Miller WL, Conte FA, Kaplan SL, Grumbach MM, Rosenthal SM, et al. Long-term outcome in children and adolescents after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab 1997; 82:3196–3202.
18. Lodish MB, Sinaii N, Patronas N, Batista DL, Keil M, Samuel J, et al. Blood pressure in pediatric patients with Cushing syndrome. J Clin Endocrinol Metab 2009; 94:2002–2008.
19. Hassan-Smith ZK1, Sherlock M, Reulen RC, Arlt W, Ayuk J, Toogood AA, et al. Outcome of Cushing's disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab 2012; 97:1194–1201.
20. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing's disease: clinical and health-related quality of life aspects. Eur J Endocrinol 2012; 167:311–326.
21. Rossi GP, Seccia TM, Maniero C, Pessina AC. Drug-related hypertension and resistance to antihypertensive treatment: a call for action. J Hypertens 2011; 29:2295–2309.
22. Hammer F, Stewart PM. Cortisol metabolism in hypertension. Best Pract Res Clin Endocrinol Metab 2006; 20:337–353.
23. Pecori GF, Moro M, Cavagnini F. Gender-related differences in the presentation and course of Cushing's disease. J Clin Endocrinol Metab 2003; 88:1554–1558.
24. Giordano R, Picu A, Marinazzo E, D’Angelo V, Berardelli R, Karamouzis I, et al. Metabolic and cardiovascular outcomes in patients with Cushing's syndrome of different aetiologies during active disease and 1 year after remission. Clin Endocrinol (Oxf) 2011; 75:354–360.
25. Magiakou MA, Mastorakos G, Zachman K, Chrousos GP. Blood pressure in children and adolescents with Cushing's syndrome before and after surgical care. J Clin Endocrinol Metab 1997; 82:1734–1738.
26. Dias R, Storr HL, Perry LA, Isidori AM, Grossman AB, Savage MO. The discriminatory value of the low-dose dexamethasone suppression test in the investigation of paediatric Cushing's syndrome. Horm Res 2006; 65:159–162.
27. Storr HL, Isidori AM, Monson JP, Besser GM, Grossman AB, Savage MO. Prepubertal Cushing's disease is more common in males, but there is no increase in severity at diagnosis. J Clin Endocrinol Metab 2004; 89:3818–3820.
28. Ulick S, Wang JZ, Blumenfeld JD, Pickering TG. Cortisol inactivation overload: a mechanism of mineralocorticoid hypertension in the ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1992; 74:963–967.
29. Saruta T, Suzuki H, Handa M, Igarashi Y, Kondo K, Senba S. Multiple factors contribute to the pathogenesis of hypertension in Cushing's syndrome. J Clin Endocrinol Metab 1986; 62:275–279.
30. Connell JM, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens 1987; 5:425–433.
31. Ritchie CM, Sheridan B, Fraser R, Hadden DR, Kennedy AL, Riddell J, Atkinson AB. Studies on the pathogenesis of hypertension in Cushing's disease and acromegaly. Q J Med 1990; 76:855–867.
32. Shibata H, Suzuki H, Maruyama T, Saruta T. Gene expression of angiotensin II receptor in blood cells of Cushing's syndrome. Hypertension 1995; 26 (6 Pt 1):1003–1010.
33. Yasuda G, Shionoiri H, Umemura S, Takasaki I, Ishii M. Exaggerated blood pressure response to angiotensin II in patients with Cushing's syndrome due to adrenocortical adenoma. Eur J Endocrinol 1994; 131:582–588.
34. Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension 2005; 46:1227–1235.
35. Quinkler M, Stewart PM. Hypertension and the cortisol-cortisone shuttle. J Clin Endocrinol Metab 2003; 88:2384–2392.
36. Stewart PM, Walker BR, Holder G, O’Halloran D, Shackleton CH. 11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1995; 80:3617–3620.
37. Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab 2006; 91:371–377.
38. Whitworth JA, Gordon D, Andrews J, Scoggins BA. The hypertensive effect of synthetic glucocorticoids in man: role of sodium and volume. J Hypertens 1989; 7:537–549.
39. Williamson PM, Kelly JJ, Whitworth JA. Dose-response relationships and mineralocorticoid activity in cortisol-induced hypertension in humans. J Hypertens Suppl 1996; 14:S37–S41.
40. Bailey MA, Mullins JJ, Kenyon CJ. Mineralocorticoid and glucocorticoid receptors stimulate epithelial sodium channel activity in a mouse model of Cushing syndrome. Hypertension 2009; 54:890–896.
41. Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB, et al. Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrinol Metab 1985; 61:536–540.
42. McMahon EG. Recent studies with eplerenone, a novel selective aldosterone receptor antagonist. Curr Opin Pharmacol 2001; 1:190–196.
43. Rickard AJ, Morgan J, Bienvenu LA, Fletcher EK, Cranston GA, Shen JZ, et al. Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis. Hypertension 2012; 60:1443–1450.
44. Nagata K, Obata K, Xu J, Ichihara S, Noda A, Kimata H, et al. Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. Hypertension 2006; 47:656–664.
45. Mannelli M, Lanzillotti R, Pupilli C, Ianni L, Conti A, Serio M. Adrenal medulla secretion in Cushing's syndrome. J Clin Endocrinol Metab 1994; 78:1331–1335.
46. Heaney AP, Hunter SJ, Sheridan B, Brew AA. Increased pressor response to noradrenaline in pituitary dependent Cushing's syndrome. Clin Endocrinol (Oxf) 1999; 51:293–299.
47. McKnight JA, Rooney DP, Whitehead H, Atkinson AB. Blood pressure responses to phenylephrine infusions in subjects with Cushing's syndrome. J Hum Hypertens 1995; 9:855–858.
48. Jyotsna VP, Naseer A, Sreenivas V, Gupta N, Deepak KK. Effect of Cushing's syndrome: endogenous hypercortisolemia on cardiovascular autonomic functions. Auton Neurosci 2011; 160:99–102.
49. Ruschitzka F, Quaschning T, Noll G, deGottardi A, Rossier MF, Enseleit F, et al. Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide. Circulation 2001; 103:3129–3135.
50. Kirilov G, Tomova A, Dakovska L, Kumanov P, Shinkov A, Alexandrov AS. Elevated plasma endothelin as an additional cardiovascular risk factor in patients with Cushing's syndrome. Eur J Endocrinol 2003; 149:549–553.
51. Kelly JJ, Martin A, Whitworth JA. Role of erythropoietin in cortisol-induced hypertension. J Hum Hypertens 2000; 14:195–198.
52. Smith L, Smith JB. Regulation of sodium-calcium exchanger by glucocorticoids and growth factors in vascular smooth muscle. J Biol Chem 1994; 269:27527–27531.
53. Radomski MW, Palmer RM, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci U S A 1990; 87:10043–10047.
54. Wallerath T, Witte K, Schäfer SC, Schwarz PM, Prellwitz W, Wohlfart P, et al. Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension. Proc Natl Acad Sci U S A 1999; 96:13357–13362.
55. Simmons WW, Ungureanu-Longrois D, Smith GK, Smith TW, Kelly RA. Glucocorticoids regulate inducible nitric oxide synthase by inhibiting tetrahydrobiopterin synthesis and L-arginine transport. J Biol Chem 1996; 271:23928–23937.
56. Kelly JJ, Tam SH, Williamson PM, Lawson J, Whitworth JA. The nitric oxide system and cortisol-induced hypertension in humans. Clin Exp Pharmacol Physiol 1998; 25:945–946.
57. Rizzoni D, Paiardi S, Rodella L, Porteri E, De Ciuceis C, Rezzani R, et al. Changes in extracellular matrix in subcutaneous small resistance arteries of patients with primary aldosteronism. J Clin Endocrinol Metab 2006; 91:2638–2642.
58. Limbourg FP, Huang Z, Plumier JC, Simoncini T, Fujioka M, Tuckermann J, et al. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest 2002; 110:1729–1738.
59. Serarslan Y, Yönden Z, Ozgiray E, Oktar S, Güven EO, Söğüt S, et al. Protective effects of tadalafil on experimental spinal cord injury in rats. J Clin Neurosci 2010; 17:349–352.
60. Colao A, Pivonello R, Ferone D, Faggiano A, Facciolli G, Di Somma C, et al. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation 2012; 125:2323–2333.
61. Knoepfelmacher M, Pradal MJ, Dio RD, Salgado LR, Semer M, Wajchenberg BL, Liberman B. Effect of corticotrophin-releasing hormone on arginine vasopressin and atrial natriuretic factor in patients with Cushing's disease. Clin Endocrinol (Oxf) 1998; 49:77–84.
62. Knoepfelmacher M, Pradal MJ, Dio RD, et al. Resistance to vasopressin action on the kidney in patients with Cushing's disease. Eur J Endocrinol 1997; 137:162–166.
63. Yamaji T, Ishibashi M, Yamada A, Takaku F, Itabashi A, Katayama S, et al. Plasma levels of atrial natriuretic hormone in Cushing's syndrome. J Clin Endocrinol Metab 1988; 67:348–352.
64. Sala C, Ambrosi B, Morganti A. Blunted vascular and renal effects of exogenous atrial natriuretic peptide in patients with cushing's disease. J Clin Endocrinol Metab 2001; 86:1957–1961.
65. Yasunari K, Kohno M, Murakawa K, Yokokawa K, Takeda T. Glucocorticoids and atrial natriuretic factor receptors on vascular smooth muscle. Hypertension 1990; 16:581–586.
66. Fujio N, Ohashi M, Nawata H, Kato K, Matsuo H, Ibayashi H. Cardiovascular, renal and endocrine effects of alpha-human atrial natriuretic peptide in patients with Cushing's syndrome and primary aldosteronism. J Hypertens 1989; 7:653–659.
67. Axelrod L. Inhibition of prostacyclin production mediates permissive effect of glucocorticoids on vascular tone. Perturbations of this mechanism contribute to pathogenesis of Cushing's syndrome and Addison's disease. Lancet 1983; 1:904–906.
68. Shimamoto K, Ura N, Nomura N, Aoyama T, Iwata M, Takagawa Y, Iimura O. Significance of renal kininases in patients with Cushing's syndrome. Clin Exp Hypertens 1995; 17:1173–1182.
69. van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest 2009; 39:81–93.
70. Giordano R, Guaraldi F, Berardelli R, Karamouzis I, D’Angelo V, Marinazzo E, et al. Glucose metabolism in patients with subclinical Cushing's syndrome. Endocrine 2012; 41:415–423.
71. Huang B, Wu P, Bowker-Kinley MM, Harris RA. Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 2002; 51:276–283.
72. Patel R, Patel M, Tsai R, Lin V, Bookout AL, Zhang Y, et al. LXRbeta is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J Clin Invest 2011; 121:431–441.
73. van Raalte DH, Brands M, van der Zijl NJ, Muskiet MH, Pouwels PJ, Ackermans MT, et al. Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial. Diabetologia 2011; 54:2103–2112.
74. Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filippella M, Di Somma C, et al. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing's disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 2003; 88:2527–2533.
75. Albiger N, Testa RM, Almoto B, Ferrari M, Bilora F, Petrobelli F, et al. Patients with Cushing's syndrome have increased intimal media thickness at different vascular levels: comparison with a population matched for similar cardiovascular risk factors. Horm Metab Res 2006; 38:405–410.
76. Pivonello R, De Leo M, Vitale P, Cozzolino A, Simeoli C, De Martino MC, et al. Pathophysiology of diabetes mellitus in Cushing's syndrome. Neuroendocrinology 2010; 92 (Suppl 1):77–81.
77. Giordano C, Guarnotta V, Pivonello R, Amato MC, Simeoli C, Ciresi A, et al. Is diabetes in Cushing's syndrome only a consequence of hypercortisolism? Eur J Endocrinol 2014; 170:311–319.
78. Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, et al. Persistence of increased cardiovascular risk in patients with Cushing's disease after five years of successful cure. J Clin Endocrinol Metab 1999; 84:2664–2672.
79. Zacharieva S, Atanassova I, Orbetzova M, Kirilov G, Nachev E, Kalinov K, Shigarminova R. Vascular endothelial growth factor (VEGF), prostaglandin E2(PGE2) and active renin in hypertension of adrenal origin. J Endocrinol Invest 2004; 27:742–746.
80. Bender SB, McGraw AP, Jaffe IZ, Sowers JR. Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease? Diabetes 2013; 62:313–319.
81. Gatenby VK, Kearney MT. The role of IGF-1 resistance in obesity and type 2 diabetes-mellitus-related insulin resistance and vascular disease. Expert Opin Ther Targets 2010; 14:1333–1342.
82. Parati G, Lombardi C, Hedner J, Bonsignore MR, Grote L, Tkacova R, et al. Position paper on the management of patients with obstructive sleep apnea and hypertension: joint recommendations by the European Society of Hypertension, by the European Respiratory Society and by the members of European COST (COoperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea. J Hypertens 2012; 30:633–646.
83. Bottini P, Tantucci C. Sleep apnea syndrome in endocrine diseases. Respiration 2003; 70:320–327.
84. Shipley JE, Schteingart DE, Tandon R, Starkman MN. Sleep architecture and sleep apnea in patients with Cushing's disease. Sleep 1992; 15:514–518.
85. Venkatram S, Vakde T, Badipatla K, Niazi M, Diaz-Fuentes G. Unusual triad of obstructive sleep apnea, uncontrolled hypertension, and severe hypokalemia due to ectopic adrenocorticotropic secretion. J Bronchology Interv Pulmonol 2014; 21:158–161.
86. Zanchetti A. What should be learnt about the management of obstructive sleep apnea in hypertension? J Hypertens 2012; 30:669–670.
87. Schein AS, Kerkhoff AC, Coronel CC, Plentz RD, Sbruzzi G. Continuous positive airway pressure reduces blood pressure in patients with obstructive sleep; a systematic review and meta-analysis with 1000 patients. J Hypertens 2014; 32:1762–1773.
88. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903–1913.
89. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31:1281–1357.
90. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin Endocrinol (Oxf) 1994; 40:479–484.
91. Clayton RN, Raskauskiene D, Reulen RC, Jones PW. Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96:632–642.
92. Dekkers OM, Horváth-Puhó E, Jørgensen JO, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, et al. Multisystem morbidity and mortality in Cushing's syndrome: a cohort study. J Clin Endocrinol Metab 2013; 98:2277–2284.
93. Carter JR, Fu Q, Minson CT, Joyner MJ. Ovarian cycle and sympathoexcitation in premenopausal women. Hypertension 2013; 61:395–399.
94. Coylewright M, Reckelhoff JF, Ouyang P. Menopause and hypertension: an age-old debate. Hypertension 2008; 51:952–959.
95. Zacharieva S, Orbetzova M, Stoynev A, Shigarminova R, Yaneva M, Kalinov K, et al. Circadian blood pressure profile in patients with Cushing's syndrome before and after treatment. J Endocrinol Invest 2004; 27:924–930.
96. Assié G, Libé R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. N Engl J Med 2013; 369:2105–2114.
97. Gagliardi L, Schreiber AW, Hahn CN, Feng J, Cranston T, Boon H, et al. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2014; 99:E1784–1792.
98. Varughese AG, Nimkevych O, Uwaifo GI. Hypercortisolism in obesity-associated hypertension. Curr Hypertens Rep 2014; 16:443.
99. Muiesan ML, Lupia M, Salvetti M, Grigoletto C, Sonino N, Boscaro M, et al. Left ventricular structural and functional characteristics in Cushing's syndrome. J Am Coll Cardiol 2003; 41:2275–2279.
100. Toja PM, Branzi G, Ciambellotti F, Radaelli P, De Martin M, Lonati LM, et al. Clinical relevance of cardiac structure and function abnormalities in patients with Cushing's syndrome before and after cure. Clin Endocrinol (Oxf) 2012; 76:332–338.
101. Ainscough JF, Drinkhill MJ, Sedo A, Turner NA, Brooke DA, Balmforth AJ, Ball SG. Angiotensin II type-1 receptor activation in the adult heart causes blood pressure-independent hypertrophy and cardiac dysfunction. Cardiovasc Res 2009; 81:592–600.
102. Mihailidou AS, Loan Le TY, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 2009; 54:1306–1312.
103. Yiu KH, Marsan NA, Delgado V, Biermasz NR, Holman ER, Smit JW, et al. Increased myocardial fibrosis and left ventricular dysfunction in Cushing's syndrome. Eur J Endocrinol 2012; 166:27–34.
104. Alexandraki KI, Kaltsas GA, Vouliotis AI, Papaioannou TG, Trisk L, Zilos A, et al. Specific electrocardiographic features associated with Cushing's disease. Clin Endocrinol (Oxf) 2011; 74:558–564.
105. Fallo F, Maffei P, Dalla Pozza A, Carli M, Della Mea P, Lupia M, et al. Cardiovascular autonomic function in Cushing's syndrome. J Endocrinol Invest 2009; 32:41–45.
106. De Leo M, Pivonello R, Auriemma RS, Cozzolino A, Vitale P, Simeoli C, et al. Cardiovascular disease in Cushing's syndrome: heart versus vasculature. Neuroendocrinology 2010; 92 (Suppl 1):50–54.
107. Akaza I, Yoshimoto T, Tsuchiya K, Hirata Y. Endothelial dysfunction aassociated with hypercortisolism is reversible in Cushing's syndrome. Endocr J 2010; 57:245–252.
108. Baykan M, Erem C, Gedikli O, Hacihasanoglu A, Erdogan T, Kocak M, et al. Impairment of flow-mediated vasodilatation of brachial artery in patients with Cushing's Syndrome. Endocrine 2007; 31:300–304.
109. Prázný M, Jezková J, Horová E, Lazárová V, Hána V, Kvasnicka J, et al. Impaired microvascular reactivity and endothelial function in patients with Cushing's syndrome: influence of arterial hypertension. Physiol Res 2008; 57:13–22.
110. Molnar GA, Lindschau C, Dubrovska G, Mertens PR, Kirsch T, Quinkler M, et al. Glucocorticoid-related signaling effects in vascular smooth muscle cells. Hypertension 2008; 51:1372–1378.
111. van den Meiracker AH, Batenburg WW. Corticosteroid-dependent, aldosterone-independent mineralocorticoid-receptor activation in the heart. J Hypertens 2008; 26:1307–1309.
112. Koh JM, Kim JY, Chung YE, Park JY, Shong YK, Hong SK, et al. Increased urinary albumin excretion in Cushing's syndrome: remission after correction of hypercortisolaemia. Clin Endocrinol (Oxf) 2000; 52:349–353.
113. Faggiano A, Pivonello R, Melis D, Alfieri R, Filippella M, Spagnuolo G, et al. Evaluation of circulating levels and renal clearance of natural amino acids in patients with Cushing's disease. J Endocrinol Invest 2002; 25:142–151.
114. Faggiano A, Pivonello R, Melis D, Filippella M, Di Somma C, Petretta M, et al. Nephrolithiasis in Cushing's disease: prevalence, etiopathogenesis, and modification after disease cure. J Clin Endocrinol Metab 2003; 88:2076–2080.
115. Biller BM, Sheppard M. The Network for the Enhancement of Endocrinology and Oncology Knowledge: a case-based consideration of current practice in Cushing's disease and acromegaly. Best Pract Res Clin Endocrinol Metab 2009; 23 (Suppl 1):S1–S4.
116. Hammer GD, Tyrrell JB, Lamborn KR, Applebury CB, Hannegan ET, Bell S, et al. Transsphenoidal microsurgery for Cushing's disease: initial outcome and long-term results. J Clin Endocrinol Metab 2004; 89:6348–6357.
117. Lindholm J, Juul S, Jørgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86:117–123.
118. Chow JT, Thompson GB, Grant CS, Farley DR, Richards ML, Young WF Jr. Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience. Clin Endocrinol (Oxf) 2008; 68:513–519.
119. Bassareo PP, Marras AR, Pasqualucci D, Mercuro G. Increased arterial rigidity in children affected by Cushing's syndrome after successful surgical cure. Cardiol Young 2010; 20:610–614.
120. Nieman LK. Medical therapy of Cushing's disease. Pituitary 2002; 5:77–82.
121. Pecori Giraldi F, Ambrogio AG, Andrioli M, Sanguin F, Karamouzis I, Corsello SM, et al. Potential role for retinoic acid in patients with Cushing's disease. J Clin Endocrinol Metab 2012; 97:3577–3583.
122. Verhelst JA, Trainer PJ, Howlett TA, Perry L, Rees LH, Grossman AB, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome. Clin Endocrinol (Oxf) 1991; 35:169–178.
123. Donadille B, Groussin L, Waintrop C, Abbas H, Tenenbaum F, Dugué MA, et al. Management of Cushing's syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para’-dichloro-diphenyl-dichloro-ethane: findings in 23 patients from a single center. J Clin Endocrinol Metab 2010; 95:537–544.
124. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, et al. The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009; 94:223–230.
125. Pivonello R, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study. Clin Endocrinol (Oxf) 2014; 81:408–417.
126. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med 2012; 366:914–924.
127. Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. N Engl J Med 2010; 362:1846–1848.
128. Bertagna X, Pivonello R, Fleseriu M, Zhang Y, Robinson P, Taylor A, et al. LCI699, a potent 11beta-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab 2014; 99:1375–1383.
129. Castinetti F, Brue T, Conte-Devolx B. The use of the glucocorticoid receptor antagonist mifepristone in Cushing's syndrome. Curr Opin Endocrinol Diabetes Obes 2012; 19:295–299.
130. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab 2012; 97:2039–2049.
131. Fallo F, Paoletta A, Tona F, Boscaro M, Sonino N. Response of hypertension to conventional antihypertensive treatment and/or steroidogenesis inhibitors in Cushing's syndrome. J Intern Med 1993; 234:595–598.
132. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A. Target blood pressure in elderly hypertensive patients and in patients with diabetes mellitus. J Hypertens 2014; 32:1551–1552.
133. Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol 2006; 48:677–685.
134. da MF, Murray C, Ezzat S. Overt immune dysfunction after Cushing's syndrome remission: a consecutive case series and review of the literature. J Clin Endocrinol Metab 2011; 96:E1670–E1674.
135. Zanchetti A, Bond MG, Hennig M, Neiss A, Mancia G, Dal Palù C, et al. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 2002; 106:2422–2427.
136. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA. Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. J Am Med Assoc 2011; 305:913–922.
137. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709–717.
138. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11–21.
139. Greenberg A. Diuretic complications. Am J Med Sci 2000; 319:10–24.
140. Mason JM, Dickinson HO, Nicolson DJ, Campbell F, Ford GA, Williams B. The diabetogenic potential of thiazide-type diuretic and beta-blocker combinations in patients with hypertension. J Hypertens 2005; 23:1777–1781.
141. Wolfgram DF, Gundu V, Astor BC, Jhagroo RA. Hydrochlorothiazide compared to chlorthalidone in reduction of urinary calcium in patients with kidney stones. Urolithiasis 2013; 41:315–322.
142. Vigen R, Weideman RA, Reilly RF. Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion? Int Urol Nephrol 2011; 43:813–819.
143. Chapman N, Chang CL, Dahlof B, Sever PS, Wedel H, Poulter NR. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial. Circulation 2008; 118:42–48.
144. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366:895–906.
145. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006; 24:3–10.
146. Laurent S, Schlaich M, Esler M. New drugs, procedures, and devices for hypertension. Lancet 2012; 380:591–600.
Keywords:

antihypertensive treatment; blood pressure; corticosteroids; Cushing's syndrome; hypercortisolism; hypertension; metabolic syndrome; vascular system

Supplemental Digital Content

© 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins