Commonly featured in all forms of CS, hypertension represents the syndrome's second most common clinical finding after weight gain 4. Hypothetically, it is more prevalent in ectopic CS ECS given its severity 5 , although one retrospective study reported that it was more common in adrenal cases with respect to pituitary-dependent ones CD 6. No gender-related differences in hypertension nor marked correlations with cortisol levels have been reported 5 , 7 , 8.
The majority of studies have shown that elevations in systolic and diastolic blood pressure BP values are of a similar entity in CS patients, and the loss of the typical physiological nocturnal fall, which represents an early hallmark, is almost certainly linked to a disruption in the cortisol circadian rhythm 9.
Although a mild degree of overproduction of cortisol seems to have a limited impact on BP 10 , prolonged excess appears to be linked to the development of hypertension due to vascular rearrangement and excessive fibrosis As pediatric CS patients tend to present hypertension even after remission, it would seem that children are prone to vascular remodeling during active disease stages, that leads to enduring hypertension even after the disease has been cured.
Persistently high BP levels in these patients could also be due to the excessive glucocorticoid replacement therapy prescribed after remission 12 , The fact that young patients are at risk for residual hypertension and require long term monitoring to avoid post-surgery cardiovascular morbidity is well-established The pathophysiology of hypertension in CS is complex. Glucocorticoids, which are to 1,fold higher with respect to aldosterone, can bind both to glucocorticoid and MR.
The blood volume expansion that follows suppresses endogenous renin secretion Figure 1. It has been hypothesized that glucocorticoid receptor activation is responsible for enhanced ENaC and glomerular hyperfiltration, as neither selective mineralocorticoids nor glucocorticoid receptor antagonists appears to be able to fully revert cortisol's effects These findings may explain why CS patients display more improvement when they are receiving mifepristone, a glucocorticoid receptor antagonist, than when they are taking MR antagonists 19 , Activation of the RAS via enhanced hepatic production of angiotensinogen has been described.
Angiotensinogen, which is highly expressed in adipose tissues when other components of the RAS system are present, is able to generate angiotensin II and other vasoactive peptides.
Low or suppressed renin levels are nevertheless quite usual in CS patients due to the negative feedback exerted by cortisol's mineralocorticoid activity, suggesting that there is a different activation mechanism In fact, CS patients show a greater sensitivity to angiotensin II and its pressor activity at the peripheral levels.
Glucocorticoids also enhance angiotensin II's action as a neurotransmitter leading to elevated sympathetic nerve activity, stimulating vasopressin release, and attenuating the arterial baroreceptor reflex Endothelin-1 ET-1 , a potent vasoconstrictor peptide with mitogenic and atherogenic effects on the smooth muscular cells, plays an important role in BP control in cortisol-induced hypertension. In fact, while it has been found to be significantly elevated in CS patients, a decline has been noted following treatment High plasma ET-1 levels probably promote early atherosclerosis and its progression in these patients 24 , although no correlation has been found with disease severity.
Persistently elevated ET-1 levels may depend in some cases on residual vascular damage In addition, glucocorticoids inhibit nitric oxide synthase NOS expression, which is essential for adequate peripheral vasodilatation and may lead to higher BP levels Glucocorticoids can also impair the production of other potent vasodilatators in the vascular endothelium such as prostacyclin, prostaglandins and kallikreins Prolonged hypertension and glucocorticoid exposure lead to vasculature remodeling.
In fact, angiogenic and growth factors including vascular endothelial growth factor VEGF and insulin lead to a higher media to lumen ratio, media thickness, and wall thickness that are responsible for enhanced small artery resistance Cortisol is needed for the survival and maintenance of chromaffin cells, permitting them to produce epinephrine through the conversion of norepinephrine operated by the phenylethanolamine N- methyltransferase enzyme whose transcription is glucocorticoid-dependent 28 , Glucocorticoids thus modulate the synthesis of neurotransmitters and the vascular response to catecholamines; they may also contribute to the detrimental effect of cortisol on blood vessels As explained above, CS has many features in common with the metabolic syndrome including dyslipidaemia, insulin resistance, and impaired glucose metabolism; all are linked to visceral adiposity and associated with hypertension.
As these conditions may persist even after there has been a remission in CS, they presumably contribute to maintaining, at least to some extent, high BP and the risk of cardiovascular morbidity 30 , In fact, symptoms of the metabolic syndrome are often noted even after CS patients have been cured Visceral obesity may contribute to the development of obstructive sleep apnea syndrome OSAS , which, surprisingly, has at times been described in lean CS patients 33 , suggesting that cortisol has a direct effect on sleep impairment OSAS can exacerbate hypertension in CS by increasing sympathetic tone during hypoxemic episodes; it is also associated with insulin resistance and diabetic autonomic neuropathy As some features of the metabolic syndrome may persist even after remission, the impairment in cytokine and adipokine secretion might persist in cured CS patients, contributing to a proinflammatory state and to maintaining high BP levels via enhanced sodium retention 37 , Since hypertension, which, as we have pointed out above, is quite prevalent in CS, is one of the major determinants of cardiovascular disease, it should be treated appropriately as soon as possible 1.
While the underlying condition must in any case be addressed, it is important to remember that surgery is not always effective and that it may take a long time for cortisol-related comorbidities to normalize in cured patients Antihypertensive treatment should be prescribed in accordance with updated guidelines both before and after surgery.
Patients should also receive lifestyle education guiding them to improve their modifiable risk factors such as smoking and alcohol consumption Other lifestyle changes such as losing weight and committing to an aerobic physical activity program may prove difficult to achieve in CS patients due to muscular myopathy, but they should, in any case, be encouraged 4 , Almost all CS patients will require drug therapy which in most cases will involve a combination of antihypertensive agents in addition to lifestyle measures to achieve optimal BP control Recently published guidelines on management of arterial hypertension have confirmed that diuretics, beta-blockers, calcium antagonists, ACE inhibitors, and sartans either as monotherapies or in combination can be used initially or at a later date to treat hypertension and to prevent cardiovascular events In view of the impairment in RAS in CS, some have proposed using ACE inhibitors and sartans as the first line therapy in these cases because of their cardioprotective effects It seems safe to say that since calcium antagonists have been found to be more effective than beta-blockers in delaying the progression of carotid atherosclerosis and in reducing left ventricular hypertrophy, proteinuria and stroke, they should be preferred to beta-blockers in the event add-on therapy is required Although beta-blockers may not represent the first-choice in CS due to their potentially unfavorable effects on glucose metabolism and heart rate, they should be taken into consideration for patients who have already experienced a myocardial infarction in which case vasodilating beta-blockers, such as labetalol, nebivolol, celiprolol, and carvedilol, should be preferred as they have fewer side effects with respect to non-selective beta-blockers 43 , 44 ; they are also associated to a lower risk of new-onset diabetes and have fewer adverse effects on sexual function, which is often already impaired in male CS patients 4.
Thiazides should nevertheless be used carefully in order to avoid aggravating hypokalemia, hyperuricemia, gout or diabetes, all risks factors for CS 47 , Caution should be used if hydrochlorothiazide therapy is prolonged as it has recently been associated with an increased risk of melanoma As diuretics can reduce serum potassium levels, they too should be used with caution Spironolactone, which has been found to have beneficial effects on heart failure patients, should be used to control hypokalemia if needed 50 , and it can also be used as a third-line drug to lower BP As spironolactone may have anti-androgenic effects, it can be used in female patients, but it should be avoided in males since it has been associated to gynecomastia.
Spironolactone metabolites such as canrenone should be preferred in male patients 51 , and eplerenone can be prescribed as an alternative to spironolactone, especially in those males who have developed anti-androgen side effects Although it is highly tolerated, eplerenone is not available in all countries and it is more expensive than amiloride and spironolactone As no data are available on aliskiren, an expensive renin inhibitor which may cause complications in diabetics, it should be considered only when less expensive blockers of the RAS have untolerated side effects Although the drug has no specific contraindications in CS, it should be reserved as an add-on therapy or as a third-line option in cases of resistant hypertension after all other treatments have failed Using formulations combining more than one antihypertensive agents should be encouraged 39 as reducing the number of medications taken daily by CS patients who may need medication for numerous comorbidities osteoporosis, diabetes, dyslipidaemia, psychiatric disorders 4 can improve their short and in particular long-term adherence and increase BP control 53 , To summarize then, hypertension in CS should first be treated with ACEi or sartans at increasing doses.
Acting practitioners must in any case take into consideration and evaluate both the possibility of drug interactions and any contraindications linked to hypercortisolemia As it is the only therapy that can lead to a long-term remission and reduce mortality, surgery should be attempted whenever possible for all types of CS.
Surgery aims to correct hypercortisolism without creating a permanent hormone deficiency 1. When feasible, it is the first line therapy, irrespective of the lesion's site 1.
Selective transsphenoidal resection of ACTH-secreting pituitary adenoma is the treatment of choice 1. When disease remission is achieved, both systolic and diastolic BP tend to improve, but approximately one-third of all adult patients continue to have systolic and three-quarters diastolic hypertension Only a weak correlation has been found between the severity of baseline BP values and post-surgery hypertension. Drugs specific for hypercortisolism are effective in controlling BP by reducing hormonal levels and thus preventing cortisone from binding to MR receptors Table 1.
Pasireotide, the somatostatin SST receptor ligand, which was the first pituitary-directed drug approved for CD treatment, can bind to four out of five SST receptors and has a particular affinity for type 5 SSTR5 , the most prevalent in corticotroph tumors The drug was also found to be effective in reducing BP in CD; in fact, after a 6 month treatment period, both systolic and diastolic levels were reduced in all the treated patients, although the fall was more marked in those with controlled urinary free cortisol UFC.
The same pattern was noted at the 12 month mark, indicating an additional benefit independently of its effect on UFC secretion. Interestingly, pasireotide treatment lowered BP even in patients suffering from hypertension previously, regardless of the antihypertensive medication used All the patients enrolled in a phase III trial receiving 10 or 30 mg pasireotide monthly showed a mean BP reduction of 3—5 mmHg accompanied by weight and waist circumference improvements Table 1.
Cortisol lowering medications, their effectiveness and effects on hypertension in CS patients. As diabetes mellitus is a frequent adverse event, which increases the risk of cardiovascular complications, in patients taking pasireotide, BP targets should probably be lowered in these patients The improvement in hypertension could be partially attributed to the drug's relaxing effect on the vascular smooth muscles causing lower peripheral resistance Originally developed as an antimycotic agent, ketoconazole has been widely used in CS because of its anti-steroidogenesis action causing inhibition of cytochrome P enzymes Castinetti et al.
The mean systo-diastolic BP before ketoconazole treatment was begun, i. Ketoconazole was also found to be superior to standard antihypertensive treatments suggesting that restoring normal cortisol levels is vital for achieving satisfactory BP control Metyrapone, another steroidogenesis inhibitor that acts by inhibiting beta-hydroxylase activity, causes an increase in intermediates with mineralocorticoid activity leading to a potential worsening in hypertension and hypokalemia.
These side effects are nevertheless counterbalanced by a reduction in UFC that has an overall neutralizing effect on BP 70 — Despite its effectiveness in controlling hypercortisolism and BP in a proof of concept study in CD and hypertension in primary aldosteronism 75 , 76 , no significant improvement was observed at the end of a week phase II study Combination therapy seemed at least as effective as each treatment prescribed separately 72 , 78 , 79 ; the improvement in BP was more evident when both UFC and late night salivary cortisol were normalized.
There was less clinical improvement when only one of the two parameters was normalized 78 , BP levels, which were studied in 62 patients treated preoperatively with ketoconazole and metyrapone alone or together, were found to be lower in the controlled group with respect to the partially controlled or uncontrolled groups Envelope icon Subscribe to our newsletter Get regular updates to your inbox.
Your Email. Share this article: Share article via email Copy article link. Print This Article. Hypertension in CS usually resolves with surgical removal of the tumor, but some patients require pharmacological antihypertensive treatment both pre- and postoperatively.
Thiazides and furosemide should be avoided, while adrenergic blockade and calcium channel antagonists are usually ineffective. The relatively selective glucocorticoid receptor antagonist Mifepristone RU could reduce blood pressure in patients with CS.
0コメント