Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy

Pas, Rob van der; Esch, Joep H.M. van; Bruin, Christiaan de; Danser, A.H. Jan; Pereira, Alberto M.; Zelissen, Pierre; Netea‐Maier, Romana T.; Sprij-Mooij, Diana; Berg-Garrelds, Ingrid M Van den; Schaik, R.H.N. van; Lamberts, Steven W. J.; Meiracker, Anton H. van den; Hofland, Leo J.; Feelders, Richard A

doi:10.1530/eje-13-0477

Cited by 20 publications

(36 citation statements)

References 45 publications

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“…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 22-week phase II study (77). 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, 79).…”

Section: Cortisol Lowering Medicationsmentioning

confidence: 92%

The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome

2019

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When hypertension, a pathology that is frequently found in the general population, presents in a young patient, secondary causes such as Cushing's syndrome (CS), a rare disease characterized by long-term elevated cortisol levels, should be considered. Present in ~80% of CS patients independently of their age and sex, hypertension is one of the pathology's most prevalent, alarming features. Its severity is principally associated with the duration and intensity of elevated cortisol levels. Prompt diagnosis and rapid initiation of treatment are important for reducing/delaying the consequences of hypercortisolism. Glucocorticoid excess leads to hypertension via a variety of mechanisms including mineralocorticoid mimetic activity, alterations in peripheral and renovascular resistance, and vascular remodeling. As hypertension in CS patients is caused by cortisol excess, treating the underlying pathology generally contributes to reducing blood pressure (BP) levels, although hypertension tends to persist in approximately 30% of cured patients. Surgical removal of the pituitary tumor remains the first-line treatment for both adrenocorticotropin hormone (ACTH) dependent and independent forms of the syndrome. In light of the fact that surgery is not always successful in curing the underlying disease, it is essential that other treatments be considered and prescribed as needed. This article discusses the mechanisms involved in the pathogenesis of CS and the pros and the cons of the various antihypertensive agents that are presently available to treat these patients.

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Section: Cortisol Lowering Medicationsmentioning

confidence: 92%

The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome

2019

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“…The most important mechanism underlying the hypertension associated with CS lies in the activation of the mineralcorticoid receptor by the excessive cortisol levels (33)(34)(35)(36). In addition, multiple factors including the activation of the renin-angiotensin system, together with increased reactivity of vasoconstrictor and decreased reactivity to the vasodilatory system, increased cardiac output and peripheral resistance, mainly the consequence of an increased sensitivity to catecholamines, may contribute to the development of hypertension in CS (33)(34)(35)(36). The circadian blood pressure rhythm is generally altered in patients with CD, showing the typical nondipping pattern, which is related to greater end-organ damage and increased mortality (37).…”

Section: Systemic Arterial Hypertensionmentioning

confidence: 99%

“…However, besides the control of hypercortisolism, different antihypertensive drugs often need to be used to control hypertension in patients with CS during active disease; recently, a pathophysiology-oriented therapeutic algorithm has been developed, and it could serve as a first attempt to rationalize the treatment of hypertension in CS (36). Moreover, hypertension can persist even after remission; this is because of either a possible coexistence of essential hypertension or permanent damage incurred by cortisol excess in the cardiovascular system (33)(34)(35)(36)(37).…”

Section: Systemic Arterial Hypertensionmentioning

confidence: 99%

The Treatment of Cushing's Disease

et al. 2015

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Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

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“…In patients with resistant hypertension, hypokalaemia and accompanied by low/normal plasma renin activity/levels and low/normal serum aldosterone levels, Cushing’s syndrome is an important diagnosis to be considered and ruled out (1, 5, 6). Cushing’s syndrome associated with this phenotype is usually clinically apparent as the principal mechanism is thought to be due to very high cortisol levels saturating renal 11β-hydroxysteroid dehydrogenase type 2, thereby preventing the inactivation of cortisol to cortisone and allowing binding to the mineralocorticoid receptor (6, 7) and/or due to elevated angiotensinogen levels in such patients (6).…”

Section: Discussionmentioning

confidence: 99%

Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy

Marques

Tufton

Bhattacharya

et al. 2019

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed. Learning points: Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels. The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing’s syndrome, Liddle’s syndrome and 11-deoxycorticosterone-producing tumours. DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase. The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.

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Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy

Cited by 20 publications

References 45 publications

The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome

The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome

The Treatment of Cushing's Disease

Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy

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