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      Demystifying “Steroid Withdrawal” During Remission in Cushing's Disease: Is Mineralocorticoid Replacement the Answer?

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          Abstract

          Objective:

          To study renin-angiotensin-aldosterone axis status (RAAS) in patients of Cushing's disease (CD) at baseline and 6 weeks after curative trans-sphenoidal surgery and evaluate the role of mineralocorticoid replacement in the resolution of “steroid withdrawal syndrome” (SWS). Postoperative RAAS status had not been evaluated in previous studies, although aldosterone levels have been shown to be suppressed during medical therapy with pasireotide and cabergoline.

          Materials and Methods:

          This was a prospective, single-center study. Patients with CD, aged between 15–75 years, undergoing curative pituitary surgery were recruited. An 8 am and 11 pm cortisol and adrenocorticotropic hormone (ACTH) were measured at baseline. An 8 am cortisol was measured 6 weeks after surgery to demonstrate remission. Plasma-renin activity and plasma-aldosterone concentration were measured at baseline and 6 weeks after curative surgery.

          Results:

          A total of 14 patients (11 female, 3 male) were recruited initially, of these 8 patients completed the study. The plasma-renin activity was not suppressed at baseline and did not rise significantly after surgery ( P = 0.717). However, plasma-aldosterone concentration was in the low-normal range at baseline and had risen significantly 6 weeks after surgery ( P = 0.013). No difference was noted in subgroups with or without hypertension.

          Conclusion:

          Curative pituitary surgery leads to normalization of plasma-aldosterone concentration in patients with CD just 6 weeks after surgery. Hence, mineralocorticoid replacement may not prove beneficial in alleviating the “SWS” in postsurgical CD patients who have achieved remission.

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          Most cited references9

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          Hypertension in Cushing's syndrome.

          Cushing's syndrome can be exogenous, resulting from the administration of glucocorticoids or adrenocorticotrophic hormone (ACTH), or endogenous, secondary to increased secretion of cortisol or ACTH. Hypertension is one of the most distinguishing features of endogenous Cushing's syndrome, as it is present in about 80% of adult patients and in almost half of children and adolescents patients. Hypertension results from the interplay of several pathophysiological mechanisms regulating plasma volume, peripheral vascular resistance and cardiac output, all of which may be increased. The therapeutic goal is to find and remove the cause of excess glucocorticoids, which, in most cases of endogenous Cushing's syndrome, is achieved surgically. Treatment of Cushing's syndrome usually results in resolution or amelioration of hypertension. However, some patients may not achieve normotension or may require a prolonged period of time for the correction of hypercortisolism. Therefore, therapeutic strategies for Cushing's-specific hypertension (to normalise blood pressure and decrease the duration of hypertension) are necessary to decrease the morbidity and mortality associated with this disorder. The various pathogenetic mechanisms that have been proposed for the development of glucocorticoid-induced hypertension in Cushing's syndrome and its management are discussed.
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            Multiple factors contribute to the pathogenesis of hypertension in Cushing's syndrome.

            The mechanisms causing high blood pressure in patients with Cushing's syndrome were investigated by measurements of humoral factors and pharmacological maneuvers. Twelve patients with adrenal adenomas were studied. The mean systolic and diastolic pressures of the patients were 171 +/- 28 and 109 +/- 15 mm Hg (+/- SEM), respectively, which were significantly higher than those of normal subjects. PRA, plasma renin concentration, plasma renin substrate, plasma cortisol, plasma aldosterone, urinary kallikrein, and urinary prostaglandin E2 were measured as the humoral factors. PC values were markedly elevated in patients with Cushing's syndrome. Among the components of the renin-angiotensin system, only plasma renin substrate was increased. Urinary kallikrein and prostaglandin E2 were decreased in patients with Cushing's syndrome. Oral administration of captopril lowered blood pressure, but infusion of an angiotensin II analog did not. Furthermore, the pressor responses to infusion of both norepinephrine and angiotensin II were increased. We conclude that blood pressure is elevated in patients with Cushing's syndrome because they have enhanced pressor responses to vasoactive substances, suppression of depressor systems, and some abnormalities of the renin-angiotensin system.
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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.

              Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone.
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                Author and article information

                Journal
                Indian J Endocrinol Metab
                Indian J Endocrinol Metab
                IJEM
                Indian Journal of Endocrinology and Metabolism
                Wolters Kluwer - Medknow (India )
                2230-8210
                2230-9500
                Jul-Aug 2019
                : 23
                : 4
                : 456-459
                Affiliations
                [1]Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
                [1 ]Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
                Author notes
                Address for correspondence: Dr. Rama Walia, Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012, India. E-mail: ramawalia@ 123456rediffmail.com
                Article
                IJEM-23-456
                10.4103/ijem.IJEM_260_19
                6844159
                9ec07c3c-cc72-47bc-a0f5-60fe2dfd694b
                Copyright: © 2019 Indian Journal of Endocrinology and Metabolism

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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                Categories
                Original Article

                Endocrinology & Diabetes
                cushing disease,mineralocorticoid replacement,steroid withdrawal syndrome

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