Best Practice & Research Clinical Endocrinology & Metabolism
2Mineralocorticoid substitution and monitoring in primary adrenal insufficiency
Introduction
In secondary adrenal insufficiency (SAI), caused by ACTH deficiency, aldosterone secretion remains largely intact, as it is mainly under the control of the renin angiotensin system. In contrast, in primary adrenal insufficiency (PAI) aldosterone secretion is usually severely impaired due to destruction (e.g. by an autoimmune adrenalitis) or removal (bilateral adrenalectomy) of the zona glomerulosa. Thus mineralocorticoid replacement is required to compensate for the loss of aldosterone secretion causing electrolyte imbalance, hypovolemia and hypotension. Intriguingly, optimal mineralocorticoid replacement has received little attention in the last two decades, certainly much less than glucocorticoid substitution. This may indicate that mineralocorticoid replacement in PAI poses no or little problems for these patients. However, it is also conceivable that neglecting optimal mineralocorticoid substitution contributes to the well-known failure to fully restore the quality of life [3], [11], [19] to normal in these patients.
Section snippets
Clinical presentation and diagnosis of mineralocorticoid deficiency
Fatigue and loss of energy are mentioned most often in patients with PAI, e.g. Addison's disease, as well as unspecific symptoms like weight loss, a loss of appetite, diarrhea, vomiting and nausea [4]. These unspecific symptoms and complaints quite often lead to the false diagnosis of psychiatric or gastrointestinal diseases [1]. In a German cohort, the more specific PAI symptoms like hypotension (55%), hyperpigmentation of patient's skin (41%) and salt craving (38%) were less frequently
Mineralocorticoid substitution
Desoxycorticosterone (DOC), a mineralocorticoid precursor in aldosterone synthesis, was identified in 1937 [29] and used since 1939 in oil and pellets in the treatment of Addison's disease [44]. Aldosterone itself is not suitable for replacement therapy because of its short half-life and rapid hepatic inactivation after oral ingestion. In 1954 9α-fluor-11β,17α,21-trihydroxy-pregnen-(4)-dion-(3,20), called 9α-fluorohydrocortison or 9α-fluorocortisol or fludrocortisone, was discovered and
Monitoring of mineralocorticoid replacement
Mineralocorticoid replacement is evaluated clinically by asking the patient about salt craving or lightheadedness, measuring blood pressure in the supine and standing positions to assess orthostatic dysregulation, and by identifying the presence of peripheral edema [21]. General well-being, electrolytes within the normal range and normal blood pressure without evidence of postural hypotension indicate adequate mineralocorticoid replacement. Furthermore, a PRA in the upper normal range has been
Pregnancy
Progesterone has anti-mineralocorticoid potency in vitro [38] and in vivo [39], and is competing with aldosterone or 9α-fluorocortisol for binding to the hMR. During pregnancy progesterone levels steadily increase and the 9α-fluorocortisol dose may need to be increased depending on blood pressure and potassium levels. PRA concentrations are not informative during pregnancy due to the pregnancy induced increase in renin substrate [10]. Oelkers and other investigators reported increasing
Conflict of interest
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Acknowledgments
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References (47)
- et al.
Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients
Am J Med Sci
(2010 Jun) - et al.
The acute effects of a mineralocorticoid receptor (MR) agonist on nocturnal hypothalamic-adrenal-pituitary (HPA) axis activity in healthy controls
Psychoneuroendocrinology
(2007 Sep) Hunt for an economical synthesis of cortisol: discovery of the fluorosteroids at Squibb (a personal account)
Steroids
(1992 Aug)- et al.
Adverse effect of phenytoin on mineralocorticoid replacement with fludrocortisone in adrenal insufficiency
Am J Med Sci
(1986 Apr) - et al.
Adrenal disease in pregnancy
Best Pract Res Clin Endocrinol Metab
(2011 Dec) - et al.
Chemical studies of the suprarenal cortex: III. The structures of compounds A, B, and H
J Biol Chem
(1937) Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure
Steroids
(1996)- et al.
Human plasma quantification of fludrocortisone using liquid chromatography coupled with atmospheric pressure chemical ionization mass spectrometry after low-dosage administration
Clin Chim Acta
(2013 May) - et al.
Evidence that patients with Addison's disease are undertreated with fludrocortisone
Lancet
(1984 Jan 7) - et al.
Renin and renin substrate in primary adrenal insufficiency: contrasting effects of glucocorticoid and mineralocorticoid deficiency
Am J Med
(1979 Jun)