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Mineralocorticoid substitution and monitoring in primary adrenal insufficiency

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Patients with primary adrenal insufficiency usually show pronounced impairment of aldosterone secretion and, therefore, require also mineralocorticoid replacement for full recovery. Clinical signs of mineralocorticoid deficiency comprise hypotension, weakness, salt craving and electrolyte disturbances (hyperkalemia, hyponatremia). Mineralocorticoid deficiency is confirmed by demonstration of profoundly decreased aldosterone and highly elevated plasma renin activity (PRA). Standard replacement consists of 9α-fluorocortisol (fludrocortisone) given once daily as a single oral dose (0.05–0.2 mg). Monitoring of mineralocorticoid replacement consists of clinical assessment (well-being, physical examination, blood pressure, electrolyte measurements) and measurement of PRA aiming at a PRA level in the upper normal range. Current replacement regimens may often be associated with mild hypovolemia. Dose adjustments are frequently needed in pregnancy to compensate for the anti-mineralocorticoid activity of progesterone and in high ambient temperature to avoid sodium depletion. In arterial hypertension a dose reduction is usually recommended, but monitoring for hyperkalemia is required.

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

None.

Acknowledgments

None.

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