Why is the Management of Glucocorticoid Deficiency Still Controversial: A Review of the Literature

Anna Crown; Stafford Lightman


Clin Endocrinol. 2005;63(5):483-492. 

In This Article

Summary and Introduction

All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is 'gated' by the 11-β-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses.

The ideal glucocorticoid replacement therapy would mirror the normal physiological state as closely as possible. In practice, the human glucocorticoid hydrocortisone is commonly given at a dose of about 20 mg daily, in two or three unequal divided doses, such that most of the dose is taken in the morning and less in the afternoon. In this review, we will start with an overview of recent advances in our understanding of the normal physiology in relation to endogenous glucocorticoid production, circulating glucocorticoids and their interconversion, the pattern of glucocorticoid secretion and pregnancy. We will discuss the impact of this knowledge on our attempts to optimize glucocorticoid replacement in hypoadrenal patients, and highlight areas where previously accepted paradigms are challenged. We will then discuss specific studies that have been performed related to optimizing glucocorticoid replacement regimens in patients with hypoadrenalism, including effects on bone, glucose metabolism, cardiovascular function and quality of life. Drawing on these sources of evidence, we will attempt to make some recommendations for clinical practice and future research.

The focus of the review is glucocorticoid replacement therapy for adults with primary and secondary hypoadrenalism. Management of children, patients with congenital adrenal hyperplasia (CAH), acute/emergency management, additional hormone replacement therapy (e.g. fludrocortisone or dehydroepiandrosterone treatment) and treatment with pharmacological doses of glucocorticoids is not included.


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