Suppression of adrenal function by low-dose prednisone: assessment with 24-hour urinary steroid hormone profiles—a review of five cases

Abstract

The impact of the synthetic glucocorticoid prednisone on adrenal steroid hormone production was examined using 24-hour urinary steroid hormone profiling. Five women, who were chronically taking low-dose prednisone, were tested, and the relevant literature was reviewed. As expected, adrenal glucocorticoid production, measured by urinary terminal cortisol and cortisone metabolites, was markedly suppressed compared to reference range values (p=0.03). Urinary cortisol and cortisone, reflecting circulating glucocorticoids, were decreased to a lesser extent than their terminal metabolites. Urinary dehydroepiandrosterone (DHEA) excretion was dramatically suppressed (p=0.03), while the downstream androgen metabolites androsterone and etiocholanolone were suppressed to a lesser extent. Aldosterone and tetrahydrocorticosterone production demonstrated modest suppression after prednisone administration, but allotetrahydrocorticosterone, which is highly sensitive to adrenocorticotropic hormone (ACTH) secretion, was suppressed to a greater extent. Prednisone administration results in a decrease in ACTH secretion by the anterior pituitary, suppressing synthesis of glucocorticoids, DHEA, and DHEA metabolites. Decreased glucocorticoid synthesis is adaptive, because prednisone is active at the glucocorticoid receptor, but suppression of DHEA synthesis is not mitigated by prednisone. DHEA is an important sex hormone precursor, neurosteroid, and endocrine and immune modulator; therefore, DHEA depletion may have significant adverse consequences in terms of sex hormone production, bone health, endocrine and immune system function, and neuropsychiatric status. Studies of DHEA replacement in patients taking prednisone for lupus demonstrate amelioration of some of these adverse effects.

Introduction

The synthetic glucocorticoid prednisone is used for its anti-inflammatory properties in the treatment of many different conditions, including rheumatologic, hormonal, allergic, respiratory, and other disorders. Prednisone administration results in numerous side effects, a number of which are the result of its suppression of adrenal cortex function. After prednisone administration, adrenal production of the endogenous glucocorticoids, cortisol and cortisone, declines. This can result in marked hypocortisolism after discontinuation of high-dose prednisone therapy, especially in seriously ill patients. (1)

Because prednisone suppresses adrenal function by reducing adrenocorticotropic hormone (ACTH) secretion by the anterior pituitary gland, other adrenal hormones normally produced after ACTH stimulation are also vulnerable as a consequence of prednisone therapy. (1) After ACTH administration to healthy adults, plasma and urinary concentrations of glucocorticoids, dehydroepiandrosterone (DHEA), and aldosterone all increase. (2) This suggests that patients treated with prednisone may experience not only declines in glucocorticoids but also declines in aldosterone and DHEA and its metabolites. The limited data available in the literature suggest DHEA may be even more sensitive to suppression by prednisone than the glucocorticoids, (3) while aldosterone is somewhat less sensitive, probably because its secretion is mediated by multiple mechanisms.

In the course of reviewing routine urinary steroid hormone profiles conducted on a large number of patients for diverse clinical purposes, the authors noticed a striking and consistent pattern in the results for the small number of patients tested who were taking prednisone. This article describes this pattern, reviews its mechanisms and the relevant literature, and discusses its clinical and research implications.

Methods

Five women who were chronically taking prednisone had 24-hour urinary steroid hormone profiles conducted at Meridian Valley Laboratory between February and June 2005. Patients submitted a questionnaire on the use of hormones, other medications, and symptoms, with their urine specimens. The questionnaires were used as part of the laboratory quality assurance program, for review of test results, and for consultation with physicians who ordered the tests. The median age was 41 years (span 32-60); one woman had regular menstrual cycles, two had irregular cycles, and two were postmenopausal. Prednisone dose was 5 mg/day for two patients, 10 mg/day for one, and not known for two, although use of prednisone was confirmed on the questionnaire.

Steroid analysis was performed as described previously. (4) Steroids were isolated from urine by solid phase extraction (C18 columns; United Chemical Technologies; Bristol, PA), eluted with methanol, and the methanolic extract was evaporated to dryness. The residue was reconstituted in acetate buffer, hydrolyzed overnight with sulfatase/beta-glucuronidase, and extracted with ethyl acetate after internal standard addition. The ethyl acetate extract was evaporated to dryness, and the MOX/TMS derivatives of the steroids were prepared. The final derivatized extracts were dissolved in hexane, washed with de-ionized water, and an aliquot of the hexane phase was injected into the gas chromatograph-mass spectrometer (GC-MS).
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