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The Effects of Glucocorticoids on Leptin Levels in Humans May Be Restricted to Acute Pharmacologic Dosing^a

Developmental Endocrinology Branch, National Institute of Child Health and Human Development Bethesda, Maryland 20892-1862

Kolacyznski et al. (1) and others (2, 3, 4, 5, 6) reported time-dependent elevations of plasma leptin concentrations after exposure of human volunteers to pharmacologic doses of dexamethasone. These studies used high total doses of dexamethasone (1–15 mg) over periods of 1–4 days. Elevated leptin levels were shown to persist for up to 24 h after the last dose (1, 2, 3, 4, 5, 6). Two reports on the effect of methylprednisolone on plasma leptin gave conflicting results (7, 8).

In contrast, in patients with chronic endogenous hypercortisolism, leptin levels were only appropriately elevated for their body mass index (BMI) and did not fall after removal of the causative pituitary adenoma, during a period of conservative glucocorticoid replacement (12–15 mg/m² per day) 10 days after complete remission of their hypercortisolism (9). Furthermore, the mild hypercortisolism that follows the iv administration of 1 mcg/kg CRH was not accompanied by an elevation of plasma leptin in normal volunteers or in patients with Cushing’s disease. Similarly, another study found no significant elevation of leptin in Cushing’s syndrome patients compared with BMI-matched controls, although a slight alteration of the relation between BMI and leptin was detected with analysis of covariance (6), while another recent study fully replicated our results (10). Also, chronic inhibition of CRH action with a novel CRH receptor type-1 antagonist did not influence leptin levels in vivo in rats (11). In patients with marked and sustained elevations of cortisol levels due to critical illness, on the other hand, elevated plasma leptin levels were found (12). However, other factors, such as the cytokines TNF- and IL-1 stimulate leptin secretion, and these are elevated in septic patients. Although diurnal levels of leptin correlated inversely with ACTH/cortisol levels in healthy humans, a direct effect of the hypothalamic-pituitary-adrenal (HPA) axis on leptin has not been demonstrated in vivo, whereas an inhibitory effect of leptin on the HPA axis has (13, 14, 15, 16, 17). Thus, most likely, the negative correlation between the HPA axis and leptin levels reflects the latter rather than the former.

We suggest that the reported glucocorticoid-induced elevations of plasma leptin levels may not be a physiologic phenomenon, but rather a pharmacologic one, occurring only with high doses of synthetic glucocorticoids (Fig. 1).The acute effect of glucocorticoids, if any, appears not to be sustained chronically, as suggested by the Cushing’s syndrome studies. A study of the dose-response relation between hydrocortisone and leptin is needed.

View larger version (19K): [in this window] [in a new window]   Figure 1. Summary of the available evidence regarding the effects of the HPA axis on leptin secretion in humans.

Footnotes

Address correspondence to: David J. Torpy, MBBS, PhD., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Building 10, Room 10 N262, 10 Center Drive, Bethesda, Maryland 20892-1862.

Received January 21, 1998.

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