The Effects of Glucocorticoids on Leptin Levels in Humans May Be Restricted to Acute Pharmacologic Dosinga
DJ Torpy,
SR Bornstein,
G Cizza and
GP Chrousos
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 (115 mg) over
periods of 14 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
(1215 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
Cushings disease. Similarly, another study found no significant
elevation of leptin in Cushings 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 Cushings syndrome studies.
A study of the dose-response relation between hydrocortisone and leptin
is needed.

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Figure 1. Summary of the available evidence regarding the effects of the HPA axis on leptin secretion in humans.
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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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