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Division of Endocrinology, Hospital Virgen del Rocio (A.L.-C., R.A., L.M.J.), and Hospital Virgen de Valme (I.F.L.), Sevilla, Spain E-41013; and Endocrine Section, Complejo Hospitalario Universitario de Santiago Department of Medicine (F.F.C.) and Department of Physiology (C.D.), University of Santiago de Compostela, Spain E-15780
Address all correspondence and requests for reprints to: F. F. Casanueva, M.D., Ph.D., PO Box 563, E-15780 Santiago de Compostela, Spain. E-mail: meffcasa{at}uscmail.usc.es
Abstract
In Cushing’s syndrome, GH secretion is blocked with all the stimuli tested. It has been reported that the acute pharmacological reduction of free fatty acids (FFA) leads to an enhancement of GH secretion in normal subjects and in pathological conditions associated with reduced GH secretion. To understand if the elevated FFA levels of hypercortisolism may be responsible for the altered GH secretion, 14 patients with active Cushing’s syndrome underwent 2 paired tests with 100 µg iv of GHRH on 2 different occasions. In one test, they were pretreated with placebo and in the other one, with acipimox 250 mg po 4 h before, and 250 mg po 1 h before GHRH. The basal FFA levels (799 ± 57 mmol/L) were reduced by acipimox throughout the whole test (values under 240 ± 28 mmol/L).
In the placebo pretreated group, GHRH-induced GH secretion was severely impeded, with a mean GH peak of 1.8 ± 0.3 µg/L and area under the curve of 121.3 ± 21.6 µg/L·120 min. All the patients showed a GHRH-mediated GH peak under 4 µg/L. Acute reduction of FFA by acipimox enhanced the GHRH action, with a mean GH peak of 11.1 ± 1.8 µg/L and area under the curve of 652.9 ± 110.3 µg/L·120 min (both P < 0.005). Individually analyzed after acipimox, all 14 subjects presented an enhancement in the GHRH-mediated GH peak, and 8 patients showed a response over 10 µg/L.
In conclusion, acute FFA reduction by acipimox increased the GH secretion elicited by GHRH in chronic hypercortisolism. Elevated FFA may be a contributing factor to the deranged GH secretion observed in Cushing’s syndrome.
GLUCOCORTICOIDS inhibit somatic growth and GH secretion (1, 2, 3, 4, 5). Furthermore, in states of chronic hypercortisolism, such as in Cushing’s syndrome, GH secretion seems blunted in response to all stimuli so far tested (6, 7, 8), even when GH secretion is challenged with the most potent somatotroph stimulus so far known, i.e. combined administration of GHRH and GHRP-6 (9). The mechanisms of action by which glucocorticoids impair GH secretion in chronic hypercortisolism are unknown, and it seems reasonable that the ensuing GH deficit may contribute to some of the deleterious and hypercatabolic effects of that syndrome.
On the other hand, GH secretion is closely linked to metabolic alterations, as well as to the intake of nutrients (10, 11, 12). A classic feedback relationship has been postulated between GH and the metabolically active component of lipids, i.e. the nonesterified fatty acids, also called free fatty acids (FFA). FFA elevations reduce or block GH secretion stimulated by a variety of stimuli or conditions, whereas FFA reduction stimulates GH secretion (11). The recent availability of acipimox, a nicotinic acid analogue that blocks lipolysis and which is devoid of significant side effects (13, 14), provided the best tool for further understanding the role of FFA depression on GH regulation. Interestingly, acipimox-mediated FFA reduction enhances or even restores GH secretion in some pathological conditions associated with substantially reduced secretion of GH, such as obesity or aging (15, 16, 17, 18).
The aim of this study was to evaluate the effect of an acute reduction of plasma FFA by acipimox, on the GH response to GHRH in patients with Cushing’s syndrome.
Subjects and Methods
Fourteen women with Cushing’s syndrome were studied. They were 43.0 ± 4.3 yr old, had a body mass index (calculated as weight in Kg divided by the square of height in meters) of 37.2 ± 2.5. Their 24-h free urinary cortisol was 500.9 ± 92.2 µg, with IGF-I values of 202.6 ± 25.9 µg/L and IGF-BP3 of 3.15 ± 0.3 mg/L. Two of them had an adrenal adenoma and the rest an ACTH-secreting pituitary adenoma (Cushing’s disease). Diagnoses were established by clinical, biochemical, and image criteria, and diabetes mellitus and partial hypopituitarism were specifically ruled out. Each diagnosis was confirmed histologically after surgery. The patients led normal life-styles and were not taking medication. Approval for this study was obtained from the Hospital Ethics Committee, and all the subjects provided informed consent.
Tests were started at 0800 h, after an overnight fast, with the subjects recumbent. An indwelling catheter was placed in a forearm vein and kept patent with a slow infusion of 150 mmol/L NaCl. Each subject was tested twice on separate occasions. On one day, placebo was administered at 0800 h and 1100 h (-240 and -60 min); and then patients underwent, at 1200 h (0 min), an iv bolus injection of 100 µg GHRH (GRF 1–29 NH2, Geref, Serono, Spain). On a separate day, they received acipimox (Olbetam, Farmitalia Carlo Erba, Milan, Italy) at the dose of 250 mg po at -240 min and again 250 mg at -60 min, followed by 100 µg iv of GHRH at 0 min. Tests were carried out single-blind and in random order, with intervals of at least 4 days.
Plasma GH was measured by an immunoradiometric assay (Bio Merieux, Spain), with intraassay coefficients of variation of 5 and 5.6% and interassay coefficients of variation of 6% (1.6 µg/L) and 4.4% (19.0 µg/L). FFA were analyzed by an enzymatic method, as described (19). Samples from each patient were assayed at the same time. The data are presented and analyzed as absolute values and are shown as mean ± SE, mean GH peak, and as areas under the secretory curve (AUC). AUC were calculated by a trapezoidal method. Results were compared by a nonparametric test (Wilcoxon). Values of P < 0.05 were considered significant.
Results
As expected, GHRH-induced GH secretion in Cushing’s syndrome
patients was severely blunted (Fig. 1
),
with a mean GH peak of 1.8 ± 0.3 µg/L and AUC of 121.3 ±
21.6 µg/L·120 min. Compared with the FFA basal values of a normal
women population from our laboratory (454 ± 23 mmol/L),
Cushing’s syndrome patients had significantly higher levels
(P < 0.05) that were reduced when pretreated with
acipimox. In fact, FFA levels at 0800, 1100, 1300, and 1400 h
were: 814 ± 61, 746 ± 50, 725 ± 62, and 934 ±
56 mmol/L after placebo (no significant change vs. basal
value) and 799 ± 57, 239 ± 26, 208 ± 21, and 240
± 28 mmol/L after acipimox pretreatment (P < 0.05
vs. basal values). This acipimox-mediated FFA reduction did
not significantly change the GH basal values, which were 0.5 ±
0.2 µg/L, 0.6 ± 0.1 µg/L, and 1.9 ± 0.5 µg/L at 0800,
1100, and 1200 h, respectively. However, the reduction in FFA
levels notably enhanced the GH secretion after the subsequent GHRH
administration (Fig. 1), with a mean GH peak of 11.1 ± 1.8 µg/L
and AUC of 652.9 ± 110.3 µg/L·120 min (both P
< 0.005 vs. placebo values).
|
), all patients in the placebo pretreated
group showed a GHRH-mediated GH secretion with peaks under 4 µg/L,
but after reduction of FFA by acipimox, only 2 out of 14 patients had
stimulated GH peaks under 4 µg/L, and 8 had responses over 10 µg/L.
In all 14 patients, acipimox increased the GH response after GHRH, with
respect to the placebo-GHRH test. Both the reduction in FFA levels and
the increase in GH secretion after acipimox pretreatment were not
correlated with any biological parameter of the subjects studied, such
as age or body mass index. Two subjects experienced a mild face
flushing after the first dose of acipimox. Discussion
Because Cushing’s syndrome is associated with a blunted GH secretion, with respect to all stimuli tested to date (10), a significant number of attempts have been made to understand the altered mechanisms implicated in such a secretory blockade. Contrary to other pathologies associated with reduced GH release (like obesity), hypercortisolism has, until now, been resistant to any pharmacological intervention aimed at correcting the problem. In fact, suppression of endogenous SRIH secretion, repetitive priming with GHRH, hypothalamic stimulation, or administration of GH secretagogues have all failed to minimally increase the blunted hormone release in man (20, 21, 22, 23). Furthermore, the combined administration of GHRH plus GHRP-6, the most potent GH releaser to date with capacity to restore GH release in late adulthood or in obesity (24, 25, 26), failed to change the GH secretion in Cushing’s syndrome (9). These results suggest that the GH blockade observed in obesity or aging are functional and potentially reversible by pharmacological treatment. On the contrary, it indicates that glucocorticoids exert a permanent inhibition or damage upon somatotroph cells that is not reversible by acute interventions. The inhibitory action ceases when hypercortisolism is eliminated by surgery, although it takes considerable time before normal GH secretion advents (27).
In the present work, the acute reduction of FFA by acipimox administration enhanced GHRH-mediated GH discharge in all patients with Cushing’s syndrome, and 8 out of 14 patients showed a response after GHRH over 10 µg/L. Cushing’s syndrome may then be added to the list of states associated with diminished GH release in which a previous FFA reduction enhances GH discharge, such as obesity, hyperthyroidism, or aging (15, 16, 17, 18, 28). This fact is relevant because it is the first pharmacological intervention that results in an increase in GH levels in chronic hypercortisolism,
More controversial is the point of action and mechanism by which FFA reduction enhances GH secretion. There is now compelling evidence indicating that FFA modulation of GH secretion is exerted at the pituitary level, probably by direct action on the somatotroph function (29, 30, 31). It has been shown that extracellular increase in FFA may alter several intracellular signaling systems in pituitary somatotrophs, leading to a reduction in GH secretion (32, 33, 34). Although direct evidence is lacking, our working hypothesis is that FFA reduction also must be operating at the somatotroph level, through a mechanism that still remains undefined. In support of this hypothesis comes the observation that acipimox induced-FFA reduction leads to a fixed increase in GH secretion that is additive to any stimuli chosen, either acting at the hypothalamus or at a pituitary level (16, 17).
In the present work, it has been shown that acute reduction of FFA practically normalizes the GHRH-mediated GH release in Cushing’s syndrome patients, an action that is not attributed to acipimox per se but to FFA reduction (35). However, the response to acipimox-GHRH in Cushing’s syndrome patients was still lower than that of normal subjects challenged with the same stimuli (16), suggesting that the elevated FFA levels may be a contributory factor, but not the only one, to the impeded GH secretion in hypercortisolism. Considerable work is necessary to fully understand the mechanisms by which glucocorticoid excess leads to a semichronic inactivation of the somatotroph function.
In conclusion, the reduction of FFA by acipimox enhanced GHRH-induced GH secretion in all patients with Cushing’s syndrome. Elevated FFA may be a contributing factor for the altered GH secretion in chronic hypercortisolism.
Acknowledgments
The expert technical help of Ms. Mary Lage is gratefully acknowledged.
Footnotes
1 This work was supported by a research grant from Fundacion
Española Contra el Cancer, Fundacion Salud 2000, and FIS (Spanish
Ministry of Health). 
Received February 10, 1997.
Revised May 2, 1997.
Accepted May 20, 1997.
References
This article has been cited by other articles:
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  M. O. van Aken, A. M. Pereira, M. Frolich, J. A. Romijn, H. Pijl, J. D. Veldhuis, and F. Roelfsema Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E63 - E70. [Abstract] [Full Text] [PDF]
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