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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 4 1234-1238
Copyright © 1999 by The Endocrine Society

Original Studies

The Control on Growth Hormone Release by Free Fatty Acids Is Maintained in Acromegaly

Roberto Lanzi, Marco Losa, Giovanna Mignogna, Andrea Caumo and Antonio Ettore Pontiroli

Divisione di Medicina Interna (R.L., G.M.), Unitá di Malattie Metaboliche (A.E.P.), Divisione di Neurochirurgia (M.L.), Unitá di Epidemiologia (A.C.), Istituto Scientifico Ospedale San Raffaele and Universitá degli Studi di Milano, 20132 Milano, Italy

Address all correspondence and requests for reprints to: Roberto Lanzi, M.D., Division of Internal Medicine, Istituto Scientifico Ospedale San Raffaele, Via Olgettina 60, 20132 Milano, Italy. E-mail: lanzi.roberto{at}hsr.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Free fatty acids (FFA) physiologically regulate GH release via a negative feedback. The aim of this study was to examine whether such feedback is preserved in acromegaly, a condition in which alterations in other regulatory mechanisms of GH release occur. Eight acromegalic patients (group 1: five women and three men, 43.0 ± 4.2 yr old, mean ± SE) received per os on two different days, at a 3 day-interval, in a random order, placebo or 250 mg of acipimox, an inhibitor of lipolysis analogous to nicotinic acid, at 0700 and 1100 h. In both tests GHRH (1–29 NH2), 50 µg, was administered iv at 1300 h. Blood samples for GH, FFA, immunoreactive insulin (IRI), and glucose were taken from 0900 to 1500 h, and the time period considered for statistical analysis was 1200–1500 h, representative of steady-state condition for FFA, IRI, and glucose. Mean plasma FFA levels (1200–1500 h) were significantly lower after acipimox than after placebo (0.05 ± 0.01 vs. 0.17 ± 0.01 g/L, P < 0.01). In contrast, both mean basal GH levels (1200–1300 h) and the mean GH response to GHRH (GH {Delta} area, 1300–1500 h) were significantly higher after acipimox than after placebo (12.0 ± 1.9 vs. 7.8 ± 1.2 µg/L, P < 0.01; 2937 ± 959 vs. 1154 ± 432 µg/L·120 min, P < 0.01). The increase in both basal GH levels and GH {Delta} area occurred in all eight patients. Acipimox also reduced mean serum IRI (83 ± 12 vs. 112 ± 14 pmol/L) and blood glucose (5.1 ± 0.1 vs. 5.7 ± 0.1 mmol/L) levels, as compared with placebo (P < 0.03 or less). Eight acromegalic patients (group 2: six women and two men, 46.6 ± 5.7 yr old) underwent a constant iv 10% lipid infusion (150 mL/h), started at 0900 h and continued until 1500 h. Mean plasma FFA levels (1200–1500 h) were significantly higher during lipid infusion than after placebo (0.27 ± 0.01 vs. 0.16 ± 0.01 g/L, P < 0.02); in contrast, mean basal GH levels (1200–1300 h) were reduced by lipid infusion, as compared with placebo (9.9 ± 3.1 vs. 16.6 ± 4.4 µg/L, P < 0.01), and the same occurred for the GH {Delta} area after GHRH (2498 ± 1643 vs. 4512 ± 1988 µg/L·120 min, P < 0.01). Serum IRI and blood glucose levels were similar after placebo and during lipid infusion.

These data indicate that, in acromegaly, the acute reduction of circulating FFA levels results in increased GH release, whereas the increase in circulating FFA levels is accompanied by a reduced GH release. Taken together, these findings suggest that, in acromegaly, the control of FFA on GH release is preserved.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH SECRETION is regulated by two specific hypothalamic neurohormones, the stimulatory GHRH and the inhibitory SRIF (1). The release of these neurohormones, in turn, is modulated by a large cohort of neurotransmitters, peptides, hormones, and metabolic variables.

Acromegaly is a pathological condition characterized by elevated circulating GH levels, which are usually detectable at all times and fluctuate widely throughout the day (2, 3). High GH levels are attributable to GH hypersecretion that is caused, with few exceptions (4, 5, 6), by a pituitary adenoma, and do not depend on an alteration in the processes of GH distribution or disappearance (7). Several abnormalities have been reported in the mechanisms governing GH secretion in acromegalic patients. In vivo GH hypersecretion occurs in spite of high circulating insulin-like growth factor I (IGF-I) levels, indicating disruption of the negative IGF-I feedback on GH release (8). Furthermore, the GH response to the normally suppressive effect of hyperglycemia is variable, because GH levels may rise, be partially suppressed, or not change after an oral glucose load (9, 10). In addition, there is often paradoxical responsiveness to L-dopa (11) and dopamine agonists (12, 13), and to stimuli that do not affect GH release in normal subjects [TRH, GnRH, CRH, vasoactive intestinal peptide (VIP), peptide histidine methionine)] (14, 15, 16, 17, 18). In the majority of acromegalic patients, however, circulating GH levels decrease after administration of SRIH and its analogs (19, 20, 21). This finding supports the hypothesis that, in acromegaly, GH secretion is not completely autonomous but is under some degree of hypothalamic regulation. Data obtained in vitro in static incubations (22, 23) and via perifusion systems (24) also indicate that most GH-secreting pituitary adenomas maintain, at least qualitatively, a normal sensitivity to the hypothalamic regulatory hormones GHRH and SRIH and also to the peripherally generated IGF-I and insulin (25).

In this complex and variable pathophysiologic circumstance, we are unaware of any information about the effects of free fatty acids (FFA). FFA exert a negative feedback on GH release under physiological conditions (26, 27, 28, 29, 30, 31). To investigate whether the FFA-negative feedback on GH release persists in acromegaly, we designed a placebo-controlled study in which GH release was analyzed after: 1) acute reduction of circulating FFA levels by pharmacologic blockade of lipolysis; and 2) acute increase of circulating FFA levels induced by iv lipid infusion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and experimental procedures

The protocol for the study was approved by the local ethics committee. Fifteen consecutive acromegalic patients, hospitalized at Ospedale San Raffaele (10 women and 5 men), were admitted to the study after giving written informed consent. Subjects characteristics are shown in Table 1Go. Diagnosis of active acromegaly was based on the clinical picture, failure of GH levels to suppress under 2 µg/L after an oral glucose load, and elevated plasma IGF-I levels. All acromegalic patients had a pituitary adenoma, by magnetic resonance imaging, confirmed at surgery.


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  		Table 1. Clinical details of acromegalic patients

 
Following an experimental protocol, previously designed by our group to investigate the interplay GH/FFA in normal subjects (27, 28), the first eight acromegalic subjects (group 1 of Table 1Go) received (per os, on two different days, at a 3 day-interval, and in a random order) placebo or 250 mg acipimox (Olbetam, Pharmacia & Upjohn, Inc., Milan, Italy) at 0700 h and at 1100 h. Acipimox is an inhibitor of lipolysis analogous to nicotinic acid that is known to act only on the adipose tissue (32, 33). In both tests, GHRH (1–29 NH2), 50 µg iv, was administered at 1300 h.

Patients no. 9–15 (group 2 of Table 1Go) underwent (on two different days, at a 3-day interval, and in random order) a 0.9% NaCl infusion or a constant lipid infusion (Intralipid 10%) (31) at the rate of 150 mL/h, started at 0900 h and continued until 1500 h. GHRH (50 µg, iv) was administered at 1300 h. Patient no. 7 underwent both tests, with acipimox or lipid infusion, and was therefore included in both groups.

In each test, blood samples for evaluation of serum GH levels were taken every 10 min, from 0900 h to 1300 h (time of GHRH injection) and 15, 30, 45, 60, 90, and 120 min after, via an indwelling catheter inserted into a forearm vein at least half an hour before the beginning of the sampling period. Blood samples for evaluation of plasma FFA, serum insulin [immunoreactive insulin (IRI)], and blood glucose levels were taken every 30 min throughout each study.

Patients no. 1, 4–8, and 10–15 also underwent a TRH test (200 µg, iv), with blood samples for GH taken at 0, 15, 30, 45, 60, 90, and 120 min. On the day of each test, all subjects were fasted overnight and remained recumbent throughout the test.

Assays

Plasma FFA levels were measured by a spectrophotometric method adapted to Cobas-Fara 2 (Roche, Basel, Switzerland) using kits supplied by Italfarmaco (Milano, Italy). Intra- and interassay coefficients of variations (CVs) were 2.3 and 3.1%, respectively. Serum IRI levels were measured by RIA using kits supplied by INCSTAR Corp. (Stillwater, MN). The minimum sensitivity of the assay was 13 pmol/L, and intra- and interassay CVs were 3.9 and 8.9%, respectively. Serum GH levels were measured by RIA using kits supplied by Farmos Diagnostic (Turku, Finland). The minimum sensitivity of the assay was 0.2 µg/L, and the median intra- and interassay CVs for GH concentrations, ranging from 0.2–50 µg/L, were less than 9 and 10%, respectively. Blood glucose levels were measured by a glucose oxidase method (Glucose Analyzer II, Beckman Coulter, Inc. Instruments, Fullerton, CA).

Calculations and statistical analysis

For all the variables, statistical analysis was performed for the interval 1200–1500 h. From 1200 h, in fact, steady-state conditions for plasma FFA, serum IRI, and blood glucose levels were evident in all tests and were maintained until 1500 h. Mean basal GH levels therefore represent the mean of seven samples between 1200 and 1300 h. The integrated GH response to GHRH (GH {Delta} area) was calculated, by the trapezoidal method, over the 2 h after GHRH injection (1300–1500 h). Because of the nonnormal distribution of the data (assessed by the Kolmogorov-Smirnov test), the comparisons of both basal GH levels and the GH {Delta} areas after placebo/acipimox (group 1) and placebo/lipid infusion (group 2) were performed by the nonparametric Wilcoxon signed-rank test. Comparisons of mean plasma FFA, blood glucose, and serum IRI levels (mean of seven samples between 1200 h and 1500 h) were performed by the Student’s t test for paired data. The Pearson product-moment correlation coefficient was used to evaluate the degree of correlation between all parameters reported in Results.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go represents plasma FFA and serum GH levels between 1200 h and 1500 h in patients of group 1, receiving placebo or acipimox at 0700 and 1100 h. In all eight patients, mean plasma FFA levels were significantly lower after acipimox than after placebo. The acute reduction of plasma FFA levels induced by acipimox was accompanied by a significant increase of both basal serum GH levels and of the GH response to GHRH (GH {Delta} area). Numeric values and statistical comparisons for all the variables are reported in the left panel of Table 2Go. Acipimox administration, besides significantly reducing plasma FFA levels and increasing GH levels, also induced a significant decrease of mean serum IRI and blood glucose levels.



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  		Figure 1. Upper panel, Plasma FFA levels (1200–1500 h), after oral placebo and acipimox administration (0700 and 1100 h), in eight acromegalic subjects of group 1; lower panel, basal serum GH levels and GH response to GHRH, after placebo and acipimox administration, in the same subjects.

 

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  		Table 2. Experimental parameters after placebo or acipimox (group 1) and after placebo and during lipid infusion (group 2)

 
In subjects of group 2, lipid infusion (started at 0900 h) progressively increased circulating FFA levels, so that by 1200 h, a new steady-state for plasma FFA was reached, and maintained until 1500 h (Fig. 2Go, upper panel). In all subjects of group 2, the increase in plasma FFA levels was accompanied by a concomitant significant reduction of basal serum GH levels, as well as of the GH {Delta} area (Fig. 2Go, lower panel). Numeric values and statistical comparisons for all the variables are reported in the right panel of Table 2Go. Mean serum IRI and blood glucose levels remained unaffected by lipid infusion. To clarify the effect of acipimox administration and of lipid infusion on GH levels in acromegaly, the GH profiles of subject no. 7 (who underwent tests with placebo, acipimox, and lipid infusion) are shown in Fig. 3Go.



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  		Figure 2. Upper panel, Plasma FFA levels (1200–1500 h), after oral placebo (0700 and 1100 h) and during iv 10% lipid infusion, in eight acromegalic subjects of group 2; lower panel, basal serum GH levels and GH response to GHRH, after placebo and during lipid infusion, in the same subjects.

 


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  		Figure 3. Basal serum GH levels and GH response to GHRH in a single representative acromegalic subject (no. 7) after oral placebo ({circ}) and acipimox (•) administration and during iv 10% lipid infusion ({blacktriangleup}). Acipimox enhanced, and lipid infusion reduced both basal and GHRH-stimulated GH release, as compared with placebo.

 
Table 3Go reports a qualitative comparison between the GH response to GHRH after placebo or acipimox, and during lipid infusion, and that to TRH after placebo (positive response: GH {Delta} peak, i.e. GH increment above basal levels, >50%). After placebo, patients of both groups showed a variable response to TRH and GHRH. In addition to the significant increase in GH {Delta} area after acipimox (Table 2Go), all subjects of group 1 showed a qualitatively positive response to GHRH (Table 3Go, upper panel). In all subjects of group 2, GH {Delta} peak after GHRH was reduced by lipid infusion; however, five of eight subjects, responsive after placebo, continued to be responsive also at higher plasma FFA levels (Table 3Go, lower panel).


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  		Table 3. Qualitative analysis of the GH response to TRH and to GHRH (GH {Delta} peak) after placebo and acipimox, and during lipid infusion in acromegalic patients of groups 1 and 2

 
In both groups of acromegalic patients, no correlations were found between mean FFA levels, basal GH levels, and the GH response to GHRH, after either placebo, acipimox administration, or lipid infusion.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Among the abnormalities in the control of GH secretion that have been described in acromegaly, refractoriness to the glucose inhibiting effect (9, 10) and the paradoxical responsiveness to several stimuli (11, 14, 15, 16, 17, 18) have been widely used as tools for diagnosis and postoperative evaluation. We are unaware of any data, however, regarding the persistence of FFA-negative feedback on GH release in acromegaly.

The results of the present study indicate that, in acromegaly, as in nonacromegalic subjects (26, 27, 28, 29, 30, 31), the acute reduction of circulating FFA levels results in increased GH release, whereas an increase in circulating FFA levels is accompanied by a reduced GH release. Of note is that enhancement of GH release after acipimox was evident in all patients, both qualitatively and quantitatively. On the other hand, lipid infusion decreased GH release in all patients, but five of eight of them continued to be responsive to GHRH (GH {Delta} peak > 50%). This could reflect a higher sensitivity of the adenoma cells to a decrease, rather than to an increase in circulating FFA levels. In any case, taken together, our findings suggest that, in acromegaly, GH-secreting adenomatous pituitary cells maintain their sensitivity to the negative control exerted by FFA.

These data are in agreement with previous reports indicating that GH secretion is not completely autonomous in acromegaly (19, 20, 21, 22, 23, 24, 25). Particularly, the normal (at least qualitatively) sensitivity to SRIH in most GH-secreting pituitary adenomas (19, 20, 22, 23, 24) may explain, in part, the persistent inhibitory effect of FFA on GH release in acromegaly, because experimental evidence suggests that FFA may trigger SRIH release from the hypothalamus (34). Other explanations include the persistence of the direct FFA inhibitory effect on the GH-secreting adenoma cells. Experimental evidence indicates that FFA may exert a nonselective blockade of spontaneous, as well as of GHRH-, TRH-, and VIP-stimulated GH release, directly at the pituitary (35, 36, 37, 38, 39). At this level, the main target for the biological actions of FFA seems to be the cellular membranes of the somatotrophs, via a perturbation of the lipid bilayer and a disruption of the lipid-lipid and lipid-protein interaction. Because plasma-borne FFA molecules are not covalently linked in the plasma membranes, but are included in the bilayer as wedges (40), they may fluctuate. Therefore, a change in the gradient of FFA from plasma toward cell membranes (as induced by acipimox and lipid infusion in this study) is able to modify the membrane FFA content (41) and to affect many biological functions, including cell-to-substrate adhesion, surface receptor capping, and transmembrane signaling (42, 43, 44, 45).

Relevant to our study are previous findings indicating that caprylic acid and cis-unsaturated FFA are able to reduce GHRH- and VIP-stimulated GH release of cultured pituitary cells via a reduction, at least in part, of the adenylate cyclase activity (36, 39). In fact, it is known that about 40% of GH-secreting pituitary adenomas show a constitutive activation of the adenylate cyclase-cAMP system, caused by a point mutation in the {alpha}-subunit of the Gs protein linked to the adenylate cyclase coupled with the GHRH receptor (46). In our preliminary study, the mutation of the Gs protein has not been evaluated in any of the acromegalic patients. Our finding that, in all acromegalic patients examined, the GHRH-stimulated GH release was increased (or even became evident when absent after placebo) after acipimox, and was reduced by lipid infusion, needs therefore to be reconsidered in relation to such a mutation. The finding that FFA could persistently regulate GH release in response to GHRH, also in the presence of the so-called gsp oncogene, could, in fact, bring new insights regarding the intracellular mechanisms involved in the FFA control of GH release. In this regard, it could also be of interest to examine, in acromegalic patients, the influence that FFA may exert on the GH release induced by stimuli acting via pathways other than the adenylate cyclase-cAMP system, such as TRH.

In conclusion, our preliminary data indicate that, in acromegaly, the acute reduction of circulating FFA levels results in increased GH release, whereas the increase in circulating FFA levels is accompanied by a reduced GH release. Taken together, these findings indicate that, in acromegaly, the control exerted by FFA on GH release is preserved. Further studies are needed to investigate the mechanisms involved, which may provide new insight about the pathophysiology of GH release in acromegaly.

Received August 4, 1998.

Revised November 13, 1998.

Accepted November 24, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals