Specific stimulation of brain serotonin mediated neurotransmission by dexfenfluramine does not restore growth hormone responsiveness in obese women.
OBJECTIVE
Growth hormone release in response to all known stimuli of GH secretion is blunted in obese subjects. Several studies, using d,l-fenfluramine (d,l-FF) as a serotoninergic tool, suggest that brain serotonin plays a role in the pathogenesis of this phenomenon. However, the effect of d,l-FF appears to be dependent on the stimulus used to induce GH release. Furthermore, d,l-FF has catecholamingergic properties apart from its capacity to stimulate serotonin release and to block its re-uptake. In this study, we investigated whether subchronic treatment with the highly selective serotoninergic drug dexfenfluramine (d-FF) affects the GH response to galanin or GHRH in obese subjects.


METHODS
The study had a randomized, cross-over, placebo controlled design. d-FF was administered in a dose of 15 mg twice daily during 6 days. On days 5 and 6 of treatment (with either d-FF or placebo) an i.v. bolus injection of 100 micrograms hGHRH(1-44) or a continuous infusion of p-galanin (40 pmol/kg/min over 40 minutes) were administered in randomized order. All tests were performed in the follicular phase of two consecutive menstrual cycles.


METHODS
Eight obese women (body mass index (BMI) 34.5 +/- 3.6 kg/m2); 7 normal weight (BMI 21.9 +/- 1.9 kg/m2) age-matched control women. All women had a regular menstrual cycle. None used oral contraceptive drugs.


METHODS
GH response to either stimulus was measured both during treatment with d-FF and during treatment with placebo.


RESULTS
The GH response to galanin and the response to GHRH were significantly smaller in obese subjects. d-FF significantly reduced the galanin induced GH secretion in obese subjects, but not in normal weight controls. It did not significantly affect GH release in response to GHRH in either group.


CONCLUSIONS
This study confirms that GH secretion in response to stimuli with varying mechanisms of action is blunted in obese subjects. A decrease of central serotonin mediated neurotransmission does not appear to play a role in the pathogenesis of this phenomenon.
Kars
M E
ME
Department of General Internal Medicine, University Hospital Leiden, Netherlands.
Pijl
H
H
Cohen
A F
AF
Frölich
M
M
Schoemaker
H C
HC
Brandenburg
H C
HC
Meinders
A E
AE
D000328:Adult; D001921:Brain / Q000378:metabolism*; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005260:Female; D005277:Fenfluramine / Q000627:therapeutic use*; D005498:Follicular Phase; D019004:Galanin / Q000627:therapeutic use; D013006:Growth Hormone / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000627:therapeutic use; D006801:Humans; D009765:Obesity / Q000188:drug therapy*; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000627:therapeutic use*; D013268:Stimulation, Chemical; D009435:Synaptic Transmission / Q000187:drug effects*
D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin; D019004:Galanin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone