Blunted growth hormone (GH) responsiveness to GH-releasing hormone in obese patients: Influence of prolonged administration of the serotoninergic drug fenfluramine

Argenio, G. F.; Bernini, Giampaolo; Sgrò, M; Vivaldi, M. S.; Corso, C. Del; Santoni, R.; Franchi, F

doi:10.1016/0026-0495(91)90091-a

Cited by 8 publications

(6 citation statements)

References 30 publications

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“…Although in the last two decades considerable insight has been gained with regard to the role played by different neurotransmitter pathways, the mechanisms underlying the serotoninergic control of GH secretion are not yet clear, with stimulatory, inhibitory or no effect having been reported [3, 4, 5, 6, 7, 8, 9, 10, 11, 12]. This limitation has mainly been due to the existence of many different receptors that mediate the serotonin (5-HT) actions, and the lack of suitable specific agonist and antagonist drugs.…”

Section: Introductionmentioning

confidence: 99%

Influence of Different Serotonin Receptor Subtypes On Growth Hormone Secretion

Valverde

Peñalva²,

Diéguez

2000

Neuroendocrinology

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The role of serotonin (5-HT) in the regulation of growth hormone (GH) secretion remains unclear due to the existence of many different receptors that mediate the 5-HT actions, and the lack of suitable specific agonist and antagonist drugs. In the present work we have taken advantage of the recent development of new selective 5-HT drugs in order to clarify the role played by different 5-HT receptor types and subtypes on GH secretion. The experiments were carried out on beagle dogs. GH-releasing hormone (GHRH) increased basal canine GH (cGH) levels from 0.8 ± 0.2 to 8.8 ± 1.7 µg/l at 15 min. Administration of 5-HT_1D receptor agonist sumatriptan (SUM) induced a cGH peak at 30 min of 12.9 ± 2.7 µg/l. The combined administration of GHRH plus SUM strikingly potentiated cGH release with a peak of 36.9 ± 6 µg/l at 30 min (p < 0.05). Pretreatment with the muscarinic receptor antagonist atropine completely abolished the cGH response to SUM, while the cholinergic agonist pyridostigmine (PYR) did not modify this response (15.3 ± 5 µg/l PYR plus SUM vs. SUM alone 12.9 ± 2.7 µg/l). On the other hand, administration of drugs with activity at 5-HT_2A/C receptors showed a stimulatory role for the 5-HT_2C receptor subtype, since LY-53857 (antagonist 5-HT_2A/C) and DOI agonist (5-HT_2A/C) both modified the GH response stimulated by GHRH (AUC 88.5 ± 30.4 and 400 ± 64.6 vs. 267.3 ± 52.6 respectively), while ketanserin (antagonist 5-HT_2A) did not modify this response. The 5-HT₃ antagonist ICS-205–930 failed to modify either basal or GHRH induced GH responses. In conclusion, our data show that 5-HT_1D receptors play a stimulatory role on GH secretion in the dog, possibly by acting through a decrease in hypothalamic somatostatin release. Similarly, the 5-HT_2C receptor subtypes also appear to play a stimulatory role. However, 5-HT_2A and 5-HT₃ receptors do not appear to be involved in the control of basal and GHRH-induced GH secretion.

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Section: Introductionmentioning

confidence: 99%

Influence of Different Serotonin Receptor Subtypes On Growth Hormone Secretion

Valverde

Peñalva²,

Diéguez

2000

Neuroendocrinology

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“…Although increased serotonin (5-HT) has been implicated in the pathogenesis of PH (10,15,26,100), especially in the femalespecific mouse models developed by MacLean et al (19)(20)(21), and after administration of an anorectic drug dexfenfluramine (22,100), the mechanistic focus has largely been on effects of 5-HT on distal vascular tissues (10,15,19-22,26,100). We note that it is already known that the PHcausing anorexigens fenfluramine, aminorex, phentermine and fluoxetine increase 5-HT in the hypothalamus (101)(102)(103)(104)(105) and that fenfluramine blunted GH responsiveness to GHRH (105). Moreover, estrogens are themselves anorexigenic through effects at the level of the hypothalamus (106,107) showing that the central effects of anorexigens can be female-biased.…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 67%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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“…Previous studies of the stimulus-induced pituitary GH secretion during treatment with serotoninergic medication in obese subjects indicate that, depending on the stimulus, enhancement of serotoninergic neurotransmission facilitates GH release (Altomonte et al, 1987;Argenio et al, 1991;Bernini et al, 1990). However, these studies used d,l-FF as a pharmacological tool.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of d,l-FF upon stimulus induced GH release in obesity appears to be dependent upon the stimulus used. In contrast to its effect upon GH release in response to arginine and insulin induced hypoglycaemia, d,l-FF treatment does not restore the blunted GH response to GHRH in obese subjects (Argenio et al, 1991). The GH release in response to insulin induced hypoglycaemia and the GH release in response to arginine are mediated by suppression of hypothalamic somatostatin secretion (Alba-Roth et al, 1988;Page et al, 1987).…”

mentioning

confidence: 87%