Paradoxical inhibitory effect of serotonin on cortisol production from adrenocortical lesions causing Cushing's syndrome.
In the human adrenal gland, serotonin (5-HT) stimulates cortisol production through a paracrine mechanism involving 5-HT4 receptors positively-coupled to adenylyl cyclase. A hyperresponsiveness of adrenocortical tissue to 5-HT has also been described in several cases of ACTH-independent bilateral macronodular adrenal hyperplasias (AIMAHs) and adenomas causing Cushing's syndrome. In the present study, we report two cases of cortisol-producing adrenocortical lesions, i.e., one AIMAH (case 1) and one adenoma (case 2), whose secretory activity was inhibited in vitro by 5-HT. The potencies (pIC50) and efficacies (Emax) of 5-HT to inhibit cortisol secretion were 8.2 +/- 0.4 and -64.1% +/- 7.5% in case 1, and 9.2 +/- 0.5 and -32.3% +/- 3.8% in case 2. The specific 5-HT4 antagonist GR 113808 failed to influence the 5-HT-induced decrease in cortisol production by the two tissues, indicating that the paradoxical inhibitory effect of 5-HT could not be accounted for by activation of eutopic 5-HT4 receptors. These results suggest that the tissues expressed aberrant 5-HT receptors. In conclusion, the present study provides the first evidence for an inhibitory effect of 5-HT on cortisol secretion in adrenocortical lesions causing Cushing's syndrome. Our data also suggest that expression of illegitimate membrane receptors by cortisol-producing adrenal hyperplasias and/or adenomas may convert a paracrine stimulatory factor into an inhibitory signal.
Louiset
E
E
European Institute of Pept. Res. (IFRMP 23), Lab. Cell. Mol. Neuroendocrinol., University of Rouen, Mont-Saint-Aignan, France.
Cartier
D
D
Contesse
V
V
Duparc
C
C
Lihrmann
I
I
Young
J
J
Bertherat
J
J
Reznik
Y
Y
Kuhn
J M
JM
Laquerrière
A
A
Vaudry
H
H
Lefebvre
Herve
H
D000236:Adenoma / Q000150:complications / Q000378:metabolism*; D000302:Adrenal Cortex / Q000473:pathology; D000303:Adrenal Cortex Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000378:metabolism*; D003480:Cushing Syndrome / Q000209:etiology*; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006965:Hyperplasia; D012701:Serotonin / Q000494:pharmacology*
D012701:Serotonin; D006854:Hydrocortisone