The potent contraceptive gestodene exerts insulinotropic effects through its a-ring reduced metabolites with intrinsic estrogen-like activity in pancreatic ß-cells.
J Endocrinol Invest
; 46(7): 1333-1341, 2023 Jul.
Article
em En
| MEDLINE
| ID: mdl-36705838
ABSTRACT
PURPOSE:
The contraceptive gestodene is a potent synthetic progestin used in several low-dose contraceptive formulations. Clinical studies reported a relationship between long-term use of combined oral contraceptives containing gestodene (GDN) and profound alterations in glucose metabolism in women. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether GDN may induce estrogen-like effects, even though GDN does not interact with estrogen receptors. The aim of this study was to investigate whether GDN affect pancreatic ß-cell activity, directly or through its conversion to other bioactive metabolites.METHODS:
The effects of GDN and its two derivatives 3ß,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN on insulin 2 (Ins II) and glucokinase (Gk) expression and glucose-stimulated insulin secretion were determined in pancreatic islets from female rats.RESULTS:
Gestodene did exert significant effects on islet ß-cells activity. The most striking finding was that 3ß,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN had greater stimulatory effects on Ins II and Gk expression than that observed with GDN, consistent with their effects on glucose-stimulated insulin secretion. The effects on gene expression induced by GDN-derivatives were abolished by ICI 182,780 and MPP. In addition, the presence of inhibitors of androgen and progestin-metabolizing enzymes eliminated gene expression induced by GDN. These results indicated that GDN is metabolized to A-ring reduced metabolites with estrogen-like activities and through this mechanism, GDN may affect ß-cell activity.CONCLUSIONS:
Altogether, the data suggest that 19-nortestosterone-derived contraceptives such as GDN, possess insulinotropic effects through their conversion into metabolites with intrinsic estrogen-like activity in pancreatic ß-cells.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Estrogênios
/
Norpregnenos
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
J Endocrinol Invest
Ano de publicação:
2023
Tipo de documento:
Article