Journal of endocrinological investigation · 2023
The potent contraceptive gestodene exerts insulinotropic effects through its a-ring reduced metabolites with intrinsic estrogen-like activity in pancreatic β-cells.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Enríquez J, Sosa-Larios T, Díaz-Díaz E, Morimoto S
Аннотация
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 β-cell activity, directly or through its conversion to other bioactive metabolites.
METHODS: The effects of GDN and its two derivatives 3β,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 β-cells activity. The most striking finding was that 3β,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 β-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 β-cells.
METHODS: The effects of GDN and its two derivatives 3β,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 β-cells activity. The most striking finding was that 3β,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 β-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 β-cells.