Combined oral contraceptive in female mice causes hyperinsulinemia due to β-cell hypersecretion and reduction in insulin clearance

Oliveira, Cremilda Amaral Roso de; Araújo, Thiago dos Reis; Aguiar, Gésily de Souza; Silva, Joel Alves da; Vettorazzi, Jean Franciesco; Freitas, Israelle N.; Oliveira, Kênia M.; Boschero, Antônio Carlos; Bonfleur, Maria Lúcia; Clarke, Julia R.; Henriques, Helene Nara; Ribeiro, Rosane Aparecida

doi:10.1016/j.jsbmb.2019.03.018

Cited by 9 publications

(3 citation statements)

References 45 publications

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“…EE, DRSP and EE+DRSP were administered via gavage when all mice were in the meta-estrus phase. Because it was thought that during this estrous cycle phase, plasma concentrations of gonadotropins, estrogen, and progesterone would be close to those induced by oral contraception (16). Female mice were given 60 µg of DRSP for DRSP group and 0,6 µg of EE for the EE group by gavage every day for 35 days.…”

Section: Methodsmentioning

confidence: 99%

Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Kidney

Kirimlioglu,

Turk,

Cernomorcenco

2024

New J Urol.

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Objective: This study aimed to analyze the effects of combined oral contraceptive active ingredients, Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone, on liver histopathological changes and endoplasmic reticulum stress levels. Material and Methods: In the study, 37 Balb/c female mice were used. Mice were randomly divided into the Control, Sham, Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone groups. The experimental groups were administered with gavage to 8-week-old female mice for 35 days. Kidney tissue sections were applied with Hematoxylin&Eosin, Orcein, Mallory’s Azan, and Periodic Acid-Schiff to detect histopathological changes, and Chop and Grp78 were used to detect Endoplasm Reticulum Stress. Results: Significant loss of microvilli and a decrease in glycogen accumulation were observed in the apical part of some of the proximal tubules of animals in the Drospirenone and Ethinyl Estradiol+Drospirenone groups. The amount of collagen fiber stained with Mallory’s Azan increased in the parietal layer of Bowman’s capsule of the kidney tissues of the Drospirenone and Ethinyl Estradiol+Drospirenone applied groups, but no difference was observed in elastic fibers in all groups. The expression level of Grp78 and Chop proteins in the kidney tubules of female mice given Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone was significantly higher compared to the control group. Conclusion: In this study, it was shown that the expression of Grp78 and Chop markers detected in the mouse kidney increased as a result of Drospirenone, Ethinyl Estradiol and Ethinyl Estradiol + Drospirenone administration, thus causing kidney cell apoptosis by inducing ER-dependent death pathway activity.

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Section: Methodsmentioning

confidence: 99%

Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Kidney

Kirimlioglu,

Turk,

Cernomorcenco

2024

New J Urol.

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“…Female mice were given 60 µg of DRSP for DRSP group and 0.6 µg of EE for the EE group by gavage every day for 35 days. 25 EE and DRSP were dissolved in 100% Ethanol. Ethanol-EE containing DRSP was mixed with sesame oil.…”

Section: Methodsmentioning

confidence: 99%

Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Liver

TÜRK,

CERNOMORCENCO,

KIRIMLIOĞLU

2024

Kocaeli Üniversitesi Sağlık Bilimleri Dergisi

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Objective: We aimed to evaluate the effects of combined oral contraceptive active ingredients ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone for histopathological changes, and endoplasmic reticulum stress levels in the liver. Methods: In the study, 37 to 8-week-old Balb/c female mice were used. Mice were randomly divided into the control, sham, ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone groups. Experimental groups were administered ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone with gavage for 35 days. In liver tissue sections, histopathological changes were detected with hematoxylin&eosin, orcein, Mallory's Azan, and periodic acid-Schiff, and the presence of endoplasmic reticulum stress was detected by Chop and Grp78 immunostaining. Results: The ethinylestradiol+drospirenone group showed significant histopathological changes compared to the control group. Some degenerative changes were noted such as swelling and size differences in hepatocytes in the ethinylestradiol+drospirenone group. When compared to the control group, an increased collagen and elastic fibers density around the vena centralis was observed in the ethinylestradiol+drospirenone group. The expression level of Grp78 protein in female mice given ethinylestradiol+drospirenone was statistically significantly increased compared to the control group. The expression level of Chop protein was significantly increased in the ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone groups. Conclusion: We concluded that the use of combined oral contraceptives increases endoplasmic reticulum stress in mouse liver tissue, and as a result, it may cause liver histopathological disorders by promoting cell death.

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“…These contraindications to OC treatment are individual components of cardiometabolic disease, likely driven by a poor diet, sedentary behaviours and obesity (Kelli et al., 2015). Despite both human studies and rodent models that show that even low dose OC use decreases glucose tolerance and leads to hyperinsulinaemia (Oelkers et al., 1995; Oliveira et al., 2019), there remains controversy in the literature regarding the metabolic effects of OC use (Chasan‐Taber et al., 1997). We attribute this knowledge gap to a lack of mechanistic studies and failure of animal models to mirror the cycle effects seen in humans.…”

Section: Introductionmentioning

confidence: 99%

Oral combined contraceptives induce liver mitochondrial reactive oxygen species and whole‐body metabolic adaptations in female mice

Fuller

McCoin

Stierwalt

et al. 2022

The Journal of Physiology

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Compared to age‐matched men, pre‐menopausal women show greater resilience against cardiovascular disease (CVD), hepatic steatosis, diabetes and obesity – findings that are widely attributed to oestrogen. However, meta‐analysis data suggest that current use of oral combined contraceptives (OC) is a risk factor for myocardial infarction, and OC use further compounds with metabolic disease risk factors to increase CVD susceptibility. While mitochondrial function in tissues such as the liver and skeletal muscle is an emerging mechanism by which oestrogen may confer its protection, effects of OC use on mitochondria and metabolism in the context of disease risk remain unexplored. To answer this question, female C57Bl/6J mice were fed a high fat diet and treated with vehicle or OCs for 3, 12 or 20 weeks (n = 6 to 12 per group) at a dose and ratio that mimic the human condition of cycle cessation in the low oestrogen, high progesterone stage. Liver and skeletal muscle mitochondrial function (respiratory capacity, H2O2, coupling) was measured along with clinical outcomes of cardiometabolic disease such as obesity, glucose tolerance, hepatic steatosis and aortic atherosclerosis. The main findings indicate that regardless of treatment duration, OCs robustly increase hepatic mitochondrial H2O2 levels, likely due to diminished antioxidant capacity, but have no impact on muscle mitochondrial H2O2. Furthermore, OC‐treated mice had lower adiposity and hepatic triglyceride content compared to control mice despite reduced wheel running, spontaneous physical activity and total energy expenditure. Together, these studies describe tissue‐specific effects of OC use on mitochondria as well as variable impacts on markers of metabolic disease susceptibility. Key points Oestrogen loss in women increases risk for cardiometabolic diseases, a link that has been partially attributed to negative impacts on mitochondria and energy metabolism. To study the effect of oral combined contraceptives (OCs) on hepatic and skeletal muscle mitochondria and whole‐body energy metabolism, we used an animal model of OCs which mimics the human condition of cessation of hormonal cycling in the low oestrogen, high progesterone state. OC‐treated mice have increased hepatic mitochondrial oxidative stress and decreased physical activity and energy expenditure, despite displaying lower adiposity and liver fat at this time point. These pre‐clinical data reveal tissue‐specific effects of OCs that likely underlie the clinical findings of increased cardiometabolic disease in women who use OCs compared to non‐users, when matched for obesity.

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Combined oral contraceptive in female mice causes hyperinsulinemia due to β-cell hypersecretion and reduction in insulin clearance

Cited by 9 publications

References 45 publications

Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Kidney

Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Kidney

Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Liver

Oral combined contraceptives induce liver mitochondrial reactive oxygen species and whole‐body metabolic adaptations in female mice

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