Background: It is well established that compared to age-matched men, pre-menopausal women are protected against metabolic disease (obesity, diabetes, hepatic steatosis) . However, both epidemiological data on menopause and pre-clinical ovariectomy models show that disruption of estrogen signaling increases disease susceptibility. Combined oral hormonal contraceptives (OC) induce loss of normal estrogen cycling, and despite widespread use, the impact of OCs on metabolic health and disease remains poorly understood.

Methods: Female C57BL/6J mice (7-8 wks old) were treated with high-fat diet (HFD; CON) or HFD + OCs (2mg estradiol/kg HFD, 200mg progestin/kg HFD; OC) for 12 wks. In each treatment group, mice either remained sedentary or had access to voluntary running wheels (VWR; n=12 per group) . Liver and skeletal muscle mitochondrial function (respiratory capacity, H2O2, coupling) were measured along with body composition, glucose tolerance, energy expenditure, and intrahepatic triglyceride.

Results: OCs decreased VWR, spontaneous physical activity, and total energy expenditure. OC treated mice had lower adiposity and hepatic triglyceride compared to CON mice, with no difference in glucose tolerance. Despite similar maximal respiratory capacity, OCs induced robust increases in hepatic mitochondrial H2O2 across all respiratory states and with both fat and carbohydrate-based substrates. There were no differences in muscle mitochondrial outcomes.

Conclusions: When combined with HFD, OC use lowers physical activity and energy expenditure while inducing tissue-specific effects on mitochondrial function in mice. These data provide pause for use of OCs in the context of elevated metabolic disease risk. Future work should explore whether OC-induced changes in physical activity blunts the ability of exercise to prevent or treat insulin resistance and steatosis and whether prolonged OC exposure leads to liver injury via elevated oxidative stress.


K. Fuller: None. C. S. Mccoin: None. H. Stierwalt: None. J. P. Thyfault: None.


AHA (20PRE35120098) , VA Merit Review Grant (1I01BX002567-01)

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