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

Oral contraception is the most commonly used interventional method in the world. However, several women employ the continuous use of these hormones to avoid pre- and menstruation discomforts. Some studies indicate that oral contraceptives are associated with disturbances in glycemia and the effects of the use of a continuous regime are poorly elucidated. Herein, we evaluated the effects of the continuous administration of a combined oral contraceptive (COC) composed by ethinyl estradiol (EE) and drospirenone (DRSP) on glucose homeostasis in female mice. Adult Swiss mice received 0.6 μg EE and 60 μg DRSP (COC group) or vehicle [control (CTL)] daily by gavage for 35 days. COC treatment had no effect on body weight or adiposity, but increased uterus weight and induced hepatomegaly. Importantly, COC females displayed normal glycemia and glucose tolerance, but hyperinsulinemia and lower plasma C-peptide/insulin ratio, indicating reduced insulin clearance. Furthermore, COC mice displayed reduced protein content of the β subunit of the insulin receptor (IRβ) in the liver. Additionally, pancreatic islets isolated from COC mice secreted more insulin in response to increasing glucose concentrations. This effect was associated with the activity of steroid hormones, since INS-1E cells incubated with EE plus DRSP also secreted more insulin. Therefore, we provide the first evidence that the continuous administration of EE and DRSP lead to hyperinsulinemia, due to enhancement of insulin secretion and the reduction of insulin degradation, which possibly lead to the down-regulation of hepatic IRβ. These findings suggest that the continuous administration of COC could cause insulin resistance with the prolongation of treatment.