Ethinyl estradiol and levonorgestrel coadministration induces hypophagia and increases energy expenditure in female rats

Oral contraceptives containing ethinyl estradiol (EE) with levonorgestrel (LNG) are common in hormonal contraceptives. EE+LNG suppresses weight gain in rodents, but the mechanisms for this remain unclear. Further, metabolic demands in adolescence are increased relative to adulthood. We tested the metabolic effect of a low dose of EE + LNG in adolescents and adult female Long-Evans rats. Rats were given EE (10 µg/kg) + LNG (20 µg/kg) or vehicle subcutaneous injections daily for 16 days. Body mass, food intake, whole-body oxygen consumption, respiratory exchange ratio, and energy expenditure were measured in Promethion phenotyping cages. Dual-energy X-ray absorptiometry (DXA), glucose tolerance, serum metabolic hormone levels, depot-specific adipose and reproductive tissues were collected. EE+LNG limited body-mass gain in both age groups by combining hypophagia with a marked elevation in total energy expenditure and no change in locomotion, implicating potential thermogenic pathways. Dual-energy X-ray absorptiometry scans showed curtailed fat accrual and the preservation of lean mass in EE + LNG-treated rats. White-adipose depots were smaller in all hormone-treated rats, whereas brown adipose tissue mass was reduced only in adults. EE+LNG-treated adults had lower leptin and C-peptide levels with enhanced glucose clearance, whereas adolescents had reductions in GLP-1, glucagon, and PYY levels without altered glucose clearance. Thus low-dose EE + LNG reduced caloric intake, increased energy expenditure, and limited white-adipose deposition irrespective of age. Age-specific effects on metabolic hormones and adipose depot UCP1 content were noted. Together, these results delineate an age-sensitive metabolic and endocrine profile of EE + LNG.