Background: A loss of ovarian function is associated with increased fat, along with metabolic pathologies including insulin resistance (IR) and type 2 diabetes. Postmenopausal estrogen deficiency in human and experimental studies has been reported to enhance overall IR. Hence, factors or intervention that could promote or prevent respectively, the development of IR, pancreatic β-cell function and diabetes will be of great public health importance, particularly in postmenopausal women. Moreso, glycogen synthase kinase-3 (GSK-3) can serve as a negative modulator of insulin action on glycogen synthesis and, potentially, on glucose transport activity. Combined oral contraceptives (COCs) are used by over 100 million women around the world and remain one of the most effective reversible contraceptive methods, although its negative impact remains unresolved. 
Aims: We therefore hypothesized that combined oral contraceptives will ameliorate IR, pancreatic beta cell dysfunction and elevated glycogen synthase kinase-3 (GSK-3) through repletion of estrogen in ovariectomized rats.
Method: Twelve week-old female Wistar rats, after acclimatization and post-surgery recovery, were divided into four groups; sham-operated and ovariectomized rats treated with or without COC (1.0µg ethinylestradiol and 5.0µg levonorgestrel) daily for 8 weeks. IR was estimated using homeostatic model assessment (HOMA) whereas homeostatic model of assessment of beta cell (HOMA-β) and 1hr post-load glucose level were estimated as pancreatic β-cell dysfunction. Circulating GSK-3 and estradiol levels were estimated by ELISA kits.
Results: Results showed that ovariectomized and sham-operated rats treated with COC led to increased HOMA-IR, 1hr post-load glucose level, impaired glucose tolerance, HOMA-β, plasma insulin, GSK-3 and decreased estrogen. On the other hand ovariectomized rats treated with COC ameliorated all these effects.
Discussion: IR is a hallmark of both the prediabetic state as well as the overt type 2 diabetes mellitus, which occurs in 20%–25% of the human population. It is rapidly becoming one of the major public health challenges, signifying an enormous global economic burden, particularly when accompanied by impaired glucose tolerance, elevated 1-hour postload glucose level and reduced pancreatic β-cell function. GSK-3 has been implicated in the development of insulin resistance, pancreatic β-cell dysfunction and diabetes. Since the introduction of COC, its impact on IR and other abnormalities remain unresolved, despite the newer generations of COC that changed the dosage and/or progestin type. 
These results showed that ovariectomized rats developed IR that is accompanied by high 1-hr postload glucose level and pancreatic β-cell dysfunction, impaired glucose tolerance, hyperinsulinemia, elevated GSK-3 and depleted estrogen level. Surprisingly however, the result also indicates that treatment with COC repleted the estrogen level in ovariectomized rats, thereby ameliorating GSK-3, impaired glucose tolerance, IR and pancreatic β-cell dysfunction. In conclusion, this study suggests a positive effect of COC in estrogen deficient state.

Elevated glycogen synthase kinase-3 induced by estrogen deficiency is ameliorated by combined oral contraceptives