Insulin resistance, secretion, and metabolism in users of oral contraceptives

Abstract

Studies of insulin employing the oral glucose tolerance test demonstrate marked differences between the effects of different oral contraceptives, but provide little insight into the underlying disturbances. We investigated the metabolic basis of these disturbances by computer modelling of iv glucose tolerance test glucose, insulin, and C-peptide concentration profiles. Insulin resistance, secretion, and metabolism were evaluated in 296 oral contraceptive users and 95 nonusers. Four estrogen/progestin combinations, with similar estrogen but differing progestin contents, and 1 progestin-only formulation were studied. Effects on iv glucose tolerance test glucose, insulin, and C-peptide concentrations varied according to progestin content, with levonorgestrel-containing combinations having the greatest effect, followed by desogestrel and norethindrone. However, these formulations increased insulin resistance to a similar extent. The progestin-only formulation did not affect insulin resistance. Levonorgestrel combinations increased second phase pancreatic insulin secretion by 60-90%, but did not affect the insulin half-life. The desogestrel combination increased the insulin half-life by 28%, but did not affect insulin secretion. The effects of different combined oral contraceptives on glucose tolerance test glucose, insulin, and C-peptide concentration profiles appears to be due to a combination of estrogen-induced insulin resistance and progestin-associated changes in insulin half-life.

PIP: Results of intravenous glucose tolerance tests on glucose, insulin, and C-peptide in women using combined and progestin-only oral contraceptives were analyzed by several computer models to dissect the effects of the steroids on insulin resistance, secretion, ad clearance. 391 subjects used monophasic, triphasic, or progestin-only oral contraceptives containing ethinyl estradiol and levonorgestrel, desogestrel or norethindrone. They consumed 200 g carbohydrate daily for 3 days, then fasted 12 hours before being tested between pill cycle Day 15-21 or menstrual cycle Day 21-27. Results of IVGTTs were analyzed for net glucose elimination constant; minimal model of glucose disappearance, to estimate insulin resistance; minimal model of posthepatic insulin delivery, for 1st and 2nd phase insulin response, insulin elimination constant and half-life. Pancreatic insulin secretion modeling also gave the fractional hepatic insulin throughput index, and elimination constants for insulin and C-peptide. There were significant differences in duration of oral contraceptive use, parity and age among study groups. The levonorgestrel combination increased glucose, insulin and C-peptide areas, the desogestrel combination increased only glucose and insulin areas, and the norethindrone combination only the glucose area. All combined pills, but not the norethindrone progestin-only pill, reduced the glucose elimination constant. Combined pills reduced insulin sensitivity 30-40%. Desogestrel increased insulin concentrations at the zero and 20 minute points, while levonorgestrel raised insulin after 30-45 minutes lasting for the rest of the 180-minute test. Levonorgestrel combinations increased 2nd phase pancreatic insulin secretion 60-90%, but did not change insulin half-life. The desogestrel combination increased insulin half-life 28%, but did not affect insulin secretion. Orals did not affect the hepatic insulin throughput index. The results suggest that estrogen causes insulin resistance, while progestins modify the response. Thus, the effects of oral contraceptives on oral ad intravenous glucose tolerance is similar, while insulin half-life varies with the progestin. It may be prudent to look for better estrogens or alternative routes to prevent estrogen-associated insulin resistance in contraceptive users.