Effects of Injectable or Implantable Progestin-Only Contraceptives on Insulin-Glucose Metabolism and Diabetes Risk

Abstract

Progestin-only contraceptives administered by injection (Depo-Provera) or subcutaneous implant (Norplant) have been available to U.S. women for about a decade. Two epidemiological studies found their use associated with increased incidence of type 2 diabetes. In reviewing publications relating progestin injections and implants to glucose metabolism, 25 studies of various study designs and laboratory methods were identified that reported at least one insulin value in nondiabetic women. Research subjects were usually nonobese and often from developing countries. Of eight studies that performed sequential oral glucose tolerance tests (OGTTs) after at least 6 months of Depo-Provera or Norplant use, seven found significant elevations (approximate doubling) of insulin at 2 or 3 h after glucose challenge; the effects on fasting, half-hour, or 1-h postchallenge insulin values were less consistent. The three studies that performed sequential intravenous glucose tolerance tests (IVGTTs) on injection users all found an increased early-phase insulin response. One study used sequential hyperglycemichyperinsulinemic clamps to demonstrate reduced total-body glucose uptake per unit of insulin after 8 weeks of Norplant use. The metabolic studies generally did not show a reduction in the glucose tolerance of their nondiabetic subjects. However, compared with the lean and low-risk women who were usually selected for metabolic research, many U.S. women receiving these injections or implants may start out with increased insulin resistance due to greater weight, sedentary lifestyle, and family or childbearing histories. Additional research could help clarify whether exposure to injectable or implantable contraceptives leads to increased risk of type 2 diabetes and gestational diabetes in women with predisposing factors. Diabetes Care 26:216 -225, 2003I n the early 1990s two new modes of progestin-only hormonal contraception became available to women living in the U.S. The following decade has been notable for the emergence of type 2 diabetes among adolescent girls (more than boys) (1) and a rising prevalence of gestational diabetes (2). The temporal overlap of a diabetes increase among young women and availability of new contraceptive methods has stimulated us to review the published literature on insulinglucose metabolism in the presence of these hormonal agents.One new contraceptive mode was a depot injection containing 150 mg medroxyprogesterone acetate (DMPA, "Depo-Provera"). Administered by the intramuscular route, it delivers medroxyprogesterone at a plasma concentration of ϳ1 ng/ml (3). The DMPA injection must be repeated every 3 months for continuing contraceptive benefit. The other new mode was a system of six Silastic capsules, each containing 36 mg of the progestin levonorgestrel (LNG), designed for longterm subcutaneous insertion in the upper arm (LNG implant, "Norplant"). This implant system delivers LNG initially at ϳ85 g/day, declining gradually to ϳ30 g/ day (4). Serum concentrations of LNG decrease from ϳ0.35 ng/ml a...

Basal Insulin Requirements after Progesterone Treatment in a Type 1 Diabetic Pregnant Woman

“…Recent studies have shown a correlation between high progesterone levels and glucose intolerance (14,(16)(17)(18)(19)(20)(21)(22)(23). Exogenous progesterone decreases insulin sensitivity with the subsequent development of hyperglycemia in rodents (14,20), and the use of 17-OHPC to prevent recurrent preterm delivery is associated with an increased risk of developing glucose intolerance and gestational diabetes mellitus in humans (16,17).…”

The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial

“…A few studies have shown that medroxyprogesterone may have deleterious effects on glucose metabolism and diabetes incidence [3,4]. For example, a study of Navajo women who used depot medroxyprogesterone intramuscularly found that users were more likely to develop diabetes than patients who had used any type of oral combination oestrogen-progestin contraception (odds ratio=3.8, 95% CI 1.8-7.9) [3].…”

Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes

“…In addition, progesterone is one of the candidates possibly implicated in the insulin resistance during pregnancy. Epidemiological studies have revealed that administration of progestin for contraceptive usage is associated with increased incidence of type 2 diabetes (13). A hyperglycemic hyperinsulinemic clamp study showed that progesterone administration for 8 wk reduced whole body glucose uptake in humans (13).…”

“…Epidemiological studies have revealed that administration of progestin for contraceptive usage is associated with increased incidence of type 2 diabetes (13). A hyperglycemic hyperinsulinemic clamp study showed that progesterone administration for 8 wk reduced whole body glucose uptake in humans (13). Concerning the role of progesterone in insulin secretion, female progesterone receptor knockout mice demonstrated a reduced fasting blood glucose level with elevation of serum insulin by increased ␤-cell proliferation (26), indicating the possible relation of progesterone with ␤-cell proliferation and/or function.…”