Using glucose tolerance tests or a glucose clamp some studies report impaired insulin sensitivity during the luteal phase of the menstrual cycle, while others find no change in insulin sensitivity. Tissue sensitivity to insulin and glucose effectiveness can be estimated using the minimal model analysis of an iv glucose tolerance test (IVGTT), but this method has never been applied to evaluate the impact of the menstrual cycle on these parameters. We, therefore, studied eight cycling women using tolbutamide-modified IVGTTs during three different phases of the same menstrual cycle: early follicular, midcycle, and midluteal. Insulin sensitivity (SI) and glucose effectiveness were derived using insulin and glucose levels obtained from tolbutamide-modified IVGTTs and analyzed with the minimal model computer program. The mean SI (x10(-4)/min.microU/mL) decreased in a stepwise fashion from the follicular level of 6.20 +/- 0.91 to a midcycle level of 4.95 +/- 0.73 and was lowest in the luteal phase (3.20 +/- 0.25; P less than 0.007). No change in glucose effectiveness occurred as a function of the menstrual cycle. These findings indicate a significant decrease in insulin sensitivity in the luteal phase of the normal menstrual cycle, but no significant change at midcycle.