To assess the role of growth hormone (GH) secretion in causing the deleterious effect of oral contraceptive agents (OCA) on carbohydrate metabolism, tolbutamide tolerance tests were performed on 13 normal females and 8 hypopituitary women on thyroid and glucocorticoid replacement before starting and 3 and 6 months after taking OCA. After a combined oral agent, the normal subjects showed no change in fasting glucose, free fatty acid (FFA), and insulin concentrations, but did manifest (after resting 45–60 min) marginally increased fasting GH and, as expected, glucocorticoid levels. There was a significant impairment of the glucose fall and an enhancement of both GH response and FFA recovery following tolbutamide. Although the insulin response was unchanged after OCA, the responses in the same subject on three separate tolbutamide tests were significantly correlated with each other. This suggests that the quickly releasable pool of insulin remains constant in a single individual and is unaffected by OCA. There was no GH response in the 8 hypopituitary patients after tolbutamide. OCA did not change the fasting glucose, FFA, insulin, or GH concentrations, but glucocorticoid levels increased in the 2 patients in whom it could be measured. In contrast to the normal subjects, tolbutamide tolerance was not affected by OCA in the hypopituitary patients. FFA and insulin responses were similarly unaffected. Five additional normal female subjects on a variety of combined OCA had a significantly increased GH response (mean ± SEM) to a moderate amount of exercise (2 flights of stairs) compared to 5 normal women using other means of contraception (16.4 ± 3.5 vs 5.0 ± 1.9, p <0.025). This suggests that women on these agents are exposed to higher levels of GH throughout most of the day. It is concluded that estrogen enhancement of GH secretion is the mechanism whereby OCA cause glucose intolerance.