Hypoandrogenemia is frequently associated with hyperinsulinemia in men with the metabolic syndrome. We questioned whether insulin or changes in blood glucose levels influence pituitary gonadotropin secretion or testicular steroidogenesis in healthy men. Also, the relationship between hypoglycemia-induced activation of the hypothalamus-pituitary-adrenal axis and altered steroidogenesis was examined. Euglycemic and hypoglycemic clamp experiments were performed in 30 healthy men over a period of 6 h. Half of the men were infused with insulin at a rate of 1.5 mU/min.kg; the other half were infused at a rate of 15.0 mU/min.kg. Plasma glucose was held constant during a euglycemic clamp session and was decreased stepwise in a hypoglycemic clamp session. LH and total/free T concentrations decreased under hypoglycemic conditions regardless of the rate of insulin infusion. With euglycemic conditions, LH and T levels remained unchanged. Dehydroepiandrosterone concentrations increased during hypoglycemia, but not during the euglycemic conditions. The FSH concentration was not affected by insulin or glycemic clamps. Hypoglycemia acutely suppresses T secretion, and this effect is apparently mediated by pituitary LH. Insulin is ineffective. As counterregulation to hypoglycemia begins at normoglycemic ranges in poorly controlled type 2 diabetes and probably also in patients with long-term perturbed glucose regulation in the metabolic syndrome, control of glucose-responsive neurons in the brain may contribute to hypoandrogenemia. Apart from down-regulation of hypothalamic release of GnRH, concurrent activation of the pituitary-adrenal axis (i.e. increased release of dehydroepiandrosterone) may add to the suppressive effect of hypoglycemia on gonadal steroidogenesis.