Differences in gender are in part responsible for the development of insulin resistance and associated hypertension. Currently, it is unclear whether these differences are dictated by gender itself or by the relative changes in plasma estrogen and/or testosterone. We investigated the interrelationships between testosterone and estrogen in the progression of insulin resistance and hypertension in vivo in intact and gonadectomized fructose-fed male rats. Treatment with estrogen significantly reduced the testosterone levels in both normal chow-fed and fructose-fed rats. Interestingly, fructose feeding induced an increase in estradiol, which did not affect insulin resistance in both intact and gonadectomized fructose-fed rats. However, increasing the estrogen concentration improved insulin sensitivity in both intact and gonadectomized fructose-fed rats. In intact males, fructose feeding increased the blood pressure (BP) (F-140±2 mmHg), which was prevented by estrogen (FE). However, the BP in these rats (FE-125±1 mmHg) was significantly higher than that of normal chow-fed (C-113±1 mmHg) and fructose-fed gonadectomized rats. Estrogen treatment did not affect the blood pressure in gonadectomized fructose-fed rats (GFE-105±2 mmHg). These data suggest the existence of a threshold value for estrogen below which insulin sensitivity is unaffected. The development of hypertension in this model is dictated solely by the presence or absence of testosterone. In summary the development of insulin resistance and hypertension are governed not by gender per se, but by the interactions of specific sex hormones such as estrogen and testosterone.