In this randomized, open-label trial, 24 subjects were studied. There were 12 subjects with essential hypertension and 12 normotensive controls who received, after an initial control period, 48 h of treatment with a transdermal estradiol patch or ketoconazole tablets every 8 h for six doses, or in combination. LHRH (100 micrograms) and ACTH (250 micrograms) were given at 48 h of each treatment. Each treatment was one week apart. In both normotensive and hypertensive men ketoconazole reduced adrenal and gonadal androgens, raised 11-deoxycortisol and 17 alpha-hydroxyprogesterone levels; blunted the rise of cortisol to ACTH and had no effect on the response of LH to LHRH. Transdermal estradiol raised serum estradiol levels, blunted the time to peak plasma concentration of LH to LHRH and produced a normal response to ACTH. Although baseline level of total and free testosterone and DHEA-S were lower in hypertensive men, the response of the pituitary (LH) to LHRH and adrenal axis with ACTH were similar in both normotensive and hypertensive men. Blood pressure was unaffected by any of the treatment interventions in either normotensive or hypertensive men. Although ketoconazole or transdermal estradiol reduce androgens, there was no evidence that this reduction in androgens was involved with the short term regulation of blood pressure in hypertensive men.