The effect of sublingual administration of 2 mg of micronized estradiol-17 beta (E2) on circulating concentrations of estrone (E1), E2, luteinizing hormone, and follicle-stimulating hormone was evaluated. Six women were studied during the early follicular phase, along with 3 hypogonadal women. Absorption of E2 was extremely rapid with a respective 9-fold and 41-fold increase over basal serum levels within 30 minutes. However, for most of the 24-hour period studied, E1 rather than E2 was the predominant circulating estrogen. Although physiologic levels of E2 can be maintained, it would appear that the sublingual route is not ideal for E2 replacement, as concomitant superphysiologic elevation of circulating E1 occurs.