Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol.

ABSTRACT

The pronounced hepatic impact of oral ethinyl estradiol has been attributed by some to its so-called first-pass effect through the liver as only some 40% of ingested ethinyl estradiol reaches the systemic circulation. Others believe that ethinyl estradiol exerts its hepatic effects because of its chemical composition, specifically its 17 alpha-ethinyl group. In an attempt to resolve this controversy, a study was undertaken to determine whether vaginal administration of ethinyl estradiol can selectively reduce the hepatic effects of oral ethinyl estradiol. To compare the effects of oral and vaginal ethinyl estradiol, a group of postmenopausal subjects received either 5 micrograms of oral and 20 micrograms of vaginal ethinyl estradiol or 10 micrograms of oral and 50 micrograms of vaginal ethinyl estradiol in either sequence, respectively. Oral ethinyl estradiol was four to five times more potent than vaginal ethinyl estradiol. The potency ratios of the oral-vaginal ethinyl estradiol doses required to suppress follicle-stimulating hormone and luteinizing hormone were 4.4 and 3.2 and those to raise sex hormone-binding globulin binding capacity, corticosteroid-binding globulin binding capacity, and high-density lipoprotein cholesterol as well as lower low-density lipoprotein cholesterol were 3.5, 5.0, 4.2, and 4.2, respectively. These essentially equal oral-vaginal route potency ratios for both central nervous system and hepatic effects indicate that vaginal administration of ethinyl estradiol does not selectively reduce its hepatic impact in relation to its central nervous system effects. The pronounced hepatic effects of ethinyl estradiol are therefore attributed to its chemical composition.

ABSTRACT

PIP This study assessed the bioavailability of vaginally administered ethinyl estradiol (EE) and determined the effects of 2 different doses of oral and vaginal EE of comparable bioavialability on serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations as well as on corticosteroid-binding globulin binding capacity (CBG-BC), sex hormone-binding globulin capacity (SHBG-BC), high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, and triglycerides. 5 healthly, regularly menstruating volunteers aged 26-31 years who used nonhormonal means of contraception participated in the initial phase in which bioavailability was assessed of EE in intravaginal suppositories containing 120 mcg of EE. 9 healthy postmenopausal women aged 48-67 years were randomly assigned to receive larger or smaller doses of oral and vaginal EE, each given over 25 consecutive days with a 6-week estrogen-free interval between. As a results of randomization, 2 subjects were given 10 mcg of EE orally followed by 50 mcg vaginally, 1 received 50 mcg vaginally followed by 10 mcg orally, 2 received 5 mcg orally followed by 20 mcg vaginally, and 4 received 20 mcg vaginally followed by 5 mcg orally. Oral EE was found to be 4 to 5 times more potent than vaginal EE. The potency ratios of the oral-vaginal EE doses required to suppress FSH and LH were 4.4 and 3. and those to raise SHBG-BG, and HDL cholesterol as well as to lower LDL cholesterol were 3.5, 5.0, 4.2, and 4.2, respectively. The essentially equal oral-vaginal route potency ratios for hepatic effects and central nervous system effects indicate that vaginal administration of EE is not associated with a lower hepatocellular effect of EE. It is therefore concluded that the pronounced hepatic effects or oral EE are attributable to its chemical composition, specifically its 17 alpha-ethinyl group, rather than to the 1st-pass effect through the liver.