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Understanding Hormone Action: Does Route of Administration Matter?
By Sarah L. Berga, MD, James Robert McCord Professor and Chairman, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, is Associate Editor for OB/GYN Clinical Alert.
Dr. Berga reports no financial relationship to this field of study.
Until recently, available information supported the notion that the transdermal route of administration of estradiol has less hepatic impact than the oral route. The basis of this contention was that the oral route of estradiol administration gave levels in the liver sinusoids that are 4-5 times higher than those found in the systemic circulation. Because the liver makes coagulation factors, an oral route of administration would elevate the risk of venous thromboembolism more than a transdermal route of administration. Indeed, the ESTHER (Estrogen and Thromboembolism Risk) Study Group found that the odds ratio (OR) for oral vs transdermal estrogen was 4.2 (confidence interval 1.5-11.6). Because the ESTHER Study was conducted in France, of 271 cases and 610 controls, only 2 cases and no controls took conjugated equine estrogen (Scarabin 2003, Canonico 2007). Most of the oral estrogen users took estradiol in doses ranging from 0.5 to 2.0 mg daily. Further, the mechanistic data on the impact of transdermal vs oral estradiol on hemostatic variables associated with venous thrombosis (Post 2003) support the observational epidemiological data. Women with prothrombotic mutations also display fewer thrombotic events when given transdermal vs oral estradiol (Straczek 2005). In aggregate, the data are consistent and supported the conclusion that the transdermal route of administration of estradiol minimizes the risk of venous thromboembolism when compared to the oral route.
Given the above considerations, the recent data showing that there was a more than two-fold increase in the venous thromboembolism rate (incidence rate ratio 2.2, CI 1.3-3.8) among women using transdermal ethinyl estradiol in a contraceptive patch as compared to women using an oral contraceptive containing 35 mcg of ethinyl estradiol are surprising (Cole 2007). Suffice it to say that this study has generated a lot of confusion over principles, particularly the understanding that route of administration of estrogen matters. However, the authors did not discuss the mechanisms that might explain this finding in the discussion. Should we abandon the notion that transdermal estrogen reduces the risk of venous thromboembolism when compared to the oral route of administration? How do we reconcile the observations in menopausal women with those obtained in younger women using contraceptives? Some have suggested that the contraceptive patch delivers a higher dose of ethinyl estradiol. But this explanation would only explain the higher risk of VTE in contraceptive patch users if route of administration did not matter for ethinyl estradiol. For the moment, the provisional conclusion has to be, then, that route of administration does not minimize the risk of VTE when the estrogen is ethinyl estradiol. This conclusion however only begs the next question.
Why would route of administration matter for estradiol and not ethinyl estradiol? Since ethinyl estradiol (EE) differs from estradiol only in the placement of an ethinyl group at carbon position 16, it is not immediately obvious that the route of administration should matter for estradiol and not for EE. However, one of the attributes that the addition of the ethinyl group confers is stability to degradation. This stability is partly conferred by the triple bond in the ethinyl group. Since the main site of degradation and metabolism is the liver, it stands to reason that both routes of administration maximally challenge the liver when the compound is EE. On a molar basis, EE has been estimated to be 400 fold more potent at the level of liver and only 100 fold more potent at the pituitary. There may be more to it than these considerations, but long story short, route of administration does appear to matter when the estrogen is the cognate ligand estradiol but not when the estrogen is ethinyl estradiol.