Frank Z. Stanczyk, PhD

Departments of Obstetrics and Gynecology and Preventive Medicine University of Southern California Keck School of Medicine Los Angeles, CA.

Estrogens used to treat postmenopausal women are administered by oral and parenteral routes. The most commonly used parenteral routes include percutaneous (by patch, cream or gel) and intravaginal (by cream, gel, tablet, or ring). Each route of administration has advantages and disadvantages.

Two beneficial effects of oral estrogens that are commonly stated are ease of administration and an overall favorable impact on the lipoprotein profile. Ease of estrogen administration may be important in patient compliance when compared with other routes such as intravaginal adminis-tration. The lipoprotein profile is considered to be beneficial overall with oral estrogen because plasma low-density lipoprotein cholesterol levels decrease, whereas plasma high-density lipoprotein cholesterol levels increase.^1,2 These effects have been demonstrated in a number of studies, mostly with 0.625 mg conjugated equine estrogens (CEEs). However, despite the expected beneficial changes in lipoprotein profiles obtained in randomized, controlled trials, these changes were not accompanied by the anticipated decrease in cardiovascular risk.^3-5 The reasons for this discordance are unclear.

Disadvantages of oral estrogen use include the following: daily dosing, requirement of a relatively high dose compared with doses used parenterally, variation in intestinal absorption, alteration in hepatic proteins, increase in plasma triglyceride levels. Elevation of triglyceride levels with oral estrogen could be an important concern because elevated triglycerides are a well-recognized risk factor for cardiovascular disease. Women with hypertriglyceridemia may develop severe hyperlipemia on oral estrogen therapy,⁶ which may lead to serious adverse effects.

The effect of oral estrogen on hepatic first-pass metabolism may also be an important concern due to the alteration of estrogen-sensitive protein levels, as the highly concentrated estrogen in splanchnic blood is presented to the hepatocytes. A variety of proteins are altered; they include sex hormone-binding globulin (SHBG), corticosteroidbinding globulin (CBG), thyroid-binding globulin (TBG), inflammation markers, as well as markers of coagulation and fibrinolysis. The increases in SHBG, CBG, and TBG are dose dependent, resulting in corresponding decreases in the free fractions of the hormones that they bind, specifically free testosterone, free cortisol, and free thyroxine, respectively. The decreased levels of these hormones have an important clinical relevance. For example, there is a growing body of evidence suggesting that serum testosterone levels have an influence on the sexual functioning of naturally and surgically postmenopausal women. By reducing free testosterone levels, orally administered estrogen may affect sexual function adversely. Also, decreases in free cortisol may be problematic in women with adrenal disease. In addition, lower free thyroxine concentrations in women receiving thyroid replacement may require increases in the dose of thyroxine.

Acute and chronic manifestations of atherosclerosis are now considered by a growing number of investigators as a consequence of a chronic inflammatory process, and certain markers of this process are affected by oral estrogen. Proinflammatory proteins are synthesized by endothelial and smooth muscle cells of large arteries once they are activated by injury. Markers of inflammation in blood include vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), chemoattractant protein-1 (MCP-1), E- selectin, thrombomodulin, interleukin-6 (IL-6), tumor necrosis factor a (TNF-a), and C-reactive protein (CRP). Studies show that orally administered estrogens significantly increase blood levels of CRP, whereas the other inflammatory markers are significantly decreased.⁷ These findings support the view that the elevation of CRP by oral estrogen is likely a hepatic first-pass effect of the estrogen. It has been pointed out that elevated CRP may have deleterious effects on vascular inflammation and may contribute to the risk of myocardial infarction observed during the first year of treatment in some randomized and observational clinical studies.⁷ However, the uncertainties regarding the clinical significance of CRP levels make it premature to conclude that changes in these levels associated with hormone therapy have a direct clinical consequence.

Oral estrogen also affects hemostasis. Hemostasis is a highly complex process involving two separate but interlinked enzyme cascades, namely, the coagulation and fibrinolytic systems, which regulate the production and breakdown of fibrin, respectively, by checks and balances. The coagulation pathway is normally suppressed by inhibitors, of which tissue factor pathway inhibitor, antiprothrombin III, protein C, and protein S are among the most important. Release of the tissue factor pathway inhibitor initiates the process of coagulation by activating factor VII, which stimulates the conversion of prothrombin to thrombin. The latter protein is the catalyst for the fibrinogen-fibrin reaction. Results of the PEPI trial show that oral administration of 0.625 mg of CEEs results in a small but significant reduction in plasma fibrinogen levels in post-menopausal women.² This effect was not influenced by addition of medroxyprogesterone acetate (cyclic, 5 mg, or continuous, 2.5 mg) or micronized progesterone (cyclic, 200 mg). However, there is also evidence showing that the coagulation system is activated with oral estrogen. Oral administration of CEEs (0.625 or 1.25 mg) daily decreases levels of thrombin inhibitors, specifically antithrombin III and protein S, and increases indices of thrombin production in a dose-dependent manner.⁸ In contrast, there appears to be a beneficial effect of oral estrogen on the fibrinolysis system. The process of fibrinolysis, which involves the enzymatic degradation of fibrin and fibrinogen by plasmin, is initiated by activation of plasminogen to plasmin through the action of tissue plasminogen activator. The latter compound is inhibited by plasminogen activator inhibitor type 1. Studies show that oral CEEs decrease plasminogen activator inhibitor type 1 levels, suggesting an enhanced potential for fibrinolysis with oral estrogen.⁷

In addition to the pharmacodynamic effects resulting from the hepatic first pass of oral estrogen, profound pharmacoki-netic effects are also found. For example, following oral administration of 1 mg micronized estradiol (E₂) in post-menopausal women, serum levels of E₂ are approximately 30 to 50 pg/mL, whereas estrone (E¹) levels are several fold higher (150-300 pg/mL).⁹ In contrast, serum E¹ and E₂ levels achieved by the transdermal E₂ patch are similar, eg, approximately 30 to 65 pg/mL and 40 to 45 pg/mL, respectively, with the 0.05-mg patch.⁹ Another example is the markedly elevated serum levels of estrone sulfate (E1S) found after long-term oral estrogen treatment.¹⁰ After 7 and 15 months of oral treatment with 1 mg of micronized E₂ in postmenopausal women, mean serum E¹S levels as high as 24.9 ng/mL and 38.8 ng/mL, respectively, were obtained. Baseline serum E¹S levels were less than 0.8 ng/mL. Conversely, in the same study,¹⁰ mean serum E¹S levels were 1.8 ng/mL and 3.2 ng/mL after 9 months of treatment with the 0.05-mg/day and 0.1-mg/day patches, respectively. These levels are in the range observed in premenopausal women. Although the clinical relevance of the markedly elevated serum E¹S levels is not known, the high E¹S levels may contribute significantly to E₂ levels found in tissues, eg, the breast, because E1S can be readily converted by the sulfatase enzyme to E¹, which can then undergo transformation to E₂ through the action of 17β-hydroxysteroid dehydrogenase.

The oral route of estrogen administration may be especially problematic when treating elderly postmenopausal women, eg, older than 65 years of age, due to differences in pharmacokinetic responses to drugs between younger and older postmenopausal women.¹¹ Oral bioavailability of many drugs is increased in the elderly due to decreased hepatic first-pass metabolism, which results from a decrease in hepatic blood flow in conjunction with a reduction in hepatic drug-metabolizing capacity.¹² It has been shown that the cytochrome P-450 content of human liver specimens is gradually reduced between the ages of 40 and 69 years in women and men and is reduced by approximately 30% after age 70.¹³

Parenteral administration of estrogen also has advantages and disadvantages. One commonly cited disadvantage of the transdermal patch is that it causes local skin irritation. This is especially true of the membrane-based systems. However, the newer matrix dispersal systems do not possess alcohol and therefore are associated with a much lower incidence of skin reactions. Another commonly cited disadvantage of transdermal E₂ administration is that studies show little or no beneficial effect on the plasma lipid/lipoprotein profile with this route of estrogen delivery, in contrast to the oral route. However, as pointed out earlier, the expected beneficial effect of higher high-density lipoprotein cholesterol and lower low-density lipoprotein cholesterol levels in oral estrogen users has not been associated with reduced cardiovascular risk in randomized, controlled trials.^3-5

Undoubtedly, the most important benefit of parenteral routes of estrogen administration is the avoidance of disadvantageous pharmacokinetic and pharmacodynamic effects that may be produced during the hepatic first pass when estrogens are administered orally. Some of the pharmacokinetic differences between oral and transdermal routes of estrogen administration were noted earlier. As for pharmacodynamic differences, first of all, transdermal E₂ therapy has a negligible effect on SHBG, CBG, and TBG levels, in contrast to the large elevation of these globulins obtained with oral estrogen. Also, triglycerides are not increased by transdermal E₂ administration.^14-17 In addition, transdermal E₂ significantly lowers^18,19 or does not alter^20,21 CRP levels as well as decreases ICAM levels²² in healthy postmenopausal women. Furthermore, transdermal E₂ does not alter²³ or decrease²⁴ fibrinogen levels and does not affect factor VII.^20,23 Finally, no change in plasminogen activator inhibitor type 1 levels was observed after 1 month of treatment with a 0.1-mg E₂ transdermal patch,²⁵ whereas the levels were reduced after 1 year of treatment with a 0.05-mg E₂ patch.²³

The impact of the route of estrogen administration on venous thromboembolism (VTE) was studied recently in a multicenter case-control study involving postmenopausal women using oral or transdermal estrogen therapy.²⁶ A total of 271 consecutive cases with a first documented episode of idiopathic VTE and 610 controls, matched for center, age, and admission date, were recruited. The odds ratios for VTE, after adjustment for potential confounding factors, in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI: 1.5-11.6) and 0.9 (95% CI: 0.4-2.1), respectively. The authors concluded that oral but not transdermal estrogen was associated with an increased VTE risk.

Considering that there is a substantial number of estrogenic and progestogenic products used for treatment of postmenopausal women, there are insufficient comparative data on pharmacokinetic and pharmacodynamic effects between oral and parenteral routes of administration of these products. The study by Shifren et al²⁷ in this issue of Menopause adds to our knowledge of pharmacodynamic changes induced by oral versus transdermal estrogen therapy on serum binding globulins (SHBG, CBG, and TBG) in naturally postmenopausal women. The results confirm previous findings that show markedly elevated levels of these globulins with oral, but not transdermal, estrogen. More importantly, the present data show that as a consequence of elevations in the concentrations of the binding proteins, oral and transdermal estrogen therapies produce differential effects on total and free concentrations of testosterone, cortisol, and thyroxine. The authors conclude that from a clinical perspective, transdermal estrogen therapy may be preferable to oral estrogen therapy in maintaining free testosterone levels, having little effect on free cortisol levels and minimizing potential interactions with thyroid replacement therapy. A notable strength of the study is the overall sound methodology. Limitations of the study, eg, use of an open-label crossover versus placebocontrolled parallel group study and lack of a second withdrawal period, are well addressed by the authors. Another limitation is that the study is short term. Long-term placebo-controlled studies are needed to compare effects of estrogen treatment between oral and parenteral routes of administration not only on hepatic globulins but especially on markers of inflammation, coagulation, and fibrinolysis. The studies should include different types and doses of estrogen and different regimens when a progestogen is used. Data from such studies should provide us with valuable information about advantages and disadvantages of both routes of administration to allow optimal treatment of postmenopausal women.

---

References

Wahl P, Walden C, Knopp R, et al. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983;308:862-867. 

The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;2073:199-208. 

Shlipak MG, Chaput LA, Vittinghoff E, et al. Lipid changes on hormone therapy and coronary heart disease events in the Heart and Estrogen/progestin Replacement Study (HERS). Am Heart J 2003;146: 870-875. 

Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-534. 

Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712. 

Glueck CJ, Scheel D, Fishback J, Steiner P. Estrogen-induced pancreatitis in patients with previously covert familiar type V hyperlipoproteinemia. Metabolism 1972;21:657-666. 

Koh KK, Yoon B-K, Bairey-Merz CN, Sakuma I, Rebar RW. The effects of hormone therapy on inflammatory, hemostatic and fibrinolytic markers in postmenopausal women. In: Lobo RA ed. Treatment of the Postmenopausal Woman, 3rd ed. Burlington, MA: Academic Press, 2007:471-480. 

Caine YG, Bauer KA, Barzegar S, et al. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992;68:392-395. 

Barnes RB, Levrant SG. Pharmacology of estrogens. In: Lobo RA ed. Treatment of the Postmenopausal Woman, 3rd ed. Burlington, MA: Academic Press, 2007:767-777. 

Slater CC, Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ. Markedly elevated levels of estrone sulfate following long-term oral, but not transdermal, administration in postmenopausal women. Menopause 2001;8:200-203. 

Stanczyk FZ, Chaikittisilpa S, Roy S. Pharmacologic deficiency in Women’s Health Initiative study. JReprodMed 2003;48:485-486. (Letter). 

Tsujimoto G, Hashimoto K, Hoffman BB. Pharmacokinetic and pharmacodynamic principles of drug therapy in old age. Part 1. Int J Clin Pharmacol Ther Toxicol 1989;27:13-26. 

Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 1997;61:331-339. 

Elkik F, Compel A, Mercier-Bodard C. Effects of percutaneous estradiol and conjugated estrogens on the level of plasma proteins and triglycerides in postmenopausal women. Am J Obstet Gynecol 1982;143:888-892. 

Basdevant A, De Lignieres B, Guy-Grand B. Differential lipemic and hormonal responses to oral and parenteral 17beta-estradiol in postmenopausal women. Am JObstet Gynecol 1983;147:77-81. 

Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N Engl J Med 1986;314:1615-1620. 

De Lignieres B, Basdevant A, Thomas G, et al. Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab 1986;62:536-541. 

Sattar N, Perera M, Small M, Lumsden MA. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet 1999;354:487-488. 

Modena MG, Bursi F, Fantini G, et al. Effects of hormone replacement therapy on C-reactive protein levels in healthy postmenopausal women: comparison between oral and transdermal administration of estrogen. Am J Med 2002;113:314-331. 

Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001;85:619-625. 

Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoidplacebo trial in healthy women. Circulation 2002;106:1224-1228. 

Koh KK, Bui MN, Mincemoyer R, Cannon RO III. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. Am J Cardiol 1997;80:1505-1507. 

Post MS, van der Mooren MJ, van Baal WM, et al. Effects of low-dose and transdermal estrogen replacement therapy on hemostatic factors in healthy postmenopausal women: a randomized placebo-controlled study. Am J Obstet Gynecol 2003;189:1221-1227. 

Zegura B, Keber I, Sebestjen M, Koenig W. Double blind randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis. Atherosclerosis 2003;168:123-129. 

Koh KK, Mincemoyer R, Bui MN, et al. Effects of hormone-replacement therapy on fibrinolysis on postmenopausal women. N Engl J Med 1997; 336:683-690. 

Canonico M, Oger E, Plu-Bureau G, et al. for the Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840-845. 

Shifren J, Desindes S, McIlwain M, Doros G, Mazer N. A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women. Menopause 2007;14:985-994.