Current status and future prospects of transdermal estrogen replacement therapy

FERTILITY AND STERILITY Copyright e 1990 The American Fertility Society Vol. 53, No.6, June 1990 Printed on acid-free paper in U.S.A. Current status and future prospects of transdermal estrogen replacement therapy Katherine Miller-Bass, M.D. Eli Y. Adashi, M.D. Division of Reproductive Endocrirwlogy, Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, Maryland Transdermal administration of drugs is not new. Babylonian clay tablets from around 600 B.C. give recipes for extracts of herbs mixed with oil and honey that were then rubbed on the stomach of the patient for cure of colic. 1 Although pharmacologic therapy has come a long way since then, there are currently only four drugs approved by the Food and Drug Administration for transdermal administration-scopolamine, nitroglycerin, clonidine, and, most recently, 17,8-estradiol (referred to herein as estradiol [E2]). The scopolamine patch was the first transdermal therapeutic system designed 2 and the others quickly followed. With the development and marketing of Estraderm (transdermal system; Ciba-Geigy Pharmaceutical Co., Summit, NJ), a new route of estrogen-replacement therapy has become available to the obstetrician-gynecologist, and a body of literature pertaining to its use and potential advantages and disadvantages has developed over the past several years. It is the objective of this communication to critically review the literature available, as well as to assess the current and future status oftransdermal E 2 therapy. "Ideal" Estrogen Replacement Therapy: The Concept Versus Reality In designing an optimal form of estrogen replacement for postmenopausal women, the following criteria would have to be met: First, and foremost, such a regimen should return the hormonal milieu, as nearly as possible, to the state that existed before loss of ovarian function. Although not absolutely necessary, the estrogen in question should ideally provide primarily E 2, the major estrogen of the reproductive years, and in amounts capable of maintaining E2 levels within the premenopausal (early follicular) range. Accordingly, the delivery of estrone (E1), or the metabolism ofthe replacement estrogen to E 1, should be such that the ratio of circulating E 2 to E 1 remains at the premenopausal level of;;:: 1. 3 Second, E 2 should be delivered in a sustained controlled fashion, in a manner resembling normal ovarian secretory patterns. Third, the amount of E 2 provided should be sufficient to alleviate vasomotor symptoms, reverse atrophic vaginal changes, prevent osteoporosis, and provide cardioprotection. Significantly, only minimal alteration of hepatic protein synthesis should occur, thereby presumably reducing the incidence of undesired side-effects of estrogen therapy. Finally, the estrogen should be administered in a form that is acceptable to the patient, easy to use, not painful or "messy", free of noticeable side-effects, and with a dosage schedule that is simple to follow. :Keeping these requirements in mind, Table 1 lists various routes of estrogen replacement. A brief review of currently available estrogen preparations follows. As will become apparent below, none of the preparations currently available truly constitutes an ideal form of estrogen replacement therapy. However, much progress has been made to a point that gives rise to the hope that idealized estrogen replacement can perhaps be approximated if not actually realized. ROUTES OF ESTROGEN REPLACEMENT Oral Estrogen-Replacement Therapy Traditionally, estrogens used for replacement therapy in postmenopausal women have been given Vol. 53, No.6, June 1990 Miller-Bass and Adashi Transdermal estrogen replacement therapy 961

Table 1 Routes of Estrogen Replacement Oral" Vaginal" Subcutaneous implants Percutaneous Sublingual Intranasal Injectable Transdermal" Indicates forms currently commercially available in the United States. orally. The commonly used preparations, and their standard daily doses, are listed in Table 2. A major disadvantage of oral estrogen replacement, regardless of brand, is immediately evident. Single daily doses result in the delivery of a large bolus of medication, with a gradual decline in blood levels until the next dose is provided. This mode of delivery is in stark contrast to the continuous sustained supply characteristic of ovarian estrogen secretion. Thus, on intuitive grounds alone, all oral estrogen replacement regimens are less than ideal in this regard. Moreover, this form of drug delivery inevitably results in the virtually direct provision of pharmacologic amounts of biologically potent estrogen to the liver, a situation foreign to normally-cycling women whose ovarian-derived estrogens are diluted in the peripheral circulation before reaching the liver at acceptable physiologic concentrations. This "first-pass" effect occurs when oral estrogens are delivered to the liver via the portal circulation after absorption from the intestines, without the benefit of prior metabolism. Significantly, many of the potential deleterious side-effects of estrogen replacement therapy (e.g., hypertension, cholelithiasis) are thought to result from this so-called firstpass phenomenon. 4 5 At first sight, it would therefore appear that alternate, that is, nonoral routes of estrogen administration should reduce the incidence of deleterious side-effects. However, the cardioprotective effect of estrogens may well be, at least in part, the result of this very first-pass phenomenon, presumably through favorable alteration of hepatic lipoprotein biosynthesis. 6 7 Indeed, the increased high-density lipoprotein cholesterol (HDLC) and decreased low-density lipoprotein cholesterol (LDLC) pattern seen in estrogen-users is the lipid pattern associated with a decreased risk of cardiovascular disease. 8 Thus, the favorable effects of oral conjugated equine estrogens on lipoprotein levels could account for the reported cardioprotective effect attributed to oral estrogen administration. In this particular respect, bypassing the liver by using nonoral forms of estrogen therapy may prove to be less than optimal, potentially depriving the patient of cardioprotection. While the above issues are far from resolved at this time, they do serve to demonstrate the difficulties associated with the evaluation of different routes of estrogen replacement. Consequently, the relative utility of oral estrogen replacement therapy as opposed to parenteral forms of treatment remains unclear pending further investigation. Premarin (Wyeth-Ayerst Laboratories, Philadelphia, PA), or conjugated equine estrogens, consists of several estrogen conjugates, primarily E 1 sulfate (>40%) and equilin sulfate (Table 3). This mixture of estrogenic conjugates is derived from the urine of pregnant mares, and as such, represents naturally-occurring estrogens. Sources within the pharmaceutical community estimate that Premarin accounts for approximately 70% of estrogen products sold in the United States. 9 Premarin has been used extensively for estrogen replacement therapy for many years, and its predictable actions have led to its continued use in a variety of situations. Significantly, a large body of literature has been devoted to the study of Premarin, its pharmacokinetics, dose requirements, efficacy, and side-effects. As such, it represents the "gold standard" against which all new preparations are measured. At doses of ~1.25 mg/d, conjugated equine estrogens have been shown to raise serum E 2 levels into the premenopausal early follicular range of 40 to 60 pg/ml 3 at 24 hours after the first dose, and to revert vaginal cytology to a premenopausal state. 4 Although Premarin (~1.25 mg/ d) has been shown to decrease the number of subjectively determined hot flashes, these data are difficult to interpret because of the fact that patients experienced significant symptomatic relief on placebo as well. 10 11 Furthermore, daily doses of 0.625 mg of Premarin have been conclusively shown to reduce postmenopausal bone loss. 12 Importantly, conjugated equine estrogens are subject to considerable enterohepatic metabolism before entering the bloodstream in a usable form. Thus, E 1 sulfate and other estrogen conjugates contained Table 2 Commonly Used Oral Estrogens Preparation Conjugated equine estrogens Piperazine estrone sulfate Micronized 17 -{J estradiol 17-01 ethinyl estradiol Brand Pre marin Ogen Estrace Estinyl Dose mg 0.625 to 1.25 0.625 to 1.25 1.0 to 2.0 0.01 to0.02 962 Miller-Bass and Adashi Transdermal estrogen replacement therapy Fertility and Sterility

Table 3 Constituents of Premarin (Conjugated Equine Estrogens) Constituent Estrone sulfate Equilin sulfate 17 a-dihydroequilin sulfate Miscellaneous estrogenic conjugates Values are percents. Representation 48 26 15 11 in this preparation undergo deconjugation and reconjugation to glucuronide and sulfate forms in the intestinal mucosa. The conjugated forms are excreted in the urine and the bile, whereas the deconjugated forms are delivered to the liver via the portal circulation where some conversion of E1 to E 2 takes place.13 14 However, the resulting E 1 levels are significantly higher than those found in premenopausal women, 3 resulting in an E 2 to E1 ratio that is <1, rather than the normal premenopausal ratio of~l. In light of the above, the oral administration of pure E 2 might seem to be the means to overcome the difficulties arising from the administration of a mixture of estrogen conjugates. If given in purified but unmodified form, however, E 2 is poorly absorbed intestinally, rendering small doses ineffective; large doses can lead to gastrointestinal upset.15 This problem has been overcome, to some extent, by the process of micronization wherein the crystal particle size is reduced, thereby increasing its surface area and thus intestinal absorption.15 A single oral dose of 2 mg of micronized E 2 (Estrace; Mead Johnson Laboratories, Evansville, IN) has been demonstrated by Yen and associates16 to significantly elevate serum E 2 concentrations above baseline within 2 hours of administration. Levels well within the premenopausal range are achieved with this standard daily dose.3 16 17 Oral micronized E 2 (2 mg/d) has also been shown to reduce the number of subjectively recorded hot flashes in postmenopausal women.15 18 Thus, micronized E 2 (Estrace) appears, at first glance, to be an appealing alternative to conjugated equine e~trogens. After all, E 2 is the primary ovarian estrogen of the reproductive years, and if given in a relatively pure form might be expected to constitute an ideal form of estrogen replacement therapy. Unfortunately, a series of relative drawbacks results in Estrace falling short of this goal. First, orally-administered Estrace, like oral Premarin, undergoes metabolism in both the gut and the liver. In fact, significant conversion ofe 2 to E 1 by 17/3-hydroxysteroid dehydrogenase (17/3-HSD) occurs in the mucosa of the small bowel.16 Some of the remaining E 2 is subject to a similar fate once it is delivered to the liver via the enterohepatic circulation. Estradiol is also subject to subsequent conjugation to sulfate and glucuronide forms in both the liver and the intestinal mucosa. A large proportion of these conjugates is excreted in the bile, reabsorbed, deconjugated in the intestine, and delivered again to the liver, where conversion to E 2 and E1 takes place.13 14 17 Thus, despite the fact that only E 2 is administered, high serum levels of E1 are still the result.16 Specifically, a fourfold increase in the circulating levels of E1 was noted 6 hours after an oral dose (2 mg) of micronized E/6 (Fig. 1). Second, although oral Estrace has proven efficacious in the relief of subjective menopausal symptoms such as sweating and hot flashes, its efficacy in the prevention of osteoporosis and cardiovascular disease has not been studied in a systematic fashion. In fact, the vast majority of patients enrolled in studies concerning cardiovascular risk have been using conjugated equine estrogens as their form of replacement therapy.19 Consequently, direct parallels cannot be drawn with respect to cardiovascular risk in Premarin and Estrace-users. In conclusion, despite its attractiveness as a naturally-occurring estrogen, orally administered Estrace suffers from a number of drawbacks that render it a less-appealing alternative (to oral Premarin therapy) than one might initially suppose. Ethinyl estradiol (EE 2) (Estinyl; Schering Corporation, Kenilworth, NJ) is a synthetic estrogen preparation commonly used as a constituent of combination oral contraceptives (OCs). Biologic effects associated with doses of 10 Jtg/d of EE 2 appear to be similar to the effects of 1.25 mg/d of conjugated estrogens.5 However, the lowest commercially available dose is a 20 Jlg tablet. In a manner similar to orally-administered E 2, EE 2 undergoes conjugation to sulfate and glucuronide forms in the intestinal mucosa and liver. Deconjugation andreconversion to E1 and E 2 occur, and again, as with micronized E 2, result in elevated E1 levels. Ethinyl estradiol is eliminated more slowly from the circulation when compared to E 2, and unlike E 2, its metabolites appear to be excreted in the feces rather than in the urine. 14 Vaginal Estrogen Replacement Therapy Vaginally administered estrogen preparations represent one form of estrogen therapy that might Vol. 53, No.6, June 1990 Miller-Bass and Adasbi Transdermal estrogen replacement therapy 963

ORAL VAGINAL Hours Hours Figure 1 Percent change in serum E 2 and E 1 levels after oral and vaginal administration of micronized 17~-estradiol. (Adapted from Yen SSC et al. 16 Reproduced by permission of the publisher.) be expected to bypass the liver and eliminate firstpass metabolism. Currently available vaginal creams are listed in Table 4. The rich vascularization of the vagina, as well as the thinning of the vaginal epithelium that occurs after menopause may aid in the absorption of medications administered vaginally. In fact, vaginal absorption of estrogen is greater in menopausal than in premenopausal women. 20 In contrast to the oral route of administration, wherein E 2 is converted, in large part, to E 1 by 17 {3-HSD in the intestinal mucosa, the vaginal route appears to allow absorption of unmodified E 2 through the (presumptively 17{3-HSDdeficient) vaginal mucosa. Once circulating, some peripheral conversion ofe2 to E 1 will, of course, occur, leading to some elevation of plasma E 1 levels. While this elevation is statistically significant, it does not begin to approach the magnitude of the rise in E 1 levels seen after oral administration of E 2 21 Thus, when E 2 is administered vaginally, the E 2-to-E 1 ratio will remain within the premenopausal range of ~1 (Fig. 1). Using vaginal doses of 0.2 or 2 mg of E 2, Rigg et al. 22 demonstrated significant elevation of the circulating levels of E 2 over baseline, with maintenance of E 2-to-E1 ratios at ~ 1. Hepatic effects were not studied. In contrast, hepatic effects resulting from the vaginal administration of both EE 2 and conjugated equine estrogens have been evaluated. Regrettably, vaginal preparations have not been as successful as might have been hoped in eliminating enhanced liver protein synthesis. While Mandel et al. 20 found significant increases in hepatic protein synthesis only at relatively high doses (1.25 mg and 2.5 mg per day) of vaginally-administered conjugated equine estrogens, such doses were necessary to raise E 2 concen- Table 4 Commonly Used Vaginal Estrogens Preparation Brand Estrogen content/ gram of cream Application schedule Conjugated equine estrogens 17~-estradiol Dienestrol Piperazine estrone sulfate Premarin vaginal cream Estrace DVcream Ogen vaginal cream mg 0.625 1. 0.1 1.5 2 to 4 g/d 3g/wk 6to 18g/wk 2 to 4 g/d 964 Miller-Bass and Adashi Transdermal estrogen replacement therapy Fertility and Sterility

trations to levels similar to those found in premenopausal women in the early follicular phase. In addition, Goebelsmann et al.23 showed that because of the decreased bioavailability of vaginally-administered EE2, vaginal doses must be three to five fold higher than oral doses to achieve similar suppression of luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels. Unfortunately, liver protein synthesis was significantly increased at these dosages, thus eliminating one of the potential advantages of vaginal administration. However, vaginal cytology has been shown to revert to the premenopausal state after vaginal administration of conjugated equine estrogens at doses as low as 0.3 mg/d,20 an effect associated with only minimal elevations of serum E1 and E2. It would thus appear that vaginal estrogen creams are best used for the reversal of atrophic vaginal changes at doses that are low enough to avoid undesirable systemic side-effects. Vaginal rings that provide continuous E 2 delivery over a period of weeks have been studied and used in some postmenopausal patients for shortterm (3 months) estrogen replacement therapy_i? They appear to maintain E 2 levels within the premenopausal range during use. 17 '24 They are, however, somewhat inconvenient to use, as they must be removed before intercourse. Moreover, these rings are not commercially available at this time. Subcutaneous E 2 Implants In theory, biodegradable subcutaneous E2-containing implants should provide constant and adequate E2 release. These expectations have in fact been met as sustained and controlled release of E 2 using these implants has been demonstrated. 25-27 Disadvantages of subcutaneous E2 implants consist of the initial need for a minor surgical procedure to implant the E 2 pellet under the skin, the consequent difficulties associated with pellet removal should the patient or physician elect to discontinue therapy, the unpredictable duration of reliable estrogen release/7 and the wide variation in E2 levels between patients.26 However, long-term follow-up (6 months) of patients after the subcutaneous implantation of two 25 mg E2 pellets has shown fairly constant serum E2 levels (mean 113 pg/ml) as early as 1 week after initiation of therapy.27 Again, such E2-containing pellets are not commercially marketed at present. Percutaneous E2 Estradiol in ointment form is available in Europe under the trade name Oestrogel (Besins-Iscovesco, Paris, France), and is administered by applying a dose containing 1.5 or 3 mg of E 2 over the abdomen every other day.17 This preparation has the advantage of bypassing hepatic metabolism, and results in a premenopausal E2-to-E1 ratio,28 but can yield extremely variable E2levels some hours after application.17 29 It is also somewhat cumbersome, as the gel must be spread oyer a large area of skin and allowed to dry before normal activities can be resumed. Sublingual, Intranasal, and Injectable Estrogens Mentioned only for the sake of completeness, both sublingual and intranasal micronized E2 preparations have been used for research purposes. Sublingual administration yields highly variable serum E2 levels, perhaps because of partial swallowing of the medication by the patient, with subsequent hepatic metabolism.17 Neither preparation is commercially available. Premarin for either intramuscular or intravenous injection is available in the United States but appears to be used primarily when oral therapy cannot be used, or in emergency situations. Transdermal Drug Administration Parenteral delivery of E 2 via a transdermal therapeutic delivery system appears to overcome many of the pitfalls noted with other modes of nonoral estrogen replacement. The general benefits of transdermal drug delivery have been well-summarized by Guy et al., 30 and include such attributes as maintenance of a relatively constant drug level within the circulation, lower overall drug dose, reduced frequency of drug dosing, and ease of termination of drug delivery by removal of the system. Additionally, the system is designed so as to control the rate of drug delivery and to minimize variable absorption between patients because of skin differences, such as color or hydration. Whereas there is some evidence to indicate that skin differences have led to differential absorption of transdermal nitroglycerin, 31 there is currently no data to indicate comparable problems with Estraderm (Ciba Geigy Pharmaceutical Co., Summit, NJ) use. The type of estrogen used for replacement therapy may be as important as the route of delivery. In a study designed to examine organ extraction of different classes of estrogens from the circulation, Steingold et al. 32 showed that all classes of estrogens are preferentially taken up by the liver when compared to other tissues (brain and uterus). How- Vol. 53, No.6, June 1990 Miller-Bass and Adashi Transdermal estrogen replacement therapy 965

Pharmacokinetics of Transdermal E 2 Figure 2 Estraderm transdermal therapeutic system (Reprinted with permission of Ciba-Geigy Pharmaceuticals, Summit, NJ). ever, oral conjugated estrogens, primarily E 1 sulfate, are poorly taken up by nonhepatic tissues, and must be deconjugated in the liver to be able to exert significant extrahepatic effects. Estradiol, on the other hand, while being preferentially taken up by hepatocytes, can act on other tissues without prior hepatic metabolism. Thus avoiding first-pass metabolism to inactive compounds by the liver will leave significantly more active E 2 available to these tissues. It appears, therefore, that E 2 may be the ideal estrogen for nonoral administration. Estradiol Transdermal Therapeutic System Like most transdermal delivery systems, an Estraderm patch consists of several layers (Fig. 2). The outermost layer, a backing membrane, serves to hold the contents within the reservoir and serves as a waterproof covering for the system. Underneath it lies the drug reservoir that contains E 2 dissolved in alcohol (ethanol). An alcohol, rather than an aqueous solvent, is used because E 2 is approximately 100,000 times more soluble in alcohol than in water. Below the reservoir is the control membrane, a plastic film that controls the rate of both alcohol and E 2 diffusion out of the reservoir and into the next layer, the adhesive layer. Not only does this latter layer serve to hold the entire system in place on the patient, but in concert with the overlying control membrane, acts as a further determinant of the rate at which E 2 leaves the system to come into contact with the skin. In effect, the two layers (control membrane and adhesive layer) act like a pair of electrical resistors in series to control the rate of E 2 diffusion from the reservoir. 33 The bottom layer is simply a protective liner that is removed before application. The E 2 contained in the reservoir is delivered at a relatively constant rate through the control membrane. 3 Two systems are currently available on the market, measuring 10 cm 2 and 20 cm 2 and delivering 0.05 mg and 0.10 mg of E 2/d, respectively. The system is applied to the lower abdomen or buttocks, and changed twice weekly, as recommended by the manufacturer. Although the pharmacokinetics of Estraderm have not been extensively studied, Powers et al. 3 have compared delivery rates and steady-state levels of E 2 after administration of oral and transdermal E 2 Using Estraderm systems delivering 0.025, 0.05, and 0.10 mg/d, these investigators demonstrated (within 4 hours of patch application) serum E 2 levels of approximately 30 pg/ml for the 0.025 mg patch, and 70 and 100 pg/ml for the 0.05 and 0.10 mg patches, respectively. Peak circulating E 2 levels were reached at about 8 hours after patch application, and steady-state levels during a single 72-hour wearing period were maintained at 40 and 75 pg/ml for the 0.05 and 0.10 mg/d patches, respectively. Significantly, these E 2 levels are well within the normal range for premenopausal women in the early follicular phase. 3 In addition, longerterm evaluation (i.e., 3 weeks of wearing the 0.05 mg/d Estraderm systems) revealed mean serum E 2 levels of 37.6 pg/ml, a value that was, again, similar to that seen in the early follicular phase of premenopausal women. 3 Daily measurement of urinary E 2 conjugates revealed average levels comparable with those produced during the follicular phase of premenopausal subjects-1, 2, and 4 1-Lg/g of creatinine for 0.025, 0.05, and 0.10 mg/d of Estraderm, respectively. Using a 0.10 mg/d patch, Stancyzk et al. 27 demonstrated mean serum E 2 levels of 52 to 89 pg/ml over a 24-week period, similar to the levels noted by Powers et al. 3 over a 72-hour wearing of the 0.10 mg/d patch. Additional information regarding the absorption oftransdermal E 2 immediately after patch application has been published by Haas et al. 34 Hourly E 2 levels obtained during the 8 hours after application of a 0.05 mg patch revealed peak serum levels of 91 pg/ml at only 2hours after application. A statistically significant decrease in mean serum E 2 levels (from 88 pg/ml to 48 pg/ml) was observed 8 hours after removal of the patch. This level was, however, still significantly greater than serum E 2 levels noted in patients who received placebo only. Since the above studies represent the only detailed studies of the pharmacokinetics of Estraderm presently available, a number of questions concerning Estraderm absorption remain unanswered. As mentioned before, skin differences, specifically racial differences, have been shown to affect absorption. Indeed, the overall absorption of transdermal nitroglycerin was reduced in black as compared with white subjects. 31 This phenomenon 966 Miller-Bass and Adashi Transdermal estrogen replacement therapy Fertility and Sterility

is probably because of differences in the thickness of the stratum corneum, which is the rate-limiting layer of the epidermis in transcutaneous absorption. Significantly, this skin layer is particularly thick in blacks. Given that some 12% of females entering the menopause will be black, this difference in stratum corneum thickness could conceivably affect rates of Estraderm absorption in this population. Moreover, both patient age and site of drug application have been reported to alter transdermal absorption of medications.35 However, Schenkel et al.,36 using urinary E 2 excretion as a measure of E2 uptake from 0.025 and 0.05 mg/ destraderm patches, found no statistically significant differences in E 2 absorption when patches were applied to several skin sites-abdomen, lateral thorax, buttocks, lower back, or upper arm. Only placement of the patches on the upper thigh resulted in significantly decreased absorption (85%) when compared with the abdominal site (100%). These and related issues are thus likely to benefit from closer scrutiny. Effects of Estraderm on Circulating Estrogen Levels There seems to be no disagreement in the literature in regard to the ability of Estraderm (~0.05 mg/d) to ensure serum E2 levels typical of those seen in premenopausal women in the early to midfollicular phase.37-39 As noted earlier, steady-state E2 levels of approximately 40 to 75 pg/ml are maintained during the 72-hour wearing periods of the 0.05 mg and 0.10 mg/d patches.3 38 39 These steady-state values are similar to those seen 24 hours after the third daily oral dose of Premarin 1.25 mg or Estrace 2 mg, for which the levels attained are 31 and 66 pg/ml, respectively. However, in contrast to the marked increase in serum E1levels seen with oral estrogen administration (increased from pretreatment values of approximately 30 to 35 pg/ml to steady-state values of 150 to 334 pg/ml), Estraderm administration resulted in only minor elevations in serum E1, with levels reaching the 30 to 60 pg/ml range for both the 0.05 and 0.10 mg/d patches.3 34 37-39 These minor increases probably reflect minimal in situ conversion of transdermal E 2 by skin as well as limited systemic metabolism, resulting in the maintenance of a premenopausal E2/E1 ratio of ~1P Effects of Estraderm on Serum Gonadotropin Levels Serum FSH and LH have been shown to decrease to levels that are significantly different from postmenopausal baseline values after the administration of Estraderm at both the 0.05 and 0.10 mg/d doses.3 37 38 A decrease in serum LH levels occurs as early as 5 hours after application in patients using a 0.05 mg/ d patch and levels that are statistically significantly lower than those seen in patients using placebo are observed within 8 hours. 34 The decreases seen with the 0.05 mg/d patch are equivalent to those produced by the daily oral administration of either 0.625 mg Premarin38 or 2 mg micronized E2.3 The 0.1 mg/d patch is approximately equivalent to 1.25 mg/d of oral Premarin in terms of gonadotropin suppression.15 None of the estrogen preparations studied, oral or transdermal, proved capable of suppressing serum FSH or LH to premenopausal levels at any dose.3 38 This incomplete gonadotropic suppression is thought to reflect the fact that other ovarian factors, such as progesterone40 and inhibin,41 may be necessary for more complete negative feedback on gonadotropin release. Effects of Estraderm on Vasomotor Symptoms From the patient's point of view, the most important result of estrogen replacement therapy is the amelioration of symptoms, especially hot flashes. Standard doses of Estraderm have been shown to reduce the number of subjectively and objectively measured hot flashes. Steingold et al.42 demonstrated a significant reduction in the number of objectively documented hot flashes in postmenopausal women treated with transdermal E2 at doses of ~0.05 mg/d. Hot flashes were measured over a 10-hour period by continuous monitoring of finger temperature and skin resistance, hot flashes being defined as notation of subjective symptoms by the patient occuring within 5 minutes of an objectively measured increase in skin temperature of > l.ooc and a decrease in skin resistance. Interestingly, a linear reduction in the number of hot flashes per hour was noted with increasing doses of E 2 provided by the Estraderm patch. This decrease was statistically significant for patients using a system providing ~0.05 mg/d.42 Based on a linear regression analysis of hot flashes/h versus circulating levels of E 2 achieved, the authors predicted that E2 levels of around 60 pg/ml should yield a 50% reduction in hot flashes, whereas levels of 122 pg/ml would be expected to completely abolish hot flashes42 (Fig. 3). The authors point out, however, that considerable individual variation was noted among patients regarding number of hot flashes Vol. 53, No.6, June 1990 Miller-Bass and Adashi Transdermal estrogen replacement therapy 967

c 1.60 Q) E ~ 1-- 1.20 0>.S 8 = ~ 0.80 0 " I... 1! "' 0.40 : g "'.. "- 0 I R = -0.6045 p<0.001 Serum Estradiol During Treatment (pg/ml) Figure 3 Linear regression analysis of hot fiashes/h versus circulating serum E 2 levels during Estraderm treatment. (From Chetkowski et al. 38 Reprinted by permission of the publisher.) that occurred at any given E 2 level. Haas et al.34 have published similar results demonstrating a 50% reduction in objectively measured hot flashes at E 2 levels of 73 pg/ml in patients using a 0.05 mg/d patch for 6 weeks, while Laufer et al.37 observed a decrease from 0. 76 to 0.25 objectivelymeasured hot flashes/h in patients using an undisclosed dose of Estraderm for 3 weeks. The data of Padwick et al.39 support the above work, showing a decrease in the number of subjectively recorded hot flashes in patients using the 0.05 mg/d system. Further reduction of hot flashes occurred with continued use. No significant differences in the weekly number of subjectively recorded hot flashes were noted between patients treated with Estraderm 0.10 mg/d and those treated with 0.625 or 1.25 mg Premarin/dY A decrease in other menopausal symptoms, including sleep disturbances, irritability, and anxiety has also been demonstrated after Estraderm administration,39 there being no statistically significant differences in the frequency of these symptoms between Estraderm users and those using Premarin.43 Thus, Estraderm appears to provide satisfactory relief of hot flashes in most patients and is at least comparable to Premarin in this respect. Effects of Estraderm on Urogenital Atrophy Another menopausal symptom of considerable concern to patients is that of vaginal discomfort or dryness secondary to atrophic or senile vaginitis. Both oral and vaginal estrogen preparations have been shown to revert vaginal cytology back to a state that is akin to that seen in premenopausal women, i.e., an increased percentage of superficial cells and a decreased percentage of parabasal cells.4 5 22 A number of studies have now shown similar beneficial effects of Estraderm on vaginal cytology at both the 0.05 mg and 0.10 mg/d doses.34 37-39 Patients using Estraderm 0.10 mg/d did not differ significantly in the number or severity of vaginal complaints recorded in a daily diary when compared with patients using Premarin 0.625 or 1.25 mg/dy While patients using the 0.05 mg/d patch demonstrated a decrease in the number of complaints related to vaginal dryness, this decrease failed to reach statistical significance.39 It appears, then, that Estraderm (0.10 mg/d) is equivalent to oral conjugated equine estrogens (0.625 mg/d) in affording relief from this menopausal symptom. Estraderm at the 0.05 mg/d dose may be ineffective in this regard, though increased improvements in vaginal complaints were rated with each successive cycle using the 0.05 mg/d patch.39 Effects of Estraderm on Endometrium Administration of Estraderm 0.05 mg/d, either cyclically (without a progestogen) or continuously (combined with progestogen) has been shown to have a proliferative effect on endometrium as evidenced by the occurrence of vaginal bleeding and the finding of an increased number of endometrial b. wpsws. yw. ld' mg pro l'" 11era t' 1ve en d orne t num.. 34,44,45 The addition of a progestational agent for 12 days of each cycle in patients using Estraderm continuously, markedly decreased the incidence of random or breakthrough bleeding when compared with patients using Estraderm only in a cyclic (3 wk/mo) fashion. The majority of patients using Estraderm continuously with norethindrone added during the last 12 days of the regimen experienced bleeding only at the completion of the progestational therapy or slightly thereafter.44 When compared with patients using oral conjugated equine estrogens (1.25 mg/d) in cyclic fashion with medroxyprogesterone acetate, patients using cyclic transdermal E 2 (0.05 mg/d) and medroxyprogesterone acetate experienced significantly fewer days of spotting and/or bleeding.45 Of the 28 subjects included in the aforementioned studies who underwent endometrial biopsy while using transdermal E 2, only one subject developed endometrial hyperplasia. This was classified as mild adenomatous hyperplasia and was obtained on biopsy after 6 weeks of treatment with Estraderm 0.05 mg/d without the addition of a progestogen.34 968 Miller-Bass and Adashi Transdermal estrogen replacement therapy Fertility and Sterility

80001 ::l 2000 0 16l 121 Renin Substrate (ng/ml). II [t] ~ j II ~ OJ EF Base- 50 100 361 TBG l~g/ml). 27 18 0 24 II rn CBG Bindmg Copoc1ty ~ :~J tfm ~ 625 EF Base- 50100 625 line Estraderm Premarin line Estraderm Premarin (mcg/24 hrl (mg) tmcg/24 hr) {mgl Figure 4 Effects of Estraderm and Premarin administration on circulating liver proteins (EF =early follicular phase levels). (From Chetkowski et al. 38 Reprinted by permission of the publisher.) Effects of Estraderm on Protein Synthesis by the Liver It has generally been predicted that transdermal E 2 administration could possibly avoid the enhanced hepatic protein synthesis seen with oral estrogens, thereby eliminating possible adverse sideeffects. Indeed, the administration of Estraderm 0.05 mg or 0.10 mg/d resulted in minimal elevation of hepatic protein levels when compared with the impact of oral Premarin administered in doses of 0.625 mg or 1.25 mg/d. 35 44 Levels of sex-hormonebinding globulin, thyroxine-binding globulin, cortisol-binding globulin, and renin substrate were not increased above baseline at any of the four doses (0.025 mg, 0.050 mg, 0.10 mg, and 0.20 mg/d) of Estraderm used (Fig. 4). In addition, the circulating levels of the above-mentioned proteins were not statistically significantly different from levels in premenopausal controls. 38 46 Padwick et al., 39 administering 0.05 mg/d of Estraderm for 3 months to 12 postmenopausal and perimenopausal patients, noted no significant difference in either plasma renin substrate levels, or in plasma renin activity at the end of the treatment period. The data of Laufer et al. 37 support these findings, demonstrating no significant changes in levels of renin substrate, thyroxine-binding globulin, sex-hormone-binding globulin, or cortisol-binding globulin after 3 weeks of treatment with Estraderm systems (no dose given), and Haas and colleagues 34 showed no significant differences in renin substrate levels or activity or in aldosterone levels after 6 weeks of therapy with Estraderm 0.05 mg/d. Taken together, these studies support the premise that transdermal E 2 administration does indeed avoid the enhancement of liver protein synthesis noted with oral estrogen replacement, at least on a short-term (3 month) basis. Effects of Estraderm on Blood Pressure Though few investigators have actually addressed the effects of Estraderm on blood pressure, some data do exist. Haas et al. 34 observed no statistically significant differences from baseline in either systolic or diastolic blood pressure of patients who had been using Estraderm 0.05 mg/d for 6 weeks. Pad wicket al. 39 observed decreases in both systolic and diastolic blood pressure in patients using 0.05 mg/d patches over a 3-month period; however, these decreases were not maintained throughout the study period, and were present only at some visits. In sum, then, Estraderm appears to have minimal, if any, effect on blood pressure. Effects of Estraderm on Serum Lipid Levels The effects of Estraderm on serum lipid levels and the long-term significance ofthese effects have been the subject of much controversy. While treatment with 1.25 mg/ d of oral Pre marin for 28 days resulted in small but significant decreases in both serum cholesterol and LDL as well as a concomitant increase in serum HDL, all doses ofestraderm studied over the same time period had no effect on any of these parameters. 38 46 Changes in lipids seen with 0.625 mg/d Premarin did not reach statistical significance. 38 Accordingly, the HDL/LDL ratio increased significantly in those patients receiving Premarin 1.25 mg/d, but did not in those patients using transdermal E 2 systems. 38 DeLignieres et al. 47 have observed a similar lack of effect of percutaneous E 2 on serum lipid levels. Specifically, patients receiving daily doses of 3 mg of percutaneous E 2 for 2 months displayed no changes in the circulating levels of either total cholesterol, LDL, or HDL cholesterol. 47 However, in a double-blind study ofestraderm 0.05 mg/d versus placebo, Haas et al. 34 noted small but significant decreases in serum LDL in the Estraderm users. Unfortunately, placebo users also experienced a decrease in LDL levels during the 6-week study period. Significantly, the above studies involved only short-term use of transdermal or percutaneous E 2 The use ofestraderm 0.10 mg/d has been shown to result in significantly increased HDL levels after 24 weeks of administration. 27 As total cholesterol Vol. 53, No.6, June 1990 Miller-Bass and Adashi Transdermal estrogen replacement therapy 969

levels did not change over this same time period, there was a corresponding decrease in the total cholesterol/hdl ratio. Low-density lipoprotein levels remained unchanged from baseline. In a more extensive study involving 2 years of percutaneous E 2 (3 mg/d) and oral micronized progesterone (200 mg/d, 12 d/cycle), Jensen et al. 48 observed somewhat different results. At the end of the first year, patients using percutaneous E 2 only for 28 days each month demonstrated statistically significant decreases in both total cholesterol and LDL cholesterol when compared with their initial values and when compared with patients using placebo. These differences were maintained after the addition of oral progesterone for 12 days each cycle during the 2nd year of therapy. In patients receiving E 2, HDL levels remained unchanged at the completion of the 1st year of treatment, but showed a small but significant increase 6 months after the addition of oral progesterone. It appears then that administration of these percutaneous E 2 preparations over a longer period of time will eventually result in small but significant favorable changes in the serum lipoprotein patterns in a manner similar to that seen with oral Premarin use. Effects of Estraderm on Clotting Factors Judd 46 and Chetkowski et al. 38 have observed no effect of either Estraderm (0.025 mg, 0.05 mg, 0.10 mg, 0.20 mg/d) or Premarin (0.625 mg or 1.25 mg/d) on any of three clotting factors measured: fibrinopeptide A, antithrombin III levels and activity, and high-molecular-weight fibrinogen. Decreases in antithrombin-iii levels have been demonstrated with oral micronized E 2 or E 2 valerate therapy, but again, no change in the circulating levels of this clotting factor was noted with percutaneous E 2 use. 46 These observations support the contention that the transdermal administration of ~ should have no measurable effects on clotting factors and that it is unlikely to lead to a hypercoagulable state. Effects of Estraderm on Bone Economy Long-term bone loss as assessed by single-photon absorptiometry has been shown to be inhibited by oral estrogen administration, the minimum dose of conjugated equine estrogens necessary to achieve this effect being 0.625 mg/dp However, the effects of Estraderm administration on bone loss have not as yet been thoroughly studied. * i.2o Urinary Calcium/Creatinine Ratio.15.10.05 0 line * Estraderm (mcg/24 hrl I * Premarin (mgl Figure 5 Effects of Estraderm and Premarin administration on urinary calcium excretion and urinary calcium/creatinine and hydroxyproline/creatinine ratios (EF = early follicular phase levels). (From Chetkowski et al. 38 Reprinted by permission ofthe publisher.) The above notwithstanding, limited studies are available on the effect of Estraderm on urinary calcium and hydroxyproline excretion. Urinary calcium/creatinine and hydroxyproline/creatinine excretion ratios have been extensively employed as an indirect measure of bone resorption. Urinary calcium excretion has been shown to increase after menopause, presumably reflecting increased bone resorption that can result in osteoporosis. 49 Similarly, given a collagen-free diet, most of the hydroxyproline found in the urine is derived from bone, its excretion increasing during the postmenopausal period. 50 Unfortunately, studies concerning the effect of Estraderm on these parameters have differed somewhat. On the one hand, all studies documented higher urinary calcium and hydroxyproline excretion in postmenopausal women as compared with their premenopausal counterparts, 37 38 a trend reduced after the administration of transdermal E 2 37 38 51 However, using an unspecified dose of Estraderm, Laufer et al. 37 failed to show any statistically significant decrease in either urinary calcium/creatinine or hydroxyproline/creatinine ratios, 37 while Chetkowski et al. 38 demonstrated statistically significant decreases in the urinary calcium/creatinine ratios only, at all doses of Estraderm tested 38 (Fig. 5). 970 Miller-Bass and Adashi Transdermal estrogen replacement therapy Fertility and Sterility

Percent Change Individual Changes Mean Changes 20 8 n=6 16 n=14 T 6 12 in 8 I Spinal BMD I 4... ). 0 --- I I I II --~--- I -4 0 6 12 18 6 12 18 Months of Treatment Figure 6 Changes in spinal bone mineral density with Estraderm (0.05 mg/d). (From Ribot et al.52 Reproduced with the permission of the publisher.) 4 2 Selby and Peacock, 51 on the other hand, observed significant decreases in urinary calcium/creatinine and hydroxyproline/creatinine ratios in patients treated with Estraderm 0.05 mg/d. The exact reason for such variable results is not readily apparent, but may be due in part to the small numbers of patients involved (11 to 20) or the extremely short time of Estraderm administration (3 to 4 weeks). No studies involving actual bone-density measurements of patients using Estraderm have yet been published, but preliminary results of a 2-year study of the effects of Estraderm on postmenopausal bone loss by Ribot et al.52 are encouraging. Thirteen patients underwent measurement of lumbar spine bone mineral density by dual photon absorptiometry after 6 and 12 months of treatment with Estraderm 0.05 mg/d. No significant decrease in bone mineral density was noted after 6 months of treatment, and a small but statistically significant increase was noted at 12 months (Fig. 6). These results suggest that Estraderm will prove effective in preventing postmenopausal bone loss. Side-Effects and Patient Compliance Patient compliance during use of E 2 transdermal systems has been good in nearly all studies, and few side-effects have been noted. As previously outlined, patients achieve good relief of vasomotor and other menopausal symptoms,39 42 43 while experiencing no significant increase in other systemic side-effects, such as nausea or breast tenderness, often associated with estrogen therapy.39 When compared with Premarin users, the incidence of the aforementioned side-effects was no different.43 In a group of 12 patients who used a total of 252 patches during the study period, only 6 instances of poor adhesion of the patch were reported.39 Patients carried out normal activities, including bathing and showering, and seldom encountered difficulties with the system. Local skin reaction to the patch, usually consisting of erythema, nearly always characterized as mild, has also been reported39 43 and rarely resulted in discontinuation of the patch by the patient. 53 For some patients, the use of an Estraderm patch might prove to be a very desirable means of estrogen replacement therapy. This is particularly true for patients who have difficulty swallowing pills or experience nausea when using oral estrogens. On the other hand, the need for progestational therapy in combination with Estraderm in patients with an intact uterus means that the patient will still need to take pills for some days each month. Such a combination of two completely different modes of drug delivery may be unacceptable to some patients. Although instances of poor patch adhesion appear to be infrequent,38 this could still prove to be a problem in patients who are extremely physically active. Perspiration and frequent showering could Vol. 53, No.6, June 1990 Miller-Bass and Adashi Transdermal estrogen replacement therapy 971

very well lead to poor adhesion and the need to replace patches more often than every 3 days. On a practical level, it may prove difficult for some patients to remember when they need to change their patch. Daily medication becomes a habit, whereas changing a patch twice weekly is less automatic. The manufacturer has attempted to overcome this by providing a "wheel" on each Estraderm package that serves as a reminder of when the patch must be changed. When set to the day of the week when the first patch is applied, it automatically indicates the day when the patch must be changed for a new one. Still, many patients may find this too inconvenient and opt for more traditional means of therapy. SUMMARY The efficacy of transdermal E 2 in restoring serum E 2 levels to the premenopausal range and in affording relief of menopausal symptoms seems well-established. Importantly, Estraderm is providing a controlled sustained supply of E 2, the prevalent premenopausal estrogenic species. In doing so, Estraderm approximates normal physiology by serving, in effect, in the capacity of an artificial ovary. The minimal elevation of liver proteins seen in patients treated with Estraderm may aid in avoiding some of the complications traditionally seen with oral estrogen-replacement therapy. The medication appears to be well-tolerated, easy to use, and side effects are few. Comparative studies suggest that Estraderm 0.05 and 0.10 mg/d are approximately equivalent to Premarin 0.625 and 1.25 mg daily37 respectively, an observation supported by others.46 However, there is some evidence that the 0.05 mg/d patch is not as effective as 0.625 mg/d Premarin in relieving some vaginal complaints,39 and that a higher Estraderm dose (0.10 mg/d) may be necessary in some patients. The effect(s), if any, of transdermal E 2 administration on serum lipids, and the relevance of such changes to long-term cardiovascular morbidity, have not been well defined. In fact, the data on the actual effects of oral estrogen administration on cardiovascular morbidity seem less than clear-cut at this point in time. The vast majority of the literature pertaining to estrogen replacement therapy and cardiovascular disease in women does seem to imply that estrogen administration may, at the least, have no statistically significant impact on cardiovascular risk, and may in fact be cardioprotective.19 In a comprehensive review of the literature on this subject, Bush and Barrett-Connor19 make the statement that "estrogens have powerful effects on certain biologic parameters, the alteration of which could influence cardiovascular disease risk," and further conclude that if this protective effect is indeed real, it would make a very compelling reason for routine estrogen replacement therapy. Currently, however, the issue remains controversial, and no long-term studies involving cardiovascular morbidity and mortality in women using transdermal E2 exist. As noted earlier, perhaps long-term administration ofestraderm would result in changes in HDL and LDL patterns similar to those seen with oral Premarin. Even if this were not the case, Estraderm administration may have beneficial effects on long-term cardiovascular endpoints, and these endpoints must be evaluated before reasonable decisions can be made regarding the appropriateness of this form of estrogen therapy. Similarly, the question as to the efficacy of Estraderm in the prevention of postmenopausal osteoporosis remains unanswered. Despite the decreases in several indirect markers of bone resorption seen with Estraderm administration, and the encouraging results of Ribot et al.52 showing increased bone mineral density after 1 year of Estraderm use, additional long-term studies are clearly essential if Estraderm is to become an acceptable form of estrogen-replacement therapy. What About the Future? With its ability to significantly increase serum E2levels with minimal side-effects, there is no reason why Estraderm could not be used in many of the situations where oral estrogens ani now used. The wearing of a patch might be more appealing and more convenient for some patients, and could, in the long run, prove more cost-effective. Estraderm has also been successfully applied toward the establishment and maintenance of pregnancy in women without ovarian function through the use of donor eggs. 54 55 Preliminary studies by Gangar et al. 56 57 of a transdermal system containing a combination of E2 and norethindrone indicate that it may eliminate some of the shortcomings associated with the administration of transdermal estrogen alone such as the necessity for the concomitant administration of oral progestins in patients with an intact uterus. This preparation has important implications for future contraceptive therapy as well. Additionally, the success of Estraderm may pave 972 Miller-Bass and Adashi Transdermal estrogen replacement therapy Fertility and Sterility

the way for the transdermal administration of other steroid preparations. Transdermal testosterone therapy has already been used successfully in the treatment of male hypogonadism. 5 8 Assuming that Estraderm can be shown to be unequivocally cardioprotective and capable of arresting osteoporosis, it is likely to provide a highly attractive form of estrogen replacement. This possibility is likely to be further enhanced if and when longer-acting patches can be devised. Thus, there is little doubt that the development and use of the transdermal therapeutic system has opened doors to a new era in hormonal replacement therapy. REFERENCES 1. Thompson CJS: The Mystery and Art of Apothecary. Bungay, Suffolk, England, R. Clay and Sons, 1929, p 8 2. Shaw JE, Urquhart J: Transdermal drug administrationa nuisance becomes an opportunity. Br Med J 283:875, 1981 3. Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA: Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17~-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol152:1099, 1985 4. Geola FL, Frumar AM, Tataryn IV, Lu KH, Hershman JM, Eggena P, Sambhi MP, Judd HL: Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 51:620, 1980 5. Mandel FP, Geola FL, Lu JKH, Eggena P, Sambhi MP, Hershman JM, Judd HL: Biological effects of various doses of ethinyl estradiol in postmenopausal women. Obstet Gynecol 59:673, 1982 6. Cedars MI, Judd HL: Normal routes of estrogen administration. Obstet Gynecol Clin North Am 14:269, 1987 7. Bush TL, Cowan LD, Barrett-Connor E, Criqui MH, Karon JM, Wallace RB, Tyroler A, Rifkind BM: Estrogen use and all-cause mortality. JAMA 249:903, 1983 8. Gordon T, Castelli WP, Hjortland MC, Dawber TR: High density lipoprotein as a protective factor against coronary heart disease: the Framingham study. Am J Med 62:707, 1977 9. Ernst W: District Sales Manager, Wyeth-Ayerst Pharmaceuticals. Personal communication 10. Coope J, Thomsen JM, Potter L: Effects of "natural estrogen" replacement therapy on menopausal symptoms and blood clotting. Br Med J 4:139, 1975 11. Campbell S, Whitehead M: Estrogen therapy and the menopausal syndrome. Clin Obstet Gynecol4:31, 1977 12. Lindsay R, Hart DM, Clark DM: The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol 63:759, 1984 13. Lievertz RW: Pharmacology and pharmacokinetics of estrogens. Am J Obstet Gynecol156:1289, 1987 14. Bolt HM: Metabolism of estrogens-natural and synthetic. Pharmacol Ther 4:155, 1979 15. Martin PL, Burnier AM, Greaney MO: Oral menopausal therapy using 17~-estradiol. Obstet Gynecol39:771, 1972 16. Yen SSC, Martin PL, Burnier AM, Czekala NM, Greaney MO, Jr, Callantine MR: Circulatory estradiol, estrone and gonadotropin levels following the administration of orally active 17~-estradiol in postmenopausal women. J Clin Endocrinol Metab 40:518, 1975 17. Nichols KC, Schenkel L, Benson H: 17~-estradiol for postmenopausal estrogen replacement therapy. Obstet Gynecol Surv 39(suppl):230, 1984 18. Callantine MR, Martin PL, Bording OT, Warner PO, Greaney MO, Jr: Micronized 17~-estradiol for oral estrogen therapy in postmenopausal women. Obstet Gynecol46:37, 1975 19. Bush TL, Barrett-Connor E: Noncontraceptive estrogen use and cardiovascular disease. Epidemiol Rev 7:80, 1985 20. Mandel FP, Geola FL, Meldrum DR, Lu JHK, Eggena P, Sambhi MP, Hershman JM, Judd HL: Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 57:133, 1983 21. Schiff!, Tulchinsky D, Ryan KJ: Vaginal absorption of estrone and 17~-estradiol. Fertil Steril28:1063, 1977 22. Rigg LA, Hermann H, Yen SSC: Absorption of estrogens from vaginal creams. N Engl J Med 298:195, 1978 23. Goebelsmann V, Mashchak CA, Mishell DR, Jr: Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol. Am J Obstet Gynecol151:868, 1985 24. Stumpf PG: Selecting constant serum estradiol levels achieved by vaginal rings. Obstet Gynecol67:91, 1986 25. Thorn MH, Collins WP, Studd JW: Hormonal profiles in postmenopausal women after therapy with subcutaneo~s implants. Br J Obstet Gynecol88:416, 1981 26. Lobo RA, March CM, Goebelsmann U, Koauss RM, Mishell DR: Subdermal estradiol pellets following hysterectomy and oophorectomy. Am J Obstet Gynecol138:714, 1980 27. Stancyzk FZ, Shoupe D, Nunez V, Macias-Gonzales P, Vijod MA, and Lobo RA: A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Dbstet Gynecol159:1540, 1988 28. Holst J, Cajander S, Carlstrom K, Dauber MG, and von Schoultz B: Percutaneous estrogen replacement therapy: effects on circulating estrogens, gonadotropins and prolactin. Acta Obstet Gynecol Scand 62:49, 1983 29. Lyrenas S, Carlstrom K, Backstrom T, and vonschoultz B: A comparison of serum estrogen levels after percutaneous and oral administration of estradiol-17~. Br J Obstet Gynaecol88:181, 1981 30. Guy RH, Hadgraft J, Bucks DAW: Transdermal drug delivery and cutaneous metabolism. Xenobiotica 17:325, 1987 31. Zwicke DL, Niazi I, Reeves WC, Wagel SS: Reduced transcutaneous nitroglycerin absorption in blacks. Circulation 74(suppl II):543, 1986 32. Steingold KA, Cefaeu W, Partridge W, Judd HL, Chandhuri G: Enhanced hepatic extraction of estrogens used for replacement therapy. J Clin Endocrinol Metab 62:761, 1986 33. Good W: CIBA-GEIGY Pharmaceuticals. Personal communication 34. HaasS, Walsh B, Evans S, Krache M, Ravnikar V, and Schiff I: The effect of transdermal estradiol on hormone and metabolic dydnamics over a six-week period. Obstet Gynecol 71:671, 1988 35. Barry BW: Properties that influence percutaneous absorption: In Dermatological Formulations: percutaneous Absorption, Edited by BW Barry. New York, Marcel Dekker, Inc., 1983, p 127 36. Schenkel L, Barlier D, Riera M: Transdermal absorption of Vol. 53, No.6, June 1990 Miller-Bass and Adasbi Transdermal estrogen replacement therapy 973