FERTILITY AND STERILITY

Vol. 53, No.6, June 1990

Copyright e 1990 The American Fertility Society

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 [E 2 ]). The scopolamine patch was the first transdermal therapeutic system designed2 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 Vol. 53, No.6, June 1990

maintaining E 2 levels within the premenopausal (early follicular) range. Accordingly, the delivery of estrone (E 1 ), 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

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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 962

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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/mL3 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

Brand

Dose

Conjugated equine estrogens Piperazine estrone sulfate Micronized 17 -{J estradiol 17-01 ethinyl estradiol

Pre marin Ogen Estrace Estinyl

0.625 to 1.25 0.625 to 1.25 1.0 to 2.0 0.01 to0.02

mg

Transdermal estrogen replacement therapy

Fertility and Sterility

Table 3 Constituents of Premarin (Conjugated Equine Estrogens) Constituent Estrone sulfate Equilin sulfate 17a-dihydroequilin sulfate Miscellaneous estrogenic conjugates

Representation •

48 26

15 11

• Values are percents.

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 E 1 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 E 1 ratio that is 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 E 2 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 flashes 42 (Fig. 3). The authors point out, however, that considerable individual variation was noted among patients regarding number of hot flashes

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c

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8 0.80 ~

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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 968

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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 . . yw . ld'mg pro l'" . 34,44,45 b wpsws 11erat'1ve en d orne t num. 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

Transdermal estrogen replacement therapy

Fertility and Sterility

Renin Substrate (ng/ml)

80001

::l 2000 0

.

361

TBG

.

l~g/ml)

~

27

II [t] ~ II rn 18

0

16l

24

121

j II OJ EF Baseline

50 100 Estraderm (mcg/24 hrl

CBG

EF Base50100 line Estraderm tmcg/24 hr)

625 Premarin {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. Vol. 53, No.6, June 1990

Effects of Estraderm on Blood Pressure

Bindmg Copoc1ty

~ :~J tfm ~

625 Premarin (mg)

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.

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. Padwicket 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

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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

Judd46 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. 970

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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 tested38 (Fig. 5).

Transdermal estrogen replacement therapy

Fertility and Sterility

Mean Changes

Individual Changes

•

20

8 n=6 n=14

16 6 Percent Change in Spinal BMD

12 8 4

... ).

0

•

• • •

- - - I I I II

•••

T

I 4

I

• •••

I

12

18

•

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2

0

-4 6

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.)

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 2transdermal 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 experiVol. 53, No.6, June 1990

encing 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

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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 litera972

Miller-Bass and Adashi

ture 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 E 2 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 E 2 levels 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 E 2 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

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the way for the transdermal administration of other steroid preparations. Transdermal testosterone therapy has already been used successfully in the treatment of male hypogonadism. 58 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 Vol. 53, No.6, June 1990

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 vonSchoultz 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

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estradiol from different body sites is comparable. J Controlled Release 4:195, 1986 Laufer LR, DeFazio JL, Lu JKH, Meldrum DR, Eggena P, Sambhi MP, Hershman JM, Judd HL: Estrogen replacement therapy by transdermal estradiol administration. Am J Obstet Gynecol146:533, 1983 Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL: Biologic effects of transdermal estradiol. N Engl J Med 314:1615, 1986 Padwick ML, Endacott J, Whitehead MI: Efficacy, acceptability, and metabolic effects oftransdermal estradiol in the management of postmenopausal women. Am J Obstet Gynecol152:1085, 1985 Casper RF, Alapin-Rubillovitz S: Progestins increase endogenous opioid peptide activity in postmenopausal women. J Clin Endocrinol Metab 60:34, 1985 DeJong FH, Sharpe RM: Evidence for inhibin-like activity in bovine follicular fluid. Nature 263:71, 1976 Steingold KA, Laufer L, Chetkowski RJ, DeFazio JD, Matt DW, Meldrum DR, Judd HL: Treatment of hot flashes with transdermal estradiol administration. J Clin Endocrinol Metab 61:627, 1985 Place VA, Powers M, Darley PE, Schenkel L, Good WR: A double-blind comparative study of estraderm and premarin in the amelioration of postmenopausal symptoms. Am J Obstet Gynecol152:1092, 1985 Whitehead Ml, Padwick ML, Endacott J, Pryse-Davies J: Endometrial responses to transdermal estradiol therapy in postmenopausal women. Am J Obstet Gynecol 152:1079, 1985 Johannisson E, Landgren B-M, Diczfalusy E: Endometrial and vaginal response to three different estrogen preparations administered by the transdermal and oral routes. Maturitas 10:181, 1988 Judd H: Efficacy of transdermal estradiol. Am J Obstet Gynecol156:1326, 1987 DeLignieres B, Basdevant A, Thomas G, Thalabard J-C, Mercier-Bodard C, Conard J, Guyene T-T, Mairon N, Corvol P, Guy-GrandB, Mauvais-Jarvis P, Sitruk-Ware R: Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab 62:536, 1986 Jensen J, Riis BJ, Strlllm V, Nilas L, Christiansen C: Longterm effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gynecol156:66, 1987

49. Young MM, Nordin BEC: Effects of natural and artificial menopause on plasma and urinary calcium and phosphorus. Lancet 2:118, 1967 50. Hodgkinson A, Thompson T: Measurement of fasting urinary hydroxyproline: creatinine ratio in normal adults and its variation with age and sex. J Clin Pathol35:807, 1982 51. Selby PL, Peacock M: The effects of transdermal oestrogen on bone, calcium-regulating hormones and liver in postmenopausal women. Clin Endocrinol 25:543, 1986 52. Ribot C, Tremollieres F, Ponilles JM, Louvet JP, Peyron R: Transdermal administration of 17~-estradiol in postmenopausal women: preliminary results of a longitudinal study. (Abstr.) Presented at the International Symposium on Osteoporosis, Aalborg, Denmark, September 27 to October 2, 1987. Published by Osteopress, Denmark in Osteoporosis 1987: International Symposiuman Osteoporosis, p 546 53. Utian WH: Transdermal estradiol: a recent advance in oestrogen therapy. Drugs 36:383, 1988 54. deZiegler D, Gagliardi C, Matt D, Steingold K, Taney F, Colon J, Weiss G, Schmidt C: Successful transdermal E 2 and vaginal P regimen for in vitro fertilization and embryo transfer (IVF-ET) of donated oocytes in premature ovarian failure (POF) (Abstr.) Presented at the 35th Annual Meeting ofthe Society for Gynecologic Investigation, Baltimore, Maryland, March 17 to 20, 1988. Published by the Society for Gynecologic Investigation in the Scientific Program and Abstracts, p 139 55. Droesch K, Scoh R, Kreiner D, Liu H-C, Rosenwaks Z: Transdermal estrogen replacement in ovarian failure for ovum donation. Fertil Steril 50:931, 1988 56. Gangar K, Fraser D, Whitehead M, Schenkel L, Fankhauser D: Endometrial response to transdermal norethindrone (Abstr.) Presented at the 44th Annual Meeting of The American Fertility Society, Atlanta, Georgia, October 10 to 13, 1988. Published by The American Fertility Society in the Program Supplement, p S90 57. Gangar K, Fraser D, Whitehead M, Schenkel L,·Pryse Davies J: The metabolic effects of norethindrone when administered transdermally (Abstr.) Presented at the 44th Annual Meeting of The American Fertility Society, Atlanta, Georgia, October 10 to 13, 1988. Published by The American Fertility Society in the Program Supplement, p S91 58. Ahmed SR, Boucher AE, Manni A, Santen RJ, Bartholomew M, Demers LM: Transdermal testosterone therapy in the treatment of male hypogonadism. J Clin Endocrinol Metab 66:546, 1988

Received October 9, 1989. Reprint requests: Eli Y. Adashi, M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Room 11-007 Bressler Research Building, 655 West Baltimore Street, Baltimore, Maryland 21201.

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