Revi ew Topical estrogens: an update Topical estrogens: an update A.J. Papadopoulos and I. Shapiro SUMMARY Topical estrogens have been used for many different dermatologic conditions. Currently, they have reemerged as a form of estrogen replacement therapy for peri/postmenopausal women. In this article we review current applications and future indications for topical estrogen therapy, with an emphasis on the transdermal estrogen patch. Introduction The use of topical estrogens has undergone many changes since the pioneering work of Zondek, who in 1936 demonstrated that estrogen could pass percu- taneously through intact skin (1). In 1945 he found a clinical application for topical estrogens as an effective treatment for vagina! a trophy in postmenopausal women (2). In the mid-20 th century, topical estrogens were used in a variety of dermatological disorders, including acne vulgaris, keratoderma climactericum, hidradenitis suppurativa, seborhea oleosa, male and female-pattern baldness, urogenital (vaginal/vulvar) atrophy and peri/postmenopausal vasomotor com- plaints (3,4). One of the authors bas conducted numerous clinical trials on the effects of topical estrogen therapy in the treatment of acne vulgaris, keratoderma climactericum and premature alopecia (5-11). Most ofthese treatments, excluding the use of estrogen creams for treatment of vagina! atrophy, are no longer employed clinically. The new millenium views the role of topical estrogens and the vehicle of application utilized, much differently from half of a century ago. Today, topical estrogen therapy has gained a newfound emphasis in the form of transdermal p atches used for hormone replacement therapy in peri and postmenopausal women. We provide a review of the current application for topical estrogens, with an emphasis on the transdermal estrogen patch. Transdermal Estrogen Patch Transdermal estrogen p atches , or tran sdermal therapeutic systems (TTSs), are a relatively new treat- ment modality in estrogen replacement therapy (ERT). Oral estrogens continue to be the mainstay of ERT, but Acta Dermatoven APA Vol 9, 2000, No 2 J7 Topical estrogens: an update transdermal estrogen patches have gained popularity in recent years (12). In 1992, 15% of ERT in the United States was in the form of transdermal estrogen patches, while TTSs are the most popular form of estrogen replacement in Great Britain for postmenopausal women who have had a hysterectomy (12,13). Transdermal estrogen patches consist of reservoir (Estraderm TTS 50®) and matrix (Climara®) patches, which deliver daily doses of 50 to 100 mg of 17b- estradiol 03-16). The matrix patch is applied to the chest or abdomen weekly, while the Estraderm® patch requires biweekly application. Studies have proven that compliance in women undergoing ERT is higher in those who use transdermal patches as opposed to oral estrogen therapy (17,18). Compliance is important in women undergoing ERT, since postmenopausal women may face thirty or more years of therapy. TTSs bypass the first pass effect through the !iver, which is encountered with oral estrogen therapy, allo- wing lower doses of estrogens to be administered per- cutaneously (13,15). Large doses of oral estradiol must be taken in order to achieve therapeutic levels and to counter metabolism by the !iver and inactivation by the gut wall. A large part of oral estradiol is converted to estrone by the !iver, causing an imbalance in the estra- diol/estrone ratio which is normally 1:1 in premeno- pausal women (13,16) In contrast, TTSs are delivered directly to the systemic circulation, allowing for a more physiologic estradiol/estrone ratio (16). In addition, the first pass effect with oral estrogen replacement produces noticeable alterations in hepatic protein synthesis and metabolism (Table 1) (13). White the elevation ofthese protein$ in the bloodstream does not seem to be directly implicated in clinical health consequences, the increased biliaiy cholesterol saturation index and decreased levels of chenodeoxycholic acid (bile acid that acts to solu- bilize cholesterol) point to an increasecl diathesis to- warcls gall stone clisease (13,19). Studies have confir- mecl tl1at the risk of gallstone clisease is increased with oral estrogen therapy (20,21). In contrast, transdermal estrogen application shows no appreciable increase in these proteins (13) . Oral estrogens also produce fluctu- ating levels of estradiol and estrone throughout the day, while TTSs procluce less fluctuation in serum estradiol levels (13,15). Thus, transdermal estradiol patches offer the advantage of bypassing the first pass effect of the !iver, minimally affecting hepatic protein synthesis and metabolism and mimicking ovarian function by delivering physiologic levels of estradiol at a constant rate. The treatment of choice for menopausal vasomotor symptoms (hot t1ashes) ancl vagina! atrophy is estrogen replacement therapy (13). It has proven effective in the treatment of these symptoms (22). In acldition to alleviating climacteric symptoms associatecl with meno- pause, it has been demonstrated that ERT can enhance and even prolong a postmenopausal woman's lifespan J8 (23). A recent retrospective study has shown that ERT can reduce the risk of cardiovascular disease by 50% (24). Oral estrogen replacement therapy has provided evidence for long-term cardioprotective effect. (13,15). Oral and transdermal estrogens affect the lipid profile (Table 2). Both forms of replacement therapy similarly decrease total cholesterol and LDL (13,15,16). In contrast, TTSs decrease triglyceride levels and maintain HDL levels, while oral estrogens show an increase in triglyceride levels and an increase in HDL levels (13, 15, 16). A study of patients receiving transdermal ERT clemonstratecl increasecl blood flow and a decreased vascular resistance (25). It has been proposed that estro- gen's cardioprotective effect is mainly influencecl by its physiologic influence on arterial endothelium and smooth muscle, including enhancement of synthesis of vasodilato1y factors (nitric oxide and prostacyclin) and inhibition of vasoconstrictive substances (15). The second major benefit of estrogen replacement therapy is for osteoeporotic changes in postmoeno- pausal women. Transdermal estrogen patches have pro- ven effective in maintaining lumbar bone density at 50 mg and increasing lumbar bone density at 100 mg, thus proving as effective as their oral counterparts in pre- venting and treating osteoporotic changes (16,26). One study showed that oral and transdermal estrogen increa- sed bone density to a similar degree (27). As summarized, transdermal estrogen patches pro- vide an exciting alternative for estrogen replacement therapy in peri/postmenopausal women for both clima- cteric symptoms and long-term health benefits. Trans- dermal estrogen therapy is also indicated in certain me- dica! conditions that preclude oral estrogens, inclucling Table 1. Metaholic changes seen with ERT13-16 Angiotensionogen Thyroid-binding globulin (TBG) Cortisol-bincling globulin (CBG) Sex hormone-binding globulin (SHBG) Growth Hormone (GH) Fibrin o gen Biliaiy cholesterol saturation index Chenodeoxycholic acid i i i i i i Review Acta Dermatoven APA Vol 9, 2000, No 2 Review hypertriglyceridemia, non-response to oral estrogens, oral estrogen-induced hypertension, and high-risk cholelithiasis patients (15). TTSs have similar systemic side effects as oral estro- gens, including the development of breast tenderness, headaches, flushing, fluid retention, and weight gain, nausea and depression (28). Skin irritation is the most frequent adverse side effect encountered with the trans- dermal estrogen patches (29). Localized dermatologic effects due to patch application include erythema, pru- ritus, vesicular rash, edema, induration and residual pig- mentation (22). Rotation of sites of patch application and application to the buttocks have praven to reduce skin irritation (30). Endometrial hyperplasia, with possible future carci- nomatous change, is a concern in the use ofunopposed transdermal estrogen patches (16). Cyclical transdermal application unopposed by a progestin caused endo- metrial proliferation and irregular bleeding in many patients (31) . Addition of an oral progestin is reco- mmended to prevent endometrial hyperplasia , with po- ssible progression to endometrial carcinoma, in women with an intact uterus (16,22). Other Vehicles oj Topical Estrogen Therapy Percutanous estradiol gels (Oestrogel®) are available for use outside of the United States (22) . The gel is applied over the abdomen and thighs and allowed to d1y for a few minutes before clothing is worn. Similarly to the transdermal patch, estrogen is absorbed percu- taneously into the systemic circulation and provicles a physiologic estradiol/estrone ratio (13,22). However, absorption of the gel into the systemic circulation is dependent on the surface area to which the gel is applied; serum estradiol level may thus flu ctuate with each application (32) . These gels have praven efflca- cious in treating vasomotor symptoms and vagina! atro- phy associated with menopause, but data on cardio- protective and osteoporotic effects are not definitive (13,22). Table 2. E.fj'ects ofERT on the Lipid Profile13•1G Tota! cholesterol LDL HDL i Triglycerides i Acta Dermatoven APA Vol 9, 2000, No 2 Topical estrogens: an update Estrogen-containing creams (Estrace®, Ogen®) for vagina! application are available in the United States (22). Their efficacy in the treatment ofvaginal atrophy has been praven (13,22,33). Systemic absorption ofthe estrogen cream does occur through vagina! epithelium, increasing the risk of endometrial hyperplasia with po- ssible progression to cancer (22). The absorption of estrogen is variable, depending on the type and dose of estrogen and the vehi de by w hich it is administered (22). For this reason, estrogen creams are not reco- mmended for long-term estrogen replacement therapy. Vagina[ rings contain a mixture of c1ystalline 17b- estradiol and an inert polymer (13). Vagina! rings are manually placed in the upper third of the vagina and maintain their position by pressure from the vagina[ walls. These vagina! rings are easily removed for hygie- nic purposes. Systemic absorption through vagina[ epi- thelium depends on the surface area of the ring (22). Estradiol levels can be maintained for up to three months (34). Sufficient data has not been published on the effi- cacy of these rings as an estrogen replacement therapy, and the rings are not currently available in the United States. Vagina! estradiol tablets (Vagifem®) are manually inserted into the vagina and have praven efficacious in the treatment ofvaginal atrophy (35,36). Biweekly do- sing has been reported to have negligible systemic and endometrial effects (22). This treatment modality is also not available in the United States. C1ystalline estradiol implants are placed subcuta- neously in the abdomen or buttock. Implants provide stable circulating levels of estradiol for a period of 4-12 months (13,37,38). Problems with implants arise from the fact that dosing is not easily adjusted and the possi- bility of endometrial stimulation even after cliscon- tinuation of thera py (22). Implants are used much more frequently for ERT in Europe. Future Direction Transdermal estrogen patches that are available in lower dosages, having longer application periods and that are less irritating to the skin will be introcluced in the near future. Combination estradiol/progrestin pa- tches are also currently being investigated, but not yet available for clinical use in the United States (39,40). This development would greatly facilitate treatment in women taking estrogen replacement therapy who also need progestin treatment. Estrogen replacement thera- py in postmenopausal women is gaining increased emphasis as today's aging population grows. The cardio- protective and osteoporotic effects of ERT have been reviewed. Other possible areas for use of topical estrogens include cosmetic facial applications in peri/postmeno- J9 Topical estrogens: an update pausal women for the treatment of skin aging and wrink- ling. The effects of topical estrogen for this application have not yet been defined, although preliminaiy studies show promising results (41-43). A decrease in wrinkle depth and an improvement of elasticity and firmness of facial skin was seen after six months of topical appli- cation ( 41). Immunohistochemistty demonstrated an increase in Type III collagen in treated skin, which may explain the clinical picture of increased firmness and decreased wrinkles in these patients ( 41). Our initial clinical trials with topical estrogens half of a century ago included the beneficial treatment of keratoderma climactericum (6). It is with great interest that we have found a recent case report in which this condition has been similarly effectively treated with topical estrogen ( 44). We have reviewed the current applications of topical estrogens , with an emphasis on estrogen replacement therapy using the transdermal estrogen patch. We are excited that topical estrogens have found important new applications, most of them much different from half of a centrny ago . . EFE b CES l. Zondek B. Folliculin. Klin Wochenschr 1929; 8: 2229-32. 2. Zondek B. Cutaneous application of follicular hormone. Lancet 1938; 1: 1107. 3. Shapiro I. Topical estrogens. Current status. 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Curr Tlier Res 1987; 42: 712-9. 31. Whitehead MI, PadwickML, EndacottJ, Pryse-Davies J. Endometrial responses to transdermal estradiol in postmenopausal women. AmJ Obstet Gynecol 1985; 152: 1079-84. 32. Sitruk-Ware R. Estrogen therapy during menopause. Practical treatment recommendations. Drugs 1990; 39: 203-17. 33. Mandel FP, Geola FL, Meldrum DR, et al. Biological effects ofvarious doses ofvaginally administered conjugated equine estrogens in postmenopausal women. J Ciin Endocrinol Metah 1983; 57: 133-9. 34. Stumpf PG. Selecting constant serum estradiol levels achieved by vagina! rings. Obstet Gynecol 1986; 67: 91-4. 35. Mattsson LA, Cullberg G, Eriksson O, Knutsson E Vagina! administration of low-dose oestradiol- effects on the endometrium and vagina! cytology. Maturitas 1989; 11: 217-22. 36. Mettler L, Olsen PG. Long-term treatment of atrophic vaginitis with low-dose oestradiol vagina! tablets. Maturitas 1991; 14: 23-31. 37. Suhonen SP, Allonen HO, Lahteenmaki P. Sustained-release subdermal estradiol implants: a new alternative in estrogen replacement therapy. AmJ Obstet Gynecol 1993; 169: 1248-54. 38. Stanczyk FZ, Shoupe D, Nunez V, et al. A randomized comparison of nonoral estradiol delivery in postmenopausal women. AmJ Obstet Gynecol 1988; 159: 1540-6. 39. Oosterbaan I-IP, van Buuren AH, SchramJH, et al. The effects of continuous combined transdermal oestrogen-progestogen treatment on bleeding patterns and the endometrium in postmenopausal women. Maturitas 1995; 21: 211-9. 40. Suhonen S, Haukkamaa M, Lahteenmaki P, I-Iolmstrom T. Endometrial effect of transdermal estradiol and progestin ST-1435 in postmenopausal women. Fertil Steril 1992; 57: 1211-5. 41. Schmidt JE, Binder M, Demschik G, et al. Treatment of skin agingwith topical estrogens. IntJ Dermatol 1996; 35: 669-74. 42. Schmidt JB, Binder M, Macheiner W, et al. Treatment of skin aging symptoms in perimenopausal females with estrogen compounds. A pilot study. Maturitas 1994; 20: 25-30. 43. Dunn LB, Damesyn M, Moore AA, et al. Does estrogen prevent skin aging'/ Results from the First National Health and Nutrition Examination Survey. Arch Dermatol 1997; 133: 339-42. 44. Zultak M, Bedeaux C, Blanc D, et al. Keratoderma climacterium treatment with topical estrogen. Dermatologica 1988; 176: 151-2. Anthony l. Papadopoulos MD,. Dermatology, New Jersey Medical School, Newark, New Jersey. 185 South OrangeAvenue, Newark, Newlersey07103-2714, USA Jrving Shapiro MD, same address Review Acta Dermatoven APA Vol 9, 2000, No 2