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CLIMACTERIC 2007;10:289–297 Effect of on skin aging and the potential role of selective receptor modulators

S. Verdier-Se´vrain

Bio-Hybrid, LLC, West Palm Beach, Florida, USA

Key words: SKIN AGING, HORMONE REPLACEMENT THERAPY, TOPICAL ESTROGEN, , SELECTIVE MODULATORS

ABSTRACT Estrogens have a profound influence on skin. The relative hypoestrogenism that accom- panies exacerbates the deleterious effects of both intrinsic and environ- mental aging. Estrogens prevent skin aging. They increase skin thickness and improve skin moisture. Beneficial effects of hormone replacement therapy (HRT) on skin aging have been well documented, but HRT cannot obviously be recommended solely to treat skin aging in menopausal women. Topical estrogen application is highly effective and safe if used by a dermatologist with expertise in endocrinology. The question of whether estrogen alternatives such as phytoestrogens and selective estrogen receptor modulators are effective estrogens for the prevention of skin aging in postmenopausal women remains unanswered. However, preliminary data indicate that such treatment may be of benefit for skin aging treatment. For personal use only.

INTRODUCTION There are approximately 40 million postmeno- Intrinsic aging is characterized by smooth, pale, pausal women in the United States, contributing finely wrinkled skin and dryness2. Photoaging is to 17% of the total population1. As the popula- characterized by severe wrinkling and pigmentary tion of older women continues to grow at a rapid changes such as solar lentigo and mottled pig- rate, the challenges of learning more about the mentation3. Estrogens affect several skin functions health-care concerns and priorities of this group of and the estrogen deprivation that accompanies Climacteric Downloaded from informahealthcare.com by University of Washington on 05/23/13 patients become apparent. The skin is one of the menopause contributes to, and exacerbates, the largest organs of the body in which aging-related deleterious effects of age on the skin. Since its first changes are visible and women are concerned by use in the 1940s, systemic estrogen therapy has the deterioration of their skin’s appearance. Skin been known to have an obvious, visible effect on aging is influenced by genetic, environmental and the skin and to be efficient in combating the hormonal factors. Numerous reviews have ade- phenomenon of skin aging4,5. quately described the difference between normal In this article, we review the effects of cutaneous aging, due to the passage of time, and estrogen on skin biology and particularly its damage from solar exposure. The prior is referred ability to prevent skin aging. We examine the role to as intrinsic aging, and the latter as photoaging. of estrogen therapy in skin aging treatment,

Correspondence: Dr S. Verdier-Se´vrain, Bio-Hybrid, LLC, 224 Datura Street, suite # 1011, West Palm Beach, FL 33401, USA

REVIEW Received 27-10-06 ª 2007 International Menopause Society Revised 15-02-07 DOI: 10.1080/13697130701467157 Accepted 23-02-07 Effect of estrogens and SERMs on skin aging Verdier-Se´vrain

discussing successively the indications of hormone and postmenopausal years, studies have attempted replacement therapy (HRT), topical estrogen to decipher the effects of estrogens on skin coll- treatment, and new drugs called selective estrogen agen. Several controlled studies have reported that receptor modulators (SERMs). estrogen therapy had a beneficial effect on collagen content and skin thickness15–19 (see Table 1). BIOLOGY OF ESTROGENS IN SKIN Estrogens affect several skin functions such as Estrogen effects on skin moisture elasticity6, water-holding capacity7, pigmentation8 The ability of the skin to hold water is related to and vascularity9. Estrogens prevent skin aging by the stratum corneum lipids which play a predomi- influencing skin thickness, skin wrinkling and skin nant role in maintaining the skin barrier moisture10. Not just the skin but also skin appen- function20 and also to the dermal glycosaminogly- dages, such as hair follicles, are influenced by cans, which have a high water-holding capacity21. estrogens11. It has been demonstrated that postmenopausal women who were not taking hormone replace- ment therapy were significantly more likely to Estrogen effects on skin thickness experience dry skin compared with those post- and collagen content menopausal women taking estrogen22. Pierard- Collagen is a main constituent of the skin and Franchimont and colleagues7 showed that provides the major support for skin resistance. transdermal estrogen therapy leads to significantly It was first noticed in 1941 by Albright and increased water-holding capacity of the stratum colleagues12 that postmenopausal women with corneum, suggesting that estrogen may play a role had skin that was noticeably atro- in the stratum corneum barrier function. Denda phied. Then, Brincat and colleagues13 demon- and colleagues23 demonstrated changes in the strated that there was a decrease in skin thickness stratum corneum sphingolipids with aging and and skin collagen content, corresponding to a suggested a possible hormonal influence. Estrogens reduction in bone mineral density, in the years also affect dermal water-holding capacity: studies following menopause, particularly in the initial in animal24 have demonstrated marked increases postmenopausal years. More recently, Affinito and in glycosaminoglycans within 2 weeks of estrogen colleagues14 showed that skin collagen decline was therapy and studies in human25 have shown closely correlated to years following menopause. estrogens to increase dermal hydroscopic qualities. For personal use only. They showed that postmenopausal women had decreased amount of types I and III collagen, as well as a decreased type III/I ratio in com- Estrogen effects on skin wrinkling parison to premenopausal women. With the Wrinkles are modifications of the skin associated correlation noted between skin collagen decline with cutaneous aging, appearing preferentially on

Table 1 Estrogen effects on skin collagen or skin thickness in human (results from controlled studies) Study Type of measurement Hormones used Results Climacteric Downloaded from informahealthcare.com by University of Washington on 05/23/13 Castelo-Branco et al.15 skin biopsy analysis conjugated equine estrogens increase in skin collagen of or transdermal 17b- 1.8–5.1% after HRT for 12 months Callens et al.16 skin thickness measured 17b-estradiol gel or increase in skin thickness by ultrasonography estradiol patches of 7–15% Maheux et al.17 skin thickness measured conjugated estrogen 0.625 mg increase in skin thickness by by ultrasonography 11.5% after HRT for 12 months Sauerbronn et al.18 skin biopsy analysis valerate estradiol and increase in dermis collagen cyproterone acetate content of 6.49% Varila et al.19 skin biopsy analysis topical 17b-estradiol increase in hydroxyproline by 38% after treatment for 3 months HRT, hormone replacement therapy

290 Climacteric Effect of estrogens and SERMs on skin aging Verdier-Se´vrain

sun-exposed areas (actinic aging). Moreover, they Niiyama and colleagues38 have demonstrated the can be increased by various intrinsic (heredity, ability of estrogen to modify androgen metabo- ethnic, hormonal and pathological) or extrinsic lism in dermal papillae of hair follicles. factors (irradiation, pollution, temperature, hu- midity). Histological studies of wrinkles have shown alterations of dermal component with MOLECULAR MECHANISMS atrophy of dermal collagen, alterations of elastic OF ESTROGEN EFFECTS IN SKIN fibers and marked decrease in glycosaminogly- Estrogens regulate cell function by binding two cans26. Creidi and colleagues27 showed that a nuclear receptors: the estrogen receptor-alpha conjugated estrogen cream applied to the facial (ER-a) and estrogen receptor-beta (ER-b)39.In skin of postmenopausal women resulted in sig- addition, the existence of a cell-surface form of nificant improvement in fine wrinkles, as clinically estrogen receptor (membrane estrogen receptor) evaluated by dermatologists. Dunn and collea- has been recently demonstrated40. The mechanism gues22 pointed out that postmenopausal women of estrogen action in skin is not well known and using estrogen were significantly less likely to there are still some controversies regarding the develop skin wrinkles. As noted earlier, estrogens expression of ER-a and ER-b. Thornton and cause an increase in collagen and glycosaminogly- colleagues41 found that ER-b is the predominant cans in the dermis15,24, which may explain the receptor in skin. Others42 found that both decrease in skin wrinkling with estrogen treat- receptors are expressed and demonstrated the ment. Decreased skin elasticity has been demon- existence of a membrane receptor in the epidermis. strated in women after menopause28, and changes in the skin elastic fibers have also been reported after application of ointments to the skin of ESTROGEN THERAPY FOR SKIN postmenopausal women29. AGING Hormone replacement therapy Estrogen effects on hair growth HRT consists of two components: estrogen and Hair growth encompasses three stages, all known progestogen. The use of estrogen alone (unop- to be influenced by estrogens: growing (anagen), posed estrogen) is associated with an increased structural regression (catagen) and resting (telo- risk of endometrial hyperplasia and/or carcinoma. gen)30. High systemic estrogen levels during In order to avoid this effect, in women with intact For personal use only. pregnancy prolong the anagen phase of the hair uterus and treated with estrogens, progestogens follicle, and the plummeting estrogen levels should be used to protect the endometrium. As the postpartum are thought to cause this excess estrogen component, natural 17b-estradiol is number of anagen follicles to enter the telogen often used in Europe, whereas the conjugated phase simultaneously, sometimes resulting in (CEE) derived from pregnant clinically significant hair loss, the so-called telogen mare’s urine is the preferred product in the US. effluvium31. Androgenetic alopecia also known as HRT carries a small increased risk of serious female pattern alopecia, is the most common hair complications, and the risk increases with dura- loss in women and is most frequently observed tion of the therapy. Recently, recognized experts after menopause32, suggesting a role of estrogens have provided practical guidelines for postmeno- Climacteric Downloaded from informahealthcare.com by University of Washington on 05/23/13 or the estrogen : androgen ratio. In men, androge- pausal HRT and have reviewed the risk of netic alopecia is a -mediated complications43–46. Endometrial cancer occurs process, characterized by continuous miniaturiza- up to four times more frequently in women with tion of androgen-sensitive hair follicles33. Indeed, a uterus who take unopposed estrogen than in it is usually treated with systemic antiandrogens non-users. The risk may be reduced by adding a such as cyproterone acetate34 in women, or progestogen. risk increases slightly steroidogenic enzyme inhibitors such as finaster- with HRT prescribed longer than 5 years. Venous ide35 in men. Topical estrogen is also used as thromboembolism is rare but increases with treatment in women, especially in Europe36. The estrogen use. mechanism involved in estrogen-mediated induc- The indication for HRT is the treatment of tion of hair growth in androgenetic alopecia is not menopausal symptoms (hot flushes, sweating, well understood. Some studies have shown an insomnia, fatigue, depressed mood and urogenital increased anagen and decreased telogen rate after atrophy). The dose and regimen of HRT need to estrogen treatment, as compared to placebo37. be individualized, based on choosing the lowest

Climacteric 291 Effect of estrogens and SERMs on skin aging Verdier-Se´vrain

appropriate dose in relation to the severity of tissue. As previously reviewed, many studies have symptoms and on the menopausal age. The demonstrated beneficial effects of HRT on skin standard higher doses used in the past (0.625 mg collagen content (Table 1). HRT also affects CEE or 2 mg 17b-estradiol) are not recommended skin elasticity; it has been reported that HRT today. Lower-dose HRT (0.3 mg CEE or 1 mg limits the age-related increase in cutaneous ex- 17b-estradiol) has been shown to be effective and tensibility, thereby exerting a preventive effect minimizes the side-effects47. Usually, after 3–4 on skin slackness6. Despite such beneficial years of hormonal treatment, it is possible to stop effects of HRT on skin aging, HRT cannot HRT with no recurrence of menopausal symp- obviously be recommended solely to treat skin toms. Currently, experts believe that limited, aging in menopausal women. Prevention of skin short-term use of HRT (55 years) administered aging with HRT should be regarded as an in the early phase of menopause is relatively safe additional benefit for menopausal women who among healthy women48. Long-term HRT may be receive this treatment for other menopausal appropriate if symptoms persist. In this case, symptoms. appropriate counseling on the risks and benefits of long-term HRT should be provided. HRT can offer long-term benefits in the central nervous, Topical estrogen treatment cardiovascular and skeletal systems. Specifically, it Studies have showed that topical estrogen may has been demonstrated that HRT is very effective prevent skin aging, as seen with HRT. Schmidt at preventing osteoporosis49. However, there are and colleagues4 examined the effects of 6-month still controversies about the long-term use of HRT treatment with topical 0.01% estradiol and 0.3% because of the risk of breast cancer with pro- estriol on skin aging on the face of perimeno- longed use of estrogens. In patients at high risk of pausal women. They found improvement similar osteoporosis and fracture, osteoporosis prevention to that seen in the studies using HRT. Both should be continued independently of manage- treatment groups showed increased skin moisture ment of menopausal symptoms, using alternatives and improvement of elasticity and firmness of to HRT such as selective estrogen receptor the skin with decreased wrinkle depth. No hor- modulators (SERMs). monal side-effects were noted, either clinically Beneficial effects of HRT on skin aging have or by hormone monitoring. Serum hormone levels been documented by several studies. An analysis and the appearance of vaginal smears showed of a large cohort of 3875 postmenopausal women no significant change as compared to before For personal use only. aged 40 and more showed that HRT prevents dry treatment. skin and wrinkling. Women under long-term Creidi and colleagues27 examined the effect of substitution had one-third fewer wrinkles than atopicallyappliedconjugatedestrogencream non-substituted patients22. A pilot study of 24 (Premarin1 0.625 mg/g of cream) in 54 women. menopausal women examined the effects of After a 24-week treatment period, they found that different regimens of HRT on skin aging50. Premarin cream produced better results than the Patients were assigned to three groups: transder- placebo cream; the difference was statistically mal estrogen only (Estraderm TTS1 50), trans- significant for skin thickness and fine wrinkles. dermal estrogen and progesterone (Estraderm Premarin cream was well tolerated locally. The TTS1 50 and 0.4 mg progesterone vaginal sup- general safety of Premarin cream was also excellent; Climacteric Downloaded from informahealthcare.com by University of Washington on 05/23/13 pository), and oral estrogen and progesterone no women had any serious drug-related study (2 mg Progynova and 0.4 mg progesterone vagi- events. However, in contrast to the previous study, nal suppository). One group served as control. a modification of the vaginal maturation index was Treatment was continued for 6 months. Epider- seen in women using the Premarin cream, demon- mal moisture, skin elasticity and skin thick- strating that the CEE has permeated the skin and ness were significantly improved in all treated exerted its effect on the vaginal mucosa. Indeed, it is groups. A comparison of epidermal hydration known that CEE and 17b-estradiol differ in their and skin elasticity revealed no significant dif- total estrogenic potency, with CEE possessing ferences between ultraviolet-exposed and non- greater estrogenic potency48.Thissuggeststhat exposed measurements sites, suggesting that both estradiol creams may provide a safer therapy for intrinsic and photoaging may be improved by skin aging compared to CEE creams, since they HRT. seem not to induce systemic effects. A leading parameter of skin aging is skin It is clear that topical estrogen is an effective thickness, which reflects the status of collagen treatment for skin aging. Menopausal women

292 Climacteric Effect of estrogens and SERMs on skin aging Verdier-Se´vrain

who are not receiving HRT and who do not treatments for menopause-associated morbidity. have any contraindications to HRT would be SERMs and estrogen agonist molecules that are candidates for topical estrogen therapy. currently available and currently in development Since studies have demonstrated a sharp are shown in Table 2. decline in skin thickness and collagen in the The question of whether estrogen alternatives years following menopause, particularly in the such as phytoestrogens and SERMs are effective initial postmenopausal years13, it would be estrogens for the prevention of skin aging in critical to begin the treatment within the first postmenopausal women remains unanswered. postmenopausal years. Additional studies are However, preliminary data indicate that such needed to definitively demonstrate the safety of treatment may be of benefit for skin aging this treatment. Further investigations should treatment. determinate the highest effective concentration of estrogens that can be used without the risk of possible systemic side-effects. Based on previous Effects of phytoestrogenic SERMs work on the use of topical estrogen for vaginal on skin aging atrophy in postmenopausal women, it is ex- Phytoestrogens are plant-derived molecules that pected that a short-term use of topical estrogen structurally resemble endogenous estrogens, con- (55 years) should prevent skin aging without taining a diphenolic chemical structure that can serious risks. Indeed, recent studies have demon- directly bind to estrogen receptor53. They have a strated the efficacy and safety of a low dose of relative greater affinity for ER-b than for ER-a. 17b-estradiol for postmenopausal vaginal atro- Phytoestrogens exhibit some estrogen agonist- phy. Neither systemic estradiol increases nor like properties54 but can also act as partial estrogenic side-effects (endometrial hyperplasia) estrogen receptor antagonists55. Because of their have been observed with this treatment51. The mixed agonist/antagonist estrogen receptor pro- choice of the form of estrogen is also important: file, phytoestrogens have received considerable as previously discussed, CEE, which possesses a attention as potential alternatives to estrogen. greater estrogenic potency than 17b-estradiol, Studies have demonstrated that may may induce systemic side-effects. Estriol, a low- prevent photoaging in human skin56. Other potency estrogen that has considerably lower studies have reported that genistein and affinity for the estrogen receptor, is commonly stimulate hyaluronic acid production in human prescribed in Europe for topical treatment of keratinocyte culture57. A recent European study For personal use only. menopausal urogenital symptoms. This treat- had examined the effect of a cosmetic cream ment has been demonstrated to be safe, with preparation including isoflavone (Novadiol1)in no increase risk of endometrial hyperplasia52 234 postmenopausal women and had showed and so may be useful for topical treatment of improvement in skin dryness and wrinkles after 12 skin aging. weeks of treatment58. Such topical estrogen treatment for skin aging will need to be administered by a derma- tologist experienced in endocrinology, given Effects of SERMs on skin aging that concentration and application areas must An effective SERM for the skin would exert be observed in order to avoid systemic side- estrogen agonist action in skin and estrogen Climacteric Downloaded from informahealthcare.com by University of Washington on 05/23/13 effects. antagonist action in breast and uterus. The ideal SERM for skin would also exert estrogen action in brain, bone and in the vagina. Among different Selective estrogen receptor modulators SERMs currently available or under development, SERMs act at the level of the estrogen receptor; only has been studied for its effects in they bind to ER-a and ER-b. They appear to have skin. Raloxifene is used in prevention and treat- either estrogenic or antiestrogenic effects, depend- ment of postmenopausal osteoporosis59. It also ing on the tissue. In some tissues such as bone, decreases the risk of breast cancer60 and does not they mimic the effects of estrogen, while in others stimulate the endometrium61. Recent studies have they act as and block unwanted demonstrated that raloxifene exerts stronger sti- estrogenic effects on uterine and breast tissues. mulative effects on collagen biosynthesis than Because of this tissue specificity activity, SERMs estradiol in human skin fibroblasts and might are potentially a versatile drug class that offers the reverse some of the postmenopausal changes in prospect of developing individualized, targeted skin62.

Climacteric 293 Climacteric Downloaded from informahealthcare.com by University of Washington on 05/23/13 For personal use only. feto srgn n EM nsi gn Verdier-Se aging skin on SERMs and estrogens of Effect 294

Table 2 Selective estrogen receptor modulators (SERMs) currently available or under development Benzothiophene Dihydronaphthalene Tetrahydronaphthalene Benzopyran Pure steroidal derivatives derivatives derivatives derivatives derivatives antiestrogens Phytoestrogens 1 (Nolvadex , raloxifene (Pfizer) ICI 182,780 genistein 1 Zeneca Pharmaceuticals) (Evista , Eli Lilly) ( 1 Faslodex ) 4-Hydroxy-tamoxifen (active nafoxidene ICI 164,384 genistein metabolite of tamoxifen) (LY353,380-JCI, (Centchroman) Eli Lilly) 1 (Fareston ) EM800 RU 39411 daidzein (SCH57050) (FC-1271a) (active ZK 119010 EM652 daidzein metabolite of toremifene) (active metabolite of EM800) ERA-923 1 (Clomid , 1 Seraphene ) (Wyeth) (TAT-59) GW 5638 GW 7604 MDL-103,323 Climacteric ´vrain Effect of estrogens and SERMs on skin aging Verdier-Se´vrain

well investigated. SERMs are drugs that CONCLUSION offer exciting opportunities for the future treat- The skin is an estrogen-responsive tissue. A better ment of skin aging but, while great strides understanding of the hormonal regulation of have been made in developing effective SERMs skin physiology and skin aging may provide the for menopausal symptoms such as osteo- basis for development of new hormonal treatment porosis, the challenge of developing an effective for skin aging. HRT cannot be recommended estrogen alternative for skin aging treatment solely to treat skin aging in menopausal women remains. but may be considered as an additional benefit in the treatment of menopausal symptoms. Topical Conflict of interest The author declares having estrogen application is highly effective and safe if no conflict of interest capable of influencing her used by a dermatologist with expertise in en- judgment. docrinology. Phytoestrogens appear to be effec- tive but their possible side-effects have not been Source of funding Nil.

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