CLIMACTERIC 2007;10:289–297 Effect of estrogens on skin aging and the potential role of selective estrogen receptor modulators S. Verdier-Se´vrain Bio-Hybrid, LLC, West Palm Beach, Florida, USA Key words: SKIN AGING, HORMONE REPLACEMENT THERAPY, TOPICAL ESTROGEN, PHYTOESTROGENS, SELECTIVE ESTROGEN RECEPTOR MODULATORS ABSTRACT Estrogens have a profound influence on skin. The relative hypoestrogenism that accom- panies menopause 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 osteoporosis 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-estradiol 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 estriol 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