Topical Estriol in Dermatology: A Review

Introduction

Estriol is one of the three main estrogens produced in the human body with estradiol and estrone. It is best know for its topical uses in gynecology, notably for management of post-menopausal vaginal atrophy and atrophic vaginitis (40, 4, 61). However, topical estriol also has several potential applications in the field of dermatology. This article reviews the clinical uses of topical estriol in acne treatment, acne scars treatment and skin aging process, which are major dermatological issues. This review is pertinent considering the adverse effects of actual hormonal acne treatments, the inefficacity of acne scars interventions and the current great interest in skin ageing therapy. This paper presents brief pathophysiologic descriptions and literature review on each of these major topics. Estriol skin absorption and safety is overviewed.

Method

Publications were identified through searches in Pubmed and Scholar Google using the following key words: Estriol, Estriol and topical, Estriol and skin, Estriol and acne, Estriol and acne and scars, topical and estriol and skin. This review excluded studies concerning mucous membranes estriol application as well as article treating solely of estradiol or estrone skin application and articles publicated before 1950 were excluded. Only clinical trials with more than 10 patients were included in this review.

Topical Estriol in Acne Scars

In the development of acne, there is a significant inflammatory process in the pilosebaceous unit. Thereafter, the distended follicular walls can break, liberating its inflammatory content into the dermis and therefore, initiate an intense inflammatory response leading clinically to papule, pustules, nodules and cysts (38, 58, 62). This inflammation combined with follicular rupture leads to acne scars formation, a permanent and definitive condition if unmanaged (38, 50). Current common treatments for atrophic acne scars include invasive dermabrasion, chemo-peeling and hyaluronic acid filler injections (22, 50).

A technique using estriol iontophoresis is a safe, non invasive treatment of atrophic acne scars. Iontophoresis is the process of increasing the penetration of drugs into the skin by application of an electric current (24, 44, 45, 55).The current being the same charge as the drug, it is repelled in the dermis thus increasing the absorption of the topical agent. In 1995, Schimdt et al (50) performed estriol iontophoresis in 18 women twice weekly for three months. Photographic, clinical follow-up of the skin and venous blood samples for serum levels of prolactin and estradiol were obtained monthly. After the treatment, improvement of acne scars was observed in 100% of women treated with estriol iontophoresis. No side effects or hormonal changes were noted with estriol treatment. Considering that actual treatments for acne scars can be invasive and have limited results, the use of estriol iontophoresis could be a very promising alternative.

Topical Estriol in Skin aging process

With aging, the skin loses its thickness, elasticity and firmness becomes drier and skin wrinkles develop (4, 27). These changes are known to be due to the decrease in skin collagen (4, 27), elastic fibers and glucosamine glycans content which are major components of skin extracellular matrix produced by fibroblasts (32). Estrogen receptors have been detected in keratinocytes, fibroblasts, sebaceous glands and blood vessels (10, 25, 42). As observed, the coincidence of perimenopause with initial signs of skin aging suggests that estrogen deficiency is an important causative factor in this skin-aging process as discussed in numerous studies (11, 17, 53). Skin aging, although occurring in both sexes, has much of the research concentrated on women.

Callens et al. (13) compared the skin of postmenopausal women on systemic oral estrogen hormonal therapy to those not receiving any hormonal treatment. The skin thickness of these 98 women was evaluated with B-mode ultrasound high resolution echography and demonstrated that those on estrogen hormonal replacement had significant greater skin thickness. In 1983, Brincat et al. (9) demonstrated that women on systemic oral estrogen hormonal replacement therapy had skin collagen content 48 % higher than women without hormonal therapy.Affinito et al. (1) evaluated the effect of aging and postmenopausal hypoestrogenism on skin collagen content. Thirty-two women, fourteen in premenopause and eighteen in postmenopause, underwent skin biopsies performed during laparotomic operation to analyze the skin collagen content. In the postmenopausal patients, a significant decrease in skin collagen has been demonstrated compared to premenopausal women suggesting that the decrease of skin collagen is an estrogen-related phenomenon.This effect as also been reported in several other studies using various strategies and measurement techniques (2, 27, 43, 57).

Other studies show that topical estrogens treat skin aging signs as seen with oral systemic replacement therapy (1, 23, 43). In 1994, Schmidt et al (51) treated the aging skin of the face of 18 perimenopausal females either with a 0.3% estriol cream or with a 0.01% estradiol cream for 6 months. Monthly dermatologic and serologic follow-up, including prolactin, follicle stimulating hormone and estradiol blood levels were performed. Both treatment groups showed significant improvement in the skin aging signs. Furthermore, no hormonal side effects were noted either clinically or by serologic monitoring.

In 1996, Schmidt et al. (49)studied the effects of topical 0,01% estradiol compared to 0,3% estriol compounds on the aging skin of 59 women. Monthly serologic dosages of prolactin, follicle stimulating hormone and estradiol were taken as well as an examination of different skin parameters using profilometry and corneometry were done including skin hydratation, pore sizes, wrinkles depth as well as skin elasticity and firmness. After 6 months, wrinkles depth and pore sizes decreased from 61 to 100 % in both groups. Wrinkles depth measured by profilometry showed significant results using 0,01% estradiol (p=0,002) and highly significant results with 0,3% estriol (p=0,0005). Overall, skin effects observed in the group treated with topical estriol were slightly superior regarding there extent and onset. Once again, no hormonal side effects were noted with facial estriol application.

Estrogen skin absorption

The interest of topical estriol application remains in the possibility of local treatment without systemic effects, although a theoric risk of systemic absorption exists if a very large skin area is treated (51). Furthermore, oral agents have the disadvantage of being subject to a considerable first-pass hepatic effect oxidation to nonestrogens, and conjugation to sulfate and glucuronide salts (34).A study using mouse skin examined the percutaneous penetration and cutaneous first- pass effect of estrogen (31). The extent of permeation of estradiol (18.0%) was greater than estriol (2.45%). The extent of cutaneous first-pass metabolism of estradiol was limited during skin translocation whereas metabolism of estriol was essentially negligible.

In another research, the penetration into layers of human skin in vitro of estradiol and estriol using radiolabeled substances was investigated (60). The epidermis and the dermis were separated by a microtome and the amount of substance in each layer was determined. Results showed that estriol can be termed epidermotropic because it tends to reaches the dermis only in low concentrations and penetrates the skin considerably slower than estradiol. Considering the presence of estrogen receptors throughout the epidermis, including on keratinocytes (36), the action of estriol is maximum on these structures. Since small amounts of topical estriol reach the dermis, it can also have mild effects on deeper dermis structures including fibroblasts, sebaceous glands and hair follicles that also possess estrogen receptors (29). Mixing topical estriol and estradiol then represent an interesting combination, targeting cutaneous estrogen receptors in the epidermis as well as deeper dermis structures. The use of iontophoresis is also an interesting mechanism to improve estriol cutaneous absoption (44).

Estriol safety

In the past,estriolwas believed to have little physiological significance due to its weak estrogenic activity when compared withestroneandestradiol (7). This might be in fact a major advantage for estriol use in cutaneous treatments.

Frequently feared effect of estrogen administration remains in the pro-estrogenic effects on breasts and endometrium. The fact that there are two distinct types of estrogen receptors,estrogen receptoralphaand estrogen receptorbeta is a crucial concept (28, 39, 41). In the breast for example, the binding of estrogen hormones to estrogen receptoralphapromotesbreast cell proliferation, whereas the binding of estrogen hormones to estrogen receptor betainhibitsbreast cell proliferation and prevents breast cancer development (5, 28). It is important to note that estrone and estradiol bind mostly to estrogen receptoralpha,thereby explaining the known breast cancer-promoting effects of these two hormones (47, 63). On the other hand, estriol binds to estrogen receptorbeta (47, 63), a characteristic that corresponds to a unique breast cancer protection effect amongst the estrogens.

Other studies report that women who used estriol in the course of hormone replacement therapy (HRT) didnothave an increased risk of breast cancer, compared to women who never used HRT (3). A study on the use of estriol as an HRT and breast cancer incidence in 31,451 postmenopausal women suggested this finding (3). Additional evidence of estriol safety was provided by a study that compared use of HRT in 3,345 women over age 50 with breast cancer to 3,454 women without breast cancer. Women who used low-dose oral or topicalestrioldidnothave an increased risk of breast cancer, compared to women who never used HRT (37).

Kainz et al. (30) examined cytological vaginal and cervical smears of 17 women (mean age 57.1±7.6 years) before and after three months of facial estrogen ointment application either using 1 g of 0.01% estradiol or 0.3% estriol once daily. Monthly measurements of serum follicle-stimulating hormone, prolactin and estradiol levels were done. Both serum hormone levels and vaginal smears showed no significant change during treatment. This is an important aspect of clinical use of topical estriol and estradiol compound.

Conclusion

Topical estriol is a safe, locally active and effective skin treatment available for major skin conditions including acne, acne scars and skin aging. Several small-scaled studies have demonstrated results equivalent to current standards of care with far fewer local and systemic side-effects. Estriol skin absorption is characterized by an epidermotrophic pattern which promotes its combination with topical estradiol for skin therapies. Current studies recommend 0.3% estriol and 0.01% estradiol compound for topical use. This article calls for large scaled studies on topical estriol use given its impressive efficacy and lack of side-effects. It would be interesting to see if the benefits of estriol also apply to male patients. Topical estriol could complement the actual skin treatment arsenal of current dermatological practice in skin aging, acne scars and acne care.

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