A Review of Uses and Clinical Evidence for Topical Estrogen Therapy in Dermatology

Key Takeaways

• Topical estrogen therapy appears to improve multiple markers of skin aging, including increased collagen production, greater skin thickness, enhanced hydration, and improved overall skin quality in postmenopausal women. 
• Most clinical studies reported no significant systemic hormonal changes following topical estrogen use, suggesting a favorable safety profile compared with systemic hormone replacement therapy. 
• Subjective improvements in skin appearance were consistently reported across studies, with many
  participants noting visible cosmetic benefits. 
• Current evidence is limited by small study populations, heterogeneous formulations and treatment protocols, and a primary focus on postmenopausal women, highlighting the need for larger, long-term studies. 
• Emerging evidence suggests topical estrogen may have a prophylactic role when initiated around the perimenopausal period by helping preserve dermal collagen before significant estrogen-related skin aging occurs.

Physiologic depletion of estrogen during menopause is known to play a role in skin aging, leading to a more wrinkled appearance due to morphological changes like decreased collagen and elastin production. Several methods for replacing estrogen exist, such as oral replacement, but concern for adverse systemic effects has favored investigation of topical or local estrogen therapy. A concise review of the current literature regarding benefits and risks of topical estrogen use in dermatology was undertaken. 

Current evidence suggests topical estrogen treatment is effective at increasing collagen levels, improving skin thickness, and enhancing subjective skin quality. Many studies report these improvements as well as an absence of systemic hormone changes following topical estrogen administration. However, analyses of larger study populations with longer observation periods remain limited, and most study populations include postmenopausal women with little evidence documenting treatment effects for women in the premenopausal or perimenopausal periods.

Introduction

Intrinsic skin aging involves molecular-, cellular-, and organ-level changes of biologic processes that range from alterations in the cell cycle to loss of functionality and regeneration.¹ Estrogen depletion is thought to play a role in skin aging as its absence directly affects the epidermis. Aging may intensify following menopause due to depletion of ovarian follicles that produce estrogen.^2,3 A decrease in estrogen levels during perimenopause, menopause, and post menopause may result in loss of fat in the subcutaneous layers of the neck, face, arms, and hands; as well as reduced repair and production of collagen and elastin within the dermal skin leading to a more wrinkled appearance from the loss of these supportive skin structures.² Aesthetic changes in skin appearance could lead to psychological, physical, and social complications for menopausal women. There are theories that loss of estrogen systemically may also lead to medical complications related to malignancies and infections as well as other health concerns such as osteoporosis, cardiovascular disease, vasomotor symptoms, urogenital atrophy, sexual dysfunction, and cognitive decline, but these will not be addressed in this review.^3,4

Replacing the endogenous estrogen that is lost as women mature via systemic hormone replacement therapy is beyond the scope of this article. Our focus is to explore uses of topical estrogens and any benefits they provide within cosmetic dermatology. 

Background

Low estrogen is an expected feature of the menopausal transition, but depletion also occurs in pathological instances that induce a premature menopausal state such as ovarian ablation, ovarian or systemic disease, or other gynecological operations.⁵ Systemic hormone replacement therapy (HRT) supplied orally or transdermally may improve symptoms but be contraindicated for some patients due to adverse systemic effects. Topical formulations, which may have less systemic effect, are becoming more popular.^5-9 Topical estrogen compounds have been shown to locally decrease wrinkles/rhytids, increase hydration, increase skin thickness, and increase collagen production.^6,7,9 These benefits as well as minimal systemic side effects contribute to the appeal of using topical estrogen therapy as a treatment for skin aging  and for cosmetic purposes.^6,10

Although various studies support an implied cosmetic benefit to topical estrogen usage, the literature remains limited in topical estrogen efficacy solely as a cosmetic therapy.¹⁰ There remains a need for investigating how concentration and application site surface area influence systemic side effects of topical estrogens,^6,10 and the risk versus benefits of topical therapy for cosmetic use outside of menopause.  

Literature Review of Uses

Estrogen is a steroid hormone made in the granulosa cells of developing follicles within the ovaries, and its production is part of regulating a woman’s normal menstrual cycle.¹¹ This hormone largely promotes development of female secondary sex characteristics as well as contributes to bone and cardiovascular health.¹¹ There are different types of estrogens that possess unique properties based on their molecular structure including estrone (E1), estradiol (E2), and estriol (E3) (Figure 1).¹² The two biologically active forms of estrogen in a non-pregnant female are E2, which is the most potent and primary form involved in the menstrual cycle, and E1.^12,13 E3 is the primary estrogen form in pregnancy and is considered to not play a role in men or non-pregnant women.^12,13

As women age, ovarian follicles, which are responsible for estrogen production, decrease along with granulosa cells, leading to a decrease of estrogen in the body.³ The low level of estrogen in the body leads to the development of menopausal symptoms and health concerns such as osteoporosis, cardiovascular disease, urogenital atrophy, sexual dysfunction, cognitive decline, potential cancers, and vasomotor and psychiatric symptoms.³ Because estrogen replacement increases collagen content by stimulating collagen production when levels are low and helps prevent collagen loss when levels are sufficient,^7,8,13 it is reasonable to hypothesize that supplementing estrogen may influence skin aging. Furthermore, there is promising preliminary data demonstrating improved skin water content with estrogen administration.¹³ Although these findings are based on the oral or transdermal replacement of estrogen, it is plausible to surmise the role topical applications of estrogen may play in skin aging and cosmeceuticals, considering topical administrations have been used to treat vaginal menopausal symptoms.⁷

To investigate the current body of literature on topical estrogen use in dermatology, the following keywords were searched in PubMed and EBSCOhost: topical estrogens, cosmetic topical estrogens, skin aging, and cosmetic dermatology. The original intention was to compose a recent literature review including studies published within the last 20 years; a few studies which were fundamental to the current body of evidence were published beyond this timeline, so the range was amended to include the earliest study. Only clinical trial studies were included; studies were excluded if they investigated skin conditions other than skin aging, vaginal estrogens or genital rejuvenation, in vitro models, non-English publications, and topical estrogen use in the context of photodamaged skin. 

Potential Risks of Topical Estrogen   

It is important to consider potential adverse effects when discussing topical estrogen therapy and how this influences eligibility for treatment. In general, there is an increased risk of endometrial cancer with estradiol usage and that risk is compounded with the increased duration of estrogen use.¹⁴ Other notable adverse effects of oral estrogens include increasing patient risk for cardiogenic effects such as cerebral vascular accidents, myocardial infarction and thromboses of the extremities and pulmonary vasculature, as well as dementia.¹⁴ These complications are related to oral estrogens; it is not clear if topical estrogen therapy may carry the same risk associations.¹⁴ In the literature, a systematic review analyzing topical estrogen safety in patients using combined facial and vaginal formulations found no evidence of endometrial changes that could suggest cancer; however, they did note one study found hyperpigmentation to be linked to E2 and E3 use as a systemic effect.¹⁵ Additionally, a meta-analysis reported breast cancer survivors using topical estrogens did not have increased mortality or recurrence, supporting the safety of topical estrogen therapy even in high-risk groups.¹⁶ These findings were noted to be congruent with other current literature findings which depicted no negative impact on mortality in breast cancer survivors using topical estrogens.¹⁶ However, the authors noted a potential risk of breast cancer recurrence if topical estrogens were used during aromatase inhibitor treatment, although this discrepancy is still poorly understood in the literature.¹⁶ The complications associated with topical estrogen therapy impact patient eligibility for treatment and should be considered when discussing topical estrogen use for combating skin aging. 

Potential Benefits of Topical Estrogen    

Analysis of the gathered data suggests there are themes of topical estrogen treatment contributing to measurable improvements in the quality of skin. Various studies have independently found that topical estrogen treatment increases collagen levels in the skin.^6,9,19,23 There is a discrepancy in the literature regarding which types of collagen show the greatest increase in response to estrogens, whereby one study, by Schmidt et al in 1996, found only Type III collagen to increase without any changes in Type I collagen,⁹ while Silva et al in 2017 noted increased levels in both Type I and III collagen.⁶ In addition, skin thickness was shown to increase in several studies.^17-19 Specifically, Fuchs et al 2003¹⁷ and Moraes et al 2009¹⁸ observed increased epidermal thickness with Patriarca et al 2007¹⁹ noting increased epidermal and dermal thickness. Epidermal thickness increased maximally with topical estrogen application compared to baseline, plant-based estrogens, and glycolic acid applications according to Fuchs et al 2003¹⁷ and Moraes et al 2009.¹⁸

Subjective improvement in facial skin appearance was a consistency found across various studies.^18-22 Skin appearance was noted to improve in 87% of subjects using topical E2 in Patriarca et al 2007¹⁹ and 88% of participants receiving topical E2 treatment compared to 50% in those receiving plant-based estrogens according to Moraes et al 2009.¹⁸ Qualitative skin enhancement was noted by investigators in Draelos 2018²⁰ and Cohen & Downie 2022²¹ showing improvement in skin atrophy, dullness, laxity, and dryness as well as dark circles, periorbital wrinkles, texture, and firmness, respectively. Subjects in Cohen and Downie 2022²¹ self-reported improvement in transparency, evening and morning dark circles, morning puffiness, wrinkles, fine lines, moisture, firmness, eye fatigue, and texture following estrogen treatment. In contrast, Creidi et al 1994²² reported no change in subject self-evaluation of skin appearance following estrogen treatment despite noted enhancement in skin laxity, roughness, mottled pigmentation, and lentigines.

Across all studies, the absence of systemic hormone changes following topical estrogen treatment was consistent.^6,9,19,23 Measurements of systemic changes included baseline and post-treatment serum levels of E2 which showed no difference in Schmidt et al 1996,⁹ Patriarca et al 2007,¹⁹ Patriarca et al 2013,²³ and Silva et al 2017.⁶ Schmidt et al 1996⁹ also found no changes in serum follicle-stimulating hormone (FSH) levels after treatment but did recognize increased prolactin levels, although these were within normal limits. Even Patriarca et al 2013²³ and Silva et al 2017,⁶ who utilized vaginal and endometrial atrophy as means to analyze systemic changes, found no difference in baseline and post-treatment. Overall, these studies support the claim that topical estrogen therapy can help to improve signs of skin aging.

However, an inconsistency was noted in Creidi et al 1994,²² depicting increased number and depth of wrinkles in the estrogen-treated group. This study proposed that increased skin thickness could have contributed to increased wrinkle depth, even if overall wrinkle appearance did improve. When considering these studies, we noted inconsistencies with inclusion and exclusion criteria, sample sizes, study durations, application methods, concentrations, and formulations of estrogen products. Conclusions may be limited in how confidently results can be generalized. Despite this heterogeneity, many studies found estrogen to have a positive impact on aging skin.^6,9,17-23

Discussion   

Across the literature, E2 cream was the most utilized formulation of topical estrogen delivery, likely due to its potency and primary role in normal physiology. Several studies investigated plant-based estrogen formulations to determine if less potent compounds would provide a dermatological benefit while minimizing systemic effects. However, variations in formulation type and concentration, application site, and treatment duration among studies makes direct comparison of efficacy challenging. In addition to variability in formulations, another notable limitation across the literature is the predominant focus of postmenopausal women as the study population. Given the physiologic decrease in estrogen associated with menopause and its contribution to age-related skin changes, this population represents an intuitive target for topical estrogen treatment. Several studies suggest that topical estrogen therapy should be initiated within a defined period following menopause onset, as early intervention may help preserve dermal collagen by preventing excessive collagen loss rather than only replacing deficits.^6,18-23 These findings raise the possibility that topical estrogen therapy administered in the years preceding menopause could provide a further dermatological benefit by amplifying the prophylactic effects. 

Future directions for topical estrogen therapy should consider treatment in premenopausal women to determine if similar dermatological benefits occur in populations without physiologic estrogen depletion. This is important because dermal collagen levels were preserved during early treatment intervention with topical estrogens,²⁴ suggesting a prophylactic association whereby early intervention may prevent rather than reverse estrogen-depleted skin changes. In addition, future studies should aim to increase sample sizes and extend observation periods to better evaluate the generalizability of study results. Prospective studies should analyze systemic effects and overdose risk when larger surface area application sites are used to clarify the safety profile of topical estrogen therapy and possible overexposure threshold.^5,6

Conclusion   

This present review suggests that topical estrogen therapy is effective in providing measurable improvements in the quality of aging skin without adverse systemic effects. Many studies report enhanced collagen levels, skin thickness, and subjective qualitative skin augmentation without notable systemic physiologic changes. The target population for treatment is postmenopausal women, especially within the perimenopausal period, due to the possible prophylactic influence of topical estrogen therapy preventing collagen loss. However, the preventative capability of topical estrogen remains a novel finding that warrants further exploration in future studies and generalizability of findings may be limited due to the population focus of postmenopausal women. Future investigations are needed to analyze optimal formulations of topical estrogens, long-term safety with larger surface area application sites, and the prophylactic benefits of topical estrogen therapy. Future studies should explore ideal formulations of topical estrogens, further characterize long-term safety with larger application surface areas, and analyze the prophylactic potential of topical estrogen therapy. 

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