Although estradiol improves many parameters of skin aging including wrinkles, skin elasticity and pore size, it cannot be recommended as an independent treatment for skin aging until more studies have been done to verify its safety.


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments




Speeds up wound closure by increasing collagen and fibronectin synthesis, decreasing elastase levels and encouraging the migration and proliferation of dermal fibroblasts.


Increased skin elasticity


Reverses the age-related decline in skin elasticity by enhancing the morphology and synthesis of elastic fibers.


Smaller pores


0.01% estradiol decreased pore size in 73% of volunteers after 6 months of treatment in one study.


Wrinkle treatment


0.01% estradiol improved wrinkle depth by 61-100%, but to a smaller extent than 0.3% estriol, in one study.


Increased skin hydration


Improves the water content of the skin via inducing an increase in hyaluronic acid, a water-binding molecule.


Increased skin thickness


Increases the thickness of the skin by 7% to 23%, likely by stimulating keratinocyte proliferation and collagen production.


Smoother skin


Increases the fineness of the skin surface texture at both the applied site and untreated sites.


Reduced hair loss


17α-estradiol increases hair counts and thickness in women suffering from hair loss, and stabilizes hair loss in men with male pattern baldness.

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Table of contents:

1. Sources

Estradiol, often abbreviated as E2, is one of the major naturally occurring estrogens in women, and also the most potent. Like the other steroid hormones, it is a derivative of cholesterol.[1]

It has been shown to play many roles in the human body, including sexual reproduction and the menstrual cycle, appetite and eating behaviour, fat metabolism, auditory and visual processing, the development of breast cancer and osteoarthritis, the prevention of heart disease and neuroprotection during cerebral ischaemia and in multiple sclerosis.[2]

The common bean Phaseolus vulgaris also produces estradiol endogenously.[3]

2. Bioavailability

The topical delivery of estradiol is very well-studied, as it is one of the options for hormone replacement therapy to relieve the vasomotor symptoms of menopause, including hot flashes and night sweats.[4]

2.1 Permeation

There are 2 penetration pathways to the dermis for topical estradiol -- through the stratum corneum and epidermis, or through the hair follicles.[5] Being lipophilic, estradiol permeates the skin more readily than cosmeceuticals that are hydrophilic, such as the polyphenols. One study found that several penetration enhancers (Azone, oleic acid, decylmethyl sulfoxide and propylene glycol) were not very effective in promoting the skin absorption of estradiol, presumably because estradiol is already relatively non-polar.[6]

Nevertheless, to further improve uptake, many transdermal delivery systems for estradiol have been developed,[7] including gels, patches, sprays, microemulsions and nanoparticles.[4][8]

A gel containing estrogen showed an uptake of 41.7% of the applied dose in reconstructed human skin while 42.9% of the applied dose of estradiol in a transdermal patch successfully penetrated pig skin.[7] In addition, 2 gel formulations containing 0.1% and 0.06% estradiol showed a penetration of 17% to 18% of the applied dose, in a separate study.[9] A comparison between a gel and a patch revealed that the extent of absorption for both formulations seemed to correspond.[10]

A topical spray with the penetration enhancer padimate O also significantly enhanced the transdermal delivery of estradiol by aiding its partition into the stratum corneum.[11][12][13]

Liposomes have been demonstrated to improve delivery over aqueous solutions as well, with experimental data suggesting that lipid vesicles increase drug partitioning into the skin,[14] and that liposome components in solution also have an additive effect.[15] Furthermore, derformable liposomes are superior to traditional liposomes in improving skin delivery.[14][16][17]

A microemulsion formulation of estradiol increases its flux dramatically, by 200 too 700-fold, due to a 1500-fold improvement in the solubilization of estradiol, but at the same time decreases permeability coefficients by 5-18 times.[18] Topical micellar nanoparticle estradiol emulsions (MNPEE) have also been validated for transdermal delivery of estradiol, with advantages including low fluctuation of plasma estradiol concentrations, infrequent skin-related adverse events and pleasant cosmetic-like moisturizing properties.[19]

2.2 Pharmacokinetics and pharmacodynamics

A significant proportion of the estradiol that penetrates the skin is metabolized -- in a study on reconstructed human skin, the proportion was found to be 42.6%. The dominating metabolite was estrone, which accounted for 36.3% of the metabolites.[7]

Percutaneous doses of estradiol elicit a slow but significant increase in serum estrogen[20][21] to levels typical of the early follicular phase in premenopausal women.[22] Serum estradiol and estrone levels also remain nearly constant through their use,[23][24][25] and serum concentrations of estradiol are proportional to the dose.[26]

Continuous administration of transdermal estradiol over 3 weeks did not result in any accumulation of estradiol or its conjugates.[22]

3. Effects on the skin

3.1 Improvements in postmenopausal skin

Estrogen has a profound influence on the skin.[27] Estrogen receptors are present in dermal fibroblasts and epidermal keratinocytes,[28] but they decline in number from the onset of menopause in women.[29] This, coupled with the lower estrogen levels in postmenopausal women, exacerbates the undesirable aging of the skin.[30]

Multiple studies and clinical trials have verified the beneficial effects of estradiol on the skin of postmenopausal women. One early study noticed improvement of various skin aging symptoms after 6 months of treatment with a 0.01% estradiol cream.[31] Another study 2 years later confirmed these results, finding that a 0.01% estradiol cream markedly improved the elasticity and firmness of the skin, and induced significant decreases in pore size and wrinkle depth.[32] Likewise, a study investigating the influence of hormone replacement therapy on skin aging found that levels of epidermal skin moisture, elasticity and skin thickness were all improved at the end of 6 months of treatment.[33]

Topical estradiol has also been demonstrated to increase the collagen and elastic fiber content of the skin when applied to the abdomen,[34][35] to increase the collagen content and skin thickness when applied to the face,[36] and to improve the texture of the skin when applied to the forearm.[37] Furthermore, 0.01% estradiol gel led to an increase in the concentration of hyaluronic acid in postmenopausal facial skin, that was more pronounced than that of treatment with a gel containing 4% genistein, a soy isoflavone.[38]

A study on 98 postmenopausal women undergoing hormone replacement therapy with estradiol gel or patches also discovered a 7-15% increase in skin thickness and a 35% increase in sebum compared to an untreated group, though skin hydration was not different in the 2 groups.[39] Similarly, a cream containing 0.01% estrogen brought about a 23% increase in epidermal thickness, which was enhanced to 38% when combined with 15% glycolic acid.[40]

Topical estradiol treatment improves wrinkling because estrogen enhances the morphology and synthesis of collagen, elastic fibres and hyaluronic acid.[30][41] The extent of the increase in collagen content appears to vary with the dose, route of administration and duration of treatment. For instance, a 3-month study found that topical estradiol led to a 38% increase in total collagen,[35] but another study examining both oral and transdermal treatment for 12 months paradoxically found only a 2-5% increase.[42] The rise in collagen levels is also proportionate to baseline collagen levels, with studies suggesting that treatment may be prophylactic for women with high skin collagen levels and both prophylactic and therapeutic for women with low skin collagen content.[43][44] However, there exist differences in estradiol responsiveness between men and women, with the rise in collagen production in men being less pronounced than that in women.[45]

Surprisingly, long-term sun exposure seems to hinder the ability of topical estradiol to stimulate collagen production in aged skin, as 2 weeks' treatment increased procollagen mRNA levels in sun-protected hip skin, but failed to do so in photoaged forearm or face skin.[45] 0.05% estradiol cream also did not affect the expression of metalloproteinase-1 (a collagen-degrading enzyme) in photo-exposed skin,[46] though it has been shown to reduce its expression in human buttock skin.[47] It is possible, though, that treatment periods longer than 2 weeks may demonstrate increases in collagen production similar to those observed in sun-protected skin.[45]

Several small trials have noted that transdermal estradiol gel and patches cause notable alterations in the water content of the skin, resulting in changes in the capacitance of the stratum corneum.[31][33] This hydrating effect is thought to be related to the increase in hyaluronic acid content induced by estradiol, as hyaluronic acid has an unusual capacity to bind water.[27] However, 1 study found no significant difference between a group treated with transdermal estradiol and an untreated group,[39] and the results from another showed an insignificant increase in skin moisture.[32]

Apart from the increase in hyaluronic acid and collagen levels, which correlates with an increase in skin thickness,[27][30][48] topical estradiol also stimulates the proliferation of keratinocytes in both young and aged skin, indicating another mechanism by which it thickens the skin.[47][49]

During aging, the skin, especially that of the face, progressively becomes more extensible and less elastic.[50] In fact, 1 study on 140 early-menopausal women over 5 years revealed that the distensibility of facial skin increased by 1.1% and elasticity decreased by 1.5% per year.[51] Topical estradiol has been shown to reverse this decline in skin elasticity,[32][33] by improving the morphology of the elastic fibers in the skin.[35]

3.2 Reduced hair loss

Estradiol is recognized as a potent modulator of hair growth,[52] profoundly altering hair follicle growth and cycling by binding to locally expressed estrogen receptors.[53]

Estradiol has been used as a topical treatment for both male pattern baldness and female pattern hair loss.[54][55] Topical 17β-estradiol accelerated hair regrowth in mice after chemotherapy-induced hair loss,[56] while 17α-estradiol increased hair counts and diameter in Korean female patients suffering from female pattern hair loss.[55]

However, 0.025% 17α-estradiol solution was shown to be less effective than 2% minoxidil solution in treating male pattern baldness in one study, as it merely decelerated or stabilized hair loss, unlike minoxidil which induced an increase in hair density and thickness.[57]

17α-estradiol, also known as alfatradiol, increased the aromatase-dependent conversion of testosterone to 17β-estradiol and androstendione to estrone in vivo. This has been put forward as a possible explanation of its beneficial effects in treating male pattern baldness.[54] It is also possible that estradiol directly inhibits 5α-reductase,[58] an important enzyme implicated in the treatment of male pattern hair loss.[59] Additionally, different estrogen receptors appear to play different roles in hair biology. The catagen-promoting properties of estradiol are mediated via estrogen receptor-α, whereas estrogen receptor-β may mainly function as a silencer of estrogen receptor-α.[52]

Topical estradiol is also known to inhibit hair growth in mice [60][61] by blocking the transition of the hair follicle from the resting phase (telogen) to the growth phase (anagen).[62]

3.3 Improved wound healing

Aged skin is more susceptible to trauma, tearing and bruising easily.[27] Aging in healthy females is also associated with a reduced rate of cutaneous wound healing.[63] This age-related delay in wound healing has been partially attributed to low levels of TGF-β1, decreased collagen synthesis and increased presence of the enzyme elastase.[27]

In a randomized, double-blind and placebo-controlled study on 36 elderly men and women, an estradiol patch placed on the site of wounds increased the extent of wound healing, showing a decrease in wound size as well as increased collagen and fibronectin levels.[64] Wound elastase levels were also decreased and neutrophil numbers, reduced.[64] In vitro studies indicated that the mechanism underlying the modified inflammatory response involves both a direct inhibition of neutrophil chemotaxis and an altered expression of neutrophil adhesion molecules.[64] This anti-inflammatory activity does not appear to be the principal factor behind estradiol's acceleration of wound healing, however.[65]

Other studies found that estradiol increased the migration and proliferation of dermal fibroblasts, which has been cited as a positive influence on healing by speeding up wound closure.[66][67] Paraxodically, however, estradiol also led to a decrease in TGF-β1 secretion in vitro.[66] As such, it has been suggested that activation of estrogen receptors may result in favourable stimulation of wound healing even without any increase in TGF-β1 production.[67]

Various cytokines have been implicated in the pathogenesis of fibrosis and wound healing.[68][69] Multiple studies on mice and rats also show that estradiol regulates cytokine levels when administrated after trauma-hemorrhage, and the beneficial effects have been shown to be mediated by both estrogen receptor-α and estrogen receptor-β.[70][71][72][73]

Finally, topical application of estradiol was also found to improve the survival of skin flap transplants in a rat model through activating endothelial nitric oxide synthase, which is thought to be another way estradiol may augment wound healing.[74]

4. Side Effects

4.1 Few adverse skin reactions

Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect.[75] It is estimated that about 20% of patients using transdermal estradiol complain of adverse local side effects.[76], but this has varied between <10% and >20% in different studies.[77][78][79] 2 case reports also described the development of contact dermatitis from transdermal estradiol and an estradiol-containing gel, though this is admittedly extremely rare.[76][80]

4.2 Risks of systemic exposure

Transdermal formulations allow estradiol to penetrate not just into the skin but through it. It has been claimed that the incidence of systemic estrogenic effects from transdermal estradiol appears to be comparable to that observed with oral administration,[75] As long-term estrogen replacement therapy has been associated with harmful systemic side effects,[30] including a higher risk for breast cancer,[81] more studies are still required to establish the minimal dose necessary to induce the beneficial effects of attenuating skin aging without causing harm to patients.[46] Until then, hormone replacement therapy using estradiol cannot be recommended solely to treat skin aging.[82][83]

4.3 Partner transfer

While not a side effect per se, it should be noted that topical estradiol can be transferred to other individuals after skin-to-skin contact, which can produce inadvertent effects.[84] Vigorous skin-to-skin contact between 14 postmenopausal women and their male partners 2 to 8 hours after the women had applied a topical emulsion of estradiol to their legs resulted in a statistically significant rise in the male partners' serum estradiol levels.[85] The use of a transdermal estradiol spray, on the other hand, did not lead to significant transfer of estradiol by skin-to-skin contact.[86]

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