Estradiol

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.

Effects


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

C

Healing

Moderate

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

C

Increased skin elasticity

Moderate

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

C

Smaller pores

Moderate

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

C

Wrinkle treatment

Moderate

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

C

Increased skin hydration

Moderate

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

C

Increased skin thickness

Moderate

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

C

Smoother skin

Mild

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

D

Reduced hair loss

Moderate

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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Scientific Research


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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]

Scientific References


  1. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. (2011)
  2. Thomas MP, Potter BV. The structural biology of oestrogen metabolism. J Steroid Biochem Mol Biol. (2013)
  3. Young IJ, Hillman JR, Knights BA. Endogenous Estradiol-17 β in Phaseolus vulgaris. Zeitschrift für Pflanzenphysiologie. (1978)
  4. Egras AM, Umland EM. The role of transdermal estrogen sprays and estradiol topical emulsion in the management of menopause-associated vasomotor symptoms. Int J Gen Med. (2010)
  5. Bidmon HJ, et. al. Estradiol distribution and penetration in rat skin after topical application, studied by high resolution autoradiography. Histochemistry. (1990)
  6. Goodman M, Barry BW. Action of penetration enhancers on human skin as assessed by the permeation of model drugs 5-fluorouracil and estradiol. I. Infinite dose technique. J Invest Dermatol. (1988)
  7. Mahmoud A, et. al. Cutaneous estradiol permeation, penetration and metabolism in pig and man. Skin Pharmacol Physiol. (2005)
  8. Kopper NW, Gudeman J, Thompson DJ. Transdermal hormone therapy in postmenopausal women: a review of metabolic effects and drug delivery technologies. Drug Des Devel Ther. (2009)
  9. Walters KA, et. al. Comparison of the transdermal delivery of estradiol from two gel formulations. Maturitas. (1998)
  10. Järvinen A, et. al. Comparative absorption and variability in absorption of estradiol from a transdermal gel and a novel matrix-type transdermal patch. Maturitas. (2001)
  11. Morgan TM, et. al. Transdermal delivery of estradiol in postmenopausal women with a novel topical aerosol. J Pharm Sci. (1988)
  12. Morgan TM, et. al. Enhanced skin permeation of sex hormones with novel topical spray vehicles. J Pharm Sci. (1998)
  13. Morgan TM, et. al. Enhanced transdermal delivery of sex hormones in swine with a novel topical aerosol. J Pharm Sci. (1998)
  14. El Maghraby GM, Williams AC, Barry BW. Skin delivery of oestradiol from deformable and traditional liposomes: mechanistic studies. J Pharm Pharmacol. (1999)
  15. El Maghraby GM, Williams AC, Barry BW. Skin delivery of oestradiol from lipid vesicles: importance of liposome structure. Int J Pharm. (2000)
  16. El Maghraby GM, Williams AC, Barry BW. Oestradiol skin delivery from ultradeformable liposomes: refinement of surfactant concentration. Int J Pharm. (2000)
  17. El Maghraby GM, Williams AC, Barry BW. Skin hydration and possible shunt route penetration in controlled estradiol delivery from ultradeformable and standard liposomes. J Pharm Pharmacol. (2001)
  18. Peltola S, et. al. Microemulsions for topical delivery of estradiol. Int J Pharm. (2003)
  19. Valenzuela P, Simon JA. Nanoparticle delivery for transdermal HRT. Nanomedicine. (2012)
  20. Lyrenäs S, et. al. A comparison of serum oestrogen levels after percutaneous and oral administration of oestradiol-17 beta. Br J Obstet Gynaecol. (1981)
  21. Padwick ML, Endacott J, Whitehead MI. Efficacy, acceptability, and metabolic effects of transdermal estradiol in the management of postmenopausal women. Am J Obstet Gynecol. (1985)
  22. Powers MS, et. al. Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol. (1985)
  23. Scott RT Jr, et. al. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol. (1991)
  24. Setnikar I, et. al. Pharmacokinetics of estradiol and of estrone during repeated transdermal or oral administration of estradiol. Arzneimittelforschung. (1996)
  25. Setnikar I, et. al. Pharmacokinetics of estradiol and of estrone during application of a new 7-day estradiol transdermal patch with active matrix. Arzneimittelforschung. (1998)
  26. Brennan JJ, et. al. Serum concentrations of 17beta-estradiol and estrone after multiple-dose administration of percutaneous estradiol gel in symptomatic menopausal women. Ther Drug Monit. (2001)
  27. Brincat MP, Baron YM, Galea R. Estrogens and the skin. Climacteric. (2005)
  28. MacLean AB, Nicol LA, Hodgins MB. Immunohistochemical localization of estrogen receptors in the vulva and vagina. J Reprod Med. (1990)
  29. Archer DF. Postmenopausal skin and estrogen. Gynecol Endocrinol. (2012)
  30. Shu YY, Maibach HI. Estrogen and skin: therapeutic options. Am J Clin Dermatol. (2011)
  31. Schmidt JB, et. al. Treatment of skin ageing symptoms in perimenopausal females with estrogen compounds. A pilot study. Maturitas. (1994)
  32. Schmidt JB, et. al. Treatment of skin aging with topical estrogens. Int J Dermatol. (1996)
  33. Sator PG, et. al. The influence of hormone replacement therapy on skin ageing: a pilot study. Maturitas. (2001)
  34. Brincat M, et. al. Skin collagen changes in post-menopausal women receiving oestradiol gel. Maturitas. (1987)
  35. Varila E, et. al. The effect of topical oestradiol on skin collagen of postmenopausal women. Br J Obstet Gynaecol (1995)
  36. Patriarca MT, et. al. Effects of topical estradiol on the facial skin collagen of postmenopausal women under oral hormone therapy: a pilot study. Eur J Obstet Gynecol Reprod Biol. (2007)
  37. Masuda Y, Hirao T, Mizunuma H. Improvement of skin surface texture by topical estradiol treatment in climacteric women. J Dermatolog Treat. (2013)
  38. Patriarca MT, et. al. Hyaluronic acid concentration in postmenopausal facial skin after topical estradiol and genistein treatment: a double-blind, randomized clinical trial of efficacy. Menopause. (2013)
  39. Callens A, et. al. Does hormonal skin aging exist? A study of the influence of different hormone therapy regimens on the skin of postmenopausal women using non-invasive measurement techniques. Dermatology. (1996)
  40. Fuchs KO, et. al. The effects of an estrogen and glycolic acid cream on the facial skin of postmenopausal women: a randomized histologic study. Cutis. (2003)
  41. Shah MG, Maibach HI. Estrogen and skin. An overview. Am J Clin Dermatol. (2001)
  42. Castelo-Branco C, Duran M, González-Merlo J. Skin collagen changes related to age and hormone replacement therapy. Maturitas. (1992)
  43. Brincat M, et. al. Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gynecol. (1987)
  44. Brincat M, et. al. A study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman. Obstet Gynecol. (1987)
  45. Rittié L, et. al. Induction of collagen by estradiol: difference between sun-protected and photodamaged human skin in vivo. Arch Dermatol. (2008)
  46. Neder L, Medeiros SF. Topical estradiol does not interfere with the expression of the metalloproteinase-1 enzyme in photo exposed skin cells. An Bras Dermatol. (2012)
  47. Son ED, et. al. Topical application of 17beta-estradiol increases extracellular matrix protein synthesis by stimulating tgf-Beta signaling in aged human skin in vivo. J Invest Dermatol. (2005)
  48. Gendimenico GJ, et. al. Topical estrogens: their effects on connective tissue synthesis in hairless mouse skin. Arch Dermatol Res. (2002)
  49. Röck K, et. al. Estradiol protects dermal hyaluronan/versican matrix during photoaging by release of epidermal growth factor from keratinocytes. J Biol Chem. (2012)
  50. Henry F, et. al. Age-related changes in facial skin contours and rheology. J Am Geriatr Soc. (1997)
  51. Piérard-Franchimont C, et. al. Climacteric skin ageing of the face--a prospective longitudinal comparative trial on the effect of oral hormone replacement therapy. Maturitas. (1999)
  52. Ohnemus U, et. al. Hair cycle control by estrogens: catagen induction via estrogen receptor (ER)-alpha is checked by ER beta signaling. Endocrinology. (2005)
  53. Ohnemus U, et. al. The hair follicle as an estrogen target and source. Endocr Rev. (2006)
  54. Hoffmann R, et. al. 17alpha-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo. Exp Dermatol. (2002)
  55. Kim JH, et. al. The Efficacy and Safety of 17α-Estradiol (Ell-Cranell® alpha 0.025%) Solution on Female Pattern Hair Loss: Single Center, Open-Label, Non-Comparative, Phase IV Study. Ann Dermatol. (2012)
  56. Ohnemus U, et. al. Topical estrogen accelerates hair regrowth in mice after chemotherapy-induced alopecia by favoring the dystrophic catagen response pathway to damage. J Invest Dermatol. (2004)
  57. Blume-Peytavi U, et. al. Comparison of the efficacy and safety of topical minoxidil and topical alfatradiol in the treatment of androgenetic alopecia in women. J Dtsch Dermatol Ges. (2007)
  58. Niiyama S, Happle R, Hoffmann R. Influence of estrogens on the androgen metabolism in different subunits of human hair follicles. Eur J Dermatol. (2001)
  59. Olsen EA, et. al. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol. (2006)
  60. Oh HS, Smart RC. An estrogen receptor pathway regulates the telogen-anagen hair follicle transition and influences epidermal cell proliferation. Proc Natl Acad Sci U S A. (1996)
  61. Smart RC, et. al. Effects of 17-beta-estradiol and ICI 182 780 on hair growth in various strains of mice. J Investig Dermatol Symp Proc. (1999)
  62. Chanda S, et. al. 17beta-estradiol and ICI-182780 regulate the hair follicle cycle in mice through an estrogen receptor-alpha pathway. Am J Physiol Endocrinol Metab. (2000)
  63. Ashcroft GS, et. al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med. (1997)
  64. Ashcroft GS, et. al. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol. (1999)
  65. Campbell L, et. al. Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of its antiinflammatory activities. J Exp Med. (2010)
  66. Stevenson S, et. al. 17beta-estradiol regulates the secretion of TGF-beta by cultured human dermal fibroblasts. J Biomater Sci Polym Ed. (2008)
  67. Merlo S, et. al. Differential involvement of estrogen receptor alpha and estrogen receptor beta in the healing promoting effect of estrogen in human keratinocytes. J Endocrinol. (2009)
  68. Gharaee-Kermani M, Phan SH. Role of cytokines and cytokine therapy in wound healing and fibrotic diseases. Curr Pharm Des. (2001)
  69. Barrientos S, et. al. Growth factors and cytokines in wound healing. Wound Repair Regen. (2008)
  70. Suzuki T, et. al. 17 beta-estradiol administration following trauma-hemorrhage prevents the increase in Kupffer cell cytokine production and MAPK activation predominately via estrogen receptor-alpha. Surgery. (2006)
  71. Suzuki T, et. al. Salutary effects of 17beta-estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor-alpha. Am J Physiol Cell Physiol. (2007)
  72. Suzuki T Estrogen receptor-alpha predominantly mediates the salutary effects of 17beta-estradiol on splenic macrophages following trauma-hemorrhage. Am J Physiol Cell Physiol. (2007)
  73. Moeinpour F, et. al. Estradiol's salutary effects on keratinocytes following trauma-hemorrhage are mediated by estrogen receptor (ER)-alpha and ER-beta. Mol Med. (2008)
  74. Shafighi M, et. al. Topical application of 17β-estradiol (E2) improves skin flap survival through activation of endothelial nitric oxide synthase in rats. Wound Repair Regen. (2012)
  75. Balfour JA, Heel RC. Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Drugs. (1990)
  76. Corazza M, et. al. Allergic contact dermatitis from transdermal estradiol and systemic contact dermatitis from oral estradiol. A case report. J Reprod Med. (2002)
  77. Frenkel Y, et. al. Acceptability and skin reactions to transdermal estrogen replacement therapy in relation to climate. Maturitas. (1994)
  78. Rozenbaum H, et. al. Comparison of two estradiol transdermal systems (Oesclim 50 and Estraderm TTS 50). I. Tolerability, adhesion and efficacy. Maturitas. (1996)
  79. Rozenbaum H, et. al. Comparison of two estradiol transdermal systems (Oesclim 50 and Estraderm TTS 50). II. Local skin tolerability. Maturitas. (1996)
  80. Boehncke WH, Gall H. Type-IV hypersensitivity to topical estradiol in a patient tolerant to it orally. Contact Dermatitis. (1996)
  81. Chen WY. Postmenopausal hormone therapy and breast cancer risk: current status and unanswered questions. Endocrinol Metab Clin North Am. (2011)
  82. Verdier-Sévrain S. Effect of estrogens on skin aging and the potential role of selective estrogen receptor modulators. Climacteric. (2007)
  83. Sator PG, et. al. Skin aging and sex hormones in women -- clinical perspectives for intervention by hormone replacement therapy. Exp Dermatol. (2004)
  84. Wester RC, Hui X, Maibach HI. In vivo human transfer of topical bioactive drug between individuals: estradiol. J Invest Dermatol. (2006)
  85. Taylor MB, Gutierrez MJ. Absorption, bioavailability, and partner transfer of estradiol from a topical emulsion. Pharmacotherapy. (2008)
  86. Schumacher RJ, et. al. The effects of skin-to-skin contact, application site washing, and sunscreen use on the pharmacokinetics of estradiol from a metered-dose transdermal spray. Menopause. (2009)