Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels
Abstract
The cellular and molecular mechanisms underlying the effects of aging on human cutaneous wound healing are poorly understood, and the possible role of reproductive hormones in this process has never been investigated. We report that aging in healthy females was associated with a reduced rate of cutaneous wound healing, but an improved quality of scarring both microscopically and macroscopically, and with reduced levels of transforming growth factor-beta1 (TGF-beta1) immunostaining and steady-state mRNA in the wound. These age-related changes were reversed by the systemic administration of hormone replacement therapy (HRT). Moreover, ovariectomized young female rodents exhibited a marked delay in repair of acute incisional wounds, which was reversed by the topical application of estrogen. The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels.
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Age-related changes can be reversed by systemic hormone replacement therapy or topical estrogen in both male and female subjects.
“Furthermore, age-related changes can be reversed by the systemic administration of hormone replacement therapy (175) or by topical estrogen in both male and female subjects (176).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [175]
Estrogen is important to wound healing, and its deficiency delays or impairs wound healing.
“Numerous studies have shown that estrogen is important to wound healing, and its deficiency delays or impairs wound healing29–33.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [29]
Cites
Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate–Phenol–Chloroform Extraction
Chomczynski, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1006/abio.1987.9999 · Cited by 65,240 · see citing works
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Chomczyński, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1016/0003-2697(87)90021-2 · Cited by 47,092 · see citing works
Transforming growth factor-beta: recent progress and new challenges.
Sporn, M. B., & Roberts, A. B. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.119.5.1017 · Cited by 774 · see citing works
Admission criteria for immunogerontological studies in man: The senieur protocol
Ligthart, G. J., Corberand, J. X., Fournier, C., Galanaud, P., Hijmans, W., Kennes, B., Müller-Hermelink, H. K., & Steinmann, G. G. (1984) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(84)90152-0 · Cited by 754 · see citing works
Piccinni, M., Giudizi, M. G., Biagiotti, R., Beloni, L., Giannarini, L., Sampognaro, S., Parronchi, P., Manetti, R., Annunziato, F., & Livi, C. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.1.128 · Cited by 743 · see citing works
Control of scarring in adult wounds by neutralising antibody to transforming growth factor β
Shah, M., Foreman, D. M., & Ferguson, M. W. J. (1992) · The Lancet · doi:10.1016/0140-6736(92)90009-r · Cited by 618 · see citing works
Self-citationPierce, G. F., Mustoe, T. A., Lingelbach, J., Masakowski, V. R., Griffin, G. L., Senior, R. M., & Deuel, T. F. (1989) · The Journal of Cell Biology · doi:10.1083/jcb.109.1.429 · Cited by 591 · see citing works
Danielpour, D., Dart, L. L., Flanders, K. C., Roberts, A. B., & Sporn, M. B. (1989) · Journal of Cellular Physiology · doi:10.1002/jcp.1041380112 · Cited by 441 · see citing works
Immunohistochemical localization of growth factors in fetal wound healing
Whitby, D. J., & Ferguson, M. W. J. (1991) · Developmental Biology · doi:10.1016/s0012-1606(05)80018-1 · Cited by 409 · see citing works
Self-citationOursler, M. J., CORTESE, C., Keeting, P. E., Anderson, M. A., Bonde, S. K., Riggs, B. L., & Spelsberg, T. C. (1991) · Endocrinology · doi:10.1210/endo-129-6-3313 · Cited by 263 · see citing works
Ashcroft, G. S., Horan, M. A., & Ferguson, M. W. J. (1997) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12289705 · Cited by 240 · see citing works
Self-citationBeck, L. S., Deguzman, L., Lee, W. P., Xu, Y., Siegel, M., & Amento, E. P. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116904 · Cited by 233 · see citing works
Reed, M. J., Vernon, R. B., Abrass, I. B., & Sage, E. H. (1994) · Journal of Cellular Physiology · doi:10.1002/jcp.1041580121 · Cited by 177 · see citing works
The effects of ageing on cutaneous wound healing in mammals.
Ashcroft, G. S., Horan, M. A., & Ferguson, M. W. J. (1995) · Europe PMC (PubMed Central) · Cited by 169 · see citing works
Self-citationEffect of Hormone Replacement Therapy for Menopause on the Mechanical Properties of Skin
Pierard, G., Letawe, C., Dowlati, A., & Piérard-Franchimont, C. (1995) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1995.tb07202.x · Cited by 158 · see citing works
Yang, N., Bryant, H. U., Hardikar, S., Sato, M., Galvin, R. J., Glasebrook, A. L., & Termine, J. D. (1996) · Endocrinology · doi:10.1210/endo.137.5.8612550 · Cited by 145 · see citing works
Colletta, A., Wakefield, L. M., Howell, F. V., et al. (1991) · Journal of Clinical Investigation · doi:10.1172/jci114983 · Cited by 117 · see citing works
Treatment of skin ageing symptoms in perimenopausal females with estrogen compounds. A pilot study
Schmidt, J. B., Binder, M., Macheiner, W., Kainz, C., Gitsch, G., & Bieglmayer, C. (1994) · Maturitas · doi:10.1016/0378-5122(94)90097-3 · Cited by 82 · see citing works
Bolognia, J. L. (1995) · The American Journal of Medicine · doi:10.1016/s0002-9343(99)80066-7 · Cited by 79 · see citing works
Tarnuzzer, R. W., Macauley, S. P., Farmerie, W. G., et al. (1996) · PubMed · doi:10.2144/19962004670 · Cited by 62 · see citing works
Self-citationMalet, C., Gompel, A., Yaneva, H., Cren, H., FIDJI, N., Mowszowicz, I., Kuttenn, F., & MAUVAIS-JARVIS, P. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-73-1-8 · Cited by 59 · see citing works
Frazier-Jessen, M. R., Mott, F. J., Witte, P. L., et al. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.8.3036 · Cited by 52 · see citing works
Overall, C. M. (1995) · Journal of Cellular Physiology · doi:10.1002/jcp.1041640104 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Wound repair and regeneration: Mechanisms, signaling, and translation
Eming, S. A., Martin, P., & Tomic-Canic, M. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009337 · Cited by 3,562 · see citing works
Inflammation in Wound Repair: Molecular and Cellular Mechanisms
Eming, S. A., Krieg, T., & Davidson, J. M. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700701 · Cited by 2,429 · see citing works
The complex role of estrogens in inflammation
Straub, R. H. (2007) · Endocrine Reviews · doi:10.1210/er.2007-0001 · Cited by 1,950 · see citing works
Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response
Ashcroft, G. S., Yang, X., Glick, A. B., Weinstein, M., Letterio, J. J., Mizel, D. E., Anzano, M., Greenwell-Wild, T., Wahl, S. M., Deng, C., et al. (1999) · Nature Cell Biology · doi:10.1038/12971 · Cited by 911 · see citing works
Self-citationScar–free healing: from embryonic mechanisms to adult therapeutic intervention
Ferguson, M. W. J., & O'Kane, S. (2004) · Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences · doi:10.1098/rstb.2004.1475 · Cited by 812 · see citing works
Self-citationRates and risk factors of liver fibrosis progression in patients with chronic hepatitis c
Poynard, T., Ratziu, V., Charlotte, F., Goodman, Z., McHutchison, J., & Albrecht, J. (2001) · Journal of Hepatology · doi:10.1016/s0168-8278(00)00097-0 · Cited by 749 · see citing works
Tobin, D. J. (2017) · Journal of Tissue Viability · doi:10.1016/j.jtv.2016.03.002 · Cited by 701 · see citing works
Photoaging: mechanisms and repair
Rabe, J. H., Mamelak, A. J., McElgunn, P. J. S., Morison, W. L., & Sauder, D. N. (2006) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2005.05.010 · Cited by 610 · see citing works
Ashcroft, G. S., Greenwell-Wild, T., Horan, M. A., Wahl, S. M., & Ferguson, M. W. J. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65217-0 · Cited by 420 · see citing works
Self-citationEstrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor
Ashcroft, G. S., Mills, S. J., Lei, K., Gibbons, L., Jeong, M.-J., Taniguchi, M., Burow, M., Horan, M. A., Wahl, S. M., & Nakayama, T. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16288 · Cited by 335 · see citing works
Self-citationInterrelation of immunity and tissue repair or regeneration
Eming, S. A., Hammerschmidt, M., Krieg, T., & Roers, A. (2009) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2009.04.009 · Cited by 321 · see citing works
Ashcroft, G. S., Mills, S. J., & Ashworth, J. J. (2002) · Biogerontology · doi:10.1023/a:1021399228395 · Cited by 309 · see citing works
Self-citationRegulatory roles of sex hormones in cutaneous biology and immunology
Kanda, N., & Watanabe, S. (2005) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2004.10.011 · Cited by 257 · see citing works
Androgen receptor–mediated inhibition of cutaneous wound healing
Ashcroft, G. S., & Mills, S. J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215704 · Cited by 255 · see citing works
Self-citationThe hormonal regulation of cutaneous wound healing
Gilliver, S. C., Ashworth, J. J., & Ashcroft, G. S. (2007) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2006.09.012 · Cited by 228 · see citing works
Self-citationSkin Aging and Menopause: Implications for Treatment
Raine-Fenning, N. J., Brincat, M. P., & Muscat-Baron, Y. (2003) · American Journal of Clinical Dermatology · doi:10.2165/00128071-200304060-00001 · Cited by 211 · see citing works
Impact of oestrogens on the progression of liver disease
Shimizu, I. (2003) · Liver International · doi:10.1034/j.1600-0676.2003.00811.x · Cited by 207 · see citing works
Gender differences in skin: A review of the literature
Dao, H., & Kazin, R. A. (2007) · Gender Medicine · doi:10.1016/s1550-8579(07)80061-1 · Cited by 199 · see citing works
Sex steroids as inflammatory regulators
Gilliver, S. C. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2009.12.015 · Cited by 198 · see citing works
Campbell, L., Emmerson, E., Davies, F., Gilliver, S. C., Krust, A., Chambon, P., Ashcroft, G. S., & Hardman, M. J. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100500 · Cited by 175 · see citing works
Self-citationAnsell, D. M., Kloepper, J. E., Thomason, H. A., Paus, R., & Hardman, M. J. (2011) · Journal of Investigative Dermatology · doi:10.1038/jid.2010.291 · Cited by 171 · see citing works
The role of estrogen in cutaneous ageing and repair
Wilkinson, H. N., & Hardman, M. J. (2017) · Maturitas · doi:10.1016/j.maturitas.2017.06.026 · Cited by 162 · see citing works
Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly
Hardman, M. J., & Ashcroft, G. S. (2008) · Genome Biology · doi:10.1186/gb-2008-9-5-r80 · Cited by 157 · see citing works
Self-citationAndrogens modulate the inflammatory response during acute wound healing
Gilliver, S. C., Ashworth, J. J., Mills, S. J., Hardman, M. J., & Ashcroft, G. S. (2006) · Journal of Cell Science · doi:10.1242/jcs.02786 · Cited by 147 · see citing works
Self-citationPotential Role of Estrogens in Wound Healing
Ashcroft, G. S., & Ashworth, J. J. (2003) · American Journal of Clinical Dermatology · doi:10.2165/00128071-200304110-00002 · Cited by 130 · see citing works
Self-citationThe role of estrogen deficiency in skin ageing and wound healing
Emmerson, E., & Hardman, M. J. (2012) · Biogerontology · doi:10.1007/s10522-011-9322-y · Cited by 118 · see citing works
Hardman, M. J., Emmerson, E., Campbell, L., & Ashcroft, G. S. (2008) · Endocrinology · doi:10.1210/en.2007-1042 · Cited by 117 · see citing works
Self-citationScarless wound healing: From development to senescence
Pratsinis, H., Mavrogonatou, E., & Kletsas, D. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.04.011 · Cited by 103 · see citing works
Cowin, A. J., Hatzirodos, N., Holding, C. A., Dunaiski, V., Rayner, T. E., Harries, R. H., Fitridge, R., Cooter, R. D., Schultz, G. S., & Belford, D. A. (2001) · Journal of Investigative Dermatology · doi:10.1046/j.0022-202x.2001.01501.x · Cited by 100 · see citing works
Self-citationThe inflammatory phase of fracture healing is influenced by oestrogen status in mice
Haffner-Luntzer, M., Fischer, V., Prystaz, K., Liedert, A., & Ignatius, A. (2017) · European Journal of Medical Research · doi:10.1186/s40001-017-0264-y · Cited by 60 · see citing works
Vascular dysfunction as a potential culprit of sarcopenia
Jeon, Y. K., Shin, M. J., Saini, S. K., Custodero, C., Aggarwal, M., Anton, S. D., Leeuwenburgh, C., & Mankowski, R. T. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2020.111220 · Cited by 60 · see citing works
Merlo, S., Frasca, G., Canonico, P. L., & Sortino, M. A. (2009) · Journal of Endocrinology · doi:10.1677/joe-08-0442 · Cited by 53 · see citing works
Qi, Q., Liu, X., Zhang, Q., & Guo, S.-W. (2020) · Scientific Reports · doi:10.1038/s41598-020-57997-6 · Cited by 44 · see citing works
Ashworth, J., Smyth, J., Pendleton, N., Horan, M., Payton, A., Worthington, J., Ollier, W., & Ashcroft, G. (2008) · Clinical Genetics · doi:10.1111/j.1399-0004.2007.00927.x · Cited by 38 · see citing works
Self-citationStem cells and aberrant signaling of molecular systems in skin aging
Peng, Y., Xuan, M., Leung, V. Y. L., & Cheng, B. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2014.10.006 · Cited by 35 · see citing works
Toraldo, G., Bhasin, S., Bakhit, M., Guo, W., Serra, C., Safer, J. D., Bhawan, J., & Jasuja, R. (2012) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2011.00757.x · Cited by 32 · see citing works
Mukai, K., Nakajima, Y., Urai, T., Komatsu, E., Nasruddin, Sugama, J., & Nakatani, T. (2016) · International Wound Journal · doi:10.1111/iwj.12336 · Cited by 27 · see citing works
Estrogen enhances wound healing in the penis of rats
CN, M., R, H., CL, M., S, J., G, H., & G, H. (2008) · Biomedical Research · doi:10.2220/biomedres.29.267 · Cited by 21 · see citing works
Carney, B. C., Oliver, M. A., Erdi, M., Kirkpatrick, L. D., Tranchina, S. P., Rozyyev, S., Keyloun, J. W., Saruwatari, M. S., Daristotle, J. L., Moffatt, L. T., et al. (2022) · Burns · doi:10.1016/j.burns.2022.01.012 · Cited by 15 · see citing works
Phuong, C., & Maibach, H. I. (2017) · Textbook of Aging Skin · doi:10.1007/978-3-662-47398-6_93 · Cited by 16 · see citing works
- Authors
- Ashcroft, G. S., Dodsworth, J., Boxtel, E. V., Tarnuzzer, R. W., Horan, M. A., Schultz, G. S., & Ferguson, M. W. J.
- Affiliations
- University of Manchester (GB)
- University of Florida Health (US)
- Venue
- Nature Medicine
- Published
- 1997-11
- Volume
- 3
- Issue
- 11
- Pages
- 1209-1215
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1975548084
- Cited by
- 573
- References
- 23
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 20 · 2023: 21 · 2022: 17 · 2021: 12 · 2020: 17 · 2019: 27 · 2018: 15 · 2017: 20 · 2016: 15 · 2015: 18 · 2014: 21 · 2013: 20 · 2012: 24
- FWCI
- 21.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- estrogen, skin wound healing, aging, TGF-β1, hormone replacement therapy, ovariectomy, reproductive hormones, scar formation, dermal fibroblasts, topical estrogen
- MeSH terms
- Administration, Topical, Adult, Aged, Animals, Cell Division, Collagen, Disease Models, Animal, Estradiol, Female, Fibroblasts, Humans, Middle Aged, Ovariectomy, Progesterone, RNA, Messenger, Skin, Wound Healing, Estrogen Replacement Therapy, Transforming Growth Factor beta, Rats, Sprague-Dawley, Rats
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