Hormonal Influences on Wound Healing: A Review of Current Experimental Data

Author(s): 
Matthew J. Hardman, PhD, and Gillian S. Ashcroft, MA, MRCP, PhD

Wounds to the skin heal via a complex series of overlapping stages involving numerous cell and tissue types.1 In young individuals, these events are tightly regulated. However, in elderly subjects, this regulation and synchronization becomes disrupted. Evidence exists that sex hormones have a modulatory function in a range of biological systems. Differences in the timing and quality of cutaneous healing between genders are strongly indicative of hormonal regulation.2,3

Aging, Hormones, and Healing

Aging is accompanied by a reduction in systemic and local hormone levels. In postmenopausal women, this reduction is swift and dramatic. A clear correlation exists between estrogen levels and the rate of healing with retarded cutaneous healing in post-menopausal women reversed by exogenous estrogen.2 The skin has recently been shown to be a steroidogenic tissue containing the full cytochrome P450 system required for the de novo production of sex steroids from cholesterol (Figure 1).4 This raises the possibility that bioactive hormones locally synthesized within the wound microenvironment may also be important in this biological system.
Increased age and the associated reduction in hormone levels are significant risk factors for development of a nonhealing skin wound, such as a venous ulcer.5 Impaired wound healing states—acute wounds that fail to heal and chronic ulcers—are characterized by excessive leukocytosis and subsequently enhanced proteolytic degradation of matrix constituents.6–8 A full discussion of the underlying pathology and treatment modalities for nonhealing wounds is beyond the scope of this article.9

Estrogen Accelerates Healing

Age-related changes in skin structure are most prominent in postmenopausal women, ie, due to low estrogen levels. While estrogens are used extensively in hormone replacement therapy (HRT), their mechanisms of action in the skin are only now beginning to be understood. A wide range of cutaneous cell types (eg, fibroblast, endothelial, epithelial, and inflammatory) express estrogen receptors, indicating potential estrogen responsiveness (G.S. Ashcroft, MA, MRCP, PhD, unpublished data 2003). In normal unwounded skin, topical estrogen treatment to some degree reverses 3 age-related skin conditions: 1) skin atrophy by stimulating keratinocyte proliferation and reducing apoptosis, increasing dermal collagen production, and inhibiting MMP expression; 2) skin dryness by altering keratinocyte function, increasing dermal water holding capacity, and increasing sebum production; and 3) skin wrinkles by increasing dermal water holding capacity and increasing number and improving orientation of elastin fibers.10
Ashcroft et al.11,12 have previously demonstrated a clear inverse correlation between age and efficiency of acute wound healing. Elderly subjects heal more slowly, and wounds are characterized by increased inflammation, delayed re-epithelization, delayed neovascularization, and reduced matrix deposition due to attenuated fibroblast function.11,12 The authors’ recent in-vivo and in-vitro studies have begun to characterize the role of hormones in cutaneous healing. In women, a profound shift in healing ability correlates with a dramatic reduction in sex steroids post-menopause. Numerous local proinflammatory cytokines and growth factors are upregulated, and the rate of wound healing declines. The early inflammatory response (neutrophil response) is increased in aged wounds, and macrophage infiltration is delayed.13,14 Quality of scarring in these estrogen-deprived wounds is substantially improved and associated with reduced local TGF-β1 levels.

References: 

References

1. Martin P. Wound healing—aiming for perfect skin regeneration. Science. 1997;276(5309):75–81.
2. Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM, Ferguson MW. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol. 1999;155(4):1137–1146.
3. Ashcroft GS, Horan MA, Herrick SE, Tarnuzzer RW, Schultz GS, Ferguson MW. Age-related differences in the temporal and spatial regulation of matrix metalloproteinases (MMPs) in normal skin and acute cutaneous wounds of healthy humans. Cell Tissue Res. 1997;290(3):581–591.
4. Thiboutot D, Jabara S, McAllister JM, Sivarajah A, Gilliland K, Cong Z, Clawson G. Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1). J Invest Dermatol. 2003;120(6):905–914.
5. Margolis DJ, Knauss J, Bilker W. Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet. 2002;359(9307):675–677.
6. Herrick S, Ashcroft G, Ireland G, Horan M, McCollum C, Ferguson M. Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest. 1997;77(3):281–288.
7. Ashcroft GS, Yang X, Glick AB, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999;1(5):260–266.
8. Ashcroft GS, Lei K, Jin W, et al. Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med. 2000;6(10):1147–1153.
9. Hardman MJ, Ashcroft GS. New and alternative treatments for diabetic foot ulcers: hormones and growth factors. In: Boulton AJ, ed. The Foot in Diabetes. 4th ed. Chichester, UK: John Wiley & Sons; in press.
10. Brincat MP. Hormone replacement therapy and the skin. Maturitas. 2000;35(2):107–117.
11. Ashcroft GS, Horan MA, Ferguson MW. Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model. J Invest Dermatol. 1997;108(4):430–437.
12. Ashcroft GS, Mills SJ, Ashworth JJ. Ageing and wound healing. Biogerontology. 2002;3(6):337–345.
13. Ashcroft GS, Horan MA, Ferguson MW. Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest. 1998;78(1):47–58.
14. Swift ME, Burns AL, Gray KL, DiPietro LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol. 2001;117(5):1027–1035.
15. Ashcroft GS, Dodsworth J, van Boxtel E, et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med. 1997;3(11):1209–1215.
16. Kovacs EJ, Plackett TP, Witte PL. Estrogen replacement, aging, and cell-mediated immunity after injury. J Leukoc Biol. 2004;76(1):36–41.
17. Ashcroft GS, Mills SJ, Lei K, et al. Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest. 2003;111(9):1309–1318.
18. Kalaitzidis D, Gilmore TD. Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol Metab. 2005;16(2):46–52.
19. Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab. 2001;12(4):152–156.
20. Ashcroft GS, Mills SJ. Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest. 2002;110(5):615–624.
21. Im S, Lee ES, Kim W, et al. Expression of progesterone receptor in human keratinocytes. J Korean Med Sci. 2000;15(6):647–654.
22. Ashworth JJ, Smyth JV, Pendleton N, et al. The dinucleotide (CA) repeat polymorphism of estrogen receptor beta but not the dinucleotide (TA) repeat polymorphism of estrogen receptor alpha is associated with venous ulceration. J Steroid Biochem Mol Biol. 2005; Sep 6 [Epub ahead of print].
23. Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003;3(10):791–800.
24. Yu CM, Lai KW, Chen YX, Huang XR, Lan HY. Expression of macrophage migration inhibitory factor in acute ischemic myocardial injury. J Histochem Cytochem. 2003;51(5):625–631.
25. Hardman MJ, Whaite A, Zeef L, Burow M, Nakayama T, Ashcroft GS. Macrophage migration inhibitory factor: a central regulator of wound healing. Am J Pathol. In press.
26. Gilliver SC, Wu F, Ashcroft GS. Regulatory roles of androgens in cutaneous wound healing. Thromb Haemost. 2003;90(6):978–985.
27. Ashcroft GS, Mills SJ, Flanders KC, et al. Role of Smad3 in the hormonal modulation of in vivo wound healing responses. Wound Repair Regen. 2003;11(6):468–473.
28. Taylor RJ, Taylor AD, Smyth JV. Using an artificial neural network to predict healing times and risk factors for venous leg ulcers. J Wound Care. 2002;11(3):101–105.
29. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 1984;59(3):551–555.
30. Mills SJ, Ashworth JJ, Hardman MJ, Ashcroft GS. The sex steroid precursor DHEA accelerates cutaneous wound healing via the estrogen receptor. J Invest Dermatol. In press.
31. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.



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