Role of Estrogens in Wound Healing - Coursework Example

Role of Estrogens in wound healing Introduction The acute healing of wounded skin is a complex process comprising a series of overlapping phases. After the coagulation, there is excess blood loss. This blood loss is prevented by the formation of scab. The degranulating platelets then release a range of proinflammatory cytokines that engage the inflammatory cells and fibroblasts to the site of scab formation. These inflammatory cells and fibroblasts then synthesize factors that mediate the later stages of the repair process. The increase in angiogenesis then facilitates the delivery of nutrients to the wound site. The epidermal barrier and basement membrane are restored by migrating keratinocytes. The dermal fibroblast aroused by growth factors like transforming growth factor (TGF)-β1 differentiate into contractile myofibroblasts, (23) which then draw the wound margins together. The dermis itself is reassembled by the matrix proteins which are fibroblast derived, are gradually remodeled, resulting in the end product which is a connective tissue scar. (21). The recent studies have emerged the key roles of a prolonged inflammatory response,(4) up-regulated protease activity,(5) and reduced matrix deposition(3) in age-related impaired healing. There is another research that indicates that sex steroid hormones have a deep effect upon the process of wound healing. Adrenocorticotropic hormone, which is synthesized in the adrenal cortex and released into the bloodstream in large quantities in response to,(1) the sex steroid precursor dehydroepiandrosterone (DHEA) which serves as a reservoir for the peripheral biosynthesis of androgenic and estrogenic effectors, which include 5α-dihydrotestosterone (DHT) and 17bestradiol. Estrogen: The critical factor of wound healing is the hormone estrogen, which speeds up repair in both human and animal models (16). Estrogen, the predominant steroid responsible for secondary sexual characteristics in girls and women, influences the function of all major organ systems within the body. The skin is the largest non-reproductive target on which the hormone, estrogen acts.(9) The levels of bio-available estrogen is changed in the elderly due to a combination of decreased circulating gonadal estrogen, particular in postmenopausal women and severely reduced levels of the adrenal sex steroid precursor dehydroepiandrosterone (DHEA), resulting in a parallel decrease in androgen and estrogen formation from DHEA aromatization in peripheral tissues(11, 14, 22). The reversal of the age-related impaired healing in females when applied topically or given systemically is caused by the estrogen and is also related with less local inflammation and increased matrix deposition(2, 10). Estrogen mediates its role via receptors: Estrogens mediate their role via both cell surface and intercellular receptors. The estrogen receptor (ER) belongs to a superfamily of nuclear receptors including those for steroid and thyroid hormones, vitamin-D3 and retinoic acid. ERα and ERβ, the classic and the recently discovered estrogen receptor respectively have provided further challenges to understanding the mechanism of estrogen action.(17) 17β-estradiol enters cell and binds with the intracellular nuclear receptors that dimerize and interact with estrogen response elements (ERE) to initiate gene transcription. Alternatively, it interacts with a plasma membrane receptor that in turn interacts with cell signaling pathway. This activates a different set of genes. This non-genomic signaling mechanism results in cellular response to estrogens (17). Multi-functional cytokine macrophage migration inhibitor factor (MIF): MIF is expressed during wound healing by the proliferating epidermis, endothelial cells and infiltrating inflammatory cells. This receptor has emerged as an important mediator in the estrogen role in the skin repair (20). MIF down regulates MIF and tumor necrosis factor (TNF-α) expression in monocytes, which leads to reduction in inflammation, higher matrix deposition and accelerated wound repair (20). Platelet-derived growth factor (PDGF): Estrogen stimulates the expression PDGF by monocytes and macrophages. It is mitogenic and chemotactic for dermal fibroblasts and stimulates fibroblast-driven wound contraction. The secretion of TGF-b1 by dermal fibroblasts is also increased in the presence of estrogen. TGF-β1 respectively induces and inhibits the formation and degradation of extracellular matrix. Also, stimulates the formation of granulation tissue, and promotes collagen deposition.(21) Table 1.In vitro effects of estrogens on specific cell types and consequences in wound healing. (7) Estrogen in wound healing: Its role Modulating the inflammatory response: Estrogen influences cutaneous wound healing by modulating the inflammatory response, cytokine expression, and matrix deposition; by accelerating re-epithelialization; by stimulating angiogenesis and wound contraction; and by regulating proteolysis. The lack of estrogen in ovariectomized female mice resulted in impaired wound healing (Figure.1). The inflammation was more enhanced, reepithelialization was delayed. The wound size also increased and the collagen deposition decreased. (21) Figure 2. Figure representing the cutaneous repair is enhanced in androgen-depleted rodents, but is impaired as a consequence of ovariectomy.(8, 16, 21) Figure 3. The deposition of matrix at day 7 was enhanced in elderly males and females by topical estrogen (2). Mitogenic effect on keratinocytes: Estrogen has a mitogenic effect on keratinocytes. The rate of reepithelialization increased after wounding(6, 10). Moreover, it also stimulated and inhibited the proliferation and oxidative stress-induced apoptosis of human keratinocytes in vitro (12, 13). Influence angiogenesis by a direct effect on endothelial cells: Estrogen is also known to influence angiogenesis by affecting the epithelial cells directly. 17β-estradiol increases in vitro attachment of human endothelial cells to laminin, collagen types I and IV, and fibronectin.(18) When a monolayer of endothelial cells is wounded by scraping, the estradiol treated cells reach to the wound three times faster than the control cells. (18) 17β -estradiol also enhances the ability of endothelial cells to form capillary-like structures when placed on a reconstituted basement membrane.(15) Summary It is becoming clear that the sex steroid hormones and the changes in their rate of biosynthesis that are responsible for chronological ageing has a major effect upon wound healing. Although the function of progesterone is not researched in detail, but estrogens have a rapid healing by restricting the level of inflammatory response. Estrogen is responsible for regulating many aspects of skin biology and immunology. These regulatory effects can be changed for the therapy of or prevention of several pathophysiological conditions. Estrogen alone or together with progesterone, may prevent chronological or photoinduced skin aging and improve psoriasis and chronic wounds such as venous, diabetic or pressure ulcers.(19) Reference: 1. Arvat E, D. V. L., Lanfranco F, et al. . 2000. Stimulatory effect of adrenocorticotropin on cortisol, aldosterone, and dehydroepiandrosterone secretion in normal humans: dose-response study. . J Clin Endocrinol Metab 85:3141- 6. 2. Ashcroft GS, G.-W. T., Horan MA, Wahl SM, Ferguson MWJ. . 1999. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol 155:1137-1146. 3. Ashcroft GS, H. M., Ferguson MW. . 1997. Ageing 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 108:430-7. 4. Ashcroft GS, H. M., Ferguson MW. . 1998. Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest 78. 5. Ashcroft GS, H. M., Herrick SE. 1997. 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 290:581-5. 6. Ashcroft GS, Y. X., Glick AB, et al. . 1999. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1:260-6. 7. Gillian S Aschcroft, J. J. A. 2003. Potential role of estrogens in wound healing. Am. J. Clin. Dermatol 4:737-743. 8. Gilliver SC, A. J., Mills SJ, et al. 2006. Androgens modulate the inflammatory response during acutewound healing. JCell Sci 119:722-32. 9. Glenda Hall, a. T. J. P. 2005. Estrogen and skin: The effects of estrogen, menopause, and hormone replacement therapy on the skin J Am Acad Dermatol 10. GS., A. 1997. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels. . Nat Med 3:1209–1215. 11. HM., P. 1999. The endocrinology of aging. Clin Chem 45:1369–1376. 12. Kanda N, W. S. 2004. 7b-estradiol stimulates the growth of human keratinocytes by inducing cyclin D2 expression. J Invest Dermatol 123:319-28. 13. Kanda N, W. S. 2003. 17b-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression. J Invest Dermatol 121:1500-9. 14. Labrie F, L.-T. V., Labrie C, Simard J. . 2001. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 22:185–212. 15. M., C. 2000. Oestrogens and wound healing. Maturitas 34:195-210. 16. Mills, G. S. A. a. S. J. 2002. Androgen receptor-mediated inhibition of cutaneous wound healing J Clin Invest. 110:615-624. 17. MJ, T. 2002. The biological actions of estrogens on skin. Experimental Dermatology 11:487-502. 18. Morales DE, M. K., Grant DS, et al. 1995. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. . Circulation 91:755-63. 19. Naoko Kanda, S. W. 2005. Regulatory roles of sex hormones in cutaneous biology and immunology. Journal of Dermatological Science 38:1-7. 20. Stephen C. Gilliver, G. S. A. 2007. Sex steroids and cutaneous wound healing: the contrasting influences of estrogens and androgens. Climacteric 10:276-288. 21. Stephen C. Gilliver, J. J. A., Gillian S. Ashcroft. . 2007. The hormonal regulation of cutaneous wound healing. Clinics in Dermatology 25:56-62. 22. Van den Beld AW, d. J. F., Grobbee DE, Pols HA, Lamberts SW. 2000. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. . J Clin Endocrinol Metab 85:3276–3282. 23. Vaughan MB, H. E., Tomasek JJ. 2000. Transforming growth factor b1 promotes the morphological and functional differentiation of the myofibroblast. . Exp Cell Res 257:180-9.  Read More