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Abstract:

Postmenopausal women are more susceptible to poor wound healing. This phenomenon can be reversed by estrogen replacement therapy in non-diabetic individuals. Postmenopausal women with type 2 diabetes are more susceptible to wound healing complications, potentially secondary to an estrogen deficiency. Few studies have examined the mechanism of action and effects of estrogens on diabetic wound healing in females. It appears that multiple factors influence delayed wound healing among individuals with diabetes including: an imbalance in cytokines, growth factors, extracellular matrix (ECM) turnover, and oxidant stress (OS). Estrogens have been shown to regulate the expression of genes important for extracellular matrix turnover, including collagen and matrix metalloproteinases (MMP). Methods. For this reason, the effects of 17β-estradiol (E₂) on MMP-2, MMP-13, and MMP-14 and estrogen receptor alpha and beta (ER-α and -β) expression in the wound tissue of estrogen-deficient female mice with established type 2 diabetes mellitus (C57BL/6J-m Leprdb/2+) were studied. Results. Topical E₂ upregulates ERα in wound tissue thereby improving and accelerating diabetic wound healing in estrogen deficient mice. Conclusion. The mechanism appears to decrease MMP-2, MMP-13, and MMP-14 mediated tissue matrix destruction and increasing collagen content.

  It has been shown clinically that postmenopausal women are more susceptible to wound complications. The decline of postmenopausal estrogens leads to dysregulation of extracellular matrix turnover (ECM) and increased inflammation in wounds.¹ This process is prevented or reversed by topical and systemic 17b-estradiol (E₂) replacement therapy.² Skin is a direct estrogen target tissue and expresses both ERa and ERb.³ In humans, both topical and systemic estrogens have been shown to improve wound healing through a number of mechanisms: inflammatory response modulation, cytokine stimulation, matrix deposition, re-epithelialization rate enhancement, angiogenesis stimulation, and proteolysis regulation.^2,4 In addition, Ashcroft et al⁴ have demonstrated that estrogen is the major reproductive hormone involved in dermal fibroblast proliferation. During the inflammatory phase of wound healing, estrogen has been shown to enhance the oxidative metabolism of activated neutrophils during phagocytosis and decrease local levels of inflammatory cell-derived proteases.⁵ Pirila et al6 further demonstrated that decreased wound collagen deposition was associated with matrix metalloproteinase (MMP)-mediated collagenolysis in ovariectomized rats. Estrogen replacement could reverse these effects thereby suggesting an important role for estrogen in the balance between matrix degradation and synthesis.
  Multiple studies have been published on estrogen’s role in improving wound healing.^1,2,4,6,7,9 However, there is a paucity of data on its ability to improve/accelerate healing in women with diabetes. This group has been found to be at a greater risk for diabetic complications when compared to men with diabetes.^9,10
  Diabetic wounds have a prolonged inflammatory phase.¹¹ This is most likely due to bacterial contamination and associated repetitive painless tissue injury. This leads to an increased response from proteases, especially MMPs and elastase. MMPs can either degrade the ECM or regulate numerous biological activities through specific cell signaling mechanisms once activated and left uninhibited.¹¹ MMPs, expressed by fibroblasts, inflammatory cells, and keratinocytes play an essential role in wound debridement, angiogenesis, epithelialization, and scar remodeling.