The mechanism and treatment progress of inhibited cutaneous ulcers healing in patients with hypercortisolism_West China Medical Journal

Authors：

REN Yan ,  WANG Chun

Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

WANG Chun, Email: snoopywc@163.com

Keywords：

Hypercortisolism; Cutaneous ulcers; Hyperglycemia

DOI：

10.7507/1002-0179.202103159

Video：

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Patients with hypercortisolism may experience cutaneous atrophy, weakened cutaneous barrier function, decreased immunity, opportunistic bacteria or fungal infections, which hinder the healing of cutaneous wounds, and even the ulcers will not heal for a long time, and may progress to chronic ulcers, which are difficult and expensive to treat. It affects the quality of life of patients, and can lead to the spread of infection and life-threatening in severe cases. The pathological mechanism of cutaneous ulcers and delayed healing caused by hypercortisolism is complicated, which is a clinical problem that needs to be solved urgently. This article explains the possible mechanism of hypercortisolism hindering the healing of cutaneous ulcers from the aspects of leading to cutaneous atrophy, pathophysiological abnormalities affecting wound healing, hyperglycemia inhibiting wound healing, and infection and hypercoagulable state, and discusses the possible mechanisms of hypercortisolism hindering the healing of cutaneous ulcers, and its treatment methods, aiming to provide a basis for more in-depth mechanism research and clinical prevention and treatment.

Citation： REN Yan, WANG Chun. The mechanism and treatment progress of inhibited cutaneous ulcers healing in patients with hypercortisolism. West China Medical Journal, 2021, 36(4): 514-518. doi: 10.7507/1002-0179.202103159 Copy

1.	Nieman LK. Recent updates on the diagnosis and management of Cushing’s syndrome. Endocrinol Metab (Seoul), 2018, 33(2): 139-146.
2.	Valette C, Ofaiche J, Severino M, et al. Fatal outcome of Netherton syndrome due to excessive use of topical corticosteroids in an adult patient. Ann Dermatol Venereol, 2020, 147(1): 36-40.
3.	Barbot M, Zilio M, Scaroni C. Cushing’s syndrome: overview of clinical presentation, diagnostic tools and complications. Best Pract Res Clin Endocrinol Metab, 2020, 34(2): 101380.
4.	Biswas M, Gibby O, Ivanova-Stoilova T, et al. Cushing’s syndrome and chronic venous ulceration-a clinical challenge. Int Wound J, 2011, 8(1): 99-102.
5.	Stratakis CA. Skin manifestations of Cushing’s syndrome. Rev Endocr Metab Disord, 2016, 17(3): 283-286.
6.	Erden F, Borlu M, Simsek Y, et al. Differences in skin lesions of endogenous and exogenous Cushing’s patients. Postepy Dermatol Alergol, 2019, 36(3): 272-275.
7.	Kobayashi T, Naik S, Nagao K. Choreographing immunity in the skin epithelial barrier. Immunity, 2019, 50(3): 552-565.
8.	Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol, 2016, 4(7): 611-629.
9.	Tafelski S, Mohamed D, Shaqura M, et al. Identification of mineralocorticoid and glucocorticoid receptors on peripheral nociceptors: translation of experimental findings from animal to human biology. Brain Res, 2019, 1712: 180-187.
10.	Serres M, Viac J, Schmitt D. Glucocorticoid receptor localization in human epidermal cells. Arch Dermatol Res, 1996, 288(3): 140-146.
11.	Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther, 2002, 96(1): 23-43.
12.	Colazo JM, Evans BC, Farinas AF, et al. Applied bioengineering in tissue reconstruction, replacement, and regeneration. Tissue Eng Part B Rev, 2019, 25(4): 259-290.
13.	Lause M, Kamboj A, Fernandez Faith E. Dermatologic manifestations of endocrine disorders. Transl Pediatr, 2017, 6(4): 300-312.
14.	Cordeiro RC, Moraes AM. Ulceration of striae distensae in a patient with systemic lupus erythematosus. J Eur Acad Dermatol Venereol, 2008, 22(3): 390-392.
15.	Arem AJ, Kischer CW. Analysis of striae. Plast Reconstr Surg, 1980, 65(1): 22-29.
16.	Chedid M, Hoyle JR, Csaky KG, et al. Glucocorticoids inhibit keratinocyte growth factor production in primary dermal fibroblasts. Endocrinology, 1996, 137(6): 2232-2237.
17.	Meisler N, Shull S, Xie R, et al. Glucocorticoids coordinately regulate type I collagen pro alpha 1 promoter activity through both the glucocorticoid and transforming growth factor beta response elements: a novel mechanism of glucocorticoid regulation of eukaryotic genes. J Cell Biochem, 1995, 59(3): 376-388.
18.	Caffarini M, Armeni T, Pellegrino P, et al. Cushing syndrome: the role of MSCs in wound healing, immunosuppression, comorbidities, and antioxidant imbalance. Front Cell Dev Biol, 2019, 7: 227.
19.	Slominski AT, Zmijewski MA. Glucocorticoids inhibit wound healing: novel mechanism of action. J Invest Dermatol, 2017, 137(5): 1012-1014.
20.	Bjelaković G, Beninati S, Pavlović D, et al. Glucocorticoids and oxidative stress. J Basic Clin Physiol Pharmacol, 2007, 18(2): 115-127.
21.	Dunnill C, Patton T, Brennan J, et al. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J, 2017, 14(1): 89-96.
22.	Jozic I, Sawaya AP, Pastar I, et al. Pharmacological and genetic inhibition of caveolin-1 promotes epithelialization and wound closure. Mol Ther, 2019, 27(11): 1992-2004.
23.	Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol, 2006, 117(3): 522-543.
24.	Lee B, Vouthounis C, Stojadinovic O, et al. From an enhanceosome to a repressosome: molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing. J Mol Biol, 2005, 345(5): 1083-1097.
25.	Scaroni C, Zilio M, Foti M, et al. Glucose metabolism abnormalities in Cushing syndrome: from molecular basis to clinical management. Endocr Rev, 2017, 38(3): 189-219.
26.	Friedman TC, Mastorakos G, Newman TD, et al. Carbohydrate and lipid metabolism in endogenous hypercortisolism: shared features with metabolic syndrome X and NIDDM. Endocr J, 1996, 43(6): 645-655.
27.	Biering H, Knappe G, Gerl H, et al. Prevalence of diabetes in acromegaly and Cushing syndrome. Acta Med Austriaca, 2000, 27(1): 27-31.
28.	Cadau S, Leoty-Okombi S, Pain S, et al. In vitro glycation of an endothelialized and innervated tissue-engineered skin to screen anti-AGE molecules. Biomaterials, 2015, 51: 216-225.
29.	Chen YH, Chen ZW, Li HM, et al. AGE/RAGE-induced EMP release via the NOX-derived ROS pathway. J Diabetes Res, 2018, 2018: 6823058.
30.	Lao G, Ren M, Wang X, et al. Human tissue inhibitor of metalloproteinases-1 improved wound healing in diabetes through its anti-apoptotic effect. Exp Dermatol, 2019, 28(5): 528-535.
31.	Lan CC, Wu CS, Huang SM, et al. High-glucose environment reduces human β-defensin-2 expression in human keratinocytes: implications for poor diabetic wound healing. Br J Dermatol, 2012, 166(6): 1221-1229.
32.	Deluyker D, Evens L, Bito V. Advanced glycation end products (AGEs) and cardiovascular dysfunction: focus on high molecular weight AGEs. Amino Acids, 2017, 49(9): 1535-1541.
33.	Evens L, Beliën H, Deluyker D, et al. The impact of advanced glycation end-products (AGEs) on proliferation and apoptosis of primary stem cells: a systematic review. Stem Cells Int, 2020, 2020: 8886612.
34.	Li M, Zhao Y, Hao H, et al. Umbilical cord-derived mesenchymal stromal cell-conditioned medium exerts in vitro antiaging effects in human fibroblasts. Cytotherapy, 2017, 19(3): 371-383.
35.	Senthil KK, Gokila VM, Mau JL, et al. A steroid like phytochemical antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1. Oncotarget, 2016, 7(39): 62836-62861.
36.	Salpea KD, Maubaret CG, Kathagen A, et al. The effect of pro-inflammatory conditioning and/or high glucose on telomere shortening of aging fibroblasts. PLoS One, 2013, 8(9): e73756.
37.	李炳旻, 王芳芳, 李倩坤, 等. 糖尿病溃疡的发生机制与治疗进展. 解放军医学院学报, 2019, 40(10): 992-994.
38.	Chang FJ, Yuan HY, Hu XX, et al. High density lipoprotein from patients with valvular heart disease uncouples endothelial nitric oxide synthase. J Mol Cell Cardiol, 2014, 74: 209-219.
39.	Arnaldi G, Mancini T, Tirabassi G, et al. Advances in the epidemiology, pathogenesis, and management of Cushing’s syndrome complications. J Endocrinol Invest, 2012, 35(4): 434-448.
40.	Kronfol Z, Starkman M, Schteingart DE, et al. Immune regulation in Cushing’s syndrome: relationship to hypothalamic-pituitary-adrenal axis hormones. Psychoneuroendocrinology, 1996, 21(7): 599-608.
41.	Orange DE, Mehta B. Rethinking the balance of risks and rewards of chronic low-dose glucocorticoids in rheumatoid arthritis. Ann Intern Med, 2020, 173(11): 933-934.
42.	Vestby LK, Grønseth T, Simm R, et al. Bacterial biofilm and its role in the pathogenesis of disease. Antibiotics (Basel), 2020, 9(2): 59.
43.	Soni P, Koech H, Silva D, et al. Cerebral venous sinus thrombosis after transsphenoidal resection: a rare complication of Cushing disease-associated hypercoagulability. World Neurosurg, 2020, 134: 86-89.
44.	Van Zaane B, Nur E, Squizzato A, et al. Hypercoagulable state in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab, 2009, 94(8): 2743-2750.
45.	Erem C, Nuhoglu I, Yilmaz M, et al. Blood coagulation and fibrinolysis in patients with Cushing’s syndrome: increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels. J Endocrinol Invest, 2009, 32(2): 169-174.
46.	Maubec E, Laouénan C, Deschamps L, et al. Topical mineralocorticoid receptor blockade limits glucocorticoid-induced epidermal atrophy in human skin. J Invest Dermatol, 2015, 135(7): 1781-1789.
47.	Jozic I, Vukelic S, Stojadinovic O, et al. Stress signals, mediated by membranous glucocorticoid receptor, activate PLC/PKC/GSK-3β/β-catenin pathway to inhibit wound closure. J Invest Dermatol, 2017, 137(5): 1144-1154.
48.	Vukelic S, Stojadinovic O, Pastar I, et al. Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. J Biol Chem, 2011, 286(12): 10265-10275.
49.	Terao M, Murota H, Kimura A, et al. 11β-hydroxysteroid dehydrogenase-1 is a novel regulator of skin homeostasis and a candidate target for promoting tissue repair. PLoS One, 2011, 6(9): e25039.
50.	Emmerich J, van Koppen CJ, Burkhart JL, et al. Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors. Eur J Med Chem, 2018, 143: 591-597.

1. Nieman LK. Recent updates on the diagnosis and management of Cushing’s syndrome. Endocrinol Metab (Seoul), 2018, 33(2): 139-146.
2. Valette C, Ofaiche J, Severino M, et al. Fatal outcome of Netherton syndrome due to excessive use of topical corticosteroids in an adult patient. Ann Dermatol Venereol, 2020, 147(1): 36-40.
3. Barbot M, Zilio M, Scaroni C. Cushing’s syndrome: overview of clinical presentation, diagnostic tools and complications. Best Pract Res Clin Endocrinol Metab, 2020, 34(2): 101380.
4. Biswas M, Gibby O, Ivanova-Stoilova T, et al. Cushing’s syndrome and chronic venous ulceration-a clinical challenge. Int Wound J, 2011, 8(1): 99-102.
5. Stratakis CA. Skin manifestations of Cushing’s syndrome. Rev Endocr Metab Disord, 2016, 17(3): 283-286.
6. Erden F, Borlu M, Simsek Y, et al. Differences in skin lesions of endogenous and exogenous Cushing’s patients. Postepy Dermatol Alergol, 2019, 36(3): 272-275.
7. Kobayashi T, Naik S, Nagao K. Choreographing immunity in the skin epithelial barrier. Immunity, 2019, 50(3): 552-565.
8. Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol, 2016, 4(7): 611-629.
9. Tafelski S, Mohamed D, Shaqura M, et al. Identification of mineralocorticoid and glucocorticoid receptors on peripheral nociceptors: translation of experimental findings from animal to human biology. Brain Res, 2019, 1712: 180-187.
10. Serres M, Viac J, Schmitt D. Glucocorticoid receptor localization in human epidermal cells. Arch Dermatol Res, 1996, 288(3): 140-146.
11. Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther, 2002, 96(1): 23-43.
12. Colazo JM, Evans BC, Farinas AF, et al. Applied bioengineering in tissue reconstruction, replacement, and regeneration. Tissue Eng Part B Rev, 2019, 25(4): 259-290.
13. Lause M, Kamboj A, Fernandez Faith E. Dermatologic manifestations of endocrine disorders. Transl Pediatr, 2017, 6(4): 300-312.
14. Cordeiro RC, Moraes AM. Ulceration of striae distensae in a patient with systemic lupus erythematosus. J Eur Acad Dermatol Venereol, 2008, 22(3): 390-392.
15. Arem AJ, Kischer CW. Analysis of striae. Plast Reconstr Surg, 1980, 65(1): 22-29.
16. Chedid M, Hoyle JR, Csaky KG, et al. Glucocorticoids inhibit keratinocyte growth factor production in primary dermal fibroblasts. Endocrinology, 1996, 137(6): 2232-2237.
17. Meisler N, Shull S, Xie R, et al. Glucocorticoids coordinately regulate type I collagen pro alpha 1 promoter activity through both the glucocorticoid and transforming growth factor beta response elements: a novel mechanism of glucocorticoid regulation of eukaryotic genes. J Cell Biochem, 1995, 59(3): 376-388.
18. Caffarini M, Armeni T, Pellegrino P, et al. Cushing syndrome: the role of MSCs in wound healing, immunosuppression, comorbidities, and antioxidant imbalance. Front Cell Dev Biol, 2019, 7: 227.
19. Slominski AT, Zmijewski MA. Glucocorticoids inhibit wound healing: novel mechanism of action. J Invest Dermatol, 2017, 137(5): 1012-1014.
20. Bjelaković G, Beninati S, Pavlović D, et al. Glucocorticoids and oxidative stress. J Basic Clin Physiol Pharmacol, 2007, 18(2): 115-127.
21. Dunnill C, Patton T, Brennan J, et al. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J, 2017, 14(1): 89-96.
22. Jozic I, Sawaya AP, Pastar I, et al. Pharmacological and genetic inhibition of caveolin-1 promotes epithelialization and wound closure. Mol Ther, 2019, 27(11): 1992-2004.
23. Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol, 2006, 117(3): 522-543.
24. Lee B, Vouthounis C, Stojadinovic O, et al. From an enhanceosome to a repressosome: molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing. J Mol Biol, 2005, 345(5): 1083-1097.
25. Scaroni C, Zilio M, Foti M, et al. Glucose metabolism abnormalities in Cushing syndrome: from molecular basis to clinical management. Endocr Rev, 2017, 38(3): 189-219.
26. Friedman TC, Mastorakos G, Newman TD, et al. Carbohydrate and lipid metabolism in endogenous hypercortisolism: shared features with metabolic syndrome X and NIDDM. Endocr J, 1996, 43(6): 645-655.
27. Biering H, Knappe G, Gerl H, et al. Prevalence of diabetes in acromegaly and Cushing syndrome. Acta Med Austriaca, 2000, 27(1): 27-31.
28. Cadau S, Leoty-Okombi S, Pain S, et al. In vitro glycation of an endothelialized and innervated tissue-engineered skin to screen anti-AGE molecules. Biomaterials, 2015, 51: 216-225.
29. Chen YH, Chen ZW, Li HM, et al. AGE/RAGE-induced EMP release via the NOX-derived ROS pathway. J Diabetes Res, 2018, 2018: 6823058.
30. Lao G, Ren M, Wang X, et al. Human tissue inhibitor of metalloproteinases-1 improved wound healing in diabetes through its anti-apoptotic effect. Exp Dermatol, 2019, 28(5): 528-535.
31. Lan CC, Wu CS, Huang SM, et al. High-glucose environment reduces human β-defensin-2 expression in human keratinocytes: implications for poor diabetic wound healing. Br J Dermatol, 2012, 166(6): 1221-1229.
32. Deluyker D, Evens L, Bito V. Advanced glycation end products (AGEs) and cardiovascular dysfunction: focus on high molecular weight AGEs. Amino Acids, 2017, 49(9): 1535-1541.
33. Evens L, Beliën H, Deluyker D, et al. The impact of advanced glycation end-products (AGEs) on proliferation and apoptosis of primary stem cells: a systematic review. Stem Cells Int, 2020, 2020: 8886612.
34. Li M, Zhao Y, Hao H, et al. Umbilical cord-derived mesenchymal stromal cell-conditioned medium exerts in vitro antiaging effects in human fibroblasts. Cytotherapy, 2017, 19(3): 371-383.
35. Senthil KK, Gokila VM, Mau JL, et al. A steroid like phytochemical antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1. Oncotarget, 2016, 7(39): 62836-62861.
36. Salpea KD, Maubaret CG, Kathagen A, et al. The effect of pro-inflammatory conditioning and/or high glucose on telomere shortening of aging fibroblasts. PLoS One, 2013, 8(9): e73756.
37. 李炳旻, 王芳芳, 李倩坤, 等. 糖尿病溃疡的发生机制与治疗进展. 解放军医学院学报, 2019, 40(10): 992-994.
38. Chang FJ, Yuan HY, Hu XX, et al. High density lipoprotein from patients with valvular heart disease uncouples endothelial nitric oxide synthase. J Mol Cell Cardiol, 2014, 74: 209-219.
39. Arnaldi G, Mancini T, Tirabassi G, et al. Advances in the epidemiology, pathogenesis, and management of Cushing’s syndrome complications. J Endocrinol Invest, 2012, 35(4): 434-448.
40. Kronfol Z, Starkman M, Schteingart DE, et al. Immune regulation in Cushing’s syndrome: relationship to hypothalamic-pituitary-adrenal axis hormones. Psychoneuroendocrinology, 1996, 21(7): 599-608.
41. Orange DE, Mehta B. Rethinking the balance of risks and rewards of chronic low-dose glucocorticoids in rheumatoid arthritis. Ann Intern Med, 2020, 173(11): 933-934.
42. Vestby LK, Grønseth T, Simm R, et al. Bacterial biofilm and its role in the pathogenesis of disease. Antibiotics (Basel), 2020, 9(2): 59.
43. Soni P, Koech H, Silva D, et al. Cerebral venous sinus thrombosis after transsphenoidal resection: a rare complication of Cushing disease-associated hypercoagulability. World Neurosurg, 2020, 134: 86-89.
44. Van Zaane B, Nur E, Squizzato A, et al. Hypercoagulable state in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab, 2009, 94(8): 2743-2750.
45. Erem C, Nuhoglu I, Yilmaz M, et al. Blood coagulation and fibrinolysis in patients with Cushing’s syndrome: increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels. J Endocrinol Invest, 2009, 32(2): 169-174.
46. Maubec E, Laouénan C, Deschamps L, et al. Topical mineralocorticoid receptor blockade limits glucocorticoid-induced epidermal atrophy in human skin. J Invest Dermatol, 2015, 135(7): 1781-1789.
47. Jozic I, Vukelic S, Stojadinovic O, et al. Stress signals, mediated by membranous glucocorticoid receptor, activate PLC/PKC/GSK-3β/β-catenin pathway to inhibit wound closure. J Invest Dermatol, 2017, 137(5): 1144-1154.
48. Vukelic S, Stojadinovic O, Pastar I, et al. Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. J Biol Chem, 2011, 286(12): 10265-10275.
49. Terao M, Murota H, Kimura A, et al. 11β-hydroxysteroid dehydrogenase-1 is a novel regulator of skin homeostasis and a candidate target for promoting tissue repair. PLoS One, 2011, 6(9): e25039.
50. Emmerich J, van Koppen CJ, Burkhart JL, et al. Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors. Eur J Med Chem, 2018, 143: 591-597.

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