Subscribe to RSS
DOI: 10.12687/phleb2123_1_2013
Endocrine mechanisms in the pathogenesis of primary varicosis
Endokrine Mechanismen in der Pathogenese der primären VarikosePublication History
Eingereicht:
15 November 2013
Angenommen:
16 January 2013
Publication Date:
30 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034913/201301/lookinside/thumbnails/10-12687-phleb-2123-1-2013-1.jpg)
Summary
Introduction: Varicose veins affect up to 40 % of men and up to 51 % of women. The patho-physiology of primary varicosis (chronic venous insufficiency, CVI) is poorly understood. Here, the available data on possible endocrine mechanisms in healthy and varicose veins are reviewed.
Methods: An extensive literature search was conducted in PubMed using the following key words: Chronic venous insufficiency, CVI, chronic venous disease, CVD, varicosis, saphenous vein, pathogenesis, hormone.
Results: Several theories ranging from incompetence of the valves to functional, biological or morphologic changes in different layers of the vein wall have been proposed. However, an increasing body of evidence suggests that endocrine mechanisms might be involved in the pathogenesis of primary varicosis. In this respect a growing number of hormones (e.g. estrogen, progesterone, relaxin-2, and oxytocin) and their receptors have been linked to primary varicosis in experimental, pharmacological and histological studies.
Conclusion: In summary, endocrine-based mechanisms seem to play a role in the pathogenesis of primary varicosis. This opens up the perspective for pharmacological treatments targeting the various described endocrine regulatory networks.
Zusammenfassung
Einleitung: Die chronische Venenerkrankung (chronisch-venöse Insuffizienz, CVI) betrifft bis zu 40 % aller Männer und bis zu 51 % aller Frauen. Trotz ihrer hohen Prävalenz und den schweren klinischen Verlaufsformen bis hin zum venösen Ulcus cruris oder dem arthrogenen Stauungssyndrom ist die Pathophysiologie der primären Varikose bis heute ungeklärt. Im vorliegenden Übersichtsartikel wurden mittels Literaturrecherche die aktuelle Datenlage sowie die bestehenden Hypothesen aufgeführt und beschrieben.
Methode: Eine intensive Literaturanalyse wurde in PubMed durchgeführt mit folgenden Schlüsselwörtern: Chronisch-venöse Insuffizienz, CVI, chronische venöse Erkrankung, CVD, Varicosis, Vena saphena magna, Pathogenese, Hormone.
Ergebnisse: Hierzu bestehen unterschiedliche Theorien, welche von einer anlagebedingten Klappeninsuffizienz bis zu biologischen und morphologischen Veränderungen in den verschiedenen Schichten der Venenwand rei-chen. Gleichzeitig findet sich in der Literatur eine wachsende Anzahl von Arbeiten, die sich mit dem möglichen Einfluss von Hormonen auf die Entstehung der CVI, bzw. einem pathologisch veränderten endokrinologischen System in der Vena saphena magna (VSM) von CVI-Patienten beschäftigen. So wurden in zahlreichen Studien unterschiedliche Muster der Exprimierung von Hormonen (u.a. Östrogen, Progesteron, Relaxin-2, Oxytocin) und ihren jeweiligen Rezeptoren nachgewiesen. Eine unterschiedliche Ansprechbarkeit in Bezug auf Vasokonstriktion und Vasodilatation von Patienten mit gesunden und varikös veränderten VSM-Präparaten konnte in pharmakologischen Studien nachgewiesen werden.
Schlussfolgerung: Zusammenfassend lässt sich feststellen, dass endokrinologische Mechanismen eine Rolle in der Pathogenese der CVI zu spielen scheinen. Dies eröffnet theoretisch erstmals pharmakologische Therapieoptionen für die Behandlung der CVI. In Anbetracht des noch relativ jungen Forschungsgebietes der “Phlebo-Endokrinologie” und der interessanten wissenschaftlichen Erkenntnisse der letzten Jahre ist eine vertiefte Grundlagenforschung dennoch unabdingbar, um die genaue Rolle der einzelnen Hormone bzw. ihres komplexen Zusammenspiels in der Pathogenese der CVI zu eruieren.
-
Reference
- 1 Adams J, Schott S, Bern A, Renz M, Ikenberg K, Garbe C, Busch C. A novel role for relaxin-2 in the pathogenesis of primary varicosis. PLoS One 2012; 7 (06) e39021
- 2 Aldasoro M, Medina P, Vila JM, Otero E, Martinez-León JB, Lluch S. Endothelium-dependent relaxation of human saphenous veins in response to vasopressin and desmopressin. J Vasc Surg 1997; 25: 696-703.
- 3 Asciutto G, Mumme A, Asciutto KC, Geier B. Oestradiol levels in varicose vein blood of patients with and without pelvic vein incompetence (PVI): diagnostic implications. Eur J Vasc Endovasc Surg 2010; 40: 117-121.
- 4 Babaei H, Azarmi Y. 17beta-estradiol inhibits calcium-dependent and-independent contractions in isolated human saphenous vein. Steroids 2008; 73: 844-850.
- 5 Bafford R, Sui XX, Park M, Miyahara T, Newfell BG, Jaffe IZ, Romero JR, Adler GK, Williams GH, Khalil RA, Conte MS. Mineralocorticoid receptor expression in human venous smooth muscle cells: a potential role for aldosterone signaling in vein graft arterialization. Am J Physiol Heart Circ Physiol 2011; 301: H41-47.
- 6 Bergan JJ, Pascarella L, Schmid-Schönbein GW. Pathogenesis of primary chronic cenous disease: Insights from animal models of venous hypertension. J Vasc Surg 2008; 47: 183-192.
- 7 Blöchl-Daum B, Schuller-Petrovic S, Wolzt M, Korn A, Böhler K, Eichler HG. Primary defect in alpha-adrenergic responsiveness in patients with varicose veins. Clin Pharmacol Ther 1991; 49: 49-52.
- 8 Borland JA, Chester AH, Morrison KA, Yacoub MH. Alternative pathways of angiotensin II production in the human saphenous vein. Br J Pharmacol 1998; 125: 423-428.
- 9 Brand FN, Dannenberg AL, Abbott RD, Kannel WB. The epidemiology of varicose veins: the Framingham Study. Am J Prev Med 1988; 4: 96-101.
- 10 Cardwell RJ, Webb RC. Diabetes and reactivity of isolated human saphenous vein. Clin Physiol 1984; 4: 509-517.
- 11 Ciardullo AV, Panico S, Bellati C, Rubba P, Rinaldi S, Iannuzzi A, Cioffi V, Iannuzzo G, Berrino F. High endogenous estradiol is associated with increased venous distensibility and clinical evidence of varicose veins in menopausal women. J Vasc Surg 2000; 32: 544-549.
- 12 Dimech J, Feniuk W, Latimer RD, Humphrey PP. Somatostatin-induced contraction of human isolated saphenous vein involves sst2 receptor-mediated activation of L-type calcium channels. J Cardiovasc Pharmacol 1995; 26: 721-728.
- 13 Elsharawy MA, Naim MM, Abdelmaguid EM, Al-Mulhim AA. Role of saphenous vein wall in the pathogenesis of primary varicose veins. Interact Cardiovasc Thorac Surg 2007; 6: 219-224.
- 14 Evans CJ, Fowkes FG, Ruckley CV, Lee AJ. Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh Vein Study. J Epidemiol Community Health 1999; 53: 149-153.
- 15 Feldner A, Otto H, Rewerk S, Hecker M, Korff T. Experimental hypertension triggers varicosis-like maladaptive venous remodeling through activator protein-1. FASEB J 2011; 25: 3613-3621.
- 16 Göstl K, Obermayer A, Hirschl M. Pathogenesis of chronic venous insufficiency by obesity. Current data and hypotheses. Phlebologie 2009; 38: 108-113.
- 17 Gutkowska J, Jankowski M, Mukaddam-Daher S. et al. Oxytocin is a cardiovascular hormone. Braz J Med Biol Res 2000; 33: 625-633.
- 18 Haas E, Meyer MR, Schurr U, Bhattacharya I, Minotti R, Nguyen HH, Heigl A, Lachat M, Genoni M, Barton M. Differential effects of 17beta-estradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis. Hypertension 2007; 49: 1358-1363.
- 19 Howell RG, Burton JL. Decreased fertility in men with venous stasis of the legs. Lancet 1982; 2 8299 630-631.
- 20 Hursting SD, Hursting MJ. Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer. Arterioscler Thromb Vasc Biol 2012; 32: 1766-1770.
- 21 Jia G, Aggarwal A, Yohannes A, Gangahar DM, Agrawal DK. Cross-talk between angiotensin II and IGF-1-induced connexin 43 expression in human saphenous vein smooth muscle cells. J Cell Mol Med 2011; 15: 1695-1702.
- 22 Kendler M, Blendinger Ch, Haas E. Elevated serum estradiol/testosterone ratio in men with primary varicose veins compared with a healthy control group. Angiology 2009; 60: 283-289.
- 23 Kendler M, Makrantonaki E, Tzellos T, Kratzsch J, Anderegg U, Wetzig T, Zouboulis C, Simon JC. Elevated sex steroid hormones in great saphenous veins in men. J Vasc Surg 2010; 51: 639-646.
- 24 Krasner LJ, Wendling WW, Cooper SC, Chen D, Hellmann SK, Eldridge CJ, McClurken JB, Jeevanandam V, Carlsson C. Direct effects of triiodothyronine on human internal mammary artery and saphenous veins. J Cardiothorac Vasc Anesth 1997; 11: 463-466.
- 25 Lowell RC, Gloviczki P, Miller VM. In vitro evaluation of endothelial and smooth muscle function of primary varicose veins. J Vasc Surg 1992; 16: 679-686.
- 26 Maffei FH, Magaldi C, Pinho SZ, Lastoria S, Pinho W, Yoshida WB, Rollo HA. Varicose veins and chronic venous insufficiency in Brazil: prevalence among 1755 inhabitants of a country town. Int J Epidemiol 1986; 15: 210-217.
- 27 Mashiah A, Berman V, Thole HH, Rose SS, Pasik S, Schwarz H, Ben-Hur H. Estrogen and progesterone receptors in normal and varicose saphenous veins. Cardiovasc Surg 1999; 7: 327-331.
- 28 Meissner MH, Gloviczki P, Bergan J, Kistner RL, Morrison N, Pannier F, Pappas PJ, Rabe E, Raju S, Villavicencio JL. Primary chronic venous disorders. J Vasc Surg 2007; 46 Suppl S 54S-67S.
- 29 Meissner MH, Moneta G, Burnand K, Gloviczki P, Lohr JM, Lurie F, Mattos MA, McLafferty RB, Mozes G, Rutherford RB, Padberg F, Sumner DS. The hemodynamics and diagnosis of venous disease. J Vasc Surg 2007; 46 Suppl S 4S-24S.
- 30 Milligan SR, Kalita JC, Heyerick A, Rong H, De Cooman L, De Keukeleire D. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab 1999; 84: 2249-2252.
- 31 Nees S, Juchem G, Weiss DR, Partsch H. Pathogenesis and therapy of chronic venous disease: New insights into structure and function of the leg venous system. Phlebologie 2012; 41: 246-257.
- 32 Padberg Jr F ., Cerveira JJ, Lal BK, Pappas PJ, Varma S, Hobson RW . 2nd. Does severe venous insufficiency have a different etiology in the morbidly obese? Is it venous?. J Vasc Surg 2003; 37: 79-85.
- 33 Perrot-Applanat M, Cohen-Solal K, Milgrom E, Finet M. Progesterone receptor expression in human saphenous veins. Circulation 1995; 92: 2975-2983.
- 34 Rizzi A, Quaglio D, Vasquez G, Mascoli F, Amadesi S, Calò G, Regoli D, Zamboni P. Effects of vasoactive agents in healthy and diseased human saphenous veins. J Vasc Surg 1998; 28: 855-861.
- 35 Rorie DK, Muldoon SM. Increased reactivity of isolated rabbit saphenous vein after treatment with estrogen and progesterone. Blood Vessels 1979; 16: 252-258.
- 36 Samuel CS, Hewitson TD, Unemori EN, Tang ML. Drugs of the future: the hormone relaxin. Cell Mol Life Sci 2007; 64: 1539-1557.
- 37 Schott S, Adams J, Bern A, Garbe C, Busch C. Expression of oxytocin and its receptor in healthy and varicose great saphenous veins. Pathology 2012. Oct 20 [Epub ahead of print]
- 38 Schuller-Petrovic S, Stessel H, Brunner F. Ca2+ mobilization in saphenous vein smooth muscle cells derived from patients with primary varicosity. Eur J Clin Invest 2002; 32: 649-656.
- 39 Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev 2004; 25: 205-234.
- 40 Somers P, Knaapen M. The histopathology of varicose vein disease. Angiology 2006; 57: 546-555.
- 41 Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M. Relaxin: review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010; 7: 75-82.
- 42 Travers JP, Brookes CE, Evans J, Baker DM, Kent C, Makin GS, Mayhew TM. Assessment of wall structure and composition of varicose veins with reference to collagen, elastin and smooth muscle content. Eur J Vasc Endovasc Surg 1996; 11: 230-237.
- 43 Várbíró S, Vajó Z, Nádasy GL, Monos E, Acs N, Lóránt M, Felicetta JV, Székacs B. Sex hormone replacement therapy reverses altered venous contractility in rats after pharmacological ovariectomy. Menopause 2002; 9: 122-126.
- 44 Vin F, Allaert FA, Levardon M. Influence of estrogens and progesterone on the venous system of the lower limbs in women. J Dermatol Surg Oncol 1992; 18: 888-892.
- 45 Yosipovitch G, DeVore A, Dawn A. Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol 2007; 56: 901-916.