free testosterone ratio can be important predictor for varicose vein recurrence in men 3376-ANGY

3376-ANGY ??? Serum estradiol/free testosterone ratio can be important predictor for varicose vein recurrence in men S. ÖZCAN 1, O. TEZCAN 2, T. KURT...
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3376-ANGY

??? Serum estradiol/free testosterone ratio can be important predictor for varicose vein recurrence in men S. ÖZCAN 1, O. TEZCAN 2, T. KURT 1, H. TÜRKÖNE 3,O. KARAHAN 2, A.T ÇALIŞKAN 2, G. ADAM 4 1Department

of Cardiovascular Surgery, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Turkey;

2Department of Cardiovascular Surgery, Faculty of Medicine, Dicle University, Diyarbakır, Turkey 3Department of Biochemistry,

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Key words: Varicose veins - Venous insufficiency - Gonadal steroid hormones.

Varicose vein recurrence is encountered frequently.1 Recurrent varicose veins are due to the unidentified connections between the deep and superficial venous system 2 or neovascularization.3, 4 The main causes of recurrences are spontaneous disease progression, inadequate surVol. 34 - No. 1

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gery, and the technical failure at the time of the original surgery (especially low ligation of the great saphenous vein [GSV] in the groin leaving behind the incompetent saphenofemoral junction [SFJ]). Most of the studies investigating the varicose vein recurrences involve patients with varicose vein surgery managed by stripping. However, only patients that underwent endovenous laser ablation (EVLA) were included in our study. There are few studies concerning the varicose vein recurrences after EVLA. Theivacumar et al. documented 118 consecutive patients with recurrence rates near identical numbers of 6.6% and 7.0% in EVLA and surgery groups.5 In our study, we investigated the recurrence of varicose veins in patients after the EVLA application. Group A consisted of patients who had androgen deficiency syndromes and basically elevated Estradiol (E2)/ free Testesterone (fT) ratio, Group B had no known steroid hormones defects and near normal E2/fT ratios.

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Aim. Recurrent varicose veins are a frustration for both the patient and the surgeon. More investigation of the exact diagnosis, proper practice, and causes for the recurrence of varicose veins is needed. Methods. We investigated a total number of 187 patients in a five year period with an estradiol-2/free testosterone (E2/ fT) ratio relationship on recurrent varicose veins in men between the ages of 20-50. Fifity years was the maximum age due to the age dependent sex steroid hormone regression that occurs after this age, which may interefere with the assessment. Fifty three men with an elevated E2/fT ratio (group A), and 143 men with no endocrinologic problems (group B) were enrolled in the study and had surgery for varicose veins. After 5 years follow up (mean 3 years), Group A (N.=29) and group B (N.=43) had recurrent varicose veins by clinical and radiologic findings. Venous blood samples were driven from all patients of both groups in the morning to detect the levels of serum E2 and fT levels. Patient history of surgery for varicose veins, physical examination, color duplex ultrasound of both limbs, and classification of CEAP were performed in both groups. Results. The serum E2/fT ratio was significantly higher in Group A (5.21 ± 0.56) compared to group B (2.54±0.27) in the recurrent varicose vein groups (p ≤ 0.05). Moreover, there was a high correlation between serum E2/fT ratio and the CEAP clinical classification in group A (5) compared to group B (2) (P≤0.05). Also, recurrence rate was higher in group A (54%) compared to group B (32%)(P≤0.05). Conclusion. Elevated serum E2/fT ratio is a precipitating factor for recurrent varicose veins in male patients. [Int Angiol 2015;34:1-2]

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Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Turkey; 4Department of Radiology, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Turkey

Material and methods All patients enrolled in the study were between the ages of 20-50 years and underwent EVLA for varicose veins. All patients read and signed the informed consent. Patients’ data including age, body mass index (BMI), family history, and medical history were recorded. Varicosities are classified according to the CEAP classification.6 Hormone assays were taken on all patients initially and on all patients at one year later of control.

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Because of diurnal variation of sex hormones, blood samples were taken from the antecubital vein only between 7.00-9.00 am in 5 mL into the vacutainer tubes. After centrifugation and separation of serum, the samples were stored for a maximum of 8h at 2-8 °C. The serum was then divided into portions and stored at -20 0C. Estradiol (E2), dehydroepiandrostendion (DHEAS) and free testosterone (fT) were measured by using chemiluminescent micro particle immunoassays (CMIA, Architect i 4000 SR, Abbott Diagnostics, USA). Both tests were fully automated competition immunoassays and were performed according to the manufacturer protocol. E2, DHEA-S, and fT assays are delayed into two step immunoassay to determine the presence of the theme. In the first step, sample, specimen diluents, assay diluents, anti- E2, DHEA-S, and fT coated paramagnetic micro particles were combined. After incubation, E2, DHEA-S, and fF acridinium labeled conjugates were added to the reaction mixture. After a second incubation and washing, pre-trigger and trigger solutions were added followed by the chemiluminescent reac-

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Biochemical study

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A Duplex ultrasound scanning (transducer frequencies between 5 and 7.5 MHz) included measuring characteristics of outflow, and reflux for the lower limbs. Venous flow was examined in longitudinal sections using color flow. Pulsed Doppler was used for measuring the reverse flow. Femoral, mid-thigh femoral, above knee popliteal, and distal posterior tibial veins were examined for deep venous reflux. The GSV and the small saphenous vein (SSV) were imaged continuously from the respective femoral or popliteal junction to the paramalleolar level. Reflux was defined as reverse flow longer than 0.5 seconds in the superficial veins or 1.0 seconds in the deep veins following a manual compression release maneuver. The examination was done while the patient was in the upright position.

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Duplex ultrasound scanning

tion measurement determined in relative light units (RLUs). Inverse relationships existed between the amount of E2, DHEA-S, and fF in the sample and RLUs detected by the optical system. The detection limit for tests was as follows: E2, 0-1000 pg/mL; testosterone, 0-15 ng/mL; and DHEA-S, 0-1500 ug/dL, respectively. The analytical sensitivity of the tests was as follows: E20.5 s Healed ulcers C5 Active ulcers C6 Superficial vein thrombosis Deep vein thrombosis Dermatoliposclerosis

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Table IV.—Venous demographics of patients who have recurrent varicose veins. Group A (N.=29)

Group B (N.=43)

P value

11.7±4.6 (5-21) 5 29 (100%) 18 (62%) 26 (89%) 3 (11%) 8 (27%) 4 (13%) 7 (24%)

12.6±3.7 (3-25) 3 43 (100%) 22 (51%) 13 (30%) 1 (2%) 6 (13%) 2 (4%) 6 (13%)

NS P≤0.05 NS P≤0.05 P≤0.05 P≤0.05 P≤0.05 P≤0.05 P≤0.05

CEAP: clinical, etiological, anatomical, pathological classification.

have been treated for primary varicose veins.7 It is estimated that approximately 20% of varicose vein surgery is for recurrent disease.8 Before the initial operation, accurate assessment of all sites of reflux is vital to ensure the correct surgical approach and reduce further recurrences.9 Recurrence grossly divided in to two categories: 1) 4

neovascularization is the new circulatory adaptation of previously occluded or non functioning vessel become the functioning vessels, especially in the granulation tissue around stump of GSV, SSV. 2) Neoangiogenesis is the development of incompetence in pre-existing collateral which is often overlooked.10, 11 Neoangiogenesis is the

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cose veins, and reflux in the GSV compared with patient’s own arm veins.21 This was a 5 year period of single center, single surgeon, single EVLA device work, and the patients followed for five years (mean 3 years) after the primary varicose vein surgeries. The age group and BMI index were identical in order to exclude the aging and fat dependent sex steroid hormone variations. In 5-year period, 53 patients who had androgen deficiency syndromes concurrently with varicose veins, and 134 patients with no known endocrinologic problems but varicose veins were enrolled in the study. After a 5 years follow-up, 29 of 53 (54%) patients in group A and 43 of 134 (32%) patients in group B had varicose vein recurrences. This is the main aspect of this article, which demonstrates that patients who have elevated E2/fT ratio have an increased varicose vein recurrence. The original group who had varicose vein surgery was 53 patients in group A and 134 patients in group B. Twenty one (72%) had varicose cluster excision in group A, 33 (76%) in group B. Thirteen (45%) had foam sclerotherapy in group A, and 16 (37%) in group B. The interpretations were nearly identical. The mean age, BMI, and other demographics were not significant, but hormone levels were significant. Interestingly, the E2/fT ratio was 3.35±0.23 in group A, and 2.40±0.21 in the followed patients. This result was statistically significant (P≤0.05). If the elevated E2/fT ratio correlated with varicose vein formation, then there may be a relationship with varicose vein recurrence. Several questions must be answered. Is the recurrence rate in group A (54%), which is higher compared to group B (32%) (P≤0.05) dependent on the inverse E2/fT ratio in these groups? The mean recurrence time was 2.3±0.3 years in group A and 3.6±0.6 years in group B (P≤0.05). The CEAP classification was also statistically different in recurrent varicose groups was 5 in group A and 3 in group B.

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form that is characterized by uniform of the lumen, multiple channel of new vessel formation, incomplete vessel wall formation, and absence of nerves fibers.12, 13 By Duplex ultrasonography, recurrences can be depicted by tortuous single lumen channels or a strand of tiny vessels.14 Briefly, varicose vein recurrence can be explained as saphenous reflux, which is the principal pathology in varicose vein disease. Termination of this clinical and pathophysiological base (saphenous reflux) restores physiological status. So what makes the recurrent varicose veins though flawlessly performed saphenous vein abolition, neoangiogenesis or neovascularization? Recek et al. stated that the hemodynamic factor-pressure difference triggers biophysical and biochemical events that entail enlargement of tiny communicating channels between the femoral vein and the saphenous system, which evokes reflux recurrence.3 Competent valves in deep lower leg veins as well as in the saphenous system preclude drainage of venous blood from the thigh into the lower leg, which ensures the physiological decrease in venous pressure during calf pump activity. In varicose veins, drainage of venous blood from the thigh into the deep lower legs during calf pump activity is a hallmark of the disease pathophysiology. Estrogens play an essential role in endocrine health in men.15 Estrogens are grossly synthesized by local tissue aromatization of androgenic precursors from the testes and adrenal gland. Physiologically, in elderly men, an increased aromatization of testosterone with a decline of androgen levels is a result of increasing aromatized activity with age and the age-associated increase in fat mass.16 Moreover, changes in endogenous sex hormone levels in men have an impact on cardiovascular diseases. For example, lower levels of free testosterone are associated with atherosclerosis and coronary artery disease.17, 18 This condition has been named partial androgen deficiency in aging men (PADAM), and results in a gradual decline in sex hormone levels over years causing physical and psychological changes such as depression, impotence, decreased sex drive, loss of muscle tone or strength, and lethargy.19 Kendler et al. reported that changed serum E2/fT ratio among men with varicose veins compared to healthy man.20 In another study, elevated serum estradiol levels were detected in men with vari-

Conclusions In conclusion, the elevated E2/fT ratio in men has an influence in the recurrence of varicose veins. However, it was not a placebo controlled double blinded study and more efforts should be exerted in that issue. Also, the pathophysiologi-

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Acknowledgments.—We are grateful to Dicle University DUBAP for their sponsorship about language editing of this manuscript. Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. Received on September 25, 2014; accepted for publication on October 1, 2014. Epub ahead of print on Corresponding author: S. Özcan, Department of Cardiovascular Surgery, Faculty of Medicine, Çanakkale Onsekiz Mart University. E-mail: [email protected]

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  1. Gad MA, Saber A, Hokkam EM. Assessment of Couses and Patterns of Recurrent Varicose viens After Surgery. N Am J Med Sci 2012;4:45-8.   2. Doran FSA, Barkat S. Annals Of the Royal College of Surgeons of England 1981;63:432-6.   3. Recek C. The hemodynamic paradox as a phenomenon triggering recurrent reflux in varicose vein disease. Int J Angiol 2012;21:181-6.   4. Jones L, Braithewaite BD, Selwyn D, Cooke S, Earnshow JJ. Neovascularization is the principal cause of varicose vein recurrence: results of a randomied trial of stripping the long saphenous vein. Eur J vasc Endovasc Surg 1996;12:442-5.   5. Theivacumar NS, Darwood R, Gough MJ. Neovascularization and recurrence 2 years after varicose vein treatment for sapheno-femoral and great saphenous vein reflux: a comparison of surgery and endvenous laser ablation. Eur J Vasc Endovasc Surg 2009;38:203-7.   6. Beebe HG, Bergan JJ, Bergquist D, Eklof E, et al. Classification and grading of chronic venous disease in the lower limbs: a consensus statement. Eur J Vasc Endovasc Surg 1996;12:487-91;   7. Larson RH, Lofgren EP, Myers TT, Lofgren KA. Longterm results after vein surgery. Study of 1000 cases after 10 years. Mayo Clin Proc 1974;49:114-7.   8. Hobbs JT. Surgery and sclerotherapy in the treatment of varicose veins. Arch Surg 1974;109:793-6.   9. Royle JP. Recurrent varicose veins. World J Surg 1986;10:944-53. 10. Geier B, Olbrich S, Barbera L, Stücker M, Mumme A. Validity of the macroscopic identification of neovascularisation of the saphenofemoral junction by the operating surgeon. J Vasc Surg 2005;41:64-8. 11. Creton D. Surgery for recurrent saphenofemoral incompetence using expanded polytetrafluoroethylene patch interposition in front of the femoral vein: Long-term outcame in extremities. Plebology 2002;16:93-7. 12. Frings N, Nelle A, Tran P, Fischer R, Krug W. Reduction

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of neoreflux after correctly performed ligation of the saphenofemoral junction. A randomized study. Eur J Vasc Endovasc Surg 2004;28:264-52. 13. Frings N, Nelle A, Tran VTP, Glowacki P. Unavoidable recurrence and neoreflux after correctly performed ligation of the saphenofemoral junction: neovascularisation? (German). Phlebologie 2003;32:96-100. 14. Redwood NFW, Lambert D. Patterns of reflux in recurrent varicose veins assessed by duplex scanning. Br J Surg 1994;81:1440-51. 15. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005;26:833-76. 16. Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I. Estradiol in elderly men. Ageing Male 2002;5:98102. 17. Folkman J. Clinical application of research on angiogenesis. Seminars in medicime of Beth Israel Hospital, Boston, MA. N Engl J Med 1995;333:1757-63. 18. Sudhir K, Komesaroff PA. Clinical review 110: cardiovascular actions of estrogens in men. J Clin Endocrinol Metab 1999;84:3411-5. 19. Frajese GV, De Martino MU, Calcagni E, Pastore R, Caprio M, Bultrini A et al. The epidemiology of partial androgen deficiency in aging men (PADAM). J Endocrinol Invest 2005;28(Suppl 3):3-7. 20. Kendler M, Blendinger Ch, Haas E. Elevated serum estradiol/testesterone ratio in man with primary varicose veins compared with a healthy control group. Angiology 2009;60:283-9. 21. Kendler M, Makrantonaki E, Kratzsch J, Anderegg U, Wetzig T, Zouboulis C et al. Elevated Sex Steroid Hormones In Great Saphenous Veins In Men. J Vasc Surg 2010;51:639-47.

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cal mechanism of elevated E2/fT ratio on recurrence of varicose veins must be answered. Is it neoangiogenesis or neovascularization?

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