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Changes in the Diameter and Valve Closure Time of Leg Veins Across the Menstrual Cycle Akram M. Asbeutah, PhD, DMU, AMS, MSVU, Maitha Al-Enezi, BSc, Noura M. Al-Sharifi, BSc, Abdullah Almajran, MSc, James D. Cameron, MD, Barry P. McGrath, MD, Sami K. Asfar, MD Objectives—The purpose of this study was to determine the changes (if any) in the diameter and valve closure time of the lower limb veins in healthy young nulliparous women at different phases of the menstrual cycle. Methods—Fifty-three young nulliparous women were asked to undergo clinical evaluations and duplex ultrasound examinations of both lower limb veins to monitor changes in the vein diameter and valve closure time at different phases of their menstrual cycles. The vein diameter on B-mode imaging and valve closure time on pulsed Doppler tracing were calculated at days 1 to 4, 14 to 16, and 25 to 28 of the menstrual cycle. Freidman and related samples Wilcoxon signed rank tests were used to determine timerelated changes in venous function.
Received June 25, 2013, from the Department of Radiologic Sciences, Faculty of Allied Health Sciences (A.M.A., M.A.-E., N.M.A.-S.), and Departments of Community Medicine and Behavioral Sciences (A.A.) and Surgery (S.K.A.), Health Sciences Center, Faculty of Medicine, Kuwait University, Kuwait; and Monash Cardiovascular Research Center, MonashHeart, Monash Health and Department of Medicine (J.D.C.), and Department of Medicine (B.P.M), Monash University, Melbourne, Victoria, Australia. Revision requested September 4, 2013. Revised manuscript accepted for publication September 8, 2013. We thank the volunteers for their participation in this study and Chinma Babu (chief technologist, Department of Radiology, Faculty of Allied Health Sciences, Kuwait University) for help and support during the study. Address correspondence to Akram M. Asbeutah, PhD, DMU, AMS, MSVU, Department of Radiologic Sciences, Faculty of Allied Health Sciences, Kuwait University, PO Box 31470, 90805 Sulaibikhat, Kuwait. E-mail: [email protected], [email protected] Abbreviations
IQR, interquartile range doi:10.7863/ultra.33.5.803
Results—The volunteers’ mean age ± SD was 20.60 ± 1.90 years, and their mean body mass index was 23.90 ± 4.90 kg/m2. There was a gradual increase in the vein diameter and valve closure time at the specified phases of the menstrual cycle. Friedman and related samples Wilcoxon signed rank tests for venous segment diameter and valve closure time changes between the different phases of the menstrual cycle were performed and showed statistical significance for each venous segment within each limb (P = .003–.025). Also, when adjusted for body mass index, statistical significance existed for the same venous segments in the same limbs (P = .001–.049). There was no statistical significance for the same venous segments at the same phase of the menstrual cycle between limbs (related samples Wilcoxon signed rank test: P = .079–.97). Conclusions—During the menstrual cycle, the lower limb veins show an increase in their diameter and valve closure time. These changes are probably mediated by the female sex hormones. Key Words—duplex ultrasound; female sex hormones; leg veins; menstrual cycle; vascular ultrasound; varicose veins
T
he prevalence of varicose veins is around 25% to 33% in women and 10% to 20% in men.1–3 The reported annual incidence of new cases of varicose veins is 2.6% in women and 1.9% in men, with associated costs to the community in terms of lost working hours, hospitalization, and management.4,5 Two theories have been proposed to describe the pathogenesis of varicose veins: the valvular theory and primary weakness of the venous wall.6,7 Both theories have the same end result: ie, the venous valves fail to maintain efficient cephalad blood flow, resulting in retrograde blood flow, which leads to dilated tortuous veins. If not treated, venous hypertension will ensue, with its consequences of hyperpigmentation, ulceration, and lipodermatosclerosis.8,9
©2014 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2014; 33:803–809 | 0278-4297 | www.aium.org
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More women are affected by varicose veins, and parous women have an increased risk of developing varicose veins compared with nulliparous women.10 Family history, age, race, weight, occupation, pregnancy, oral contraceptives, and cardiovascular disease have been identified as possible etiologic risk factors.10–13 The influence of increased levels of female sex hormones, especially during pregnancy, on venous disorders of the legs has been noted by many investigators.1–5,14–20 In addition, estrogen and progesterone receptors were found in sections of venous walls, suggesting an involvement of sex hormones in the pathogenesis of varicose veins by a mechanism that has yet to be identified.21–24 To elucidate any effect of sex hormones on veins containing these receptors, we performed this in vivo study during the menstrual cycle in young women. The aim of this study was to explore the changes (if any) in the diameter and valve closure time of the lower limb veins in healthy young nulliparous women at different phases of the menstrual cycle.
Materials and Methods Participants From September 2012 to May 2013, 53 healthy young nulliparous female volunteers (106 limbs) were asked to participate in this study investigating the effect of sex hormones on the vein diameter and valve closure time at different menstrual phases. They were recruited from the Health Sciences Center of Kuwait University through an advertisement in the local university newspaper and telephone calls. The study was approved by the Human Research and Ethics Committee of the Kuwait University Health Sciences Center. Informed consent was obtained from all participants before entry into the study. Inclusion criteria included women in the age group of 18 to 25 years with normal and regular menstrual cycles for the previous 4 months, no gynecologic problems, no personal or family history of varicose veins, no history of previous deep venous thrombosis, no oral contraceptive use, no smoking, no medication use for any reason, no previous pregnancy, no history of leg injury or fracture, and no history of malignancy, blood clotting disorders, or hypertension. Clinical Assessment All participants underwent a clinical review and a physical examination of both legs by a single experienced vascular physician (S.K.A.) at each visit. The venous status of the legs was classified according to the 7-point CEAP (clinical, etiologic, anatomic, and pathophysiologic) scale (classes 0–6) of the International Consensus Committee of the American Venous Forum.25,26
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Duplex Ultrasound Scanning B-mode imaging, color flow imaging, and pulsed Doppler spectral analysis were performed in both legs with a MicroMaxx scanner (FUJIFILM SonoSite, Inc, Bothell, WA) and a linear 12–5-MHz transducer on the low-flow setting. All examinations were performed in a temperaturecontrolled room at 22°C ± 2°C. Before the study, all participants changed into a loose gown and removed their undergarments. The participants rested for at least 10 minutes before the examinations to exclude exercise-associated hyperemia. The study was performed at days 1 to 4 (menstrual phase), 14 to 16 (proliferative phase), and 25 to 28 (secretory phase) of the participants’ menstrual cycles. We examined the following veins: common femoral vein at 1 cm above the saphenofemoral junction, femoral vein at 1 cm from its junction to the common femoral vein, popliteal vein at the knee crease, great saphenous vein at 1 cm from the saphenofemoral junction, and short saphenous vein at the knee crease. The investigation proceeded in defined steps: (1) both limbs were checked for deep venous thrombosis using a B-mode sonographic compression method27 with the participant in the supine position; and (2) the vein diameter and valve closure time at each of the 5 venous segments were evaluated in both limbs with the participant in a standing position. The examination commenced with a study of the common femoral vein, femoral vein, and great saphenous vein with the participant facing the examiner. The popliteal vein and short saphenous vein were then examined with the participant facing away from the examiner and slightly flexing the knee. All veins were examined with the participants standing and holding onto a frame with the weight mainly on the opposite leg, keeping the leg under examination in a relaxed position with the knee slightly flexed. B-mode images were used to measure venous diameters from venous wall to wall in a longitudinal section, ignoring venous wall luminal irregularities, using the electronic calipers incorporated in the ultrasound machine. Venous diameters were measured during quiet respiration. Pulsed wave Doppler imaging was used to measure the valve closure time. Venous flow augmentation was accomplished by manual compression immediately distal to the venous segment under examination. The valve closure time was measured by means of the time scale of the Doppler trace. Venous reflux in the deep or superficial venous system was detected when the valve closure time was longer than 1 second.28,29 Typical vein diameter and valve closure time measurements are shown in Figure 1.
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Figure 1. Changes in the diameter and valve closure time of the great saphenous vein at 1 cm from saphenofemoral junction in one of the volunteers at the menstrual phase (A and B; diameter, 7.4 mm; valve closure time, 0.17 seconds), proliferative phase (C and D; diameter, 7.5 mm; valve closure time, 0.33 seconds), and secretory phase (E and F; diameter, 8.5 mm; valve closure time, 0.40 seconds). A
B
C
D
E
F
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Each participant had the 3 scans performed at the same time of day. The measurements were performed by a single experienced vascular technologist (A.M.A.). While performing the scheduled venous studies, the operator was blinded to the earlier results. The data from all participants were stored on the hard disk of the ultrasound machine. None of the operators had access to these data; at the completion the study, they were independently analyzed by a statistician (A.A.). Statistical Methods The participants’ characteristics, venous segment diameters, venous segment valve closure times, and clinical assessments of each limb were recorded. The data were analyzed with SPSS version 19 software for Windows (IBM Corporation, Armonk, NY). Median ± interquartile range (IQR) values for the vein diameter and valve closure time in the various venous segments of both limbs were calculated at different phases of the menstrual cycle. The Friedman test was used to assess changes in the vein diameter and valve closure time for each venous segment in each limb at different phases of the menstrual cycle. A related samples Wilcoxon signed rank test was used to test the same venous segment for the diameter and valve closure time at the same and different phases of the menstrual cycle within each limb and between limbs in the same participant. P < .05 was considered statistically significant.
each limb (P = .003–.025). When adjusted for body mass index, the statistical significance remained for the venous segment diameter and valve closure time for the same segment in the same limb (P = .001–.049). In addition, the related samples Wilcoxon signed rank test showed no statistical significance for the venous segment diameter and valve closure time in identical venous segments between the limbs in the same participant (P = .079– .97). Median ± IQR values for the diameter and valve closure time of superficial and deep venous segments in both lower limbs during different phases of the menstrual cycle are summarized in Tables 1 and 2 and Figure 2.
Discussion To our knowledge, no longitudinal studies exploring the effect of hormonal changes on lower limb veins at different stages of the menstrual cycle in nulliparous women have been reported previously; thus, our study is the first of its kind. This baseline study will enable a better fundamental understanding of the natural progression of the pathophysiologic mechanisms involved in varicose veins and hence provide a basis for possible prophylactic therapy for those women at risk. Table 1. Median ± IQR Values for Changes in the Diameter and Valve Closure Time of Deep Venous Segments in Both Lower Limbs During Different Phases of the Menstrual Cycle
Results Parameter
Fifty-three healthy young nulliparous female volunteers (106 limbs) participated in the study. Their mean age ± SD was 20.60 ± 1.90 years, and their mean body mass index was 23.90 ± 4.90 kg/m2. Thirteen participants (25%) had a body mass index of 25 kg/m2 or higher. All participants were classified as class 0 (no venous disease) according to the 7-point clinical scale of the International Consensus Committee of the American Venous Forum.25,26 None ofthe volunteers developed any deep venous thrombosis throughout the study, as documented by B-mode compression sonography, color flow imaging, and pulsed Doppler imaging. In general, there was a gradual and progressive increase in the diameter and valve closure time from the menstrual through the proliferative to the secretory phase of the menstrual cycle. The Friedman test for venous segment diameter and valve closure time changes between baseline (menstrual phase), mid cycle (proliferative phase), and late cycle (secretory phase), and the related samples Wilcoxon signed rank between two menstrual cycle phases showed a statistically significant increase for each venous segment in
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Menstrual Phase
Common femoral vein Right leg Diameter, mm 11.80 ± 1.60 Valve closure time, s 0.22 ± 0.12 Left leg Diameter, mm 11.40 ± 1.65 Valve closure time, s 0.22 ± 0.12 Femoral vein Right leg Diameter, mm 8.40 ± 1.95 Valve closure time, s 0.19 ± 0.11 Left leg Diameter, mm 8.50 ± 1.60 Valve closure time, s 0.17 ± 0.06 Popliteal vein Right leg Diameter, mm 7.40 ± 1.15 Valve closure time, s 0.16 ± 0.08 Left leg Diameter, mm 7.30 ± 1.15 Valve closure time, s 0.16 ± 0.06
Proliferative Phase
Secretory Phase
12.30 ± 1.70 0.26 ± 0.11
12.90 ± 1.85 0.35 ± 0.16
12.00 ± 1.75 0.25 ± 0.14
12.30 ± 1.95 0.31 ± 0.17
9.00 ± 1.165 0.23 ± 0.12
9.50 ± 1.50 0.25 ± 0.18
9.00 ± 1.70 0.20 ± 0.09
9.30 ± 1.70 0.24 ± 0.12
7.90 ± 1.30 0.19 ± 0.07
8.00 ± 1.30 0.23 ± 0.07
7.90 ± 1.25 0.18 ± 0.06
8.00 ± 0.95 0.20 ± 0.06
Friedman and related samples Wilcoxon tests: P = .003–.025 within each limb; related samples Wilcoxon test: P = .079–.97 between limbs.
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In the normal menstrual cycle, sex hormone levels are lowest at the time of menstruation. The estrogen peak occurs at mid cycle (ovulation), and a slight decrease in estrogen with elevation in progesterone levels occurs during the latter half of the cycle.30 The results of our study are in accord with the hypothesis reported by others18,19 that hormonal changes in women have a major effect on the development of varicose veins. It is possible that the influence of altered levels of sex hormones play an important role in the development of venous insufficiency in pregnancy via their action on the smooth muscles of the lower limb veins.18 Wenner19 showed that there is increased venous distensibility associated with high endogenous estradiol levels and clinical evidence of varicose veins in menopausal women.
Table 2. Median ± IQR Values for Changes in the Diameter and Valve Closure Time of Superficial Venous Segments in Both Lower Limbs During Different Phases of the Menstrual Cycle Parameter Great saphenous vein Right leg Diameter, mm Valve closure time, s Left leg Diameter, mm Valve closure time, s Short saphenous vein Right leg Diameter, mm Valve closure time, s Left leg Diameter, mm Valve closure time, s
Menstrual Phase
Proliferative Phase
Secretory Phase
6.30 ± 1.30 0.18 ± 0.11
6.90 ± 1.35 0.25 ± 0.16
7.40 ± 1.35 0.27 ± 0.15
6.60 ± 1.15 0.17 ± 0.08
7.10 ± 1.50 0.22 ± 0.09
7.40 ± 1.40 0.23 ± 0.11
3.30 ± 1.70 0.15 ± 0.04
3.60 ± 2.00 0.15 ± 0.06
3.80 ± 2.00 0.18 ± 0.06
3.30 ± 1.75 0.14 ± 0.06
3.60 ± 1.80 0.17 ± 0.04
4.00 ± 1.60 0.18 ± 0.04
Friedman and related samples Wilcoxon tests: P = .003–.025 within each limb; related samples Wilcoxon test: P = .079–.97 between limbs. Figure 2. Median ± IQR values for changes in the diameter and valve closure time of deep venous segments (A and B) and superficial venous segments (C and D) in both lower limbs at different phases of the menstrual cycle (dotted lines, menstrual phase; dashed lines, proliferative phase; and solid lines, secretory phase). Friedman and related samples Wilcoxon tests: P = .003–.025 within each limb; related samples Wilcoxon test: P = .079–.97 between limbs. CFV indicates common femoral vein; FV, femoral vein; GSV, great saphenous vein; POPV, popliteal vein; and SSV, short saphenous vein. A
B
C
D
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In our study, we found that there was a significant gradual increase in the vein diameter as well as the valve closure time when we compared the baseline (menstrual) phase to the midcycle (proliferative) phase and late-cycle (secretory) phase (P = .003–.025). Perhaps these monthly changes in the vein diameter and valve closure time would, over the years, lead to weakening of the vein wall, causing incompetence of the valves and leading to the development of varicose veins in women. To prove this theory, a study should be extended for more than 10 to 20 years following the same participants to see how many of them would develop varicose veins in the long run. Designing such a study may not be possible, as most of these young women may get married (which might introduce the effect of pregnancy) or move to other geographic areas. Perhaps a more doable longitudinal study should be undertaken to substantiate the potential relevance of the findings from this study. The results of this study apply only to nulliparous young women, who may not be representative of the entire female population. Results may be different in women taking oral contraceptives and postmenopausal women receiving hormone replacement therapy. Also, the results might be different in older women who have undergone total hysterectomy and oophorectomy, in whom there are no hormonal changes. A further limitation of this study was the relatively small sample size. Moreover, manual vein augmentation was used, as it was easier to apply and more comfortable for the participants, but automated cuff compression would be more reproducible and give consistent output.
References 1.
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Abramson JH, Hopp C, Epstein LM. The epidemiology of varicose veins: a survey of western Jerusalem. J Epidemiol Community Health 1981; 35:213–217. Sadick NS. Predisposing factors of varicose veins and teangiectatic leg veins. J Dermatol Surg Oncol 1992; 18:883–886. Hanrahan LM, Kechejiaan J, Cordts RR, et al. Patterns of venous insufficiency in patients with varicose veins. Arch Surg 1991; 126:687–691. Widmer LK, Stahelin HB, da Silva A. Peripheral Venous Disorders: Prevalence and Socio-Medical Importance—Observations in 4529 Apparently Healthy Persons: Basel III Study. Bern, Switzerland: Hans Huber; 1978:1– 10. Brand FN, Dannenberg AL, Abbott RD, Kannel WB. The epidemiology of varicose veins: the Framingham study. Am J Prev Med 1988; 4:96–101. Bylebyl JJ. Boyle and Harvey on the valves in the veins. Bull Hist Med 1982; 56:351–367.
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Rose SS, Ahmed A. Some thoughts on the aetiology of varicose veins. J Cardiovasc Surg 1986; 27:534–543. Hoare MC, Nicolaides AN, Miles CR, et al. The role of primary varicose veins in venous ulceration. Surgery 1982; 92:450–453. Nicolaides AN, Hussein MK, Szendro G, Christopoulos D, Vasdekis S, Clarke H. The relation of venous ulceration with ambulatory venous pressure measurements. J Vasc Surg 1993; 17:414–419. Dindelli M, Parazzini F, Basellini A, Rabaiotti E, Corsi G, Ferrari A. Risk factors for varicose veins before and during pregnancy. Angiology 1993; 44:361–367. Franks PJ, Wright DD, McCollum CN. Epidemiology of venous disease: a review. Phlebology 1989; 4:143–151. Scott TE, LaMorte WW, Gorin DR, Menzoian JO. Risk factors for chronic venous insufficiency: a dual case-control study. J Vasc Surg 1995; 22:622–628. Hairai M, Kenichi N, Nakayama R. Prevalence and risk factors of varicose veins in Japanese women. Angiology 1990; 41:228–232. Maffei FH, Magaldi C, Pinho SZ, et al. Varicose veins and chronic venous insufficiency in Brazil: prevalence among 1755 inhabitants of a country town. Int J Epidemiol 1986; 15:210–217. Arnoldi CC. The aetiology of primary varicose veins. Dan Med Bull 1957; 4:102–107. Fanfera FJ, Palmer LH. Pregnancy and varicose veins. Arch Surg 1968; 96:33–35. Ciardullo AV, Panico S, Bellati C, et al. 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. Cohen J. Venous insufficiency and oral contraception [in French]. Rev Fr Gynecol Obstet 1991; 86:187–189. Wenner L. Varicosity, hormones and pregnancy [in German]. Vasa1979; 8:258–262. Wood JE. The cardiovascular effects of oral contraceptives. Mod Concepts Cardiovasc Dis 1972; 41:37–40. Mashiah A, Berman V, Thole HH, et al. Estrogen and progesterone receptors in normal and varicose saphenous veins. Cardiovasc Surg 1999; 7:327–331. Perrot-Applanat M. Estrogen receptors in the cardiovascular system. Steriods 1996; 61:212–215. 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. Schmidt JB, Seidl K, Spona J. Hormone interactions in varicose veins: receptor analysis and hormone level [in German]. Vasa 1986; 15:224– 227. Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995; 21:635–645. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40:1248–1252.
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27. Raghavendra BN, Horii SC, Hilton S, Subramayam BR, Rosen RJ, Lam S. Deep venous thrombosis: detection by probe compression of veins. J Ultrasound Med 1986; 5:89–95. 28. van Bemmelen PS, Bedford G, Beach K, Strandness DE. Quantitative segmental evaluation of venous valvular reflux with duplex ultrasound scanning. J Vasc Surg 1989; 10:425–431. 29. Labropoulos N, Tiongson J, Pryor L, et al. Definition of venous reflux in lower-extremity veins. J Vasc Surg 2003; 38:793–798. 30. Pemble LB, Effeney DJ, Thomas BJ. Cross-sectional area changes in leg vein at different stages of the menstrual cycle. J Vasc Technol1996; 20:143– 147.
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Changes in the Diameter and Valve Closure Time of Leg Veins Across the Menstrual Cycle Akram M. Asbeutah, PhD, DMU, AMS, MSVU, Maitha Al-Enezi, BSc, Noura M. Al-Sharifi, BSc, Abdullah Almajran, MSc, James D. Cameron, MD, Barry P. McGrath, MD, Sami K. Asfar, MD Objectives—The purpose of this study was to determine the changes (if any) in the diameter and valve closure time of the lower limb veins in healthy young nulliparous women at different phases of the menstrual cycle. Methods—Fifty-three young nulliparous women were asked to undergo clinical evaluations and duplex ultrasound examinations of both lower limb veins to monitor changes in the vein diameter and valve closure time at different phases of their menstrual cycles. The vein diameter on B-mode imaging and valve closure time on pulsed Doppler tracing were calculated at days 1 to 4, 14 to 16, and 25 to 28 of the menstrual cycle. Freidman and related samples Wilcoxon signed rank tests were used to determine timerelated changes in venous function.
Received June 25, 2013, from the Department of Radiologic Sciences, Faculty of Allied Health Sciences (A.M.A., M.A.-E., N.M.A.-S.), and Departments of Community Medicine and Behavioral Sciences (A.A.) and Surgery (S.K.A.), Health Sciences Center, Faculty of Medicine, Kuwait University, Kuwait; and Monash Cardiovascular Research Center, MonashHeart, Monash Health and Department of Medicine (J.D.C.), and Department of Medicine (B.P.M), Monash University, Melbourne, Victoria, Australia. Revision requested September 4, 2013. Revised manuscript accepted for publication September 8, 2013. We thank the volunteers for their participation in this study and Chinma Babu (chief technologist, Department of Radiology, Faculty of Allied Health Sciences, Kuwait University) for help and support during the study. Address correspondence to Akram M. Asbeutah, PhD, DMU, AMS, MSVU, Department of Radiologic Sciences, Faculty of Allied Health Sciences, Kuwait University, PO Box 31470, 90805 Sulaibikhat, Kuwait. E-mail: [email protected], [email protected] Abbreviations
IQR, interquartile range doi:10.7863/ultra.33.5.803
Results—The volunteers’ mean age ± SD was 20.60 ± 1.90 years, and their mean body mass index was 23.90 ± 4.90 kg/m2. There was a gradual increase in the vein diameter and valve closure time at the specified phases of the menstrual cycle. Friedman and related samples Wilcoxon signed rank tests for venous segment diameter and valve closure time changes between the different phases of the menstrual cycle were performed and showed statistical significance for each venous segment within each limb (P = .003–.025). Also, when adjusted for body mass index, statistical significance existed for the same venous segments in the same limbs (P = .001–.049). There was no statistical significance for the same venous segments at the same phase of the menstrual cycle between limbs (related samples Wilcoxon signed rank test: P = .079–.97). Conclusions—During the menstrual cycle, the lower limb veins show an increase in their diameter and valve closure time. These changes are probably mediated by the female sex hormones. Key Words—duplex ultrasound; female sex hormones; leg veins; menstrual cycle; vascular ultrasound; varicose veins
T
he prevalence of varicose veins is around 25% to 33% in women and 10% to 20% in men.1–3 The reported annual incidence of new cases of varicose veins is 2.6% in women and 1.9% in men, with associated costs to the community in terms of lost working hours, hospitalization, and management.4,5 Two theories have been proposed to describe the pathogenesis of varicose veins: the valvular theory and primary weakness of the venous wall.6,7 Both theories have the same end result: ie, the venous valves fail to maintain efficient cephalad blood flow, resulting in retrograde blood flow, which leads to dilated tortuous veins. If not treated, venous hypertension will ensue, with its consequences of hyperpigmentation, ulceration, and lipodermatosclerosis.8,9
©2014 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2014; 33:803–809 | 0278-4297 | www.aium.org
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More women are affected by varicose veins, and parous women have an increased risk of developing varicose veins compared with nulliparous women.10 Family history, age, race, weight, occupation, pregnancy, oral contraceptives, and cardiovascular disease have been identified as possible etiologic risk factors.10–13 The influence of increased levels of female sex hormones, especially during pregnancy, on venous disorders of the legs has been noted by many investigators.1–5,14–20 In addition, estrogen and progesterone receptors were found in sections of venous walls, suggesting an involvement of sex hormones in the pathogenesis of varicose veins by a mechanism that has yet to be identified.21–24 To elucidate any effect of sex hormones on veins containing these receptors, we performed this in vivo study during the menstrual cycle in young women. The aim of this study was to explore the changes (if any) in the diameter and valve closure time of the lower limb veins in healthy young nulliparous women at different phases of the menstrual cycle.
Materials and Methods Participants From September 2012 to May 2013, 53 healthy young nulliparous female volunteers (106 limbs) were asked to participate in this study investigating the effect of sex hormones on the vein diameter and valve closure time at different menstrual phases. They were recruited from the Health Sciences Center of Kuwait University through an advertisement in the local university newspaper and telephone calls. The study was approved by the Human Research and Ethics Committee of the Kuwait University Health Sciences Center. Informed consent was obtained from all participants before entry into the study. Inclusion criteria included women in the age group of 18 to 25 years with normal and regular menstrual cycles for the previous 4 months, no gynecologic problems, no personal or family history of varicose veins, no history of previous deep venous thrombosis, no oral contraceptive use, no smoking, no medication use for any reason, no previous pregnancy, no history of leg injury or fracture, and no history of malignancy, blood clotting disorders, or hypertension. Clinical Assessment All participants underwent a clinical review and a physical examination of both legs by a single experienced vascular physician (S.K.A.) at each visit. The venous status of the legs was classified according to the 7-point CEAP (clinical, etiologic, anatomic, and pathophysiologic) scale (classes 0–6) of the International Consensus Committee of the American Venous Forum.25,26
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Duplex Ultrasound Scanning B-mode imaging, color flow imaging, and pulsed Doppler spectral analysis were performed in both legs with a MicroMaxx scanner (FUJIFILM SonoSite, Inc, Bothell, WA) and a linear 12–5-MHz transducer on the low-flow setting. All examinations were performed in a temperaturecontrolled room at 22°C ± 2°C. Before the study, all participants changed into a loose gown and removed their undergarments. The participants rested for at least 10 minutes before the examinations to exclude exercise-associated hyperemia. The study was performed at days 1 to 4 (menstrual phase), 14 to 16 (proliferative phase), and 25 to 28 (secretory phase) of the participants’ menstrual cycles. We examined the following veins: common femoral vein at 1 cm above the saphenofemoral junction, femoral vein at 1 cm from its junction to the common femoral vein, popliteal vein at the knee crease, great saphenous vein at 1 cm from the saphenofemoral junction, and short saphenous vein at the knee crease. The investigation proceeded in defined steps: (1) both limbs were checked for deep venous thrombosis using a B-mode sonographic compression method27 with the participant in the supine position; and (2) the vein diameter and valve closure time at each of the 5 venous segments were evaluated in both limbs with the participant in a standing position. The examination commenced with a study of the common femoral vein, femoral vein, and great saphenous vein with the participant facing the examiner. The popliteal vein and short saphenous vein were then examined with the participant facing away from the examiner and slightly flexing the knee. All veins were examined with the participants standing and holding onto a frame with the weight mainly on the opposite leg, keeping the leg under examination in a relaxed position with the knee slightly flexed. B-mode images were used to measure venous diameters from venous wall to wall in a longitudinal section, ignoring venous wall luminal irregularities, using the electronic calipers incorporated in the ultrasound machine. Venous diameters were measured during quiet respiration. Pulsed wave Doppler imaging was used to measure the valve closure time. Venous flow augmentation was accomplished by manual compression immediately distal to the venous segment under examination. The valve closure time was measured by means of the time scale of the Doppler trace. Venous reflux in the deep or superficial venous system was detected when the valve closure time was longer than 1 second.28,29 Typical vein diameter and valve closure time measurements are shown in Figure 1.
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Figure 1. Changes in the diameter and valve closure time of the great saphenous vein at 1 cm from saphenofemoral junction in one of the volunteers at the menstrual phase (A and B; diameter, 7.4 mm; valve closure time, 0.17 seconds), proliferative phase (C and D; diameter, 7.5 mm; valve closure time, 0.33 seconds), and secretory phase (E and F; diameter, 8.5 mm; valve closure time, 0.40 seconds). A
B
C
D
E
F
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Each participant had the 3 scans performed at the same time of day. The measurements were performed by a single experienced vascular technologist (A.M.A.). While performing the scheduled venous studies, the operator was blinded to the earlier results. The data from all participants were stored on the hard disk of the ultrasound machine. None of the operators had access to these data; at the completion the study, they were independently analyzed by a statistician (A.A.). Statistical Methods The participants’ characteristics, venous segment diameters, venous segment valve closure times, and clinical assessments of each limb were recorded. The data were analyzed with SPSS version 19 software for Windows (IBM Corporation, Armonk, NY). Median ± interquartile range (IQR) values for the vein diameter and valve closure time in the various venous segments of both limbs were calculated at different phases of the menstrual cycle. The Friedman test was used to assess changes in the vein diameter and valve closure time for each venous segment in each limb at different phases of the menstrual cycle. A related samples Wilcoxon signed rank test was used to test the same venous segment for the diameter and valve closure time at the same and different phases of the menstrual cycle within each limb and between limbs in the same participant. P < .05 was considered statistically significant.
each limb (P = .003–.025). When adjusted for body mass index, the statistical significance remained for the venous segment diameter and valve closure time for the same segment in the same limb (P = .001–.049). In addition, the related samples Wilcoxon signed rank test showed no statistical significance for the venous segment diameter and valve closure time in identical venous segments between the limbs in the same participant (P = .079– .97). Median ± IQR values for the diameter and valve closure time of superficial and deep venous segments in both lower limbs during different phases of the menstrual cycle are summarized in Tables 1 and 2 and Figure 2.
Discussion To our knowledge, no longitudinal studies exploring the effect of hormonal changes on lower limb veins at different stages of the menstrual cycle in nulliparous women have been reported previously; thus, our study is the first of its kind. This baseline study will enable a better fundamental understanding of the natural progression of the pathophysiologic mechanisms involved in varicose veins and hence provide a basis for possible prophylactic therapy for those women at risk. Table 1. Median ± IQR Values for Changes in the Diameter and Valve Closure Time of Deep Venous Segments in Both Lower Limbs During Different Phases of the Menstrual Cycle
Results Parameter
Fifty-three healthy young nulliparous female volunteers (106 limbs) participated in the study. Their mean age ± SD was 20.60 ± 1.90 years, and their mean body mass index was 23.90 ± 4.90 kg/m2. Thirteen participants (25%) had a body mass index of 25 kg/m2 or higher. All participants were classified as class 0 (no venous disease) according to the 7-point clinical scale of the International Consensus Committee of the American Venous Forum.25,26 None ofthe volunteers developed any deep venous thrombosis throughout the study, as documented by B-mode compression sonography, color flow imaging, and pulsed Doppler imaging. In general, there was a gradual and progressive increase in the diameter and valve closure time from the menstrual through the proliferative to the secretory phase of the menstrual cycle. The Friedman test for venous segment diameter and valve closure time changes between baseline (menstrual phase), mid cycle (proliferative phase), and late cycle (secretory phase), and the related samples Wilcoxon signed rank between two menstrual cycle phases showed a statistically significant increase for each venous segment in
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Menstrual Phase
Common femoral vein Right leg Diameter, mm 11.80 ± 1.60 Valve closure time, s 0.22 ± 0.12 Left leg Diameter, mm 11.40 ± 1.65 Valve closure time, s 0.22 ± 0.12 Femoral vein Right leg Diameter, mm 8.40 ± 1.95 Valve closure time, s 0.19 ± 0.11 Left leg Diameter, mm 8.50 ± 1.60 Valve closure time, s 0.17 ± 0.06 Popliteal vein Right leg Diameter, mm 7.40 ± 1.15 Valve closure time, s 0.16 ± 0.08 Left leg Diameter, mm 7.30 ± 1.15 Valve closure time, s 0.16 ± 0.06
Proliferative Phase
Secretory Phase
12.30 ± 1.70 0.26 ± 0.11
12.90 ± 1.85 0.35 ± 0.16
12.00 ± 1.75 0.25 ± 0.14
12.30 ± 1.95 0.31 ± 0.17
9.00 ± 1.165 0.23 ± 0.12
9.50 ± 1.50 0.25 ± 0.18
9.00 ± 1.70 0.20 ± 0.09
9.30 ± 1.70 0.24 ± 0.12
7.90 ± 1.30 0.19 ± 0.07
8.00 ± 1.30 0.23 ± 0.07
7.90 ± 1.25 0.18 ± 0.06
8.00 ± 0.95 0.20 ± 0.06
Friedman and related samples Wilcoxon tests: P = .003–.025 within each limb; related samples Wilcoxon test: P = .079–.97 between limbs.
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In the normal menstrual cycle, sex hormone levels are lowest at the time of menstruation. The estrogen peak occurs at mid cycle (ovulation), and a slight decrease in estrogen with elevation in progesterone levels occurs during the latter half of the cycle.30 The results of our study are in accord with the hypothesis reported by others18,19 that hormonal changes in women have a major effect on the development of varicose veins. It is possible that the influence of altered levels of sex hormones play an important role in the development of venous insufficiency in pregnancy via their action on the smooth muscles of the lower limb veins.18 Wenner19 showed that there is increased venous distensibility associated with high endogenous estradiol levels and clinical evidence of varicose veins in menopausal women.
Table 2. Median ± IQR Values for Changes in the Diameter and Valve Closure Time of Superficial Venous Segments in Both Lower Limbs During Different Phases of the Menstrual Cycle Parameter Great saphenous vein Right leg Diameter, mm Valve closure time, s Left leg Diameter, mm Valve closure time, s Short saphenous vein Right leg Diameter, mm Valve closure time, s Left leg Diameter, mm Valve closure time, s
Menstrual Phase
Proliferative Phase
Secretory Phase
6.30 ± 1.30 0.18 ± 0.11
6.90 ± 1.35 0.25 ± 0.16
7.40 ± 1.35 0.27 ± 0.15
6.60 ± 1.15 0.17 ± 0.08
7.10 ± 1.50 0.22 ± 0.09
7.40 ± 1.40 0.23 ± 0.11
3.30 ± 1.70 0.15 ± 0.04
3.60 ± 2.00 0.15 ± 0.06
3.80 ± 2.00 0.18 ± 0.06
3.30 ± 1.75 0.14 ± 0.06
3.60 ± 1.80 0.17 ± 0.04
4.00 ± 1.60 0.18 ± 0.04
Friedman and related samples Wilcoxon tests: P = .003–.025 within each limb; related samples Wilcoxon test: P = .079–.97 between limbs. Figure 2. Median ± IQR values for changes in the diameter and valve closure time of deep venous segments (A and B) and superficial venous segments (C and D) in both lower limbs at different phases of the menstrual cycle (dotted lines, menstrual phase; dashed lines, proliferative phase; and solid lines, secretory phase). Friedman and related samples Wilcoxon tests: P = .003–.025 within each limb; related samples Wilcoxon test: P = .079–.97 between limbs. CFV indicates common femoral vein; FV, femoral vein; GSV, great saphenous vein; POPV, popliteal vein; and SSV, short saphenous vein. A
B
C
D
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In our study, we found that there was a significant gradual increase in the vein diameter as well as the valve closure time when we compared the baseline (menstrual) phase to the midcycle (proliferative) phase and late-cycle (secretory) phase (P = .003–.025). Perhaps these monthly changes in the vein diameter and valve closure time would, over the years, lead to weakening of the vein wall, causing incompetence of the valves and leading to the development of varicose veins in women. To prove this theory, a study should be extended for more than 10 to 20 years following the same participants to see how many of them would develop varicose veins in the long run. Designing such a study may not be possible, as most of these young women may get married (which might introduce the effect of pregnancy) or move to other geographic areas. Perhaps a more doable longitudinal study should be undertaken to substantiate the potential relevance of the findings from this study. The results of this study apply only to nulliparous young women, who may not be representative of the entire female population. Results may be different in women taking oral contraceptives and postmenopausal women receiving hormone replacement therapy. Also, the results might be different in older women who have undergone total hysterectomy and oophorectomy, in whom there are no hormonal changes. A further limitation of this study was the relatively small sample size. Moreover, manual vein augmentation was used, as it was easier to apply and more comfortable for the participants, but automated cuff compression would be more reproducible and give consistent output.
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