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Proposal for a protocol for sex hormones level sampling in patients with varices to evidence pelvic reflux
Abstract
Sex hormonal direct action on venous system has been advocated for explaining further dilatation of already present limb varices, or stimulate recurrences after varicose veins removal, or even dilate normal veins inducing valves incompetence, typically in women, but also in men. Hormones can directly reach leg vein trough Pelvic Veins Incontinence. This event is frequent and quite well evidenced by Ultrasound or Radiology. Blood sampling of hormones from antecubital vein (as a control) compared with blood from varicose veins could more easily (and less costly) make possible to evidence this hormonal discrepancy whose ratio could become the index of this hormonal influence and, indirectly, pelvic reflux. Many clinical situations could benefit from this study, which may provide reasons for taking a less aggressive approach, for directing attention to leaking points and the identification of cases at risk of recurrences, suggesting a regular use of compression stockings.
... Finally, the gonadal vein, which is the main source of pelvic venous reflux, is strongly influenced by sex hormones and is the main cause of cyclic pelvic pain. Sex hormones stimulate and influence the dilation of the vessels depending on their concentration, which can cause pelvic venous reflux [28]. However, there was a lack of analysis of the causative factors of reflux, and it is believed that future studies could improve this research by including recurrent patients in the study. ...
Objective:
The purpose of this study was to evaluate the incidence of gonadal vein refluxes associated with lower-extremity varicose veins with Doppler ultrasonography (DUS).
Method:
A total of 6279 patients with venous disease-related symptoms of the lower extremity were evaluated with DUS in the vascular lab. Gonadal vein reflux using abdominal ultrasound was further evaluated in patients with unusual varices, defined as varices in the inguinal, inner or upper thigh and the vulvar area without refluxes in the saphenofemoral junction (SPJ). Those patients who showed gonadal vein reflux were diagnosed as having pelvic-origin varicosity.
Results:
Unusual varices were found in a total of 237 patients (3.8%), and of these patients, pelvic-origin varicosity was discovered with transabdominal ultrasound in 156 (65.8%). A total of 66.7% (n = 38/57) of unusual varix patients with pelvic pain had gonadal vein reflux. The measurement of gonadal vein diameter was larger in ultrasonography than CT scans (8.835 vs. 8.81, p < 0.001). Two patients with severe symptoms but no obstructive venous diseases were treated with gonadal vein embolization.
Conclusion:
The incidence of pelvic-origin varicosities was 2.5% (n = 156/6279). However, more than half of the patients with unusual varices had gonadal vein reflux and 24.4% of these patients also presented with pelvic pain. The evaluation of pelvic-origin varicosities should be performed in patients who present with unusual forms of varices of the lower extremity.
Objective:
The association between pregnancy and the development of varicose veins is uncertain. We aimed to determine whether a history of pregnancy is associated with the development of varicose veins.
Methods:
We performed a systematic literature search using the databases of PubMed, Embase, Robert Koch-Institut, and Cochrane Central and the references of included papers. Eligible studies were all epidemiologic observational studies in which the outcome "varicose veins" and pregnancy history were assessed. The quality of each study was evaluated on the basis of the Dutch Cochrane review checklist and by the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. For our meta-analysis, a random effects model was applied to pool odds ratios and 95% confidence intervals across studies.
Results:
We found nine eligible studies enrolling 17,109 women. Pregnancy was associated with a significant risk increase in developing varicose veins. The results of our meta-analysis suggest that the odds for women with a history of pregnancy in developing varicose veins significantly increases by 82% (odds ratio, 1.82; 95% CI, 1.43-2.33) compared with women with no history of pregnancy. As expected for epidemiologic observational studies, the heterogeneity was considerably high (I(2) = 81%).
Conclusions:
Our meta-analysis strongly supports the hypothesis that there is a significant and strong association between a history of pregnancy and varicose veins. However, qualitative and quantitative differences among studies were evident and were also reflected in a considerably high heterogeneity.
The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, the goal of this review is to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared with men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis, and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine, and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. Although consensus opinions are emphasized, controversial views are presented to stimulate future research.
Pelvic veins incompetence may cause varicose veins formation in the lower extremity due to leak points of the pelvic circulation. This observation is particularly frequent in recurrence cases especially in multi parity. The cause of pelvic vein dilatation is still not clear. Traditional mechanism for varicose veins formation referred to leg varices cannot be transferred to pelvic circulation where a strong efficient pumping mechanism and a high hydrostatic column is missing. An alternative explanation is possible if hormonal factors are considered to contribute to vasodilatation (estrogen is a potent vasodilator), and pelvic veins are naturally exposed to high doses of ovarian hormones. Pelvic veins dilatation/hypertension , rich in estrogens, may be directed through leak points to leg veins where estrogens effect of vasodilation is maintained. Then, at every Valsalva like action, some blood rich in estrogens passes in the leg network giving rise, among others, to perineal veins dilatation, recurrence after groin dissection for SFJ high ligation, intermittent leg pain/discomfort. Estrogens sampling studies could confirm this hypothesis and guide alternative treatments.
Testosterone (T) is the predominant endogenous androgen in the bloodstream. At the vascular level, T presents genomic and non-genomic effects, and both effects may overlap. The genomic actions assume that androgens can freely cross the plasma membrane of target cells and bind to nuclear androgen receptors, inducing gene transcription and protein synthesis. The non-genomic effects have a more rapid onset and may be related to the interaction with protein/receptor/ion channels of the plasma membrane. The key T effect at the vascular level is vasorelaxation, which is primarily due to its rapid effect. Thus, the main purpose of this review is to discuss the T non-genomic effects at the vascular level and the molecular pathways involved in its vasodilator effect observed in in vivo and in vitro studies. In this sense, the nuclear receptor activation, the influence of vascular endothelium and the activation or inhibition of ion channels (potassium and calcium channels, respectively) will be reviewed regarding all the data that corroborated or not. Moreover, this review also provides a brief update on the association of T with the risk factors for cardiovascular diseases, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia, and hypertension. In summary, in this paper we consider the non-genomic vascular mode of action of androgen in physiological conditions and the main risk factors for cardiovascular diseases.
The pelvic congestion syndrome definition includes two not so frequently overlapping scenarios: (i) pelvic venous engorgement with lower abdomen symptomatology; and (ii) lower limb varicose veins fed by pelvic escape points that are generally less prone to develop the abdominal clinical manifestation typical for pelvic congestion syndrome. We retrospectively evaluated 985 female patients (43±11 years old; 23±5kg/m² BMI) who visited our offices for lower limb varicose veins of pelvic origin. Second-level imaging was needed for 229 patients. The remaining 756 patients underwent direct echo-guided foam sclerotherapy in proximity of the pelvic escape points. At a mean follow-up of 4.1±1.4 years, 595 patients were successfully treated. Among the successfully treated group, mild lower abdomen heaviness and occasional dyspareunia was reported by 14 and 11 women, respectively, prior to the injection. At the end of the follow up, a significant reduction in the symptomatology was reported for both lower abdomen heaviness and dyspareunia. In traditional pelvic congestion syndrome, an accurate diagnosis protocol eventually ends in an interventional radiology suite. Conversely, in cases of lower limb varicose veins of pelvic origin, the phlebologist can, and in our opinion should, assume a pivotal role both in the diagnostic and therapeutic part.
To assess the difference in the oestradiol levels of blood taken from varicose veins in patients with and without pelvic vein incompetence (PVI).
Women of child-bearing age with symptomatic primary or recurrent varicose veins of the great saphenous vein (GSV) were included in a prospective study. Patients underwent duplex ultrasonography and pelvic vein phlebography. They were divided into a group with PVI (PVI group) and a control group with GSV reflux alone (VV group). Blood samples were collected from the GSV at the sapheno-femoral junction or lower in the thigh as well as from the arm. Oestradiol levels were determined by electroluminescence.
Between January and December 2007, 40 women were studied, of which 19 showed phlebographic evidence of PVI (PVI group), while 21 were included in the VV group. Phlebography revealed an incompetent ovarian vein in 14 (74%) patients of the PVI group, dilated uterine and ovarian plexuses in 12 (63%) and an incompetent internal iliac vein in six cases (32%). In the PVI group, the median oestradiol level in GSV samples was 121 pgml(-1) (range: 12-4300), while in the VV group the median level was 75 pgml(-1) (range: 9-1177). In the upper limb, the PVI group patients had a median level of 78 pgml(-1) (range: 15-121) and the VV group patients 68 pgml(-1) (range: 13-568). The ratio of lower limb/upper extremity was significantly higher (p<0.002) in patients of PVI group (median: 1.9; range: 0.7-33) than in those of the VV group (median: 1.1; range: 0.8-13). A threshold ratio of 1.4 showed the highest combined sensitivity and specificity in differentiating patients with PVI from those without.
In patients with varicose veins arising from the GSV, oestradiol levels were significantly higher in the lower limb than in the upper extremity in the subgroup with associated PVI. It may be possible to use this observation as a diagnostic test in patients with suspected PVI. This deserves further study.
High serum levels of estradiol are associated with clinical evidence of varicose veins in women; however, the relationship between serum sex steroid hormones and varicose veins in men is unclear. To address this issue, serum levels of testosterone, estradiol, and androstenedione were determined in the great saphenous (GSV) and cubital veins of men with varicose veins. Messenger RNA (mRNA) expression of sex steroid hormones, metabolizing enzymes, and their receptors was investigated in tissue samples of leg veins.
This prospective study included 40 men, comprising 20 with varicose veins and reflux of the GSV (VM) and 20 with healthy veins (HM). All limbs were assessed by duplex ultrasound scanning of selected superficial and deep leg veins. Blood samples were taken from the cubital vein and from the GSV. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis for sex steroid hormones, their metabolizing enzymes, and receptors in saphenous veins was performed in tissue samples of varicose (n = 6) and healthy veins (n = 6).
The VM group had significantly higher (P < .001) mean levels for serum testosterone (44.9 nmol/L; range, 8.8-225.1) and estradiol (242.2 pmol/L; range, 79-941) in varicose saphenous veins compared with cubital veins (testosterone, 15.5 nmol/L; range, 8.4-23.3; estradiol, 93.2 pmol/L; range, 31-147). Moreover, significantly (P < .001) higher mean serum estradiol levels (133.2 pmol/L; range, 63-239) were detected in the saphenous veins of the HM group compared with cubital veins (88.15 pmol/L; range, 37-153). Both groups had similar blood counts and serum androstenedione levels in the upper and lower extremity. Interestingly, qRT-PCR revealed that the mRNA expression of 5alpha-reductase type 1, 5alpha-reductase type 2, 17, 20 lyase, 17beta-hydroxysteroid dehydrogenase (17beta-HSD), aromatase and 3beta-HSD type 2, androgen and estrogen receptor 1 was down-regulated (P < .05) in all samples of varicose veins vs veins obtained from healthy men.
Elevated serum estradiol and testosterone levels were detected in men with varicose veins and reflux in the GSV compared with the patient's own arm veins. Enzymes and hormonal receptors involved in steroid metabolism were down-regulated in patients with GSV reflux and varicose veins, suggestive of a negative feedback regulation. These data support the notion of a possible causal relationship between sex steroids and varicose veins in men.
Mounting evidence suggests that pelvic vein reflux is an important contributing factor to recurrent varicose veins. We compared the incidence in our specialist private unit (Unit A) with that of a District General Hospital (Unit B).
Results of all female patient lower limb duplex ultrasound (LLDUS) and transvaginal pelvic ultrasound (TVUS) scans performed over a one-year period were retrospectively reviewed. Patients with refluxing veins emanating from the abdomen or pelvis on LLDUS (non-saphenous reflux) routinely proceeded to TVUS in Unit A.
In Unit A, non-saphenous reflux on LLDUS was present in 90-462 female patients (19.5%). In 81.1% of these, TVUS confirmed reflux in truncal pelvic veins (incidence 15.8%). In Unit B, non-saphenous reflux was present in 60-279 female patients (21.5%).
One in five women presenting with varicose veins have reflux of non-saphenous origin. This is the case in specialist and non-specialist units. One in six has associated pelvic vein reflux.
Perivulval varices appear during pregnancy and usually disappear after delivery but become more prominent with subsequent pregnancies. They may extend over the buttock and may be associated with recurrent leg varices. Some patients have extensive varices in the broad ligaments and present with the pelvic congestion syndrome. These patients have been shown to have grossly dilated ovarian veins. Elimination of this proximal incompetence relieves the symptoms.
The purpose of this study was to determine if there is an association between elevated sex hormones (ie, serum estradiol, sex hormone binding globulin [SHBG], testosterone) and increased venous distension and clinical evidence of varicose veins in menopausal women.
Participants were 104 healthy volunteer menopausal women, aged 48 to 65 years, who were not undergoing hormonal treatment. Of these 104, 14 were excluded from analyses because their estradiol levels were compatible with a premenopausal condition (4), because they had missing values for insulin concentration (5), and because they did not show up at venous vessel examination (5). Patients underwent a physical examination to determine the presence of varicose veins; a venous strain-gauge plethysmographic examination to compute instrumental measures of venous distensibility; and laboratory analyses of blood so serum testosterone, estradiol, SHBG, glucose, and insulin could be measured. There were also prevalence ratios and odds ratios used to test the presence of an association between biochemical and instrumental variables.
Serum levels of estradiol in the upper tertile of the frequency distribution were significantly associated with clinical evidence of varicose veins (prevalence odds ratios 3.6; 95% CI 1.1-11.6) and with increased lower limb venous distensibility (prevalence odds ratios 4.4; 95% CI 1.2-15.5). No association was found for SHBG and testosterone.
Our finding that high serum levels of estradiol are associated with clinical evidence of varicose veins and instrumental measurements indicating increased venous distensibility in menopausal women suggests that endogenous estrogens may play a role in the development of this very common venous vessel abnormalities.
Vulval varices and perivulval veins are common though often unrecognised, and pelvic pain is a common complaint, sometimes without an obvious cause, hence treatment is not always successful. An association between these two problems has long been established, and some cases of pelvic pain are clearly associated with venous pathology. Often, these patients present to the vein clinic with recurrent varicose veins, because the standard procedures have failed and the pelvic origin was not recognised. The understanding of the pathology has evolved and will be reviewed.
To establish diagnosis, the communication from the atypical varicose veins in the legs to the ovarian veins must be shown and incompetence of one or both ovarian veins must be demonstrated.
Treatment requires elimination of the retrograde flow in the ovarian veins. This can be by either surgical ligation and removal or obliteration with coils and sclerosant. Having removed the cause and relieved the pelvic symptoms, the leg veins can then be successfully treated.
Aim:
To identify in patients with recurrent varices after surgery (REVAS) the clinical, etiologic, anatomic, and pathophysiologic patterns according to the CEAP classification, as well as the site, source, causes of recurrence, and contributory factors by using the REVAS classification.
Methods:
Centers from eight countries enrolled patients with superficial vein reflux that had had a previous operation. A physical examination and a duplex ultrasound scan were performed at the first visit. This was repeated between 2 to 8 weeks after by the same physician and by another physician within the same time frame. The perforator, deep, and superficial veins systems as well as their accessories and tributaries were examined. A form based on the CEAP and the REVAS classification was used and the data were entered in a customized database.
Results:
Fourteen institutions enrolled 170 patients (199 lower limbs) in 1 year. Their mean age was 56 years, and 69% were women. Most of them had undergone one surgical procedure before enrollment (76.6%). Most had varicose veins and swelling (70.9%), and the rest had skin damage (29.1%). More than 90% had primary etiology. The saphenofemoral junction (47.2%) and leg perforators (54.7%) were the areas most often involved by recurrent reflux. Reflux in deep veins was detected in 27.4%. Class 2 (varicose veins) alone was present in 24.6% of limbs, two classes were present in 43%, and three in 24%. Neovascularization was as frequent as technical failure (20% vs 19%); both were seen in 17%. In 35%, the cause was uncertain or unknown. When recurrence occurred at a different site, development of reflux in new sites was found in 32% of limbs. Of the contributing factors, family history and lifestyle had the highest prevalence. Women had significantly more procedures than men, despite a clear trend toward more severe disease in the latter.
Conclusions:
Most patients were symptomatic with several clinical forms of presentation. The REVAS classification, together with CEAP, gives significant and more appropriate information for evaluating and following-up patients with chronic venous disease who have had an intervention.
This article reports the investigation and treatment of 24 women presenting with recurrent lower limb varicosities secondary to reflux within the pelvic venous circulation. Diagnosis based on selective retrograde pelvic phlebography enabled precise identification and classification of sites of incompetence. A total of 74 veins were treated by embolization with platinum coils and glue prior to repeat surgery to the lower limb veins. At 4-year follow-up, signs of stasis had disappeared in all patients. Repeat phlebography revealed no evidence of recurrent reflux at the sites of treatment. One patient developed recurrent varices due to incomplete embolization of incompetent pelvic veins. Endovascular occlusion of incompetent pelvic veins is an effective treatment for varicose veins secondary to pelvic venous incompetence.
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Accessed on 16-02.2021.