Effects of micronised purified flavonoid fraction on pain, semen analysis and scrotal color Doppler parameters in patients with painful varicocele; results of a randomized placebo-controlled study
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- Söylemez, H., Kiliç, S., Atar, M. et al. Int Urol Nephrol (2012) 44: 401. doi:10.1007/s11255-011-0038-3
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Aim of this study is to evaluate the effects of micronised purified flavonoid fraction (Daflon®) on pain, semen analysis and color Doppler parameters in patients with painful varicocele.
Materials and methods
Forty varicocele patients whom have normal sperm concentration (>20 million/ml) were involved in the study. The patients were divided into two groups such as Daflon (n = 20) and placebo (n = 20) group. Pain score, semen analyses and Doppler sonography were performed in all patients before and after the treatment.
In the first group, mean pain scores at 1, 3, 6 and 12 months were 1.80 ± 1.32, 1.15 ± 0.93, 1.05 ± 0.95 and 0.95 ± 0.89, respectively, all were significantly lower (P < 0.001 for each) than baseline (5.25 ± 1.07). While semen volume, total sperm count, sperm concentration and morphology were not changed significantly, the motility of sperm increased significantly (P = 0.015) due to decrease in grade 1 sperms at the 6th month in the first group. Reflux time of left spermatic vein during the Valsalva maneuver decreased significantly (P < 0.001).
Results of this study suggest the safety and efficacy of Daflon in the treatment of varicocele-associated pain. However, these results of the present study must be confirmed by randomized placebo-controlled studies by using different drug doses and durations before making any recommendation for the use of Daflon.
KeywordsConservative treatmentMicronised purified flavonoid fractionPainSemen analysisVaricocele
Varicocele, defined as elongated, dilated and tortuous spermatic veins within the pampiniform plexus, is accepted as the most commonly identifiable, surgically correctable lesion associated with male-factor infertility . It is found in approximately 15% of the general population, in 19–41% of men with primary infertility and in 45–81% of men with secondary infertility . Despite current knowledge on the pathophysiology of varicocele-associated male infertility, the exact mechanism or mechanisms by which varicoceles impair fertility remain elusive. However, it is a fact that treatment for varicocele improves sperm concentration, motility and morphology, increases the volume of the testis and the chance of conception in spite of uncertainty regarding the varicocele-associated pathophysiologic mechanism in spermatogenesis disorders [2–4]. Varicocele is currently corrected by radiologic (transvenous percutaneous embolisation) or essentially by surgical (open or laparoscopic varix ligation) methods. These therapies prevent the retrograde reflux of venous blood into the testis by ligating or occluding the varicose veins. In the literature, studies about the medical treatment for varicocele are limited.
Although the major indication for the treatment of varicocele is subfertility, on the other hand, a small part of the patients present with the scrotal pain associated with varicocele. In the literature, the estimated incidence of pain caused by varicocele is 2–10% . Treatment for painful varicocele traditionally consists of conservative measures, followed by surgical or radiological techniques if the conservative measures fail to treat pathology. Although several studies have been performed to assess the effectiveness of surgical and radiological methods, to our knowledge, there is no study addressing the effect of any kind of conservative modality or comparing conservative versus surgical therapy.
Micronised purified flavonoid fraction (MPFF), which consists of 90% micronised diosmin (a flavone derivative) and 10% flavonoids expressed as hesperidin (a flavonone derivative), is an oral phlebotrophic drug which improves venous tone and elasticity and decreases venous distensibility and venous emptying times in patients with functional or organic chronic venous insufficiency (CVI) . MPFF also improves lymphatic drainage in the advanced stage of CVI, reduces reflux time of venous blood in patients with CVI and capillary hyperpermeability in patients suffering from idiopathic cyclic edema and symptomatic capillary fragility, and has antioxidant activities [6–8]. It has an excellent safety profile as documented by both toxicological animal studies and clinical studies and has a tolerability profile similar to that of placebo. Most studies have shown that MPFF is an effective and well-tolerated drug in patients with chronic venous insufficiency.
Our first study on the MPFF with painful varicocele was done by Kiliç et al.  in 2005, but it was a pilot and non-controlled study. Results of this study showed that MPFF is a safe and effective drug for treating varicocele-associated pain medically, at least within the treatment period, and in improving semen analysis and color Doppler parameters. Then we stressed that these preliminary results of the study must be confirmed by randomized placebo-controlled studies. To our knowledge, to date no placebo-controlled study has dealt with the effects of it in patients with clinical varicocele, which is a kind of venous insufficiency. Therefore, we performed this randomized placebo-controlled study to determine whether MPFF as a conservative treatment modality might be effective in varicocele patients. This report aims to present the results about the effects of drug on varicocele-associated pain and the drug-associated changes in semen analysis and scrotal color Doppler sonography parameters. This is the second study of the literature about the effect of a venoactive drug in painful varicocele patients as a conservative treatment modality and also is important because of the evaluation of the Doppler sonographic changes in spermatic vein following treatment.
Materials and methods
This study was designed as a prospective, randomized placebo-controlled trial. After informed consents, 40 varicocele patients with normal sperm concentration (>20 million/ml) were involved in the study between September 2008 and July 2009. They were divided into two groups, as Daflon (n = 20) and placebo (n = 20) group. Patients with previous corrective surgery for cryptorchidism, hydrocele, epididymal cyst, testicular torsion, alteration in the external genitalia, and evidence of any other disorders such as urinary tract infection, ureteral calculus, prostatitis, sexually transmitted diseases, or epididymitis that could suggest scrotal pain and alteration in spermatogenesis were excluded from the study.
Varicoceles identified in a heated room at scrotal examination in the supine and upright positions before and during Valsalva’s maneuver were classified clinically as grade 1—palpable only during the Valsalva’s maneuver, grade 2—palpable without the need for Valsalva’s maneuver, and grade 3—visible from a distance without palpation . During color Doppler sonography performed in the supine position with and without Valsalva’s maneuver, length and width measurements of both testicles and the duration of venous reflux were recorded. Varicoceles were graded sonographically according to the duration and characteristic of reflux as grade 1—slight reflux (<2 s) during Valsalva; grade 2—reflux (>2 s) during Valsalva, but no continuous reflux during the maneuver, or grade 3 reflux in rest during normal respiration or continuously during the entire Valsalva maneuver .
Two semen specimens for analyses were collected by masturbation after 2–7 days of sexual abstinence and processed within 1 h of ejaculation in the same andrology laboratory according to World Health Organization criteria . Semen examinations were performed to analyze volume, sperm concentration, total sperm count, percentages of the sperm motility and morphology. Sperm motility was graded according to World Health Organization criteria  as grade 3—progressive motility (PR): spermatozoa moving actively, either linearly or in a large circle, regardless of speed, grade 2—non-progressive motility (NP): all other patterns of motility with an absence of progression, e.g., swimming in small circles, the flagellar force hardly displacing the head, or when only a flagellar beat can be observed, grade 1—immotility (IM): no movement.
For more objective assessment, the degree of pain was graded according to a visual analogue scale scored between 0 and 10 .
During 6 months, patients in group 1 were administered with 1,000 mg/day MPFF (Daflon®), and the others were administered with 2 gr granule/day Pancreatin + Metylpolysiloksan (Pankreoflat®) which has no known effect on vascular system. Patients were controlled during hospital visits at 1, 3 and 6 months of the drug therapy by physical examination, semen analysis and color Doppler sonography. Pain score, patient satisfaction with outcome and side effects of the drug were recorded. Pain scores were also questioned by means of telephone contacts at 12 months.
Statistical analysis was done with SPSS 10.0 statistical software. After the distribution of all parameters tested using Kolmogorov–Smirnov test, analysis was carried out with Friedman test for testing statistical significance of repeated measurements, followed by Wilcoxon signed-ranks tests to compare mean pre- and post-treatment pain scores, semen analysis and Doppler parameters. Mann–Whitney U test was used to compare mean pre- and post-treatment pain scores, semen analysis and Doppler parameters between Daflon and placebo group. Bivariate correlation test (Spearman) was used to determinate the relationship between varicocele grade, pre and post-treatment pain scores. P value less than 0.05 was used as a threshold for statistical significance. Data were presented as mean plus or minus standard deviation.
Mean patient age was 20.3 ± 1.0 (range 19–27). All patients completed 12 months of follow-up. Drug-associated side effects were encountered clinically and biochemically in no patient. There was no statistically difference according to the age, varicocele side, varicocele grade, pretreatment pain scores and sperm parameters in terms of both groups.
Varicoceles were on the left side in 31 patients and bilateral in 9. Grade 1 varicoceles were on the left side in 2 patient and right side in 3, grade 2 varicoceles were on the left side in 24 and bilateral in 6, and grade 3 varicoceles were on the left side in 14. Color Doppler sonography revealed significant left venous reflux in all patients, but right reflux in only 6 of 9 patients with bilateral varicocele diagnosed by physical examination.
Classifying varicoceles according to duration and characteristics of reflux, unilateral varicocele was grade 1 in 2 patients, grade 2 in 21 patients and grade 3 in 8. Bilateral varicoceles were grade 2 in 3 patients and grade 3 in 6 on the left side, and grade 1 in 3 patients and grade 2 in 6 patients on the right side. Testicular atrophy or soft testis was established in only 1 patient aged 27.
The mean duration of the pain was 6.8 ± 5.9 months (range 2–18). Pain was only in the left scrotum in all patients. Thirty-six (90.0%) patients described their pain as a dull or throbbing ache while 4 (10.0%) as a sharp pain. All patients had previously undergone conservative therapy consisting of non-steroidal anti-inflammatory drugs, scrotal elevation, and physical activity limitations.
Values of pain score before and after treatment in both groups
5.25 ± 1.07
1.80 ± 1.32
1.15 ± 0.93
1.05 ± 0.95
0.95 ± 0.89
5.10 ± 1.17
4.80 ± 0.95
5.20 ± 1.01
4.70 ± 0.87
5.15 ± 0.88
Values of pain score before and after treatment in the Daflon group
5.25 ± 1.07
1.80 ± 1.32
1.15 ± 0.93
1.05 ± 0.95
0.95 ± 0.89
Changes in reflux time of the left spermatic veins during the valsalva maneuver in the Daflon group
4.95 ± 1.28
3.95 ± 0.99
3.20 ± 1.01
2.10 ± 0.97
In the placebo group, there were no differences between pretreatment and post-treatment pain scores and other parameters (P > 0.05).
Mean pain score and the reflux time of left spermatic vein were showed statistically significant difference between two groups after the treatment period (P < 0.01). No significant change was observed in the other parameters between two groups before or after the treatment except mean percentages of motile and immotile sperms at the 6th month.
In spite of several studies, the treatment of painful varicocele has not been standardized. In these studies, patients were treated either surgically (open or laparoscopic ligation) or radiologically (transvenous percutaneous embolisation), and complete resolution of pain was reported to be between 48 and 88% [5, 14–19]. Although surgical treatment is effective, it has some potential complications (wound infection, epididymo-orchitis, hydrocele, hematoma, testicular atrophy). Radiological management is invasive and not routinely performed by most centers. In fact, application of conservative therapy methods such as scrotal support or physical activity limitation is usually very difficult in young, physically and sexually active patients. In such cases, use of an oral drug for conservative treatment is seen as a reasonable approach to treat pain, especially in non-oligozoospermic fertile varicocele patients who do not want any invasive approach, but, to our knowledge, a small number of conservative treatments are present in the literature. This is our first placebo-controlled study and contains a small patient population due to difficulties in finding the patients covering all criteria of the study, because, in our region, patient groups with high risk of varicocele-associated pain due to the heavy physical activity and exercises, which help unmask previously unnoticed pain, such as soldiers, police academy students, and workers, are generally treated in other centers (Military, State, and Social Insurance Hospitals) by surgery. The majority of varicocele patients who are admitted to our institution usually complain of infertility, and patients with painful varicocele consist of a very small part.
Zampieri et al.  carried out a longitudinal trial to study the role of bioflavonoids in the management of subclinical varicocele, focusing on the clinical development of varicocele and on the evolution of vein reflux using Doppler velocimetry. One hundred and sixty-eight patients with left subclinical varicocele were included in the study. Long-term results showed a possible correlation between use of bioflavonoids and lower rate of clinical progression to palpable varicocele (11 vs. 31%), higher rate of stable vein reflux (47 vs. 38%) and higher resolution rates (41 vs. 31%) (P < 0.05). Then they concluded that subclinical varicocele should be considered as the starting point of varicocele, and although the use of bioflavonoids in patients with subclinical varicocele could reduce the development of palpable varicocele, it cannot prevent the onset of testicular growth arrest .
Biggers and Soderdahl  obtained pain resolution in only 24 (48%) of 50 patients operated with high ligation. However, in the study by Peterson et al.  of 35 patients, 10 (28.6%) underwent high inguinal, 24 (68.6%) subinguinal and 1 (2.9%) laparoscopic ligation. Thirty (86%) patients reported complete resolution of preoperative pain. Yaman et al.  obtained 87.8% full response in 82 patients with microsurgical subinguinal ligation. Strict patient selection based on duration, type and description of pain as well as prior conservative management, and the type of surgical method applied have been suggested as characteristic factors for the success of surgery [16, 17]. Existence of a dull, aching and throbbing pain without components of sharp or radiating pain, administration of conservative treatment as an initial trial, and subinguinal ligation increase the success rate. However, Iselin et al.  and Maghraby  reported high success rates (80 and 84.5%, respectively) with laparoscopic ligation. Yeniyol et al.  also obtained 82.8% full response with high ligation in 87 patients. Maghraby  suggested that it was uncertain whether character and duration of pain or varicocele grade and location play a decisive role in outcome. From the present study, it is difficult to determine the importance of pain character, since 90% of patients had a dull or throbbing ache, while 4 patients (10%) had sharp pain. The importance of preoperative duration of pain is also unclear. In spite of lower mean pain durations in the present (6.8 months) and Maghraby’s studies (5.2 months) than Peterson’s (17.8 months) and Yeniyol’s studies (16 months), similar success rates were reported in all. We also noted no significant correlation between duration of pretreatment pain and post-treatment change in pain score.
Compared to other studies of the literature except the study by Peterson et al. , our results were more objective because of the use of pain score. In our study, we had no treatment failures. Satisfaction rate was 100%. At this stage, the mechanism of action of MPFF on pain resolution is unclear, so further studies are warranted. However, outcomes are very satisfactory in order to offer medical treatment. But, despite 8 patients having had no pain at the end of the 12th month, it is difficult for us to say that the therapeutic effects of the drug are permanent. It seems that MPFF is effective during administration since drug removal caused a significant increase in pain score compared to mean score at the 6th month. New studies are needed to determine the optimum duration for drug use.
It has been suggested that pain generally occurs in the patients with high-grade varicocele . In the study by Yaman et al. , postoperative resolution of the pain also correlated positively with the preoperative varicocele grades. Although we conversely could not establish such a correlation probably due to the small patient population, grade 1 varicoceles were on the left side in only 2 patient and right side in 3, and the majority of our patients had grade 2 varicoceles.
The exact mechanism of varicocele-associated pain is unclear. In our and Maghraby’s  studies, pain in bilateral cases was unilateral, on the left side, where the lesion was of a higher grade. But to explain the pain resolution only with a higher grade may be wrong, because while pain resolved completely in our 5 bilateral patients, it persisted in 4 of 9 bilateral cases of a later study in spite of successful surgery proven by postoperative clinical and sonographic follow-up examinations. So, it may be thought that bilateralism of varicocele rather than the existence of higher-grade varicocele plays a role on the results. As Maghraby suggested, we believe that pretreatment venographic studies in bilateral cases may provide important clues.
Currently, it has been generally accepted that the findings of semen abnormalities and testicular hypotrophy constitute the main indication for varicocele surgery in infertile patients . However, some studies of medical therapy have stressed the effectiveness of medical treatment in selected cases [22–27]. Comparison between 3 treatment groups (1—medical with human chorionic gonadotropin, fluoxymesterone or clomiphene citrate, 2—surgical, 3—surgical plus medical) demonstrated no significant statistical difference in the analysis of semen analysis parameters before and after treatment in all groups, but significantly higher pregnancy rates for the surgical (47.4%) and medical plus surgical groups (60.9%)—not a statistically significant difference—than for the medical group (25%) . Gonadotropin and clomiphene citrate have been shown to improve semen quality and pregnancy rate in patients with sperm counts of less than 10 million/ml [22, 23]. Both clomiphene citrate and subclinical varicocelectomy increased sperm density, motility and morphology, but only increases in density and motility after varicocelectomy were significant . However, no significant difference was found in seminal improvement and pregnancy rate (12.5% for varicocelectomy and 6.7% for clomiphene) between the two groups.
Both testolactone and anastrozole were shown to increase significantly the testosterone-to-estradiol ratios in conjunction with significant improvement of serum estradiol concentration (better for anastrozole) and semen parameters in varicocele patients with low testosterone-to-estradiol ratio .
In a comparative study performed in the patients with varicocele associated with oligoasthenozzospermia, cinnoxicam was found to be a safe and reliable therapeutic option for men with grade 3 varicocele, but surgery was better for those with grades 2, 4 and 5 . However, stopping cinnoxicam therapy caused a decline in the baseline values for sperm quality.
The present study showed that MPFF provided limited improvement on the motility rates of the sperms by decreasing the sperms with no movement and increasing those with non-progressive-to-progressive motility. No statistically significant change was observed in sperm concentration, total sperm counts and morphology. Venous reflux did not cease completely in any of the patients in spite of the significant decrease in reflux time and sonographic grade, especially patients with sonographic grade 3 varicocele achieved grade regression following drug treatment. It is not clear whether the dose and duration of drug therapy are effective on the results. Also, a study including only fertile non-oligozoospermic men may limit the ability of it to show the effects on spermatogenesis. However, to draw more definitive conclusions, further placebo-controlled studies must be performed in the patients with varicocele-associated subfertility by using different drug doses and durations. Reduction of reflux might be an effect of venoconstriction.
Hendin et al.  showed elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity in non-oligozoospermic (total sperm count greater than 15 million) men with varicocele irrespective of infertility status and suggested that these results might provide a rationale for antioxidant supplementation among infertile, non-oligozoospermic men with varicocele. Taking this rationale into consideration, we treated our non-oligozoospermic patients with varicocele using MPFF, since it has been shown to act as an antioxidant drug . However, at this stage, it is difficult for us to determine whether increased sperm motility in the study patients resulted from venoprotective properties or antioxidant activities of MPFF or both. Further laboratory and clinical studies are warranted in large series to explain the mechanism of action.
Results of the study showed us that MPFF did not ensure complete recovery of the varicocele in any of the patients. So we think that MPFF alone is not an alternative for surgery in the treatment of varicocele. However, MPFF was found to be a safe and effective drug for treating varicocele-associated pain medically, at least within the treatment period, and in improving semen analysis and color Doppler parameters. Although the results suggest that MPFF may be tried for the treatment of fertile non-oligozoospermic patients with varicocele-associated scrotal pain who do not want to undergo any invasive treatment procedure, these results of the present study must be confirmed by randomized placebo-controlled studies by using different drug doses and durations before making any recommendation for the use of MPFF. Effects of MPFF on the fertility status of patients with varicocele-associated subfertility may be the subject of another study. In addition, further studies could be performed to determine whether MPFF has additive effects in conjunction with surgery.