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Escin improves sperm quality in male patients with varicocele-associated infertility.

ABSTRACT

Purpose: To evaluate the efficacy of escin to improve sperm quality in Chinese male patients with varicocele-associated infertility.

Methods: This study included 219 male patients with varicocele-associated infertility. These patients were randomly assigned into three groups: the control, the surgery and the escin group. 106 patients, with a mean age of 30 years old and a mean period of infertility of 5.0 years, were recruited in the escin group and a daily dose of 60 mg (30 mg every 12 h) of escin was administered orally during an uninterrupted period of 2 months. The diameter of spermatic vein was also measured using color Doppler ultrasonography before and after treatment in the escin group. Patients in all groups took composite medicines favorable for sperm quality and semen were obtained and analyzed before and after treatment.

Results: In response to treatment, the improvement rates in sperm density in the control, the surgery and the escin group, were 38.5%, 68.8%, and 57.5%, respectively. The differences in the surgery and the escin groups were significant compared to that in the control group (68.8% or 57.5% vs. 38.5%, P<0.05). The improvement rates in sperm motility in the control, the surgery and the escin group were 46.2%, 77.1%, and 55.7%, respectively. Significant difference was only observed between the surgery and the control group (77.1% vs. 46.2%, P<0.05). In the escin group, when severity of varicocele was classified to mild, moderate or severe degree according to the diameter of the spermatic vein, the improvement rates in disease severity were higher in the mild (41.7% vs. 20.0%, P<0.05) and moderate severity subgroups (64.4% vs. 20.0%, P<0.05) when compared to that in the severe subgroup (20.0%). The improvement rate in disease severity was also higher in the moderate subgroup when compared to that in the mild subgroup (64.4% vs. 41.7%, P<0.05). During the period of treatment, only very low frequencies of mild adverse effects were observed, most of which resolved without further symptomatic drug therapy after advising the patients to take escin after meal. Escin has little effect on vital signs, blood counts, liver or kidney function.

Conclusion: Escin is a safe and effective drug to improve sperm quality in Chinese male patients with varicocele-associated infertility.

[C] 2009 Elsevier GmbH. All rights reserved.

ARTICLE INFO

Keywords: Escin Aesculus hippocastanum Infertility Varicocele

Introduction

Spermatic varicocele is a condition of varicosity and tortuosity of the pampiniform plexus in the spermatic cord. The rate of clinical varicocele in adult male population is estimated to be 15-20%, whereas the rate among patients attending male infertility clinics is 30-40%, suggesting that this disorder is an important risk factor for male factor infertility (Jarow 2001; Kamischke and Nieschlag 2001). Though four possible mechanisms, including (a) reflux of toxic metabolites from adrenal or renal origin, (b) impairment of the hypothalamic-gonadal axis, (c) venous stasis leading to testicular hypoxia and elevated testicular temperature and (d) testicular oxidative stress, have been proposed based on numerous studies on human and animals (Jarow 2001; Kamischke and Nieschlag 2001; Naughton et al. 2001; Marmar 2001), the pathogenic mechanisms by which varicocele induces infertility are still not fully understood. Presently, though the regular treatment for male infertility associated with varicocele is surgery, many studies have been challenging this method (Kamischke and Nieschlag 2001; Naughton et al. 2001; Marmar 2001). Furthermore, it is well-known that surgery is invasive and might lead to recurrence and relevant complications, and the financial burden of surgical treatment is usually higher than most non-surgical treatments. It becomes a trend and notable characteristic to pursue minimal invasive or noninvasive treatment for modern medicine.

At present, several drugs such as clomiphene, testosterone, pentoxifylline, carnitine and cinnoxicam have be used alone or combined together as an alternative method to improve sperm quality for male patients with varicocele (Cavallini et al. 2003, 2004; Oliva et al. 2008), but the overall efficacy is not higher. Therefore, it is necessary and important to develop new effective medicine to use alone or combine with other medicines to improve sperm quality for male patients with varicocele-associated infertility.

Recently, escin, the main ingredient of which is extract of Aesculus hippocastanum seed (Sirtori 2001; Carrasco and Vidrio 2007) has been shown to be effective in treating chronic venous malfunction, such as hemorrhoids, deep venous varicocele of lower extremities, valve insufficiency and postoperative edema (Mouly 1974; Otto and Arfeen 1974; Hefti and Kappeler 1975; Devin et al. 1976; Pirard et al. 1976; Gualtieri 1978; Pittler and Ernst 1998; Bielanski and Piotrowski 1999; Frick 2000; Kamischke and Nieschlag 2001). Thus, the purpose of the present study was designed to evaluate the efficacy of escin to improve sperm quality in male patients with varicocele.

Materials and methods

Patients

This study included 219 patients consulting for treatment of infertility at the authors' institutions from January 2001-October 2008. Written informed consent for participation was obtained, and the study was approved by the ethics committee for research involving human subjects at the authors' institutions. In all patients, a detailed medical history, including men's occupation, smoking habits, alcohol intake and the use of prescription medications, was obtained. All subjects with evidence of urogenital infections, leukocytospermia, a history of smoking and excessive alcohol and drug consumption were excluded from the study. General physical examination indicated that there was no obvious reason other than varicocele that could cause infertility. Their female spouses' reproductive abilities evaluated by gynecologists were normal. The patients included did not have obvious clinical symptoms. The physical examinations including palpation of scrotum of both sides were performed before the treatment. Varicocele was detected by palpation when patients stood up and mitigated when laid down. Valsalva test further confirmed the diagnosis. All subjects underwent semen analysis. Patients with a sperm density less than 5 x [10.sup.6]/ml or with no sperm were excluded from this study. All the patients included were randomly recruited to three groups: the control, the surgery and the escin group.

In the control group, a daily dose of 20 mg of Vitamin E, together with 400 mg of pentoxifylline and 50 mg of clomiphene, was administered orally during an uninterrupted period of 2 months, which was regarded as one course of treatment. 65 patients were included in this group. The mean age of this group was 29 years old (range, 22-44) and the mean period of infertility was 4.5 years (range, 1-13). 51 patients in this group were diagnosed as left-sided spermatic varicocele and the left 14 as both sides by palpation.

In the surgical group, high position ligation of spermatic vein was performed and the composite medicines mentioned above were also administered after surgery. 48 patients were included in this group. The mean age of this group was 32 years old (range, 23-45) and the mean period of infertility was 4.8 years (range, 2-10). 38 patients in this group were diagnosed as left-sided spermatic varicocele and the left 10 as both sides by palpation.

In the escin group, a daily dose of 300 mg (150 mg every 12 h) of Aescuven Forte (Cesra, Germany), which is equivalent to a daily dose of 60 mg (30 mg every 12 h) of escin was administered. In this group, composite medicines taken by the control group were also administered. 106 patients were included in this group. The mean age of this group was 30 years old (range, 22-46) and the mean period of infertility was 5.0 years (range, 1-14). 83 patients in this group were diagnosed as left-sided spermatic varicocele and the left 23 as both sides by palpation.

In the escin group, according to the diameter of spermatic vein determined by color Doppler ultrasonography, 61 patients were detected with left-sided spermatic varicocele and 45 with both sides. The dilated of spermatic veins (61+45 x 2 = 151) were further classified into three subgroups: 96 mild (2.1-3.0 mm), 45 moderate (3.1-4.0 mm) and 10 severe (>4.0 mm).

Semen collection and analysis

Semen samples were obtained after 3-7 d of sexual abstinence and were analyzed within 1 h of collection. In all patients, the analysis was performed by the computer assisted semen analysis (CASA) technology, according to the WHO criteria (WHO 1999). We mainly observed sperm density, sperm motility (Grade a+Grade b) and sperm morphology.

2.3. Evaluation of efficacy of treatment

The following criteria were used to evaluate if sperm quality was improved: an increase in sperm density by 100% was considered as highly effective, by 30-100% as effective, and by < 30% as not effective. An increase in sperm motility (Grade a+Grade b) by 100% was considered as highly effective, by 30-100% as effective, and by < 30% as not effective. The following criteria were used to evaluate the improvement in spermatic varicocele severity: a decrease of the diameter of the internal spermatic vein detected by color Doppler ultrasonography by < 15% was considered as not effective; by 15-35% as effective; and by > 35% as highly effective.

Observation of adverse effect

During the whole study, various adverse effects such as fatigue, nausea, stomach irritation were monitored before and after treatment in each group. Vital signs including temperature, pulse, breath, blood pressure were also monitored. To monitor the blood counts, liver and renal functions, 5 ml venous blood was also withdrawn from peripheral veins before and after treatment in each group.

Statistical analysis

Data was analyzed using the chi-square test by SPSS 11.0. Significance was set at P < 0.05.

Results

There was no statistical significance in regard to the age of the patient, as well as the side, the severity or the course of the disease of spermatic varicocele in each group. Sperm quality before the treatment was also comparable for all three groups. No obvious drug side effect was observed in all groups. Since sperm density is an important index for semen or sperm quality, we first investigated if escin can improve sperm density in male patients with varicocele. In control group, after taking composite medicines for 2 months, sperm density improved in only 38.5% of patients, but improved in 57.5% and 67.9% of patients in the surgery group and the escin group, respectively and the differences in the improvement rates for sperm density in these two groups were significant compared to that in control group (P < 0.05), though the improvement rate for sperm density in these two groups was comparable (Table 1). These results suggest that escin, as well as surgery improves sperm density in male patients with varicocele-associated infertility.
Table 1
The improvement of sperm density after escin treatment.

              Control group       Surgery group        Escin group
                (n = 65)            (n = 48)            (n = 106)

           No.  Percentage (%)  No.  Percentage (%)  No.  Percentage
                                                             (%)

Highly      9      13.8         16       33.3        34      32.1
effective

Effective  16      24.6         17       35.4        27      25.5

Overall    25      38.5         33       68.8 *      61      57.5 *
effective

Not        40       61.5        15       31.3        45      42.5
effective

Note: Compared to the control group.
* P < 0.05.


Sperm motility is another important index for sperm quality and thus, was also investigated in all groups. The improvement rate in sperm motility was significantly higher (77.1% vs. 46.2%) in the surgery group, while comparable in the escin group (55.7% vs. 46.2%) when compared to that in the control group (46.2%, Table 2), suggesting that escin has little effect on the improvement in sperm motility in male patients with varicocele-associated infertility.
Table 2
The improvement of sperm motility (Grade a+Grade b) after escin
treatment.

             Control group      Surgery group         Escin group
              (n = 65)           (n = 48)             (n = 106)

           No.  Percentage (%)  No.  Percentage (%)  No.  Percentage
                                                             (%)

Highly     10      15.4         21       43.8        30      28.3
effective

Effective  20      30.8         16       33.3        29      27.4

Overall    30      46.2         37       77.1*       59      55.7
effective

Not        35      53.8         11       22.9        47      44.3
effective

Note: Compared to the control group.
* P < 0.05.


When severity of varicocele was classified into mild, moderate or severe degree according to the diameter of the spermatic vein by ultrasonography, our results showed that the improvement rate in disease severity was significantly higher in the mild (41.7% vs. 20.0%) and moderate severity subgroup (64.4.7% vs. 20.0%) when compared to that in the severe subgroup (Table 3). Interestingly, the improvement rate in disease severity was also significantly higher in the moderate subgroup than that in the mild subgroup (64.4% vs. 41.7%, Table 3). These results suggest that escin significantly improves the disease severity in patients with mild and moderate varicocele and it is more effective in patients with moderate varicocele.
Table 3
The improvement of the diameter of spermatic vein of 151 sides in 106
cases after escin treatment.

             Mild (n = 96)       Moderate (n = 45)   Severe (n = 10)

           No.  Percentage (%)  No.  Percentage (%)  No.  Percentage
                                                             (%)

Highly     11       11.5        13      28.9          0       0.0
effective

Effective  29       30.2        16      35.6          2      20.0

Overall    40       41.7        29      64.4 *,**     2      20.0
effective

Not        56       58.3        16      35.6          8      80.0
effective

            Total (n = 151)

           No.  Percentage (%)

Highly     24      15.9
effective

Effective  47      31.1

Overall    71      47.0
effective

Not        80      53.0
effective

Note: Compared to the severe subgroup.
* P < 0.05. Compared to the mild subgroup.
** P < 0.05.


In this study, the adverse effects of escin were carefully monitored. In the escin group, only 5.7% of patients complain of stomach irritation, 4.7% of patients complain of fatigue, 3.8% of patients complain of nausea, 2.8% of patients complain of anorexia, 1.9% of patients complain of vomiting (Table 4). The frequencies of adverse effects of escin were very low and most adverse effects were quite similar in the escin group when compared to the control or the surgery group (Table 4). All these adverse effects were very mild and most of them resolved without further symptomatic drug therapy after advising the patients to take escin or other drugs after meal. Escin has no significant effect on vital signs, blood counts, liver or kidney function since these parameters are all normal in each group before and after treatment. These results indicate that escin is a safe drug to improve sperm quality in male patients with varicocele-associated infertility.
Table 4
Adverse effects observed during treatment.

              Control group    Surgery group     Escin group
                (n = 65)          (n = 48)          (n = 106)

              No.  Percentage  No.  Percentage  No.  Percentage
                      (%)              (%)              (%)

Fatigue       3       4.6       3      6.3       5      4.7

Stomach       2       3.1       2      4.2       6      5.7
irritation

Anorexia      1       1.5       1      2.1       3      2.8

Nausea        3       4.6       1      2.1       4      3.8

Vomiting      0       0.0       1      2.1       2      1.9

Diarrhea      0       0.0       0      0.0       0      0.0

Constipation  0       0.0       0      0.0       0      0.0

Skin rash     0       0.0       0      0.0       0      0.0

Other         0       0.0       0      0.0       0      0.0


Discussion

Improving sperm quality is the key to treat male varicocele-associated infertility, since higher sperm quality is absolutely important not only to physiological fertility, but also helpful in patients who opt for FIVET (fertilization in vitro and embryo transfer) or ICSI (intracytoplasmic sperm injection) procedures. The purpose of this study is to evaluate the efficacy of escin to improve sperm quality for Chinese male patients with varicocele-associated infertility. Despite the lack of consensus on the usefulness of treating varicocele-associated infertility in the latest literature due to poor knowledge about the pathogenic mechanisms for this disorder (Zucchi et al. 2006; Kim and Goldstein 2008), this study clearly suggests that both escin and surgery can improve the sperm density, even though escin has little effect on the improvement in sperm motility. More importantly, this study suggests that escin is more effective to ameliorate the disease severity in patients with moderate varicocele. To the best of our knowledge, this is the first study which contains more than 200 patients and done cooperatively at different institutions to evaluate the efficacy of escin to improve sperm quality in male patients with varicocele-associated infertility.

Among the four possible mechanisms by which varicocele results in male infertility stated in the Introduction part, venous stasis and testicular oxidative stress have been paid much attention in recent clinical studies (Cavallini et al. 2003; Oliva et al. 2008; Turner and Lysiak 2008). Escin has the function of anti-oxidative stress which directly targets at one of the proposed mechanisms mentioned above (Jarow 2001; Kamischke and Nieschlag 2001; Marmar 2001; Naughton et al. 2001; Sirtori 2001; Carrasco and Vidrio 2007; Oliva et al. 2008). In fact, the primary pathological changes of spermatic varicocele include venous tortuosity, thinner venous wall, dysplasia of venous wall muscles, fibrosis of vessel wall and atrophy of outer membrane and middle layer. These chronic inflammation and changes in hemodynamic finally cause this disorder (Jarow 2001; Kamischke and Nieschlag 2001; Marmar 2001; Naughton et al. 2001). Escin can inhibit lysosome in serum and reduces the permeability of capillary vessel (Sirtori 2001; Carrasco and Vidrio 2007). It can also protect collagen fiber of venous wall and increase wall tension and strength, which will help the recovery of tension and contraction function damaged by lesions on venous wall. Furthermore, it can increase venous drainage which will reduce venous congestion (Sirtori 2001; Carrasco and Vidrio 2007). Thus, escin presents two pharmacodynamic actions: anti-edematous properties and venotonic properties. In fact, it also has antiinflammatory activities (Carrasco and Vidrio 2007; Sirtori 2001). In this study, escin helped reduce the diameter of 47.0% of the spermatic veins (Table 3), which might be one of the anatomical and physiological bases for escin to improve sperm quality. Therefore, escin targets not only in the testis oxidative stress, but also in the venous stasis and chronic inflammation of the vein, which are the three important proposed pathogenic mechanisms causing varicocele-associated infertility. Thus, it is not surprising that escin can improve sperm quality in male patients with varicocele-associated infertility.

It is worthwhile to point out that this study showed that the escin treatment was not effective for patients with severe varicocele (the diam of the spermatic vein > 4 mm). This suggests that there is some degree of correlation between the severity of varicocele and the efficay of escin. One explanation might be due to the fact that the venous walls in patients with severe varicocele have been destroyed severely so that they lost their ability to recover their tension and function.

In fact, this study demonstrates that escin is not only very effective to improve sperm quality but also it is well tolerated. Only very low frequencies of mild adverse effects were observed during treatment, most of which resolved without further symptomatic drug therapy after advising the patients to take escin after meal. Escin has little effect on vital signs, blood counts, liver or kidney function. Therefore, escin is a safe drug to improve sperm quality in male patients with varicocele-associated infertility.

In this study, all groups including the control group are given composite medicines due to ethic consideration. Thus, it is difficult to pinpoint that the improvement in sperm quality is due to escin alone or it is because escin has synergistic effect with the composite medicines. Obviously, in the future, it is necessary to design a study in animal models for spermatic varicocele which includes a pure placebo group and an escin group.

In conclusion, escin is a safe and effective drug to improve semen quality in male patients with varicocele-associated infertility probably by reducing testis oxidative stress, decreasing inflammatory responses, promoting the recovery of tension and contraction function damaged by lesions on venous walls. It provides new alternative treatment for male varicocele-associated infertility, especially for patients with mild or moderate varicocele.

Conflict of interest

The authors have no conflict of interest.

Disclosure statement: The authors have nothing to disclose.

Acknowledgments

We thank Dr. Vincent DeMarco and Mr. Edward Downey from the University of Missouri for their helpful discussion.

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Yujiang Fang (a), (b), *, Lei Zhao (c), (1), Feng Yan (d), (1), Xiaoyan Xia (e), (1), Donghui Xu (c), Xijun Cui (f)

(a) Department of Internal Medicine, University of Missouri, Columbia, MO 65212, USA

(b) Department of Urology, the third affiliated hospital of Peking University, Beijing 100083, China

(c) Department of Surgery, the first affiliated hospital of Qjqihar Medical University. Qiqihar 161006, China

(d) Department of Internal Medicine, the second affiliated hospital of Wannan Medical College. Wuhu 241004, China

(e) Beijing Obstetric and Gynecologic Hospital, Capital University of Medical Sciences. Beijing 100026. China

(f) Department of Surgery, People's Hospital of Ningjin. Ningjin 253400, China

* Corresponding author at: Department of Internal Medicine, University of Missouri, Columbia, MO 65212. USA. Tel.: +1573 882 4325; fax: +1573 8821380.

E-mail address: fangy@health.missouri.edu (Y. Fang).

(1) These authors contribute equally.

0944-7113/$-see front matter[C] 2009 Elsevier GmbH. All rights reserved.

doi: 10.1016/j.phymed.2009.07.014
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Author:Fang, Yujiang; Zhao, Lei; Yan, Feng; Xia, Xiaoyan; Xu, Donghui; Cui, Xijun
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2010
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