Varicocele, which is considered to be the second major cause of male infertility after idiopathic infertility, is diagnosed in ~30%–40% of male patients with infertility1. Varicocele is an abnormal dilation and tortuosity of the pampiniform venous plexus within the spermatic cord, which adversely affects the testes, semen parameters, and sperm DNA through heat stress and an increased level of reactive oxygen species and oxidative stress2,3. The incidence of varicocele is ~15% of the total adult male population with or without infertility4. Thus, varicocele may not always cause infertility, and it does not always need to be repaired. In the current guidelines, varicocele repair should be considered when the varicocele is palpable, and the patient has an abnormality in their semen parameters5,6. The American Society of Reproductive Medicine guideline stated that varicocele treatment should be considered when most or all of the following conditions are met: (1) the varicocele is palpable on physical examination; (2) the couple has known fertility problems; (3) the female partner has normal fertility or a potentially treatable cause of infertility, and the time until conception is not a concern; and (4) the male partner has abnormal semen parameters6. However, varicocele repair for subclinical varicocele or varicocele in patients with normal semen parameters is not recommended.
Varicocele are classified into grades from 1 to 36. Although grades 1–3 varicocele are all clinical and palpable, varicocele repair has a higher efficacy in improving semen parameters for high-grade varicocele than for low-grade varicocele7,8. Okubo et al9 reported that varicocelectomy had a positive effect on the sperm concentration and motility and pregnancy rates in grades 2 and 3 varicocele, whereas it had no significant effect in patients with grades 0 and 1 varicocele. Considering the aforementioned findings, although varicocele repair is recommended for male infertile patients with palpable varicocele, it is controversial whether varicocele repair should be performed in patients with low-grade varicocele. In our facility, on the basis of this evidence, we usually do not recommend varicocele repair for patients with subclinical or grade 1 varicocele. Although we start treating these patients with medications, such as antioxidants, this treatment has no clinically significant effect in some patients with grade 1 varicocele. In such cases, we consider varicocele repair after discussing the available evidence with the patients.
Evaluating the efficacy of varicocelectomy for grade 1 varicocele can aid in making clinical decisions regarding whether surgical intervention should be offered. This study aimed to evaluate the efficacy of varicocelectomy for patients with grade 1 varicocele by comparing the semen parameters between patients treated with an oral antioxidant and traditional herbal medicine alone and those who additionally underwent microsurgical varicocelectomy.
This study was approved by the Yokohama City University Review Board. Written informed consent was obtained from each patient prior to study initiation.
Study design and patients
We retrospectively analyzed data of 38 male infertility patients with grade 1 varicocele who visited the Reproduction Center, Yokohama City University Medical Center, between April 2013 and July 2017 and could be followed up for more than 6 months after treatment. We excluded patients with bilateral varicocele. Patients were divided into two groups: those treated with an oral antioxidant and traditional herbal medicine alone [tocopheryl acetate (600 mg/d) and keishibukuryogan (7.5 g/d)] and those who additionally underwent microscopic subinguinal varicocelectomy (Fig. 1). In all patients in both groups, semen samples were obtained before treatment, and 3 and 6 months after the start of treatment. The sperm parameters; sperm concentration, motility, and motile sperm concentration were evaluated at each time point and the results were compared between the groups.
Subinguinal micro-varicocelectomy was performed with the patient under general or spinal anesthesia and in the supine position at the Yokohama City University Medical Center. A 3-cm trans-incision was made above the left external inguinal ring. Subsequently, the spermatic cord was identified, and then the external spermatic fascia was peeled off. External spermatic veins were carefully identified and cut off. After identifying and separating the vas deferens, all the internal spermatic veins were identified and cut off, while all of the arteries and lymphatic vessels were preserved under microscopic guidance. An ultrasound Doppler blood flowmeter (ES-100V3, Hadeko, Kawasaki, Japan) was used to distinguish the vessels.
Patients’ characteristics and pretreatment and posttreatment semen parameters were compared between the groups using unpaired t tests and χ2 tests. Statistical analyses were performed using the Statistical Package for the Social Sciences, version 21 (IBM Corp., Armonk, NY). For all tests, P-values ≤0.05 were considered statistically significant.
Twenty-four patients were treated with oral medication (medication group) alone, and 14 underwent surgery in addition to receiving medication (surgery group). Parameters of the pretreatment semen analysis were not significantly different between the groups (Table 1). There was no significant difference in sperm motility and concentration between the groups at 3 and 6 months (Table 2).
Table 1 -
Comparison of patients’ characteristics and preoperative semen analysis between the medication and surgery groups.
||Medication Group (n=24)
||Surgery Group (n=14)
|Partner’s age (y)
|Observation period (d)
|Pretreatment semen analysis
| Sperm concentration (×106/mL)
| Motility (%)
| Motile sperm concentration (×106/mL)
|Posttreatment motile sperm concentration at 6 mo (×106/mL)
|Δ motile sperm concentration at 6 mo (×106/mL)
Δ: amount of change.
Table 2 -
Comparison of postoperative semen analysis between the medication and surgery groups.
|Sperm concentration at 3 mo (×106/mL)
|Motility at 3 mo (%)
|Motile sperm concentration at 3 mo (×106/mL)
|Δ motile sperm concentration at 3 mo (×106/mL)
|Sperm concentration at 6 mo (×106/mL)
|Motility at 6 mo (%)
|Motile sperm concentration at 6 mo (×106/mL)
|Δ motile sperm concentration at 6 mo (×106/mL)
Δ: amount of change.
Six months after the treatment started, motile sperm counts (MSC) were 4.939±6.257×106/mL and 9.853±16.8×106/mL in the medication and surgery groups, respectively (P=0.26) (Fig. 2). The amount of change (Δ) in the MSC was significantly higher in the surgery group than in the medication group at 6 months (−0.94±5.82×106/mL and 4.33±5.46×106/mL, respectively; P=0.029), but not at 3 months (Fig. 3). The pregnancy rate was not significantly different between the surgery and medication groups during the observation period (29.2% and 50%, respectively; P=0.298).
Herein, we showed that varicocelectomy with oral medication for patients with grade 1 varicocele improved the MSC at 6 months more significantly than oral medication alone. In the current guidelines, the grade of varicocele is based on a physical examination according to the Dubin and Amelar classification system: in the standing position, grade 1 varicocele is palpable only during the Valsalva maneuver; grade 2 varicocele is palpable under resting conditions, and grade 3 varicocele is visible without palpation5,6,10. Color Doppler ultrasonography has been considered a useful tool to support the diagnosis of varicocele and even predict the treatment outcomes by visualizing the vein reflex flow11. Although the pathophysiology of varicocele-associated infertility is not completely understood, the following mechanisms are thought to contribute to the pathogenesis of varicocele and affect testicular function: hypoperfusion leading to hypoxia, heat stress, oxidative stress, hormonal imbalances, and exogenous toxicants2. The increase in venous pressure due to reflex in the internal spermatic vein elicits a compensatory vasoconstriction of pre-capillary arterioles as a mechanism to downregulate arterial flow, which is important for maintaining intratesticular pressure. This vasoconstriction leads to hypoperfusion of the testes, thereby decreasing the delivery of oxygen and nutrients to the cells of the testicular microenvironment12. The temperature of the scrotum is a few degrees below one’s body temperature, which is essential for normal testicular function13. This temperature is considered to be controlled by the heat exchange mechanism proposed in 1959, that is, the inflowing arterial blood from the testicular artery is cooled by the outflowing venous blood in the pampiniform plexus14. Because of varicocele, venous stasis and retrograde vessel flow in the pampiniform venous plexus occur and disrupt the balance of heat exchange, resulting in scrotal hyperthermia13.
Considering these mechanisms, in regard to hypoxia and heat stress, greater vein reflex is likely to have a more adverse effect on spermatogenesis. Varicocele repair improves spermatogenesis by occluding the retrograde vessel flow, which results in a positive effect, such as a decrease in the scrotal surface15. Therefore, it seems appropriate that patients with a larger varicocele grade had a greater improvement in semen quality postoperatively, while those with a smaller varicocele had less significant postoperative changes7–9,16,17. However, one study stated that there was no relationship between treatment outcomes and the degree of vein reflex flow18. Although grade 1 varicocele are clinically palpable, as they are regarded as low-grade varicocele, surgery is not strongly recommended. Nevertheless, this grade of varicocele may include a subgroup which exert a certain amount of reflex flow, which was not detected on physical examination. Regarding ultrasound imaging, there is no widely accepted precise consensus on the examination technique, diagnostic criteria, and classification. The latest report from the European Society of Urogenital Radiology working group will help unifying these criteria19. This kind of research effort may indicate a more precise application for varicocele repair among clinical varicocele cases in the near future.
Gual-Frau et al20 reported that an oral antioxidant containing various vitamins including vitamin C and E (tocopheryl), L-carnitine, and zinc improved the integrity of sperm DNA in patients with grade 1 varicocele. CoQ10 has also been reported as an effective oral antioxidant for patients with low-grade varicocele21. Keishibukuryogan (Guizhi-Fuling-Wan) is a traditional herbal medicine that is used for its various expected effects including improvement in blood stasis. This medicine has been reported to improve sperm concentration and motility in patients with varicocele and to even cure or downgrade varicocele22. On the basis of these studies’ findings and consideration of the cost, we prescribed tocopheryl acetate and keishibukuryogan to patients in this study in whom antioxidant and vessel flow acceleration effects could be expected. In practice, however, the effectiveness of these medications is often limited, and there is no obvious subsequent treatment choice.
Our study’s result can serve as evidence to propose microsurgical varicocelectomy as a treatment option for patients with grade 1 varicocele. In general, an ~3-month interval is recommended after varicocele treatment for the evaluation of semen parameters5. Our study showed that some patients had a clinically significant and positive effect at 6 months postoperatively, even if they did not experience any effect at 3 months. At the same time, we need to carefully consider the risk of aging while couples wait for the effect of surgery.
The retrospective study design and limited number of patients from a single facility were limitations of the study. Randomized and prospective studies should be planned to provide further perspective on this topic. In particular, a more precise evaluation of the retrograde flow in patients using ultrasonography is considered to be essential for further discussion on patient selection for microsurgical varicocelectomy. In conclusion, the MSC was significantly improved in the surgery group compared to that in the medication group. On the basis of our results, we consider microsurgical varicocelectomy as a treatment option for medication-resistant patients with grade 1 varicocele.
Human rights statements and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from all patients to be included in the study.
Approved by ethics committee
The study was approved by the Yokohama City University Review Board.
Data availability statement
The data that supports the findings of this study are available upon request from the corresponding author (S.K.).
S.K., T.T., and Y.Y.: conceptualization. S.K., K.U., K.M., H.S., T.T., and Y.Y.: data curation. S.K., T.T., and Y.Y.: methodology. S.K.: writing—original draft. S.K., T.T., T.K., H.U., and Y.Y.: writing—review and editing.
Conflict of interest disclosures
The authors declare that they have no financial conflict of interest with regard to the content of this report.
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