Controlled trial of high spermatic vein ligation for varicocele infertile men* Avraham Karasik, M.D.:j: Benad Goldwasser, M.D.t

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1 Urology-andrology FERTILITY AND STERILITY Copyright 1995 American Society for Reproductive Medicine Vol. 63, No. I, January 1995 Printed on acid-free paper in U. S. A. Controlled trial of high spermatic vein ligation for varicocele infertile men*. 1n!gael Madgar, M.D.t Ruth Weissenberg, Ph.D.:j: Bruno Lunenfeld, M.D.:j: Avraham Karasik, M.D.:j: Benad Goldwasser, M.D.t Sheba Medical Center, Tel Hashomer, Israel Objective: To determine whether high ligation is an effective treatment for infertile men with clinical varicocele. Design: A randomized, controlled trial of high spermatic vein ligation was carried out. The patients were treated and observed for 3 years. Setting: Infertility treatment clinic and andrology laboratory in a hospital. Patients: Infertile men with abnormal semen analysis because of varicocele only. Intervention: High ligation 1 year postrecruitment (group A) and at the beginning of the study (group B). Results: Among the 20 couples in group A, 2 pregnancies (10%) were achieved within the 1st year of observation period. During the year after high ligation, there were 8 pregnancies (44.4%), and during the 2nd year after high ligation, there were 4 more pregnancies (22.2%). In group B, 15 pregnancies (60%) occurred within the 1st year after operation. Three pregnancies (12%) and 1 pregnancy (4%) occurred during the 2nd and 3rd year, respectively. After operation in all patients of both groups, there was significant improvement in semen parameters, regardless of pregnancy occurrence. The difference in pregnancy rate (PR) between the operated group B and nonoperated group A during the 1st year of study was found to be highly significant. Conclusions: It is concluded that in a population of infertile men presenting varicocele as the only demonstrable factor of infertility, the varicocele is clearly associated with infertility and reduced testicular function, and its correction by ligation improves sperm parameters and fertility rate. Furthermore, the highest PR in both groups occurred during the 1st year postoperation. Fertil Steril 1995;63:120-4 Key Words: Male infertility, varicocele, high spermatic vein ligation, fertility Approximately 15% to 20% of the general male population are afflicted by varicocele (1, 2). How- Received February 22, 1994; revised and accepted August 1, * Supported by the special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland. t Department of Urology. :j: Institute of Endocrinology. Reprints requests: Ruth Weissenberg, Ph.D., Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Israel (FAX: ). ever, among patients attending male infertility treatments clinics, the prevalence is 30% to 40% (1-3). In a multicentered study on the investigation and diagnosis of the infertile couple conducted by the World Health Organization (WH 0) special program of research in human reproduction (project 78923), varicocele was present in 11.7% of the total male population and in 25.4% of men with abnormal semen parameters (4). The same study reported deterioration in sperm concentration and motility over time in men with varicocele and direct relation between the size of varicocele and severity of the depression of sperm count. 120 Madgar et al. High spermatic vein ligation Fertility and Sterility

2 The mechanism by which varicocele impairs fertility and spermatogenesis is not clear. Nevertheless, ligation of the left spermatic vein has been established as current therapy when varicocele is diagnosed. Improvement in semen parameters after varicocele repair has been reported by some authors (3, 5-10). Despite the extensive use of spermatic vein ligation in the management of varicocele, no controlled study for this form of therapy has ever been performed. In addition, recent reports question the relationship between varicocele and infertility and the effect of surgery in these patients on fertility and spermatogenesis (11-14). In view of the proportion of patients at infertility treatments clinics who exhibit varicocele, it would be of interest to determine whether high spermatic vein ligation in cases of varicocele results in significant improvement of semen parameters and in relatedly improved fertility. In the present study (part of multicenter trial organized by the WHO), it is attempted to assess whether high ligation of the left spermatic vein is an effective treatment for infertile men with clinical varicocele. The study includes a prospective randomized and controlled trial of high spermatic vein ligation in a population of infertile married men presenting demonstrable factors of infertility, as outlined by WHO. MATERIALS AND METHODS Subjects with infertility for at least 12 months, between 21 and 45 years of age, with a visible or palpable left varicocele only, with no history of severe renal, liver, or any other physical illness or long-term medication affecting male fertility were selected for the study. The subjects had to exhibit abnormal semen analysis (on 2 different occasions) according to WHO criteria (15), with the restriction of sperm count 5 X 10 6 to 20 X 10 6 /ml, and no signs of accessory gland infection, as inferred from the following criteria: [1] history with no urogenital infection; [2] no abnormal rectal palpation; [3] <1 X 10 6 leukocytes per ml ejaculate; and [4] no disturbance in secretory function of accessory glands. Their LH, FSH, and T levels were within the normal range. The hormones were measured by RIA using reagents of Diagnostic Product Coorporation (Los Angeles, CA). The intra-assay and interassay coefficients of variation (CVs) of the RIA was 7% and 8.5%, respectively, for LH and 6.5% and 8%, respectively, for FSH. Testosterone was determined using a direct solid-phase kit. The intra-as- say and interassay CVs were 9% and 12%, respectively. Demonstrable causes of infertility in the female partner had to be ruled out using WHO criteria (15, 16), that is, normal sexual function, menstrual pattern and ovulation, PRL levels, and bilateral tubal patency. Ovulatory cycle was determined based on BBT and luteal phase P measurement. Two hundred ten infertile couples were seen in the outpatient fertility clinic during 1984 to They were allocated to a detailed investigation program (protocol or 84914) of the WHO "Standardized Investigation of the Infertile Couple." Of these 210 couples, 30 dropped out unwilling to complete couple evaluation, and 64 were excluded because of additional male factors such as sperm count < 5 X 10 6 /ml, accessory gland infection, or primary germinal failure. Fifty-nine couples were excluded because of female infertility factor. Three patients induced spontaneous pregnancy during the evaluation period, and 9 patients dropped out for unknown reasons. The remaining 45 couples, whose condition of infertility was assumed to result from a visible or palpable varicocele only and whose female partner had no demonstrable cause of infertility, were randomized into two groups. Group A (n = 20) did notreceive any treatment for 12 months after recruitment. If no pregnancy occurred at the end of this observation period, high ligation of the left spermatic vein was performed according to the method described by Fenster and Me Loughlin (17). After surgery, all patients were observed for a further period of 36 months. During the observation period and the year after surgery, semen analysis was performed every 3 months or until pregnancy occurred. In group B (n = 25), high ligation of the left spermatic vein was performed within 45 days of recruitment. After surgery, all patients were observed for a further period of 36 months. During the 1st year after surgery, semen analysis was performed every 3 months or until pregnancy was reported. Semen analysis was done according to the WHO manual for the examination of human semen and semencervical mucus interaction (18). To assess differences between groups, one-way analysis of variance was applied for statistical analysis. Differences between values were calculated using the two-sample t-test. RESULTS The mean age, period of infertility before recruitment, and hormonal blood levels (FSH, LH, and T) Vol. 63, No.1, January 1995 Madgar et al. High spermatic vein ligation 121

3 Table 1 Patients' Profile at Time of Recruitment Group A Group B 80~ ~ _:,.. A B ~----~=ca No. of patients Age (y) 28.7 ± 3.8* 28.7 ± 4.5 Infertility (mo) 25.3 ± ± 17.3 FSH (IU/L)t 4.6 ± ± 1.24 LH (IU/L)t 3.89 ± ± 1.31 T (nmol/l) ± ± 3.32 *Values are mean± SD. t Conversion factor to SI unit, Q) 60-1ii a: 1)' 1ii4oc: g>. Observation Period c: j ~ : HL o 201- I ' ' of both groups were similar at the time of recruitment (Table 1). The mean seminal parameters with respect to volume, count, motility, and morphology of both groups were also similar at the time of recruitment (Fig. 1) Figure Months Accumulative PR. 70~ A Volume (ml) Count (1 0 /ml) Motility (%) Normal sperm (%) 70, , B Motility(%) Normal sperm (%) Figure 1 (A), Mean sperm parameters at recruitment (D), after 12 months of observation (->), and at 12 months after ligation of group A patients who did not achieve pregnancy (!!!II) and of those who did (fi!il). (B), The same for group B but without observation period. Among patients of group A (n = 20) who did not receive treatment for the 1st year after recruitment, spontaneous conception occurred in 2 couples (10%). During this observation period of 1 year, the seminal parameters were similar to the two performed during the enrollment phase and similar to those of patients of group B at the time of recruitment. After the 1-year observation period, high ligation of the left spermatic vein was performed. During the 1st year after surgery, eight conceptions (44.4%) occurred. Within the 2nd, four more pregnancies (22.2%) were recorded. During the 3rd and final year after surgery, no further pregnancy was reported. The overall PRof the group was 66.7% (Fig. 2). Within the first 12 months after high ligation, the sperm count, motility, and morphology improved significantly, irrespective of whether pregnancy occurred (P = 0.001) or not (P = 0.005) (Fig.1). Semen parameters between 3 and 12 months after high ligation were significantly better than those observed during the enrollment period and the year of observation (P < 0.001). The most significant improvement in sperm parameters was observed after 3 and 6 months postsurgery, whereas between 6 and 12 months no further improvement was observed. In patients of group B (n = 25), high ligation of the left spermatic vein was performed within 45 days of recruitment, and all patients were observed for 3 years thereafter. After the 1st 12 months postsurgery, 15 pregnancies (60%) were recorded. In the 2nd year of observation, 3 pregnancies (12%) were 122 Madgar et al. High spermatic vein ligation Fertility and Sterility

4 observed, and during the 3rd year, one additional spontaneous pregnancy occurred. The overall PR of group B was 76% (Fig. 2). Of the remaining six couples, three preferred IVF. In these three cases eggs, were fertilized, but after transfer no clinical pregnancy developed. Two couples chose donor insemination with resulting pregnancies. Within the first 12 months after surgery, the sperm count, motility, and morphology improved significantly, irrespective of whether pregnancy occurred (P = ) or not (P = 0.01) (Fig. 1). DISCUSSION The association between left varicocele, abnormal semen parameters, and infertility is generally accepted but is not fully elucidated (1-6, 11-14). A study (4) recently published by the WHO on 9,034 male partners of infertile couples supports the concept that varicocele is associated with impaired fertility. There is a higher frequency of varicocele (25.4%) among men with abnormal semen analysis than in those with normal semen quality (11.7%). Moreover, sperm quality is worse in men with varicocele than in those without (4). The effect of varicocele correction on improvement of sperm quality and on PR is reportedly variable (5-10). Besides, there are patients who remain infertile despite surgical correction of varicocele and, conversely, patients who become fertile without therapeutic intervention. This suggests that varicosity may not necessarily cause infertility in men with clinical varicocele, and, on the other hand, no significant improvement in semen parameters or fertility rates should always be expected after varicocele correction. Pregnancies after varicocelectomy have been reported in up to 53% of treated couples (3, 7). Yet, other investigators obtained less impressive results and even doubted the efficacy of the operation as far as fertility was concerned (11-14). These divergent results may be due to differences in the selection of patients treated, therapeutic regimens, duration of infertility before treatment, and a minor gynecological abnormality in the female partner of the patients who did not benefit from treatment. Moreover, because all studies were done retrospectively, most of them lack an untreated control group that could undergo the same investigation protocol as the treated group. The present study is the first one performed as a prospective, randomized, and controlled trial. After randomization of patients, there were two comparable groups in whom the mean age, period of infertility, hormonal status, and seminal parameters were statistically similar at the time of recruitment. In both groups, the highest PR was achieved within the 1st year after operation (44.4% and 60% in groups A and B, respectively). This observation is in agreement with reported data (1-10). In group A, during the 1-year observation period, there was 10% spontaneous pregnancy as compared with 44.4% PR during the 1st year after high ligation. During the 2nd and 3rd year after surgery, there was a decrease in the number of pregnancies. However, at the end of the 3-year study period, there was no difference between the groups regarding the cumulative PR (66.6% in group A and 76% in group B). The high PR obtained in the present study can be attributed to the well-defined criteria for patient selection and to the uniform criteria for semen evaluation before and after high ligation. The difference in PRs between the untreated group (A = 10%) and the treated group (A = 44.4%, B = 60%) during the 1st year after high ligation is highly significant (P < 0.001). Semen parameters were improved after surgery in all patients, both in those who induced pregnancy and in those who did not. Postponing operation by 1 year had no adverse effect on sperm parameters and did not affect the fertility rate at the end of the study. It is therefore concluded that varicocele is associated with reduced fertility and reduced testicular function. Varicocele correction improves sperm parameters and fertility rates. REFERENCES 1. Vestroppen GR, Steeno OP. Varicocele and pathogenesis of the associated subfertility: a review of various theories. II. Results of surgery. Andrologia 1977; 9: Greenberg SH. Varicocele and male fertility. Fertil Steril 1977; 28: Dubin L, Amelar RD. Etiologic factors in 1,294 consecutive cases of male infertility. Fertil Steril1971;22: World Health Organization: The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril 1992;57: Comhaire FH. Varicocele and its role in male infertility. In: Clarke JR, editor. Oxford reviews of reproductive biology. Oxford: Clarendon Press 1986: Stewart BH. Varicocele in infertility: incidence and results of surgical therapy. J Urol 1974; 112: Vol. 63, No. 1, January 1995 Madgar et al. High spermatic vein ligation 123

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