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Effect of Infertility Duration on Postvaricocelectomy Sperm Counts and Pregnancy Rates
Infertility Effect of Infertility Duration on Postvaricocelectomy Sperm Counts and Pregnancy Rates Unal O. Zorba, Oner M. Sanli, Murat Tezer, Fikret Erdemir, Shavkat Shavakhabov, and Ates Kadioglu OBJECTIVE
METHODS
RESULTS
CONCLUSIONS
The deterioration of seminal parameters in men with varicocele suggests a vascular lesion producing progressive damage to the testes over time. The aim of this study was to analyze the relationship between the duration of infertility in infertile men with varicocele and the postoperative sperm counts to determine whether the infertility period is a parameter for predicting the pregnancy rate. The medical records of 574 patients with palpable varicoceles were retrospectively reviewed. According to the duration of unprotected intercourse without conception (infertility period), the patients were divided into 4 groups: group 1, 0-3 years (n ⫽ 353); group 2, 3-6 years (n ⫽ 132); group 3, 6-9 years (n ⫽ 47); and group 4, ⬎9 years (n ⫽ 42). The mean age of these groups was 28.5 ⫾ 5.3 years (range 19-58), 30 ⫾ 4.9 years (range 22-52), 31.6 ⫾ 4.1 years (range 25-42), and 36.4 ⫾ 4.2 years (range 29-50), respectively. The preoperative and postoperative total motile sperm counts (TMCs) and postoperative pregnancy rates among these groups were compared statistically, including multivariate analysis. An overall spontaneous pregnancy rate of 41.3% was achieved after microscopic varicocelectomy. The greatest pregnancy rate was achieved in group 1 (43.9%) and the lowest pregnancy rate in group 4 (31.7%; P ⬍ .05). The mean postoperative TMC in these groups was 34.9 ⫾ 3.5 ⫻ 106 and 24.6 ⫾ 1.7 ⫻ 106, the only statistically significant difference in terms of postoperative TMC and pregnancy among the 4 groups. According to our data, the pregnancy rates and TMCs after varicocelectomy correlate negatively with the infertility period. This finding supports the perspective that varicocele has deleterious effects on the testicular biology over time. UROLOGY 73: 767–771, 2009. © 2009 Elsevier Inc.
V
aricocele is known to be the most commonly detected correctable cause of infertility. The incidence of varicocele in men presenting to an infertility clinic with primary and secondary infertility is 35%-40% and 69%-81%, respectively.1-4 The greater incidence in the secondary infertility group supports the idea that varicocele is a progressive disorder, rather than static, resulting in progressive damage to testicular biology over time. Hotchkiss5 reported as early as the 1940s that surgical correction of a varicocele is probably only effective as a prophylactic measure against the testicular damage that might ensue with passing years and that varicocelectomy has benefits other than just cosmetic in patients with long-standing varicocele and small soft testes. From the clinical perspective, Lipshultz and Corriere6 reported a ⬎50% decrease in sperm density of older From the Department of Urology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey ¨ roloji AD, I˙stanbul U ¨ niReprint requests: Ates Kadioglu, M.D., Department of U versitesi, ˙Istanbul Tıp Fakültesi, Fatih, Istanbul 34 080 Turkey Submitted: January 29, 2008, accepted (with revisions): June 5, 2008
© 2009 Elsevier Inc. All Rights Reserved
men with varicoceles compared with younger men. Moreover, in 2 different studies of adolescents with varicoceles, Sayfan et al.7 and Okuyama et al.8 demonstrated severe disturbances in the seminal variables in the older boys compared with the younger ones. In 1 of the first experimental studies of varicocele, Fussel et al.9 reported increased thermal and ultrastructural damage to the testes in monkeys by inducing varicocele that was demonstrated to be progressive during 18 months of follow-up. Similarly, Shafik et al.10 demonstrated increases in testicular temperature, abnormally formed sperm, and decreases in the total sperm count and sperm motility in varicocele-induced dogs compared with the control group. Moreover, they noted that the normal preoperative testicular histologic features degenerated in a progressive fashion after varicocele was induced.10 Accordingly, the aim of the present study was to report the outcome of microscopic varicocelectomy in an infertile cohort of men stratified by the infertility period. Additionally, we analyzed the relationship between the duration of the infertility period and the postoperative 0090-4295/09/$34.00 doi:10.1016/j.urology.2008.06.014
767
semen parameters to determine whether the infertility period is a predictive factor for future pregnancy.
MATERIAL AND METHODS The present study was a retrospective evaluation of 574 men examined in our institution from 1992 to 2002 with palpable clinical varicoceles. All men underwent a standard, basic infertility evaluation, including a detailed history, complete physical examination, and semen analyses. The varicocele, identified at scrotal examination performed with the patient in the standing position before and during the Valsalva maneuver, was classified as grade 1 (palpable only during the Valsalva maneuver), grade 2 (palpable without the Valsalva maneuver), or grade 3 (visible without the need for palpation).2 Semen for analysis was obtained by masturbation after 2-5 days of abstinence and was processed within 1 hour of ejaculation. A minimum of 2 specimens were collected, separated by a 2-4 –week interval. All analyses were performed in the same andrology laboratory according to the World Health Organization guidelines.11,12 The preoperative and postoperative total motile sperm counts (TMCs) were calculated by the following formula: TMC ⫽ ejaculate volume (mL) ⫻ concentration per mL ⫻ motile fraction (World Health Organization 3 and 4 motility).13 In addition, to confirm the adequacy of testicular function, the follicle-stimulating hormone (FSH) level (normal range 1.37-13.58 mIU/mL; Architect FSH, Chemiluminescent, Microperticle Immunoassay, i4000, Abbott Laboratories, North Chicago, IL) and total testosterone level (normal range 2.8-8 ng/mL; Radioimmunoassay, Diagnostic System Laboratories, Webster, TX) were determined before varicocelectomy. Patients with any FSH or total testosterone abnormalities were excluded from the study. No other hormonal evaluation was performed after varicocelectomy. The spouses of this cohort were evaluated for female factors of infertility and patients whose spouse might have had concomitant female factors for infertility were excluded from the study. All men with palpable varicoceles underwent varicocelectomy using a microsurgical artery and lymphatic-sparing surgical technique with an inguinal approach, as described previously by Goldstein et al. and routinely performed at our center.14 All patients were divided into 4 groups according to the duration of unprotected intercourse without conception (infertility period): group 1, 0-3 years (n ⫽ 353); group 2, 3-6 years (n ⫽ 132); group 3, 6-9 years (n ⫽ 47); and group 4, ⬎9 years (n ⫽ 42). The postoperative evaluation included serial semen analysis with ongoing assessment of spontaneous pregnancy. The average of 2 preoperative semen analyses and 4 postoperative semen analyses in the first year after surgery were used for the comparison of the pre- and postoperative TMCs and pregnancy rates, stratified by the infertility period. The preoperative TMC was accepted as the mean value of the 2 preoperative TMCs. The postoperative TMCs used for analysis were the last performed semen analyses postoperatively. The laboratory technicians of the andrology laboratory were unaware of the diagnosis of the patients. The number of patients needed in each group for the comparative tests was determined by calculating the study’s power. A total of 38 patients in each group would be needed to detect a power of 100%, with an ␣ of 5%. Statistical analysis was performed using one-way analysis of variance and 2 tests to compare the preoperative and postoperative TMCs and preg768
nancy rates among the 4 groups. Statistical analysis was also performed in each group according to varicocele grade. The side that had the greater varicocele grade was used for the statistical analysis in the patients with bilateral varicoceles. In addition, multivariate analyses was performed using female and male age, varicocele grade (in the bilateral cases, the side with the greater grade was selected), and infertility period as covariates to establish their effect on the pregnancy rate.
RESULTS The mean age of the 574 patients with varicocele and the mean age of their spouses was 29.8 ⫾ 5.6 years (range 19-58) and 26.8 ⫾ 4.9 years (range 18-42), respectively. The mean age of the patients in groups 1-4 was 28.5 ⫾ 5.3 years (range 19-58), 30 ⫾ 4.9 years (range 22-52), 31.6 ⫾ 4.1 years (range 25-42), and 36.4 ⫾ 4.2 years (range 29-50; P ⬎ .05), respectively. The corresponding age of the spouses were 25.3 ⫾ 4.6 years (range 18-42), 27.5 ⫾ 4.8 years (range 20-41), 28.1 ⫾ 3.7 years (range 22-38), and 32.1 ⫾ 3.2 years (range 24-40; P ⬎ .05). Of the 121 patients with unilateral varicocele, 79 (65.3%) had grade 1, 39 (32.2%) had grade 2, and 3 (2.5%) had grade 3 varicocele. In patients with bilateral disease, the varicocele grade was 1, 2, and 3 in 221 (48.7%), 180 (39.8%), and 52 (11.5%) on the left side and 340 (75%), 105 (23.2%), and 8 (1.8%) on the right side, respectively. The varicocele grade stratifications of each group were similar. Overall, the mean FSH and testosterone level was 4.3 ⫾ 2.1 nIU/mL and 5.3 ⫾ 1.3 ng/mL, respectively. The TMC increased from 10.7 ⫾ 1.6 ⫻ 106 to 30.2 ⫾ 2.4 ⫻ 106 after varicocelectomy (P ⬍ .05). Moreover, we noted that the preoperative TMCs decreased with an increasing duration of infertility. The greatest TMC was 16.1 ⫾ 1.7 ⫻ 106, detected in group 1. Patients in group 4 had the lowest TMC (7.6 ⫾ 0.7 ⫻ 106), and the second lowest sperm count was detected in group 3 (8.1 ⫾ 0.9 ⫻ 106). The only statistically significant difference in the preoperative TMC was detected between groups 1 and 3 and groups 1 and 4 (P ⬍ .05; Table 1). Comparable to the preoperative period, the greatest and the lowest postoperative TMC was detected in groups 1 and 4, respectively. Despite the greatest increase in group 3 in TMC, the increase in TMC after varicocelectomy was similar in all groups (P ⬎ .05). In addition, the only statistically significant difference in the postoperative TMC was detected between groups 1 (34.9 ⫾ 3.5 ⫻ 106) and 4 (24.6 ⫾ 1.7 ⫻ 106; P ⬍ .05; Table 1). The deterioration in TMC after varicocelectomy correlated with the preoperative TMC (Fig. 1). Spontaneous pregnancy was achieved in 237 of 574 couples (41.3%) after an average duration of 8.8 ⫾ 3.4 months postoperatively. The vast majority of the couples achieved pregnancy within the first year after varicocelectomy (n ⫽ 215, 90.7%). The average time to pregnancy for groups 1 through 4 was 8.7 ⫾ 3.4 months (range 2-21), 8.8 ⫾ 3.6 months (range 1-20), 8.7 ⫾ 2.7 months (range 4-14), and 9.6 ⫾ 3.6 months (range 4-16), UROLOGY 73 (4), 2009
Table 1. Total motile sperm count before and after varicocelectomy and pregnancy rates after varicocelectomy (*P ⬍ .05) Infertility Period (y)
Preoperative TMC (⫻106)
Postoperative TMC (⫻106)
Increase in TMC (⫻106)
Pregnancy Rate (%)
0-3 3-6 6-9 ⬎9
16.1 ⫾ 1.7* 11.8 ⫾ 1.4 8.1 ⫾ 0.9† 7.6 ⫾ 0.7*
34.9 ⫾ 3.5* 32.1 ⫾ 2.9 28.9 ⫾ 2.4 24.6 ⫾ 1.7*
18.8 20.3 20.8 17
43.9 38.6 38.3 31.7*
* Statistically significant difference between groups 1 and 4. † Statistically significant difference between groups 1 and 3.
Figure 1. Preoperative and postoperative TMC, postoperative TMC increase (⫻106), and pregnancy rates.
respectively. No statistically significant difference was found among the groups in the interval to conception after varicocelectomy (P ⬎ .05). Stratification by varicocele grade revealed no statistically significant difference in the achievement of pregnancy in each group. A total of 57 patients had severe oligospermia and 20 had azoospermia before varicocelectomy. Of the 20 azoospermic patients, 12 had pellet-positive and 8 pellet-negative findings. In groups 1 through 4, the number of patients with azoospermia was 9 (2.5%), 7 (5.3%), 2 (4.3%), and 2 (4.8%), respectively. None of the patients with azoospermia could father a child after varicocelectomy. The number of patients in groups 1 through 4 with severe oligospermia was 31 (8.7%), 13 (9.8%), 5 (10.6%), and 8 (19%), respectively. In group 1, the pregnancy rate was 6.4% (n ⫽ 2); the corresponding rates 7.7% (n ⫽ 1), 0%, and 0% in the 3 remaining groups. When patients with azoospermia and oligospermia were excluded from analysis, the corresponding pregnancy rates were 48.8%, 44.6%, 45%, and 40.6% in these 4 groups. The only statistically significant difference was between groups 1 and 4. UROLOGY 73 (4), 2009
The postoperative pregnancy rate correlated negatively with the duration of infertility. The greatest and lowest pregnancy rate was achieved in groups 1 (43.9%) and 4 (31.7%; P ⬍ .05), respectively. When groups 1 and 4 were compared, the pre- and postoperative TMCs had increased from 16.1 ⫾ 1.7 ⫻ 106 to 34.9 ⫾ 3.5 ⫻ 106 and 7.6 ⫾ 0.7 ⫻ 106 to 24.6 ⫾ 1.7 ⫻ 106, respectively. The pregnancy rates and TMCs decreased with an increasing infertility period (Fig. 1). Multivariate analysis revealed that the infertility period was the only factor significantly affecting the achievement of pregnancy.
COMMENT Although the incidence of varicocele in the general male population is approximately 15%, it has been implicated as a factor in about one third of the infertile population.4 Thus, varicocele is a common cause of infertility, but most men with varicoceles can father children and remain asymptomatic. Nevertheless, a statistically significant deterioration in sperm density and motility throughout the follow-up period of untreated varicoceles has been previously docu769
mented.2-4,15 More importantly, histologic changes and atrophy have been demonstrated in the testes associated with varicoceles.3 In the present study, the difference in the preoperative TMCs between groups 1 and 4 and 1 and 3 was significant (P ⬍ .05). Moreover, we detected an inverse correlation between a deterioration in sperm parameters and the duration of the infertility period. On multivariate analysis, including male and female age, varicocele grade, and infertility period, the infertility period was the unique independent factor for the achievement of pregnancy. Therefore, even though the mechanisms affecting the testes in patients with varicocele are ambiguous, it would be rational to consider varicocelectomy early after the diagnosis. However, additional studies with aged-matched control groups are needed to confirm the outcomes obtained from the present study. In a retrospective study, Matkov et al.16 reported that patients with TMCs ⬎5 ⫻ 106 had significant improvement in the seminal parameters after treatment. On the basis of this finding, one would have expected a good response to varicocelectomy for all patients in the present study because the TMCs were ⬎5 ⫻ 106 in all groups. However, after varicocelectomy, the greatest TMCs were achieved in group 1, which had had the greatest preoperative TMC. In contrast, the postvaricocelectomy results correlated negatively with the duration of infertility. Thus, it can be assumed that seminal improvement is better in patients with a shorter infertility period because of less testicular damage. We were also interested in evaluating the correlation between the increases in TMCs and pregnancy rates. The greatest increase in TMCs was encountered in group 3 and the pregnancy rate in this group was 38.3%. Although the increase in the TMC was lower than that in group 3, the pregnancy rate was 43.9% in group 1. Therefore, one could assume that an increase in TMC might not reflect directly on the pregnancy rate in each of these groups and that the duration of infertility is another factor significantly affecting the pregnancy rate. Witt and Lipshultz4 reported that the incidence of varicocele in men with secondary infertility is greater than that of primary infertility. Of 255 of their patients with primary infertility, 50% had a varicocele with no other identifiable abnormalities, and 69% of their patients with secondary infertility had an identifiable varicocele contributing to their fertility. From the outcomes of a prospective randomized study, Madgar et al.17 recommended early varicocelectomy for this group of patients, because they found a pregnancy rate of 60% in patients undergoing immediate varicocelectomy vs 10% in patients who were treated expectantly. In addition, Matkov et al.16 reported that men who achieved a TMC ⬎20 ⫻ 106 were likely to induce pregnancy with lessinvasive techniques. In the present study, we achieved a TMC ⬎20 ⫻ 106 in all groups, and the overall pregnancy rate was 41.3%, which was quite comparable to that in other studies analyzed retrospectively. However, we detected the only statistically significant difference for the 770
pregnancy rate in the groups with an infertility period of 0-3 years (group 1) and ⬎9 years (group 4). Although not significant, the differences between group 1 and groups 2 and 3 were notable. Some recent meta-analyses have concluded that the treatment of varicoceles in male partners of infertile couples does not make any difference in the spontaneous pregnancy rate.18-20 We, and others, believe that in the studies reviewed for the meta-analyses, reliable, randomized, controlled trial data and randomization in the surgical technique were lacking. It has been established that the reference standard for varicocele treatment is a microsurgical technique. In addition, before reporting on the ineffectiveness of varicocele treatment, the outcomes of a wellestablished treatment technique within the principles of evidence-based medicine should be evaluated. The low pregnancy rates in these studies might have resulted from the ineffectiveness of the surgical technique and varicocele recurrence after treatment.21 In a recent meta-analysis with a more precise method, Marmar et al.22 concluded that surgical varicocelectomy is an effective treatment for improving the spontaneous pregnancy rates for couples with an infertile male partner who has poor semen parameters and a palpable varicocele.
CONCLUSIONS The results of the present study have revealed that infertile men with varicoceles have a risk of subsequent deterioration of seminal parameters. Current noninvasive modalities such as semen analysis and measurement of testicular size and serum gonadotropins should be used to identify early changes in testicular physiology caused by a varicocele. The goal of varicocele management is to improve testicular function and the seminal parameters and to increase the likelihood of the ultimate goal (ie, an increased pregnancy rate). From the historical data, we found that the factors associated with improved outcomes after varicocele treatment were larger varicoceles, a lack of testicular atrophy, normal FSH levels, positive gonadotropin-releasing hormone stimulation test, a TMC ⬎5 ⫻ 106, and motility ⬎60%.23 According to our data, the duration of the infertility period should be considered as another predictive factor for a positive seminal response to varicocelectomy and achieving pregnancy. If considering expectant management for patients with varicocele, one should take the duration of the infertility period into account. References 1. Green KF, Turner TT, Howards SS. Varicocele: Reversal of testicular blood flow and temperature effects by varicocele repair. J Urol. 1984;131:1208-1211. 2. Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril. 1993;59:613-616. 3. Saypol DC, Howards SS, Turner TT, et al. Influence of surgically induced varicocele on testicular blood flow, temperature, and histology in adult rats and dogs. J Clin Invest. 1981;68:39-45. 4. Witt MA, Lipshultz LI. Varicocele: A progressive or a static lesion? Urology. 1993;42:541-543.
UROLOGY 73 (4), 2009
5. Hotchkiss RS. Fertility in Men: A Clinical Study of the Causes, Diagnosis, and Treatment of Impaired Fertility in Men. Philadelphia: JB Lippincott; 1944:194-196. 6. Lipshultz LJ, Corriere JN Jr. Progressive testicular atrophy in the varicocele patient. J Urol. 1977;117:175-176. 7. Sayfan J, Soffer Y, Mannor H, et al. Varicocele in youth. Ann Surg. 1988;207:223-226. 8. Okuyama O, Koide T, Itatani H, et al. Pituitary-gonadal function in school boys with varicocele and indications of varicocelectomy. Eur Urol. 1981;7:92-97. 9. Fussell E, Lewis R, Roberts J, et al. Early ultrastructural findings in experimentally induced varicocele in the monkey’s testis. J Androl. 1981;2:111-115. 10. Shafik A, Wall M, Abdel-Azis Y, et al. Experimental model of varicocele. Eur Urol. 1989;16:298-302. 11. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen–Cervical Mucus Interaction, 3rd ed. Cambridge: Cambridge University Press; 1992. 12. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen–Cervical Mucus Interaction, 4th ed. Cambridge: Cambridge University Press; 1999. 13. Çayan S, Erdemir F, Özbey ˙I, et al. Can varicocelectomy significantly change the way couples use assisted reproductive technologies? J Urol. 2002;167:1749-1752. 14. Goldstein M, Gilbert BR, Dicker AP, et al. Microsurgical in guinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. J Urol. 2002;167:1749-1752.
UROLOGY 73 (4), 2009
15. Chehval MJ, Purcell MH. Deterioration of semen parameters over time in men with untreated varicocele: Evidence of progressive testicular damage. Fertil Steril. 1992;57:174-177. 16. Matkov TG, Zenni M, Sandlow J, et al. Preoperative semen analysis as a predictor of seminal improvement following varicocelectomy. Fertil Steril. 2001;75:63-68. 17. Madgar I, Weissenberg R, Lunenfeld B, et al. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril. 1995;63:120-124. 18. Evers JLH, Collins JA, Vandekerckhove P. Surgery of embolisation for varicocele in subfertile men. Cochrane Database Syst Rev. 2001; 1:CD000479. 19. Evers JLH, Collins JA. Assessment of efficacy of varicocele repair for male subfertility: A systematic review. Lancet. 2003;361:18491852. 20. Evers JL, Collins JA. Surgery or embolisation for varicocele in subfertile men. Cochrane Database Syst Rev. 2004;3:CD000479. 21. Ficarra V, Cerruto MA, Liguori G, et al. Treatment of varicocele in subfertile men: The Cochrane Review—A contrary opinion. Eur Urol. 2006;49:258-263. 22. Marmar JE, Agarwal A, Prabakaran S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril. 2007;88:639-648. 23. Fretz PC, Sandlow JI. Varicocele: Current concept in pathophysiology, diagnosis and treatment. Urol Clin North Am. 2002;29:921937.
771
METHODS
RESULTS
CONCLUSIONS
The deterioration of seminal parameters in men with varicocele suggests a vascular lesion producing progressive damage to the testes over time. The aim of this study was to analyze the relationship between the duration of infertility in infertile men with varicocele and the postoperative sperm counts to determine whether the infertility period is a parameter for predicting the pregnancy rate. The medical records of 574 patients with palpable varicoceles were retrospectively reviewed. According to the duration of unprotected intercourse without conception (infertility period), the patients were divided into 4 groups: group 1, 0-3 years (n ⫽ 353); group 2, 3-6 years (n ⫽ 132); group 3, 6-9 years (n ⫽ 47); and group 4, ⬎9 years (n ⫽ 42). The mean age of these groups was 28.5 ⫾ 5.3 years (range 19-58), 30 ⫾ 4.9 years (range 22-52), 31.6 ⫾ 4.1 years (range 25-42), and 36.4 ⫾ 4.2 years (range 29-50), respectively. The preoperative and postoperative total motile sperm counts (TMCs) and postoperative pregnancy rates among these groups were compared statistically, including multivariate analysis. An overall spontaneous pregnancy rate of 41.3% was achieved after microscopic varicocelectomy. The greatest pregnancy rate was achieved in group 1 (43.9%) and the lowest pregnancy rate in group 4 (31.7%; P ⬍ .05). The mean postoperative TMC in these groups was 34.9 ⫾ 3.5 ⫻ 106 and 24.6 ⫾ 1.7 ⫻ 106, the only statistically significant difference in terms of postoperative TMC and pregnancy among the 4 groups. According to our data, the pregnancy rates and TMCs after varicocelectomy correlate negatively with the infertility period. This finding supports the perspective that varicocele has deleterious effects on the testicular biology over time. UROLOGY 73: 767–771, 2009. © 2009 Elsevier Inc.
V
aricocele is known to be the most commonly detected correctable cause of infertility. The incidence of varicocele in men presenting to an infertility clinic with primary and secondary infertility is 35%-40% and 69%-81%, respectively.1-4 The greater incidence in the secondary infertility group supports the idea that varicocele is a progressive disorder, rather than static, resulting in progressive damage to testicular biology over time. Hotchkiss5 reported as early as the 1940s that surgical correction of a varicocele is probably only effective as a prophylactic measure against the testicular damage that might ensue with passing years and that varicocelectomy has benefits other than just cosmetic in patients with long-standing varicocele and small soft testes. From the clinical perspective, Lipshultz and Corriere6 reported a ⬎50% decrease in sperm density of older From the Department of Urology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey ¨ roloji AD, I˙stanbul U ¨ niReprint requests: Ates Kadioglu, M.D., Department of U versitesi, ˙Istanbul Tıp Fakültesi, Fatih, Istanbul 34 080 Turkey Submitted: January 29, 2008, accepted (with revisions): June 5, 2008
© 2009 Elsevier Inc. All Rights Reserved
men with varicoceles compared with younger men. Moreover, in 2 different studies of adolescents with varicoceles, Sayfan et al.7 and Okuyama et al.8 demonstrated severe disturbances in the seminal variables in the older boys compared with the younger ones. In 1 of the first experimental studies of varicocele, Fussel et al.9 reported increased thermal and ultrastructural damage to the testes in monkeys by inducing varicocele that was demonstrated to be progressive during 18 months of follow-up. Similarly, Shafik et al.10 demonstrated increases in testicular temperature, abnormally formed sperm, and decreases in the total sperm count and sperm motility in varicocele-induced dogs compared with the control group. Moreover, they noted that the normal preoperative testicular histologic features degenerated in a progressive fashion after varicocele was induced.10 Accordingly, the aim of the present study was to report the outcome of microscopic varicocelectomy in an infertile cohort of men stratified by the infertility period. Additionally, we analyzed the relationship between the duration of the infertility period and the postoperative 0090-4295/09/$34.00 doi:10.1016/j.urology.2008.06.014
767
semen parameters to determine whether the infertility period is a predictive factor for future pregnancy.
MATERIAL AND METHODS The present study was a retrospective evaluation of 574 men examined in our institution from 1992 to 2002 with palpable clinical varicoceles. All men underwent a standard, basic infertility evaluation, including a detailed history, complete physical examination, and semen analyses. The varicocele, identified at scrotal examination performed with the patient in the standing position before and during the Valsalva maneuver, was classified as grade 1 (palpable only during the Valsalva maneuver), grade 2 (palpable without the Valsalva maneuver), or grade 3 (visible without the need for palpation).2 Semen for analysis was obtained by masturbation after 2-5 days of abstinence and was processed within 1 hour of ejaculation. A minimum of 2 specimens were collected, separated by a 2-4 –week interval. All analyses were performed in the same andrology laboratory according to the World Health Organization guidelines.11,12 The preoperative and postoperative total motile sperm counts (TMCs) were calculated by the following formula: TMC ⫽ ejaculate volume (mL) ⫻ concentration per mL ⫻ motile fraction (World Health Organization 3 and 4 motility).13 In addition, to confirm the adequacy of testicular function, the follicle-stimulating hormone (FSH) level (normal range 1.37-13.58 mIU/mL; Architect FSH, Chemiluminescent, Microperticle Immunoassay, i4000, Abbott Laboratories, North Chicago, IL) and total testosterone level (normal range 2.8-8 ng/mL; Radioimmunoassay, Diagnostic System Laboratories, Webster, TX) were determined before varicocelectomy. Patients with any FSH or total testosterone abnormalities were excluded from the study. No other hormonal evaluation was performed after varicocelectomy. The spouses of this cohort were evaluated for female factors of infertility and patients whose spouse might have had concomitant female factors for infertility were excluded from the study. All men with palpable varicoceles underwent varicocelectomy using a microsurgical artery and lymphatic-sparing surgical technique with an inguinal approach, as described previously by Goldstein et al. and routinely performed at our center.14 All patients were divided into 4 groups according to the duration of unprotected intercourse without conception (infertility period): group 1, 0-3 years (n ⫽ 353); group 2, 3-6 years (n ⫽ 132); group 3, 6-9 years (n ⫽ 47); and group 4, ⬎9 years (n ⫽ 42). The postoperative evaluation included serial semen analysis with ongoing assessment of spontaneous pregnancy. The average of 2 preoperative semen analyses and 4 postoperative semen analyses in the first year after surgery were used for the comparison of the pre- and postoperative TMCs and pregnancy rates, stratified by the infertility period. The preoperative TMC was accepted as the mean value of the 2 preoperative TMCs. The postoperative TMCs used for analysis were the last performed semen analyses postoperatively. The laboratory technicians of the andrology laboratory were unaware of the diagnosis of the patients. The number of patients needed in each group for the comparative tests was determined by calculating the study’s power. A total of 38 patients in each group would be needed to detect a power of 100%, with an ␣ of 5%. Statistical analysis was performed using one-way analysis of variance and 2 tests to compare the preoperative and postoperative TMCs and preg768
nancy rates among the 4 groups. Statistical analysis was also performed in each group according to varicocele grade. The side that had the greater varicocele grade was used for the statistical analysis in the patients with bilateral varicoceles. In addition, multivariate analyses was performed using female and male age, varicocele grade (in the bilateral cases, the side with the greater grade was selected), and infertility period as covariates to establish their effect on the pregnancy rate.
RESULTS The mean age of the 574 patients with varicocele and the mean age of their spouses was 29.8 ⫾ 5.6 years (range 19-58) and 26.8 ⫾ 4.9 years (range 18-42), respectively. The mean age of the patients in groups 1-4 was 28.5 ⫾ 5.3 years (range 19-58), 30 ⫾ 4.9 years (range 22-52), 31.6 ⫾ 4.1 years (range 25-42), and 36.4 ⫾ 4.2 years (range 29-50; P ⬎ .05), respectively. The corresponding age of the spouses were 25.3 ⫾ 4.6 years (range 18-42), 27.5 ⫾ 4.8 years (range 20-41), 28.1 ⫾ 3.7 years (range 22-38), and 32.1 ⫾ 3.2 years (range 24-40; P ⬎ .05). Of the 121 patients with unilateral varicocele, 79 (65.3%) had grade 1, 39 (32.2%) had grade 2, and 3 (2.5%) had grade 3 varicocele. In patients with bilateral disease, the varicocele grade was 1, 2, and 3 in 221 (48.7%), 180 (39.8%), and 52 (11.5%) on the left side and 340 (75%), 105 (23.2%), and 8 (1.8%) on the right side, respectively. The varicocele grade stratifications of each group were similar. Overall, the mean FSH and testosterone level was 4.3 ⫾ 2.1 nIU/mL and 5.3 ⫾ 1.3 ng/mL, respectively. The TMC increased from 10.7 ⫾ 1.6 ⫻ 106 to 30.2 ⫾ 2.4 ⫻ 106 after varicocelectomy (P ⬍ .05). Moreover, we noted that the preoperative TMCs decreased with an increasing duration of infertility. The greatest TMC was 16.1 ⫾ 1.7 ⫻ 106, detected in group 1. Patients in group 4 had the lowest TMC (7.6 ⫾ 0.7 ⫻ 106), and the second lowest sperm count was detected in group 3 (8.1 ⫾ 0.9 ⫻ 106). The only statistically significant difference in the preoperative TMC was detected between groups 1 and 3 and groups 1 and 4 (P ⬍ .05; Table 1). Comparable to the preoperative period, the greatest and the lowest postoperative TMC was detected in groups 1 and 4, respectively. Despite the greatest increase in group 3 in TMC, the increase in TMC after varicocelectomy was similar in all groups (P ⬎ .05). In addition, the only statistically significant difference in the postoperative TMC was detected between groups 1 (34.9 ⫾ 3.5 ⫻ 106) and 4 (24.6 ⫾ 1.7 ⫻ 106; P ⬍ .05; Table 1). The deterioration in TMC after varicocelectomy correlated with the preoperative TMC (Fig. 1). Spontaneous pregnancy was achieved in 237 of 574 couples (41.3%) after an average duration of 8.8 ⫾ 3.4 months postoperatively. The vast majority of the couples achieved pregnancy within the first year after varicocelectomy (n ⫽ 215, 90.7%). The average time to pregnancy for groups 1 through 4 was 8.7 ⫾ 3.4 months (range 2-21), 8.8 ⫾ 3.6 months (range 1-20), 8.7 ⫾ 2.7 months (range 4-14), and 9.6 ⫾ 3.6 months (range 4-16), UROLOGY 73 (4), 2009
Table 1. Total motile sperm count before and after varicocelectomy and pregnancy rates after varicocelectomy (*P ⬍ .05) Infertility Period (y)
Preoperative TMC (⫻106)
Postoperative TMC (⫻106)
Increase in TMC (⫻106)
Pregnancy Rate (%)
0-3 3-6 6-9 ⬎9
16.1 ⫾ 1.7* 11.8 ⫾ 1.4 8.1 ⫾ 0.9† 7.6 ⫾ 0.7*
34.9 ⫾ 3.5* 32.1 ⫾ 2.9 28.9 ⫾ 2.4 24.6 ⫾ 1.7*
18.8 20.3 20.8 17
43.9 38.6 38.3 31.7*
* Statistically significant difference between groups 1 and 4. † Statistically significant difference between groups 1 and 3.
Figure 1. Preoperative and postoperative TMC, postoperative TMC increase (⫻106), and pregnancy rates.
respectively. No statistically significant difference was found among the groups in the interval to conception after varicocelectomy (P ⬎ .05). Stratification by varicocele grade revealed no statistically significant difference in the achievement of pregnancy in each group. A total of 57 patients had severe oligospermia and 20 had azoospermia before varicocelectomy. Of the 20 azoospermic patients, 12 had pellet-positive and 8 pellet-negative findings. In groups 1 through 4, the number of patients with azoospermia was 9 (2.5%), 7 (5.3%), 2 (4.3%), and 2 (4.8%), respectively. None of the patients with azoospermia could father a child after varicocelectomy. The number of patients in groups 1 through 4 with severe oligospermia was 31 (8.7%), 13 (9.8%), 5 (10.6%), and 8 (19%), respectively. In group 1, the pregnancy rate was 6.4% (n ⫽ 2); the corresponding rates 7.7% (n ⫽ 1), 0%, and 0% in the 3 remaining groups. When patients with azoospermia and oligospermia were excluded from analysis, the corresponding pregnancy rates were 48.8%, 44.6%, 45%, and 40.6% in these 4 groups. The only statistically significant difference was between groups 1 and 4. UROLOGY 73 (4), 2009
The postoperative pregnancy rate correlated negatively with the duration of infertility. The greatest and lowest pregnancy rate was achieved in groups 1 (43.9%) and 4 (31.7%; P ⬍ .05), respectively. When groups 1 and 4 were compared, the pre- and postoperative TMCs had increased from 16.1 ⫾ 1.7 ⫻ 106 to 34.9 ⫾ 3.5 ⫻ 106 and 7.6 ⫾ 0.7 ⫻ 106 to 24.6 ⫾ 1.7 ⫻ 106, respectively. The pregnancy rates and TMCs decreased with an increasing infertility period (Fig. 1). Multivariate analysis revealed that the infertility period was the only factor significantly affecting the achievement of pregnancy.
COMMENT Although the incidence of varicocele in the general male population is approximately 15%, it has been implicated as a factor in about one third of the infertile population.4 Thus, varicocele is a common cause of infertility, but most men with varicoceles can father children and remain asymptomatic. Nevertheless, a statistically significant deterioration in sperm density and motility throughout the follow-up period of untreated varicoceles has been previously docu769
mented.2-4,15 More importantly, histologic changes and atrophy have been demonstrated in the testes associated with varicoceles.3 In the present study, the difference in the preoperative TMCs between groups 1 and 4 and 1 and 3 was significant (P ⬍ .05). Moreover, we detected an inverse correlation between a deterioration in sperm parameters and the duration of the infertility period. On multivariate analysis, including male and female age, varicocele grade, and infertility period, the infertility period was the unique independent factor for the achievement of pregnancy. Therefore, even though the mechanisms affecting the testes in patients with varicocele are ambiguous, it would be rational to consider varicocelectomy early after the diagnosis. However, additional studies with aged-matched control groups are needed to confirm the outcomes obtained from the present study. In a retrospective study, Matkov et al.16 reported that patients with TMCs ⬎5 ⫻ 106 had significant improvement in the seminal parameters after treatment. On the basis of this finding, one would have expected a good response to varicocelectomy for all patients in the present study because the TMCs were ⬎5 ⫻ 106 in all groups. However, after varicocelectomy, the greatest TMCs were achieved in group 1, which had had the greatest preoperative TMC. In contrast, the postvaricocelectomy results correlated negatively with the duration of infertility. Thus, it can be assumed that seminal improvement is better in patients with a shorter infertility period because of less testicular damage. We were also interested in evaluating the correlation between the increases in TMCs and pregnancy rates. The greatest increase in TMCs was encountered in group 3 and the pregnancy rate in this group was 38.3%. Although the increase in the TMC was lower than that in group 3, the pregnancy rate was 43.9% in group 1. Therefore, one could assume that an increase in TMC might not reflect directly on the pregnancy rate in each of these groups and that the duration of infertility is another factor significantly affecting the pregnancy rate. Witt and Lipshultz4 reported that the incidence of varicocele in men with secondary infertility is greater than that of primary infertility. Of 255 of their patients with primary infertility, 50% had a varicocele with no other identifiable abnormalities, and 69% of their patients with secondary infertility had an identifiable varicocele contributing to their fertility. From the outcomes of a prospective randomized study, Madgar et al.17 recommended early varicocelectomy for this group of patients, because they found a pregnancy rate of 60% in patients undergoing immediate varicocelectomy vs 10% in patients who were treated expectantly. In addition, Matkov et al.16 reported that men who achieved a TMC ⬎20 ⫻ 106 were likely to induce pregnancy with lessinvasive techniques. In the present study, we achieved a TMC ⬎20 ⫻ 106 in all groups, and the overall pregnancy rate was 41.3%, which was quite comparable to that in other studies analyzed retrospectively. However, we detected the only statistically significant difference for the 770
pregnancy rate in the groups with an infertility period of 0-3 years (group 1) and ⬎9 years (group 4). Although not significant, the differences between group 1 and groups 2 and 3 were notable. Some recent meta-analyses have concluded that the treatment of varicoceles in male partners of infertile couples does not make any difference in the spontaneous pregnancy rate.18-20 We, and others, believe that in the studies reviewed for the meta-analyses, reliable, randomized, controlled trial data and randomization in the surgical technique were lacking. It has been established that the reference standard for varicocele treatment is a microsurgical technique. In addition, before reporting on the ineffectiveness of varicocele treatment, the outcomes of a wellestablished treatment technique within the principles of evidence-based medicine should be evaluated. The low pregnancy rates in these studies might have resulted from the ineffectiveness of the surgical technique and varicocele recurrence after treatment.21 In a recent meta-analysis with a more precise method, Marmar et al.22 concluded that surgical varicocelectomy is an effective treatment for improving the spontaneous pregnancy rates for couples with an infertile male partner who has poor semen parameters and a palpable varicocele.
CONCLUSIONS The results of the present study have revealed that infertile men with varicoceles have a risk of subsequent deterioration of seminal parameters. Current noninvasive modalities such as semen analysis and measurement of testicular size and serum gonadotropins should be used to identify early changes in testicular physiology caused by a varicocele. The goal of varicocele management is to improve testicular function and the seminal parameters and to increase the likelihood of the ultimate goal (ie, an increased pregnancy rate). From the historical data, we found that the factors associated with improved outcomes after varicocele treatment were larger varicoceles, a lack of testicular atrophy, normal FSH levels, positive gonadotropin-releasing hormone stimulation test, a TMC ⬎5 ⫻ 106, and motility ⬎60%.23 According to our data, the duration of the infertility period should be considered as another predictive factor for a positive seminal response to varicocelectomy and achieving pregnancy. If considering expectant management for patients with varicocele, one should take the duration of the infertility period into account. References 1. Green KF, Turner TT, Howards SS. Varicocele: Reversal of testicular blood flow and temperature effects by varicocele repair. J Urol. 1984;131:1208-1211. 2. Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril. 1993;59:613-616. 3. Saypol DC, Howards SS, Turner TT, et al. Influence of surgically induced varicocele on testicular blood flow, temperature, and histology in adult rats and dogs. J Clin Invest. 1981;68:39-45. 4. Witt MA, Lipshultz LI. Varicocele: A progressive or a static lesion? Urology. 1993;42:541-543.
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5. Hotchkiss RS. Fertility in Men: A Clinical Study of the Causes, Diagnosis, and Treatment of Impaired Fertility in Men. Philadelphia: JB Lippincott; 1944:194-196. 6. Lipshultz LJ, Corriere JN Jr. Progressive testicular atrophy in the varicocele patient. J Urol. 1977;117:175-176. 7. Sayfan J, Soffer Y, Mannor H, et al. Varicocele in youth. Ann Surg. 1988;207:223-226. 8. Okuyama O, Koide T, Itatani H, et al. Pituitary-gonadal function in school boys with varicocele and indications of varicocelectomy. Eur Urol. 1981;7:92-97. 9. Fussell E, Lewis R, Roberts J, et al. Early ultrastructural findings in experimentally induced varicocele in the monkey’s testis. J Androl. 1981;2:111-115. 10. Shafik A, Wall M, Abdel-Azis Y, et al. Experimental model of varicocele. Eur Urol. 1989;16:298-302. 11. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen–Cervical Mucus Interaction, 3rd ed. Cambridge: Cambridge University Press; 1992. 12. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen–Cervical Mucus Interaction, 4th ed. Cambridge: Cambridge University Press; 1999. 13. Çayan S, Erdemir F, Özbey ˙I, et al. Can varicocelectomy significantly change the way couples use assisted reproductive technologies? J Urol. 2002;167:1749-1752. 14. Goldstein M, Gilbert BR, Dicker AP, et al. Microsurgical in guinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. J Urol. 2002;167:1749-1752.
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15. Chehval MJ, Purcell MH. Deterioration of semen parameters over time in men with untreated varicocele: Evidence of progressive testicular damage. Fertil Steril. 1992;57:174-177. 16. Matkov TG, Zenni M, Sandlow J, et al. Preoperative semen analysis as a predictor of seminal improvement following varicocelectomy. Fertil Steril. 2001;75:63-68. 17. Madgar I, Weissenberg R, Lunenfeld B, et al. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril. 1995;63:120-124. 18. Evers JLH, Collins JA, Vandekerckhove P. Surgery of embolisation for varicocele in subfertile men. Cochrane Database Syst Rev. 2001; 1:CD000479. 19. Evers JLH, Collins JA. Assessment of efficacy of varicocele repair for male subfertility: A systematic review. Lancet. 2003;361:18491852. 20. Evers JL, Collins JA. Surgery or embolisation for varicocele in subfertile men. Cochrane Database Syst Rev. 2004;3:CD000479. 21. Ficarra V, Cerruto MA, Liguori G, et al. Treatment of varicocele in subfertile men: The Cochrane Review—A contrary opinion. Eur Urol. 2006;49:258-263. 22. Marmar JE, Agarwal A, Prabakaran S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril. 2007;88:639-648. 23. Fretz PC, Sandlow JI. Varicocele: Current concept in pathophysiology, diagnosis and treatment. Urol Clin North Am. 2002;29:921937.
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