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Does a clinical varicocele influence the relationship between testicular volume by ultrasound and testicular function in patients with infertility?
Does a clinical varicocele influence the relationship between testicular volume by ultrasound and testicular function in patients with infertility? Hideo Sakamoto, M.D., and Yoshio Ogawa, M.D. Department of Urology, Showa University Hospital, Tokyo, Japan
Objective: To determine whether varicocele influences the testicular volume–function relationship. Design: Retrospective clinical study. Setting: University hospital. Patient(s): One hundred fifty infertile patients with varicocele and 299 without varicocele. Intervention(s): Semen analyses, scrotal ultrasound, and serum FSH, LH, and T levels. Main Outcome Measure(s): The mean testicular volume was measured by ultrasound. To evaluate the testicular volume–function relationship in infertile patients with varicocele and in those without varicocele, the patients were divided into seven and 10 groups, respectively, according to the mean testicular volume. Result(s): The semen density, total sperm count, and serum FSH levels significantly correlated with the mean testicular volume in both patient groups, but patients without varicocele had a greater correlation coefficient than those with varicocele. The mean testicular volume with mean sperm densities indicating oligozoospermia was greater in the patients with varicocele than in patients without varicocele (12.5 and 10.0 mL, respectively). The mean testicular volume with mean FSH concentration exceeding the normal range was higher in patients with varicocele (15.0 mL) than in patients without varicocele (12.5 mL). Conclusion(s): The testicular volume–function correlation differed between patients with varicocele and those without varicocele. The presence of varicocele therefore influences the relationship between the testicular volume and the testicular function. (Fertil Steril 2009;92:1632–7. 2009 by American Society for Reproductive Medicine.) Key Words: Varicocele, testicular volume, testicular function
Since the seminiferous tubules make up 70%–80% of the testicular mass, the testicular volume reflects spermatogenesis (1). The testicular volume has shown a relationship with the semen profiles in infertile men, and its measurement has been used to estimate spermatogenesis (2–7). In contrast, a varicocele is found in approximately 15% of the general male population and adolescents, in 30% of men with primary infertility, and in 80% of men with secondary infertility (8). Detrimental effects of varicoceles on testicular volume and catch-up growth of the affected testis after varicocele repair have been reported in adolescents (8). Clinical varicocele may be associated with relative ipsilateral testicular hypotrophy compared with the contralateral testis in adulthood (9– 12). Repair of varicocele may be associated with increased testicular volume (13–17). Therefore, the clinical varicocele may influence the testicular volume–function relationship. While varicoceles are associated with male factor infertility, the causal relationship between varicoceles and subfertility has not been verified (18–22). In addition, few studies have Received April 27, 2008; revised July 29, 2008; accepted August 18, 2008; published online October 20, 2008. H.S. has nothing to disclose. Y.O. has nothing to disclose. Presented at the 99th Annual Meeting of Japanese Urological Association, which was held in Yokohama, Japan, on April 25–27, 2008. Reprint requests: Hideo Sakamoto, M.D., Department of Urology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666 Japan (FAX: 81-3-3784-1400; E-mail: hs-showa-u@med. showa-u.ac.jp).
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so far considered the presence of varicoceles when evaluating the testicular volume–function relationships. This study evaluates whether the presence of varicocele influences the relationship between the testicular function and testicular volume measured by ultrasound.
MATERIALS AND METHODS Infertile patients were defined as a couple who could not conceive a child after 1 year of regular unprotected intercourse. Infertile patients with abnormal semen analyses, testicular volume measurements obtained by ultrasound, the availability of a history, and physical examinations were included in this study. Patients were excluded from this study if they had any apparent pathology influencing their fertility status, such as a ductal obstruction and chromosomal abnormality other than varicocele. In addition, patients with a history of a genitourinary infection and inguinoscrotal surgery were excluded because these factors may influence the testicular volume or semen profiles. Moreover, patients with only a unilateral testis were excluded because of the impossibility of measuring the mean of right and left testicular volume. Therefore, this study included patients with an idiopathic male factor infertility or varicocele. The presence of a clinical varicocele was determined by palpation and observations in the standing position before and during the Valsalva
Fertility and Sterility Vol. 92, No. 5, November 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.08.105
maneuver and confirmed by color Doppler ultrasound. All infertile men with abnormal semen findings underwent scrotal ultrasound with color Doppler imaging to either confirm a clinically diagnosed varicocele or, alternatively, to detect a subclinical varicocele. However, the importance of scrotal ultrasound with color Doppler imaging in male factor infertility practice remains controversial, as does evaluation of subclinical varicocele and testicular volume measurement. Therefore, all patients gave informed consent before scrotal ultrasound with color Doppler imaging. In addition, this retrospective study was performed according to Institutional Review Board guidelines. High-frequency ultrasound with color Doppler imaging was performed by one experienced examiner using 5-, 7.5-, and 10-MHz transducers (ALOKA SSD 2000 and SSD 2400, Tokyo, Japan) with the subjects in a supine position. At least three separate transverse and longitudinal gray scale images of each testis were obtained using light pressure to avoid a distortion of the testicular shape. Testicular length, width, and depth were measured using electronic calipers, excluding the epididymis. The largest measurement obtained for each testicular dimension was used for volume calculation and statistical analysis. The testicular volumes were calculated using the formula, length width depth 0.71, which has been reported to provide the closest estimate of the actual volume (23, 24). A clinical varicocele was confirmed when two or more tortuous dilated veins were identified, reflux flow persisted for more than 1 second based on Doppler color change, and retrograde flow increased in the pampiniform plexus before or during a Valsalva maneuver in either the supine or standing position (25, 26). Semen analyses were performed according to the World Health Organization criteria (27). The semen sample was collected by masturbation after 2–7 days of sexual abstinence. Then it was delivered to the laboratory and analyzed within 1 hour after ejaculation. The semen volume, sperm density, total sperm count, and total motile sperm count were determined. Using blood samples obtained during the morning, serum FSH and LH were measured using chemiluminescent immunoassays. The mean intra- and interassay coefficients of variation were below 5.0% for LH, FSH, and T. To evaluate the relationship between the testicular volume by ultrasound and the testicular function, the testicular volume was obtained from both the right and left testes, and the mean of the right and left testicular volumes was used for the analysis in all patients irrespective of the presence of varicocele. A simple linear regression analysis, a multiple linear regression analysis, Student’s t- test, and the KruskalWallis test were used for statistical analysis. The results are reported as the mean SD. P<.05 was considered statistically significant. RESULTS Among 569 infertile men, 120 were excluded. Of these 120 patients, 47 had a history of a genitourinary infection, 20 Fertility and Sterility
had a history of inguinoscrotal surgery (hernioplasty, n ¼ 12; varicocelectomy, n ¼ 6; scrotal plastic surgery, n ¼ 1; and hydrocelectomy, n ¼ 1), 16 had a ductal obstruction, 12 had an ejaculatory dysfunction, 10 had a history of cryptorchidism, eight had a chromosomal abnormality, four had a history of chemotherapy for a malignant tumor, two had a history of an orchiectomy for unilateral testicular tumor, and one had chronic renal failure. Further analyses were performed in the remaining 449 infertile men (898 testes; mean age SD, 35.9 5.3 years). Of 449 patients, 150 patients had clinical varicoceles (varicocele patients), while 299 had no clinical varicoceles (nonvaricocele patients). In addition, the patients with clinical varicoceles and those without were divided into seven and 10 groups, respectively, thus representing 2.5-mL increments of the mean of the right and left testicular volumes (MTV, Tables 1 and 2). The mean FSH was greater in 299 patients without varicocele than in 150 patients with varicocele (12.4 11.3 vs. 9.5 5.9 mIU/mL, P¼.0034). However, between the 150 varicocele patients and 299 nonvaricocele patients, the mean age (35.6 5.3 and 36.0 5.4 years, respectively; P¼.4992), LH (3.4 1.6 and 3.8 2.7 mIU/mL, respectively; P¼.1627), T (4.3 1.9 and 4.3 2.3 ng/mL, respectively; P¼.9073), abstinence period (5.0 1.6 and 5.0 1.7 days, respectively; P¼.9155), sperm density (29.5 36.2 and 33.2 42.9 106/mL, respectively; P¼.3631), total sperm count (91.9 121.9 and 104.3 161.7 106/mL, respectively; P¼.4109), and MTV (14.1 3.7 and 13.3 5.2 mL, respectively; P¼.0516) did not differ. Moreover, the mean total motile sperm count did not differ between the 147 nonazoospermic patients with varicocele and the 260 nonazoospermic patients without varicocele (31.2 45.8, and 39.4 58.4 106/mL, respectively; P¼.144). The sperm density, total sperm count, and total motile sperm count were significantly correlated with the MTV, but the correlation coefficient was greater in patients without varicocele than in patients with varicocele (Tables 1 and 2). Oligozoospermic mean sperm densities (below 20 106/ mL) were seen in the varicocele patients with an MTV below 12.5 mL and in nonvaricocele patients with an MTV below 10 mL. Subnormal mean total sperm counts (below 40 106/ejaculate) were seen in patients with an MTV below 10 mL in both patient groups. Serum FSH and LH were negatively correlated with the MTV but correlated more strongly with the MTV in nonvaricocele patients than in varicocele patients (Tables 1 and 2). The mean FSH concentration exceeded the normal range in varicocele patients with an MTV below 15 mL and in nonvaricocele patients with an MTV below 12.5 mL. The mean LH concentration exceeded the normal range in patients with an MTV below 7.5 mL in both patient groups. In contrast, the serum T concentration did not correlate with the MTV in either group, and the mean concentrations were normal in all groups. In all 449 patients, a multiple regression analysis was performed between a response variable (one of parameters of 1633
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TABLE 1 Relationship between the mean testicular volume measured by ultrasound and the testicular function in 299 patients without clinical varicocele.
Varicocele and testicular function
Group A B C D E F G H I J Pb Correlation coefficient for MTV Pc
Total sperm count, 3106/ ejaculate
Total motile sperm count, 3106/ ejaculate
MTV, mL
No. of patientsa
FSH, mIU/mL
LH, mIU/mL
T, ng/mL
Sperm density, 3106/mL
<5 5–7.5 7.5–10 10–12.5 12.5–15 15–17.5 17.5–20 20–22.5 22.5–25 R25
15 (6) 22 (13) 52 (40) 52 (47) 63 (61) 40 (38) 25 (25) 16 (16) 8 (8) 6 (6)
39.2 17.5 26.6 11.7 17.9 9.7 11.1 6.1 7.8 3.8 6.2 3.3 4.9 2.2 5.9 2.1 4.8 1.9 3.2 1.3 < .0001 0.65
9.6 5.7 6.5 3.6 4.1 2.0 3.6 1.5 3.0 1.6 2.6 1.1 2.4 1.1 2.9 1.4 2.8 1.1 2.4 0.9 < .0001 0.473
3.7 1.3 3.7 1.2 4.1 1.4 4.7 1.6 4.3 1.9 4.4 1.6 4.2 1.4 4.6 1.1 4.7 0.7 3.9 0.9 .1451 0.101
1.6 5.0 3.3 6.2 10.3 16.1 20.4 27.4 39.4 41.7 49.2 40.4 60.5 54.6 79.9 58.9 52.5 38.2 95.3 73.5 < .0001 0.521
4.2 11.3 8.9 18.8 32.7 50.3 57.7 72.3 101.3 99.2 179.8 202.4 177.5 192.1 237.9 227.4 245.4 210.1 405.7 475.4 < .0001 0.498
4.1 6.7 5.3 11.4 14.9 24.6 21.9 29.2 31.5 36.1 63.3 83.8 70.7 88.7 65.6 59.3 84.6 72.2 115.3 79.0 < .0001 0.409
< .0001
< .0001
.0805
< .0001
< .0001
< .0001
Vol. 92, No. 5, November 2009
Note: FSH normal range, 2.9–8.2 mIU/mL; LH normal range, 1.8–5.2 mIU/mL; T normal range, 2.7–10.7 ng/mL. a The number of patients without azoospermia evaluated for total motile sperm count are shown in parentheses. b The Kruskal-Wallis test was used among 10 testicular volume groups. c Simple linear regression was used to evaluate the relationship between the mean testicular volume and each of the parameters for the testicular function. Sakamoto. Varicocele and testicular function. Fertil Steril 2009.
Fertility and Sterility
TABLE 2 Relationship between the mean testicular volume measured by ultrasound and the testicular function in 150 patients with a left clinical varicocele.
Group A B C D E F G Pb Correlation coefficient for MTV Pc
Total sperm count, 3106/ ejaculate
Total motile sperm count, 3106/ ejaculate
MTV, mL
No. of patientsa
FSH, mIU/mL
LH, mIU/mL
T, ng/mL
Sperm density, 3106/mL
5–7.5 7.5–10 10–12.5 12.5–15 15–17.5 17.5–20 20–22.5
5 (4) 19 (18) 34 (33) 32 (32) 29 (29) 21 (21) 10 (10)
27.3 10.4 13.4 6.2 10.6 4.2 8.7 4.1 6.4 2.8 6.5 3.0 6.9 3.3 < .0001 0.561
5.4 1.8 3.6 1.9 3.7 1.5 3.3 1.5 3.3 1.6 2.8 1.2 3.3 1.6 .1165 0.219
3.9 1.4 4.7 0.9 4.3 1.6 4.4 1.5 4.4 1.3 4.1 1.3 4.0 1.2 .517 0.093
8.6 11.0 14.2 20.5 17.7 26.6 29.4 31.8 32.4 40.2 44.9 31.0 68.3 64.0 < .0001 0.398
23.2 30.3 39.3 49.9 57.4 80.6 80.4 85.5 101.3 123.2 133.4 92.9 260.9 273.1 < .0001 0.411
15.6 16.8 13.1 19.5 17.5 21.3 29.3 39.8 28.8 36.8 52.8 56.8 83.0 95.6 .0005 0.367
< .0001
.0071
.26
< .0001
< .0001
< .0001
Note: Of 150 patients, 139 had a left clinical varicocele and 11 had right and left clinical varicoceles. a The number of patients without azoospermia evaluated for total motile sperm count are shown in parentheses. b The Kruskal-Wallis test was used among seven testicular volume groups. c Simple linear regression was used to evaluate the relationship between the mean testicular volume and each of the parameters for the testicular function. Sakamoto. Varicocele and testicular function. Fertil Steril 2009.
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testicular function) and two explanatory variables (MTV and presence of varicocele) to confirm whether the correlation coefficients of both patient groups were significantly different, and it showed that the presence of varicocele significantly and independently was related to FSH levels, sperm density, and total sperm count (Table 3).
DISCUSSION Testicular volume as measured by either Prader orchidometry, a punched-out orchidometer, or ultrasound is significantly correlated with the testicular function, including the sperm density, total sperm count, and serum FSH and LH (2–7, 28). While a cutoff value for testicular volume indicating normal testicular function has not been established, previous studies using a punched-out orchidometer showed that the critical MTV was 14 mL (5) and that the critical total testicular volume was 30 mL (6). A recent study showed that the critical total testicular volume using a Prader orchidometer and using the ultrasound formula length width depth 0.71 was 30–35 and 20 mL, respectively (7). Thus, the relationship between the testicular volume and testicular function is well-known. In contrast, approximately one-third of the infertile men had a clinical varicocele, and the relationship between clinical varicoceles and ipsilateral testicular hypotrophy has also been described (9–12). Moreover, testicular volumes may increase after varicocele repair with and without improvement of semen parameters (13– 17). Therefore, varicoceles may influence the relationship between testicular volume and testicular function. However, few evaluations of the testicular volume–function relationship have considered the presence of varicoceles. In addition, there is no consensus on the relationship between varicoceles and fertility (18). Moreover, recent studies reported that varicocele repair was not an effective treatment in infertile men (19–22). Therefore, the relationship between the testicular function and testicular volume was evaluated in infertile men with and without varicoceles to determine whether varicoceles influence the testicular volume–function relationship. In addition, testicular volume was measured using the most accurate ultrasound formula (length width depth 0.71) to correctly evaluate the testicular volume–function relationship (23, 24). In this study, the sperm density, total sperm count, total motile sperm count, and serum FSH and LH significantly correlated with the mean testicular volume in both varicocele patients and nonvaricocele patients, but the correlation coefficients in patients without varicoceles were greater than those in patients with varicoceles. Moreover, the mean serum FSH concentration was significantly greater in the nonvaricocele patients than in the varicocele patients, and the mean MTV tended to be greater in varicocele patients than in nonvaricocele patients. However, the mean sperm density and total sperm count did not differ between the two patient groups. In addition, oligozoospermic mean sperm densities were seen in the varicocele patients with an MTV below 12.5 mL and in nonvaricocele patients with an MTV below 10 1636
Sakamoto and Ogawa
TABLE 3 Influence of the varicocele to relationship between the mean testicular volume and the testicular function in 449 infertile patients. Explanatory variable
Response variable
MTV, regression coefficient (P)a
Presence of varicocele, regression coefficient (P)a
FSH LH SD TSC TMSC
1.302 (< .0001) 0.213 (< .0001) 4.188 (< .0001) 15.0 (< .0001) 4.73 (< .0001)
1.687 (.0288) 0.134 (.5352) 7.629 (.0333) 26.897 (.0429) 9.377 (.0688)
a
Analyzed by multiple linear regressions analysis between a response variable and two explanatory variables.
Sakamoto. Varicocele and testicular function. Fertil Steril 2009.
mL. The mean FSH concentration exceeded the normal range in varicocele patients with an MTV below 15 mL and in nonvaricocele patients with an MTV below 12.5 mL. Moreover, mean sperm densities above 40 106/mL, which is reported to be the threshold between subfertile men and fertile men, were seen in the varicocele patients with an MTV below 17.5 mL and in the nonvaricocele patients with an MTV below 15 mL (29). The present study showed the presence of varicocele to be independently related to the FSH levels, sperm density, and total sperm count. Therefore, these findings suggest that a varicocele influences the testicular volume–function relationship in infertile patients. Testicular function, especially the seminiferous tubule function, in varicocele patients may be impaired at a greater testicular volume and a lower serum FSH level than that in nonvaricocele patients. In contrast, our previous study showed the testicular function, including the serum FSH and sperm density, to not differ between infertile varicocele patients with and without ipsilateral testicular hypotrophy (12). These findings suggest that testicular hypotrophy due to varicocele may not indicate an early impairment of the testicular function by varicocele. An impairment of spermatogenesis may therefore begin before the occurrence of ipsilateral testicular hypotrophy. However, this study did not reflect the relationship between varicoceles and the fertility potential for achieving a pregnancy and did not justify the effectiveness of varicocele repair as an infertility treatment. In addition, the small number of patients and the difference in the patient distribution for both the varicocele and nonvaricocele groups may have influenced the results of this study. Further studies are required to confirm the influence of varicoceles on the relationship between testicular volume and testicular function.
Varicocele and testicular function
Vol. 92, No. 5, November 2009
In the present study, the testicular volume–function relationship was found to be different between the patients with varicocele and those without varicocele. The presence of a varicocele therefore influences the relationship between the testicular volume and the testicular function, especially regarding the seminiferous tubule function. REFERENCES 1. Setchell BP, Brooks DE. Anatomy, vasculature, innervation and fluids of the male reproductive tract. In: Knobil E, Neill JD, eds. The Physiology of Reproduction. New York: Raven Press, 1988:753–836. 2. Lenz S, Thomsen JK, Giwercman A, Hertel NT, Hertz J, Skakkebæk NE. Ultrasonic texture and volume of testicles in infertile men. Hum Reprod 1994;9:878–81. 3. Bujan L, Mieusset R, Mansat A, Moatti JP, Mondinat C, Pontonnier F. Testicular size in infertile men: relationship to semen characteristics and hormonal blood levels. Br J Urol 1989;64:632–7. 4. Takihara H, Sakatoku J, Fujii M, Nasu T, Cosentino MJ, Cockett ATK. Significance of testicular size measurement in andrology. I. A new orchidometer and its clinical application. Fertil Steril 1983;39:836–40. 5. Takihara H, Cosentino MJ, Sakatoku J, Cockett ATK. Significance of testicular size measurement in andrology. II. Correlation of testicular size with testicular function. J Urol 1987;137:416–9. 6. Arai T, Kitahara S, Horiuchi S, Sumi S, Yoshida K. Relationship of testicular volume to semen profiles and serum hormone concentrations in infertile Japanese males. Int J Fertil Womens Med 1998;43:40–7. 7. Sakamoto H, Ogawa Y, Yoshida H. Relationship between testicular volume and testicular function: comparison of the Prader orchidometetric and ultrasonographic measurements in patients with infertility. Asian J Androl 2008;10:319–24. 8. Jarow JP. Effects of varicocele on male fertility. Hum Reprod Update 2001;7:59–64. 9. World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril 1992;57:1289–93. 10. Sigman M, Jarow JP. Ipsilateral testicular hypotrophy is associated with decreased sperm counts in infertile men with varicoceles. J Urol 1997;158:605–7. 11. Zini A, Buckspan M, Berardinucci D, Jarvi K. The influence of clinical and subclinical varicocele on testicular volume. Fertil Steril 1997;68: 671–4. 12. Sakamoto H, Ogawa Y, Yoshida H. Relationship between testicular volume and varicocele in patients with infertility. Urology 2008;71:104–9.
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13. Gentile DP, Cockett ATK. The effect of varicocelectomy on testicular volume in 89 fertile adult males with varicoceles. Fertil Steril 1992;58: 756–62. 14. C ¸ ulha M, Mutlu N, Acar O, Baykal M. Comparison of testicular volumes before and after varicocelectomy. Urol Int 1998;60:220–3. 15. Pasqualotto FF, Lucon AM, de Goes PM, Hallak J, Sobreiro B, Pasqualotto EB, et al. Testicular growth, sperm concentration, percent motility, and pregnancy outcome after varicocelectomy based on testicular histology. Fertil Steril 2005;83:362–6. 16. Zucchi A, Mearini L, Mearini E, Fioretti F, Bini V, Porena M. Varicocele and fertility: relationship between testicular volume and seminal parameters before and after treatment. J Androl 2006;27:548–51. 17. Sakamoto H, Katsuyuki S, Ogawa Y, Yoshida H. Effects of varicocele repair in adults on ultrasonographically determined testicular volume and on semen profile. Urology 2008;71:485–9. 18. Silber SJ. The varicocele dilemma. Hum Reprod Update 2001;7:70–1. 19. Kamischke A, Nieschlag E. Varicocele treatment in the light of evidencebased andrology. Hum Reprod Update 2001;7:65–9. 20. Nieschlag E, Hertle L, Fischedick A, Abshagen K, Behre HM. Update on treatment of varicocele: counselling as effective as occlusion of the vena spermatica. Hum Reprod 1998;13:2147–50. 21. Evers JLH, Collins JA. Assessment of efficacy of varicocele repair for male subfertility: a systematic review. Lancet 2003;361:1849–52. 22. Evers JL, Collins JA. Surgery or embolization for varicocele in subfertile men. Cochrane Database Syst Rev 2004;3:CD000479. 23. Sakamoto H, Saito K, Oohta M, Inoue K, Ogawa Y, Yoshida H. Testicular volume measurement: comparison of ultrasonography, orchidometry, and water displacement. Urology 2007;69:152–7. 24. Paltiel HJ, Diamond DA, Di Canzio J, Zurakowski D, Borer JG, Atala A. Testicular volume: comparison of orchidometer and US measurements in dogs. Radiology 2002;222:114–9. 25. Trum JW, Gubler FM, Laan R, van der Veen F. The value of palpation, varicoscreen contact thermography and colour Doppler ultrasound in the diagnosis of varicocele. Hum Reprod 1996;11:1232–5. 26. Cornud F, Amar E, Hamida K, Helenon O, Moreau JF. Ultrasound findings in male hypofertility and impotence. Eur Radiol 2001;11:2126–36. 27. World Health Organization. Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th. Cambridge, UK: Cambridge University Press, Cambridge, 1999. 28. Prader A. Testicular size: assessment and clinical importance. Triangle 1966;7:240–3. 29. Bonde JPE, Ernst E, Jensen TK, Hjollund NHI, Kolstad H, Henriksen TB, et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998;352: 1172–7.
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Objective: To determine whether varicocele influences the testicular volume–function relationship. Design: Retrospective clinical study. Setting: University hospital. Patient(s): One hundred fifty infertile patients with varicocele and 299 without varicocele. Intervention(s): Semen analyses, scrotal ultrasound, and serum FSH, LH, and T levels. Main Outcome Measure(s): The mean testicular volume was measured by ultrasound. To evaluate the testicular volume–function relationship in infertile patients with varicocele and in those without varicocele, the patients were divided into seven and 10 groups, respectively, according to the mean testicular volume. Result(s): The semen density, total sperm count, and serum FSH levels significantly correlated with the mean testicular volume in both patient groups, but patients without varicocele had a greater correlation coefficient than those with varicocele. The mean testicular volume with mean sperm densities indicating oligozoospermia was greater in the patients with varicocele than in patients without varicocele (12.5 and 10.0 mL, respectively). The mean testicular volume with mean FSH concentration exceeding the normal range was higher in patients with varicocele (15.0 mL) than in patients without varicocele (12.5 mL). Conclusion(s): The testicular volume–function correlation differed between patients with varicocele and those without varicocele. The presence of varicocele therefore influences the relationship between the testicular volume and the testicular function. (Fertil Steril 2009;92:1632–7. 2009 by American Society for Reproductive Medicine.) Key Words: Varicocele, testicular volume, testicular function
Since the seminiferous tubules make up 70%–80% of the testicular mass, the testicular volume reflects spermatogenesis (1). The testicular volume has shown a relationship with the semen profiles in infertile men, and its measurement has been used to estimate spermatogenesis (2–7). In contrast, a varicocele is found in approximately 15% of the general male population and adolescents, in 30% of men with primary infertility, and in 80% of men with secondary infertility (8). Detrimental effects of varicoceles on testicular volume and catch-up growth of the affected testis after varicocele repair have been reported in adolescents (8). Clinical varicocele may be associated with relative ipsilateral testicular hypotrophy compared with the contralateral testis in adulthood (9– 12). Repair of varicocele may be associated with increased testicular volume (13–17). Therefore, the clinical varicocele may influence the testicular volume–function relationship. While varicoceles are associated with male factor infertility, the causal relationship between varicoceles and subfertility has not been verified (18–22). In addition, few studies have Received April 27, 2008; revised July 29, 2008; accepted August 18, 2008; published online October 20, 2008. H.S. has nothing to disclose. Y.O. has nothing to disclose. Presented at the 99th Annual Meeting of Japanese Urological Association, which was held in Yokohama, Japan, on April 25–27, 2008. Reprint requests: Hideo Sakamoto, M.D., Department of Urology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666 Japan (FAX: 81-3-3784-1400; E-mail: hs-showa-u@med. showa-u.ac.jp).
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so far considered the presence of varicoceles when evaluating the testicular volume–function relationships. This study evaluates whether the presence of varicocele influences the relationship between the testicular function and testicular volume measured by ultrasound.
MATERIALS AND METHODS Infertile patients were defined as a couple who could not conceive a child after 1 year of regular unprotected intercourse. Infertile patients with abnormal semen analyses, testicular volume measurements obtained by ultrasound, the availability of a history, and physical examinations were included in this study. Patients were excluded from this study if they had any apparent pathology influencing their fertility status, such as a ductal obstruction and chromosomal abnormality other than varicocele. In addition, patients with a history of a genitourinary infection and inguinoscrotal surgery were excluded because these factors may influence the testicular volume or semen profiles. Moreover, patients with only a unilateral testis were excluded because of the impossibility of measuring the mean of right and left testicular volume. Therefore, this study included patients with an idiopathic male factor infertility or varicocele. The presence of a clinical varicocele was determined by palpation and observations in the standing position before and during the Valsalva
Fertility and Sterility Vol. 92, No. 5, November 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.08.105
maneuver and confirmed by color Doppler ultrasound. All infertile men with abnormal semen findings underwent scrotal ultrasound with color Doppler imaging to either confirm a clinically diagnosed varicocele or, alternatively, to detect a subclinical varicocele. However, the importance of scrotal ultrasound with color Doppler imaging in male factor infertility practice remains controversial, as does evaluation of subclinical varicocele and testicular volume measurement. Therefore, all patients gave informed consent before scrotal ultrasound with color Doppler imaging. In addition, this retrospective study was performed according to Institutional Review Board guidelines. High-frequency ultrasound with color Doppler imaging was performed by one experienced examiner using 5-, 7.5-, and 10-MHz transducers (ALOKA SSD 2000 and SSD 2400, Tokyo, Japan) with the subjects in a supine position. At least three separate transverse and longitudinal gray scale images of each testis were obtained using light pressure to avoid a distortion of the testicular shape. Testicular length, width, and depth were measured using electronic calipers, excluding the epididymis. The largest measurement obtained for each testicular dimension was used for volume calculation and statistical analysis. The testicular volumes were calculated using the formula, length width depth 0.71, which has been reported to provide the closest estimate of the actual volume (23, 24). A clinical varicocele was confirmed when two or more tortuous dilated veins were identified, reflux flow persisted for more than 1 second based on Doppler color change, and retrograde flow increased in the pampiniform plexus before or during a Valsalva maneuver in either the supine or standing position (25, 26). Semen analyses were performed according to the World Health Organization criteria (27). The semen sample was collected by masturbation after 2–7 days of sexual abstinence. Then it was delivered to the laboratory and analyzed within 1 hour after ejaculation. The semen volume, sperm density, total sperm count, and total motile sperm count were determined. Using blood samples obtained during the morning, serum FSH and LH were measured using chemiluminescent immunoassays. The mean intra- and interassay coefficients of variation were below 5.0% for LH, FSH, and T. To evaluate the relationship between the testicular volume by ultrasound and the testicular function, the testicular volume was obtained from both the right and left testes, and the mean of the right and left testicular volumes was used for the analysis in all patients irrespective of the presence of varicocele. A simple linear regression analysis, a multiple linear regression analysis, Student’s t- test, and the KruskalWallis test were used for statistical analysis. The results are reported as the mean SD. P<.05 was considered statistically significant. RESULTS Among 569 infertile men, 120 were excluded. Of these 120 patients, 47 had a history of a genitourinary infection, 20 Fertility and Sterility
had a history of inguinoscrotal surgery (hernioplasty, n ¼ 12; varicocelectomy, n ¼ 6; scrotal plastic surgery, n ¼ 1; and hydrocelectomy, n ¼ 1), 16 had a ductal obstruction, 12 had an ejaculatory dysfunction, 10 had a history of cryptorchidism, eight had a chromosomal abnormality, four had a history of chemotherapy for a malignant tumor, two had a history of an orchiectomy for unilateral testicular tumor, and one had chronic renal failure. Further analyses were performed in the remaining 449 infertile men (898 testes; mean age SD, 35.9 5.3 years). Of 449 patients, 150 patients had clinical varicoceles (varicocele patients), while 299 had no clinical varicoceles (nonvaricocele patients). In addition, the patients with clinical varicoceles and those without were divided into seven and 10 groups, respectively, thus representing 2.5-mL increments of the mean of the right and left testicular volumes (MTV, Tables 1 and 2). The mean FSH was greater in 299 patients without varicocele than in 150 patients with varicocele (12.4 11.3 vs. 9.5 5.9 mIU/mL, P¼.0034). However, between the 150 varicocele patients and 299 nonvaricocele patients, the mean age (35.6 5.3 and 36.0 5.4 years, respectively; P¼.4992), LH (3.4 1.6 and 3.8 2.7 mIU/mL, respectively; P¼.1627), T (4.3 1.9 and 4.3 2.3 ng/mL, respectively; P¼.9073), abstinence period (5.0 1.6 and 5.0 1.7 days, respectively; P¼.9155), sperm density (29.5 36.2 and 33.2 42.9 106/mL, respectively; P¼.3631), total sperm count (91.9 121.9 and 104.3 161.7 106/mL, respectively; P¼.4109), and MTV (14.1 3.7 and 13.3 5.2 mL, respectively; P¼.0516) did not differ. Moreover, the mean total motile sperm count did not differ between the 147 nonazoospermic patients with varicocele and the 260 nonazoospermic patients without varicocele (31.2 45.8, and 39.4 58.4 106/mL, respectively; P¼.144). The sperm density, total sperm count, and total motile sperm count were significantly correlated with the MTV, but the correlation coefficient was greater in patients without varicocele than in patients with varicocele (Tables 1 and 2). Oligozoospermic mean sperm densities (below 20 106/ mL) were seen in the varicocele patients with an MTV below 12.5 mL and in nonvaricocele patients with an MTV below 10 mL. Subnormal mean total sperm counts (below 40 106/ejaculate) were seen in patients with an MTV below 10 mL in both patient groups. Serum FSH and LH were negatively correlated with the MTV but correlated more strongly with the MTV in nonvaricocele patients than in varicocele patients (Tables 1 and 2). The mean FSH concentration exceeded the normal range in varicocele patients with an MTV below 15 mL and in nonvaricocele patients with an MTV below 12.5 mL. The mean LH concentration exceeded the normal range in patients with an MTV below 7.5 mL in both patient groups. In contrast, the serum T concentration did not correlate with the MTV in either group, and the mean concentrations were normal in all groups. In all 449 patients, a multiple regression analysis was performed between a response variable (one of parameters of 1633
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TABLE 1 Relationship between the mean testicular volume measured by ultrasound and the testicular function in 299 patients without clinical varicocele.
Varicocele and testicular function
Group A B C D E F G H I J Pb Correlation coefficient for MTV Pc
Total sperm count, 3106/ ejaculate
Total motile sperm count, 3106/ ejaculate
MTV, mL
No. of patientsa
FSH, mIU/mL
LH, mIU/mL
T, ng/mL
Sperm density, 3106/mL
<5 5–7.5 7.5–10 10–12.5 12.5–15 15–17.5 17.5–20 20–22.5 22.5–25 R25
15 (6) 22 (13) 52 (40) 52 (47) 63 (61) 40 (38) 25 (25) 16 (16) 8 (8) 6 (6)
39.2 17.5 26.6 11.7 17.9 9.7 11.1 6.1 7.8 3.8 6.2 3.3 4.9 2.2 5.9 2.1 4.8 1.9 3.2 1.3 < .0001 0.65
9.6 5.7 6.5 3.6 4.1 2.0 3.6 1.5 3.0 1.6 2.6 1.1 2.4 1.1 2.9 1.4 2.8 1.1 2.4 0.9 < .0001 0.473
3.7 1.3 3.7 1.2 4.1 1.4 4.7 1.6 4.3 1.9 4.4 1.6 4.2 1.4 4.6 1.1 4.7 0.7 3.9 0.9 .1451 0.101
1.6 5.0 3.3 6.2 10.3 16.1 20.4 27.4 39.4 41.7 49.2 40.4 60.5 54.6 79.9 58.9 52.5 38.2 95.3 73.5 < .0001 0.521
4.2 11.3 8.9 18.8 32.7 50.3 57.7 72.3 101.3 99.2 179.8 202.4 177.5 192.1 237.9 227.4 245.4 210.1 405.7 475.4 < .0001 0.498
4.1 6.7 5.3 11.4 14.9 24.6 21.9 29.2 31.5 36.1 63.3 83.8 70.7 88.7 65.6 59.3 84.6 72.2 115.3 79.0 < .0001 0.409
< .0001
< .0001
.0805
< .0001
< .0001
< .0001
Vol. 92, No. 5, November 2009
Note: FSH normal range, 2.9–8.2 mIU/mL; LH normal range, 1.8–5.2 mIU/mL; T normal range, 2.7–10.7 ng/mL. a The number of patients without azoospermia evaluated for total motile sperm count are shown in parentheses. b The Kruskal-Wallis test was used among 10 testicular volume groups. c Simple linear regression was used to evaluate the relationship between the mean testicular volume and each of the parameters for the testicular function. Sakamoto. Varicocele and testicular function. Fertil Steril 2009.
Fertility and Sterility
TABLE 2 Relationship between the mean testicular volume measured by ultrasound and the testicular function in 150 patients with a left clinical varicocele.
Group A B C D E F G Pb Correlation coefficient for MTV Pc
Total sperm count, 3106/ ejaculate
Total motile sperm count, 3106/ ejaculate
MTV, mL
No. of patientsa
FSH, mIU/mL
LH, mIU/mL
T, ng/mL
Sperm density, 3106/mL
5–7.5 7.5–10 10–12.5 12.5–15 15–17.5 17.5–20 20–22.5
5 (4) 19 (18) 34 (33) 32 (32) 29 (29) 21 (21) 10 (10)
27.3 10.4 13.4 6.2 10.6 4.2 8.7 4.1 6.4 2.8 6.5 3.0 6.9 3.3 < .0001 0.561
5.4 1.8 3.6 1.9 3.7 1.5 3.3 1.5 3.3 1.6 2.8 1.2 3.3 1.6 .1165 0.219
3.9 1.4 4.7 0.9 4.3 1.6 4.4 1.5 4.4 1.3 4.1 1.3 4.0 1.2 .517 0.093
8.6 11.0 14.2 20.5 17.7 26.6 29.4 31.8 32.4 40.2 44.9 31.0 68.3 64.0 < .0001 0.398
23.2 30.3 39.3 49.9 57.4 80.6 80.4 85.5 101.3 123.2 133.4 92.9 260.9 273.1 < .0001 0.411
15.6 16.8 13.1 19.5 17.5 21.3 29.3 39.8 28.8 36.8 52.8 56.8 83.0 95.6 .0005 0.367
< .0001
.0071
.26
< .0001
< .0001
< .0001
Note: Of 150 patients, 139 had a left clinical varicocele and 11 had right and left clinical varicoceles. a The number of patients without azoospermia evaluated for total motile sperm count are shown in parentheses. b The Kruskal-Wallis test was used among seven testicular volume groups. c Simple linear regression was used to evaluate the relationship between the mean testicular volume and each of the parameters for the testicular function. Sakamoto. Varicocele and testicular function. Fertil Steril 2009.
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testicular function) and two explanatory variables (MTV and presence of varicocele) to confirm whether the correlation coefficients of both patient groups were significantly different, and it showed that the presence of varicocele significantly and independently was related to FSH levels, sperm density, and total sperm count (Table 3).
DISCUSSION Testicular volume as measured by either Prader orchidometry, a punched-out orchidometer, or ultrasound is significantly correlated with the testicular function, including the sperm density, total sperm count, and serum FSH and LH (2–7, 28). While a cutoff value for testicular volume indicating normal testicular function has not been established, previous studies using a punched-out orchidometer showed that the critical MTV was 14 mL (5) and that the critical total testicular volume was 30 mL (6). A recent study showed that the critical total testicular volume using a Prader orchidometer and using the ultrasound formula length width depth 0.71 was 30–35 and 20 mL, respectively (7). Thus, the relationship between the testicular volume and testicular function is well-known. In contrast, approximately one-third of the infertile men had a clinical varicocele, and the relationship between clinical varicoceles and ipsilateral testicular hypotrophy has also been described (9–12). Moreover, testicular volumes may increase after varicocele repair with and without improvement of semen parameters (13– 17). Therefore, varicoceles may influence the relationship between testicular volume and testicular function. However, few evaluations of the testicular volume–function relationship have considered the presence of varicoceles. In addition, there is no consensus on the relationship between varicoceles and fertility (18). Moreover, recent studies reported that varicocele repair was not an effective treatment in infertile men (19–22). Therefore, the relationship between the testicular function and testicular volume was evaluated in infertile men with and without varicoceles to determine whether varicoceles influence the testicular volume–function relationship. In addition, testicular volume was measured using the most accurate ultrasound formula (length width depth 0.71) to correctly evaluate the testicular volume–function relationship (23, 24). In this study, the sperm density, total sperm count, total motile sperm count, and serum FSH and LH significantly correlated with the mean testicular volume in both varicocele patients and nonvaricocele patients, but the correlation coefficients in patients without varicoceles were greater than those in patients with varicoceles. Moreover, the mean serum FSH concentration was significantly greater in the nonvaricocele patients than in the varicocele patients, and the mean MTV tended to be greater in varicocele patients than in nonvaricocele patients. However, the mean sperm density and total sperm count did not differ between the two patient groups. In addition, oligozoospermic mean sperm densities were seen in the varicocele patients with an MTV below 12.5 mL and in nonvaricocele patients with an MTV below 10 1636
Sakamoto and Ogawa
TABLE 3 Influence of the varicocele to relationship between the mean testicular volume and the testicular function in 449 infertile patients. Explanatory variable
Response variable
MTV, regression coefficient (P)a
Presence of varicocele, regression coefficient (P)a
FSH LH SD TSC TMSC
1.302 (< .0001) 0.213 (< .0001) 4.188 (< .0001) 15.0 (< .0001) 4.73 (< .0001)
1.687 (.0288) 0.134 (.5352) 7.629 (.0333) 26.897 (.0429) 9.377 (.0688)
a
Analyzed by multiple linear regressions analysis between a response variable and two explanatory variables.
Sakamoto. Varicocele and testicular function. Fertil Steril 2009.
mL. The mean FSH concentration exceeded the normal range in varicocele patients with an MTV below 15 mL and in nonvaricocele patients with an MTV below 12.5 mL. Moreover, mean sperm densities above 40 106/mL, which is reported to be the threshold between subfertile men and fertile men, were seen in the varicocele patients with an MTV below 17.5 mL and in the nonvaricocele patients with an MTV below 15 mL (29). The present study showed the presence of varicocele to be independently related to the FSH levels, sperm density, and total sperm count. Therefore, these findings suggest that a varicocele influences the testicular volume–function relationship in infertile patients. Testicular function, especially the seminiferous tubule function, in varicocele patients may be impaired at a greater testicular volume and a lower serum FSH level than that in nonvaricocele patients. In contrast, our previous study showed the testicular function, including the serum FSH and sperm density, to not differ between infertile varicocele patients with and without ipsilateral testicular hypotrophy (12). These findings suggest that testicular hypotrophy due to varicocele may not indicate an early impairment of the testicular function by varicocele. An impairment of spermatogenesis may therefore begin before the occurrence of ipsilateral testicular hypotrophy. However, this study did not reflect the relationship between varicoceles and the fertility potential for achieving a pregnancy and did not justify the effectiveness of varicocele repair as an infertility treatment. In addition, the small number of patients and the difference in the patient distribution for both the varicocele and nonvaricocele groups may have influenced the results of this study. Further studies are required to confirm the influence of varicoceles on the relationship between testicular volume and testicular function.
Varicocele and testicular function
Vol. 92, No. 5, November 2009
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