VARICOCELECTOMY IN THE SUBFERTILE MALE: A TEN-YEAR EXPERIENCE WITH 295 CASES*

FERTILITY AND STERILITY Copyright 1976 The American Fertility Society Vol. 27, No.9, September 1976 Printed in U.S A. VARICOCELECTOMY IN THE SUBFERTILE MALE: A TEN-YEAR EXPERIENCE WITH 295 CASES* JORDAN S. BROWN, M.D.t Department of Urology, New York University School of Medicine, New York, New York 10016 During a 1 0-year period 295 varicocelectomies were performed in sub fertile males. Results of follow-up studies indicate the following: (1) Semen quality improved in a meaningful manner in 58% of men following varicocelectomy. The improvement, except at times for motility, was often only modest. The semen improved in 46% of men with a preoperative average count of less than 10 million/ml and in 70% whose count was 10 million/ml or more. (2) The stress pattern of sperm morphology was seen prior to surgery in 93% of the men. (3) The pregnancy rate for the entire series was about 41%. Men with a preoperative count of 10 million!ml or more achieved a 48% conception rate and those with a count of less than 10 million!ml succeeded 35% of the time. Only 7% of the pregnancies occurred without a concomitant improvement in the semen quality. ( 4) Men with moderate- and large-sized left varicoceles fared better than those with small-sized varicoceles. (5) Varicocelectomy, when varicocele and poor semen quality coexist, is a justified procedure in the treatment of the infertile couple. Varicocele is potentially detrimental to the male reproductive state and is a common cause of male infertility.1 Varicocelectomy has been reported to restore impaired spermatogenesis and to result in desired progeny. 2 5 Currently, varicocelectomy is the most effective therapeutic modality in the field of male infertility. V aricoceles occur more commonly in subfertile males than in a fertile population.6 7 In a prospective study, 8 63% of 93 unmarried air force inductees who had varicoceles and permitted semen analysis were found to be subfertile. Macomber and Sanders 9 in 1929 and Wilhelm10 in 1937 were among the earliest Accepted April 15, 1976. *Presented at the Thirty-Second Annual Meeting of The American Fertility Society, April 5 to 9, 1976, Las Vegas, Nev. treprint requests: Dr. Jordan S. Brown, 566 First Avenue, New York, N.Y. 10016. to report favorable results following varicocelectomy. The British in the 1950s and early 1960s should be credited with further establishing and popularizing this effective procedure. 11 13 Varicocele, a pathologic alteration in the venous anatomy of the testes, appears almost exclusively on the left. The left internal spermatic venous system, unlike the right, regularly terminates in the renal vein. These veins normally contain competent valves14 which prevent the retrograde flow of blood. When these valves are congenitally absent or become incompetent, the renal vein blood flows abnormally down into the scrotum and, by means of cross-collateral communications, into the contralateral testicular circulation.15 16 These collateral vessels were first demonstrated in patients in 1966 by means of venography. 16 The presence of these vessels helps to estab- 1046

, Vol. 27, No.9 VARICOCELECTOMY IN THE SUBFERTILE MALE 1047 lish the bilaterality of this seemingly unilateral venous abnormality. ~ The mechanism by which the varicocele-like state impairs spermatogenesis continues to remain elusive. The postulation that varicocele adversely affects spermatogenesis by significantly elevating the testicular temperature is not as yet cona vincingy 18 The attitude that a toxic metabolic or endocrine substance passing in the retrogressing blood is responsible remains an attractive, but still unproven, premise. 19-22 MATERIALS AND METHODS During a 10-year period (January 1965 through December 1974), 295 varicocelectomies were performed by the author in subfertile males. The operations performed in 44 of these men were excluded from the series for the following reasons: 8 patients were azoospermic, 8 patients were no longer married at the time of surgery, and the remaining 28 patients, primarily for geographic reasons, had inadequate follow-up. The first 42 men reported herein were also included in another study. 5 The ages of the 251 men ranged from 19 to 59 years, with a mean of 31 years. The subjects had unsuccessfully attempted to have children for a period of 6 to 168 months, with a mean of 39 months. This mean figure, of more than 3 years, helps to attest to the infertile status of the group under study. Of the 251 patients, 237 were examples of primary infertility. The remaining 14 men had offspring either earlier in their marriage or during a prior marriage. Of the 251 men, 223 had left varicoceles, 23 had bilateral varicoceles, and 5 had right varicoceles. Of the left varicoceles, 88 were considered to be small, 80 were moderate, and 50 were large. The wives of all of the men studied were examined by gynecologists and were thought to be fertile. Endocrine studies, including 17-ketosteroid, serum testosterone, pregnanetrio!, luteinizing hormone, and folliclestimulating hormone determinations and pituitary gonadotropin assays, were carried out in the majority of patients. Varicocelectomy was not performed in any male with an established endocrinopathy. At least two semen analyses were performed on each patient, prior to surgery. Postoperative semen studies were requested at 2-month intervals. The outcome of the first semen analysis, when obtained at 2 months, was not included in the tabulated results. The semen was considered to be improved when the postoperative ejaculate was normal in one parameter in which it had been significantly lacking and when the semen quality in general was so much better that it did not resemble the individual's preoperative ejaculate. Semen improvement in this study did not necessarily mean that the semen was entirely adequate. The parameters of the semen analysis most closely scrutinized included the ejaculate volume, sperm count, motility (percentage and grade), and morphology. All of the semen analyses were performed in one outside laboratory under the direction of a single experienced observer. The author did not perform any of the semen studies, thus eliminating a source of bias. A sperm count of 20 million/ml, motility of 40%, grade 3 (or motility index of 120), and morphology of 60% oval forms were considered the minimal normal standards for acceptable semen. Varicocelectomy was not performed on any individual who had semen quality comparable to or 'better than this standard. The varicocelectomies performed consisted of a complete, high ligation of the internal spermatic venous system, superior to the internal inguinal ring in the extraperitoneal space. The technique is fully described in a movie 23 and in writing elsewhere. 24 An effort should be

1048 BROWN September 1976 TABLE 1. Semen before and after Varicocelectomy (Average Value, 251 Subjects) Ejaculate volume Sperm count Motility indexa Oval forms ml 10 6 /ml % Before ligation 3.2 16 46.9 32.9 After ligation 3.1 34.3 93.9 48.1 The motility index is obtained by multiplying the percentage of active cells by the quality of forward progression, e.g., 40% grade 3 would be equal to 120. A motility index of 120 is generally thought to be necessary under most circumstances to achieve pregnancy. made to preserve the internal spermatic artery and lymphatics which course in close proximity to the internal spermatic veins. Inadvertent injury to the artery may produce damaging histologic changes in the seminiferous tubules, which would be particularly inappropriate in individuals undergoing surgery to improve their fertility potential. Preserving the lymphatics should tend to minimize the infrequent complication of hydrocele of the tunica vaginalis. The patients in this series were followed postoperatively for a minimum of 12 months. RESULTS Table 1 discloses the semen quality in the 251 subjects before and after varicocelectomy. The semen volume was unchanged. The sperm count and motility rose substantially, whereas improvement in morphology was more modest. The semen quality improved in a meaningful manner in 145 (58%) of the 251 men (Table 2). Of the 251 subjects, 130 had an average count of less than 10 million/ ml. Of this more infertile group, 60 ( 46%) had significant improvement in semen quality, while 85 (70%) of the 121 with an average count of 10 million!ml or more fared in the same favorable manner (Table 2). The semen quality before and after varicocele ligation in the 103 men who succeeded in impregnating their wives is recorded in Table 3. The sperm count rose in a comparably impressive fashion, as it did for the entire group, while the motility and morphology attained even better levels. The greater improvement in motility seen in the successful group was thought to be a major factor in the favorable outcome. Sperm Count. The average sperm count rose from 16 million!ml to 34.3 million!ml (Table 1). In the successfully treated group the average sperm count improved from 20.3 million/ml to 46.4 million/ml (Table 3). The distribution of the sperm counts before and after surgery is outlined in Table 4. Preoperatively, 130 (53%) of the men had a sperm count of less than 10 million!ml, and 184 (75%) had a count of less than 20 million!ml; only 23 (9%) had a count in the normal range ( 40 million/ ml or more). After ligation, 68 (28%) of the men had a sperm count of less than 10 million/ml and 121 (50%) had a count of less than 20 million/mi. After varicocelectomy, 71 (30%) ofthe men had a sperm count of 40 million/ml or more. Sperm Motility. The motility index was used as the single indicator of sperm viability. The motility index encompasses both the percentage of active sperm TABLE 2. Semen Quality following Varicocelectomy in Men with Counts Less Than 10 Million/Ml and 10 Million/Ml or More Entire series Count less than 10 million/ml Count 10 million/ml or more No. of men 251 130 121 No. with improved semen 145 (58%) 60 (46%) 85 (70%)

Vol. 27, No.9 VARICOCELECTOMY IN THE SUBFERTILE MALE 1049 ; TABLE 3. Semen of Men Whose Wives Became Pregnant after Varicocelectomy (Average Values, 103 Subjects) Ejaculate volume Sperm count Motility indexa Oval forms ml JO'ml % Before ligation 4.2 20.3 58 35 After ligation 2.9 46.4 121.4 54 See footnote to Table 1. and the grade of individual sperm activity. It is obtained by multiplying the percentage of active sperm by the quality of forward progression. A motility index of 120 is thought to be the minimal standard for normalcy. The average motility index for the entire series improved from 46.9 to 93.9 (Table 1), while in the successfully treated group it rose from 58 to an adequate level of 121.4 (Table 3). The distribution of the motility indices before and after varicocele ligation is outlined in Table 5. Preoperatively, 113 ( 46%) of the men had a motility index of 30 or less (little or none), while only 11 (4%) had a normal index of 120 or more. After surgery, 67 (28%) of the men had a motility index of 30 or less, while 79 (33%) of the men achieved a normal level of 120 or more. The periodic dramatic improvement in sperm motility achieved by some individuals with a motility index of 30 or less is not adequately appreciated in previously recorded statistics. When this group was scrutinized more closely, it was noted that 26 (23%) of these 113 subjects achieved a normal motility index. The normal motility attained by this group of men who had had essentially no viable sperm constitutes the most impressive improvement in semen quality achieved following varicocelectomy. Hence, patients with varicoceles who have a motility index of 30 or less, usually a rather hopeless category, can at times succeed in having children. Pregnancies have been attained by this same group of men, even though the count and morphology did not reach what have customarily been considered to be the minimal necessary levels. In certain individuals the substantial improvement in sperm motility is apparently able to compensate for remaining coexisting inadequacies in count and morphology. Sperm Morphology. Sperm morphology is an important and, unfortunately, often neglected aspect of semen quality. The healthy seminiferous tubule generally produces a preponderance of adult sperm with oval-shaped heads. The abnormalappearing sperm have been classified by MacLeod 19 as small, large, tapering, bicephalic, and amorphous. Under certain abnormal conditions, immature sperm or spermatogenic precursor cells may also appear in the ejaculate. Varicocele commonly produces a disturbance in the spermatogenic process and results in abnormal sperm morphology. Normally, at least 60% of the adult sperm seen in semen should be oval-shaped. TABLE 4. Sperm Count before and after Varicocelectomy Sperm count (10'/mll 0-9 10-19 20-39 40-59 60+ Before ligation 130 54 39 12 11 (53%) (22%) (16%) (5%) (4%) 75% 9% After ligation 68 53 47 22 49 (28%) (22%) (20%) (9%) (21%) 0% 0%

1050 BROWN September 1976 TABLE 5. Motility lndexa before and after Varicocelectomy Motility index (% l 0-29 30-59 60-89 90-119 120+ Before ligation 113 56 43 25 11 (46%) (23%) (17%) (10%) (4%) 96% After ligation 67 30 26 36 79 (28%) (13%) (11%) (15%) (33%) 67% a See footnote to Table 1. The average percentage of normal, oval-shaped sperm for the 251 subjects improved from 32.9 to a postoperative level of 48.1 (Table 1). In the successfully treated group, the percentage of oval forms rose from 35 to a postsurgical level of 54 (Table 3). The distribution of the percentage of oval-shaped sperm seen in the semen prior to and after varicocele ligation is depicted in Table 6. Preoperatively, 211 (86%) of the men had abnormal sperm morphology, that is, fewer than 60% oval forms. Only 33 (14%) of the subjects had normal sperm morphology. Postoperatively, 142 (63%) of the men had fewer than the necessary level of ovalshaped sperm, and 82 (37%) had 60% or more oval sperm. Varicocelectomy rerluced the number of men with fewer than 60% oval sperm, but the improvement was not numerically impressive. Stress Pattern. MacLeod 19 has demonstrated that varicocele commonly produces a stress pattern of abnormal sperm morphology. The testes will often respond to stressful stimuli by producing an excessive number of tapering sperm and by exfoliating into the ejaculate spermatogenic precursor sperm, primarily spermatids. These precursor cells are also referred to as immature sperm. The classic stress pattern is considered to exist when 10% or more tapering forms and 4% or more immature sperm appear simultaneously in the ejaculate. The distribution of the stress pattern of sperm morphology before and after surgery is outlined in Table 7. Preoperatively, 226 (93%) of the men exhibited some evidence of the stress pattern, and 169 (75%) of the men continued to demonstrate this abnormality after surgery. Before varicocelectomy, 143 (59%) of the subjects had the classic pattern (10% or more tapering plus 4% or more immature sperm); this figure declined postoperatively to 88 (39%) men. Subfertile males with varicoceles who do not have the commonly appearing stress-type pattern of abnormal sperm are not good candidates for varicocele ligation. Pregnancy. It is difficult to ascertain the pregnancy rate accurately in this type of clinical study. The number of conceptions was primarily determined by voluntary communications from the involved couples and, to a lesser extent, with the TABLE 6. Percentage of Oval Forms before and after Varicocelectomy Sf/ Oval forms 0-19 20-39 40-59 60-79 80+ Before ligation 52 91 68 33 0 (21%) (37%) (28%) (14%) 86% After ligation 31 44 67 73 9 (13%) (20o/o) (30%) (33o/o) (4%) 63%

Vol. 27, No.9 VARICOCELECTOMY IN THE SUBFERTILE MALE 1051 TABLE 7. Stress Patterns" of Sperm Morphology Tapering 109b+, immature 4% Tapering 109b+ Immature 4%+ No stress cells (classic stress pattern) Before ligation 143 44 39 17 (59%) (18%) (16%) (7%) 93% After ligation 88 52 29 56 (39%) (23%) (13%) (25%) 75% r "Stress pattern is characterized by the presence of an excess of tapering and immature sperm forms in the ejaculate. aid of a questionnaire. The true pregnancy rate is thought to be more favorable than that reported. At the time of this writing, 103 (41%) of the 251 men who had had varicocelectomies succeeded in impregnating their wives. Of the 223 men who had left varicocelectomies, 93 succeeded in impregnating their wives. Similarly successful were 9 of the 23 with bilateral varicocelectomies and 1 ofthe 5 with right varicocelectomies. Those men with a count of less than 10 million sperm/ml achieved a pregnancy rate of 35%, whereas those with 10 million sperm/ml or more achieved a 48% conception rate (Table 8). Only 7% of the pregnancies occurred without some form of concomitant improvement in semen quality. The pregnancies occurred an average of 12.1 months after the varicocelectomy. The size of the varicoceles was estimated in almost all of the patients. Admittedly, this determination is not necessarily precise and is often somewhat arbitrary. There were 88 small, 80 moderate, and 50 large left varicoceles. A 32% pregnancy rate (28 of 88) resulted following surgery for small-sized left varicoceles, a 50% pregnancy rate (40 of 80) following surgery for moderate-sized left varicoceles, and a 50% pregnancy rate (25 of 50) following surgery for largesized left varicoceles. A more favorable outcome was documented following varicocelectomy for moderate- and largesized left varicoceles. The 103 wives became pregnant 140 times and delivered 127 babies. There were nine miscarriages, two stillbirths, and two abortions. There was one known set of twins. DISCUSSION Varicocelectomy is an easy and often effective therapeutic modality in the management of the select subfertile male. Ligation of the internal spermatic venous system should be considered in all subfertile men, particularly in those with the stress pattern of abnormal sperm morphology. The mechanism by which varicocele adversely affects spermatogenesis is still not entirely clear. The varicocele in itself is not likely to be directly responsible for the impairment. The varicocele may well be only one manifestation of a more basic pathologic process which can produce oligospermia. The presence of the varicocele enables the examiner to identify the existence of this abnormal state. The varicocelectomy not only treats the TABLE 8. Pregnancy Rate following Varicocelectomy for Men with Counts Less Than 10 Million!Ml and 10 Million!Ml or More No. ofmen No. of pregnancies Entire series 251 103 (41%) Count less than 10 millionlml 130 46 (35%) Count 10 million/ml or more 121 57 (48%)

1052 BROWN September 1976 varicocele but also often corrects the underlying deleterious, pathologic process. Varicocelectomy has frequently been noted to result in a modest improvement in semen quality and yet a rather impressive pregnancy rate. Pregnancies have occurred often when the sperm motility has significantly improved but when the count and morphology have never attained what are customarily considered to be the minimal necessary levels for conception. This finding further supports the existing attitude that sperm motility is the single most important parameter of sperm quality. The wives of the men in this group probably had substantial fertility potential and were able to compensate for the continued existing deficiencies in their husband's semen quality. This observation reinforces the acknowledged need for continuing re-evaluation of the existing minimal criteria for adequate fertility potential in the male. Despite the established effectiveness of varicocelectomy, certain inconsistencies continue to exist. V aricoceles are admittedly not uniformly detrimental. Many men with varicoceles are fertile. The range of normal semen quality is rather broad. Men with 40 million sperm/ml as well as those with 300 million sperm/ml are considered fertile. Those males with varicoceles who remain fertile in all likelihood would have even better sperm quality without their varicoceles. In addition these same fertile males may at a late; age, when they are no longer desirous of offspring, unknowingly be rendered infertile. Varicocelectomy often restores impaired semen to normal levels. However, this same operation, performed for the same abnormality in different patients, does not always prove to be beneficial. The failure noted in some individuals could be attributed in part to an element of irreversible damage or, more appropriately, to the presence of some other unknown coexisting damaging process. The reason for the lack of uniformity still remains to be determined. As expected, the surgical morbidity encountered was negligible. Postoperative complications included three hydroceles of the tunica vaginalis. These were seen early in the series and were thought to be attributable to failure at that time to preserve the lymphatics which course in close proximity to the veins. Two incisional hematomas that spontaneously resolved were also noted. In addition, two persistent or recurrent varicoceles were known to have formed. At the time of the re-ligation, intraoperative internal spermatic venography demonstrated persistent, patent, venous channels. The continued presence of the varicoceles in these two cases were thought to be attributable to incomplete ligation at the time of the original surgery. REFERENCES 1. Dubin L, Amelar RD: Etiologic factors in 1294 consecutive cases of male infertility. Fertil Steril 22:469, 1971 2. Dubin L, Amelar RD: Varicocelectomy as therapy in male infertility: a study of 504 cases. Fertil Steril 26:217, 1975 3. Charny CW: Effect of varicocele on fertility: results of varicocelectomy. Fertil Steril 13:47, 1962 4. Brown JS, MacLeod J, Hotchkiss RS: Results of Varicocelectomy in Subfertile Men. Exhibit at the Twenty-Fifth Annual Meeting of The American Fertility Society, Miami Fla, 1969 5. MacLeod J: Further observations on the role of varicocele in human male infertility. Fertil Steril 20:545, 1969 6. Russell JK: Varicocele in groups of fertile and subfertile men. Br Med J 1:1231, 1954 7. Hammer R: Studies on Impaired Fertility in Man. London, Oxford University Press 1954 p 22,, 8. Johnson DE, Pohl DR, Rivera-Correa H: Varicocele: an innocuous condition? South Med J 63:34, 1970 9. Macomber D, Sanders MB: The spermatozoa count: its value in the diagnosis, prognosis and treatment of sterility. N Eng! J Med 200: 981, 1929

Vol. 27, No.9 VARICOCELECTOMY IN THE SUBFERTILE MALE 1053 10. Wilhelm SF: Sterility in the Male. Oxford Loose Leaf Surgery. New York, Oxford University Press, 1937, p 746 11. Tulloch WS: Varicocele in subfertility: results of treatment. Br Med J 2:356, 1955 12. Davidson HA: Treatment of male subfertility: testicular temperature and varicoceles. Practitioner 173:703, 1954 13. Scott LS, Young D: Varicocele: a study of its effects on human spermatogenesis, and of the results produced by spermatic vein ligation. Fertil Steril 13:325, 1962 14. Rivington W: Valves in renal veins. J Nat Physiol 7:163, 1873 15. Ahlberg NE, Bartley 0, Chidekel N, Fritjofsson A: Phlebography in varicocelescroti. Acta Radiol [Ther) (Stockh) 4:517, 1966 16. Brown JS, Dubin L, Hotchkiss RS: The varicocele as related to fertility. Fertil Steril18:46, 1967 17. Hanley HG: Surgical correction of errors of temperature regulation. In Proceedings of the Second World Congress of Fertility Sterility, Naples, 1956 18. Tessler AN, Krahn HP: Varicocele and testicular temperature. Fertil Steril 17:201, 1966 19. MacLeod J: Seminal cytology in the presence of varicocele. Fertil Steril 16:735, 1965 20. Koumans J, Steeno 0, Heyns W, Michelson JP: Dehydroepiandrosterone sulfate, androsterone sulfate and corticords in spermatic vein blood of patients with left varicocele. Andrologie 1:87, 1969 21. Mobley DF: Left spermatic vein cortisol in subfertile men with varicocele. Urology 3:461, 1974 22. Cohen MS, Plaine L, Brown JS: The role of internal spermatic vein plasma catecholamine determinations in subfertile men with varicocele. Fertil Steril 26:1243, 1975 23. Brown JS: Movie: Extraperitoneal Varicocelectomy (High Ligation of Internal Spermatic Veins) in the Treatment of Male Infertility. Presented at the Twenty-Seventh Annual Meeting of The American Fertility Society, New Orleans La, 1971, and American Urological Association Meeting, 1971 24. Brown JS: Varicocelectomy in subfertile men. In Current Operative Urology. New York, Harper & Row, 1975, p 1186