F. Comhaire

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Occlusion of the  internal spermatic vein(s), preferentially through non-surgical  techniques (Kunnen, 1980; Kunnen & Comhaire, 1985), constitutes  priority treatment for both the prevention and the cure of male  infertility. I will prove this statement on scientific arguments in the  field of epidemiology and physio-pathoglogy, as well as evidence based  medicine.





       Clinically palpable varicocele is detected in between 8 and 10% of  adolescents (Steeno, 1976; for review: Saypol, 1981), and in between  25% and 40% (WHO, 1987) of men coming to consultation for infertility.  Among couples investigated for infertility and in whom the male partner  has “normal” semen quality 12% present varicocele, as compared to 25% of  those with “abnormal” semen quality.  There is a significant inverse  correlation between the clinical degree of varicocele and total  testicular volume as well as sperm concentration (WHO, 1992). 

       These data prove the association between varicocele, testicular  damage and reproductive failure. Larger varicoceles cause smaller  testicular volume and more severe oligozoospermia, but impairment of  sperm motility and morphology are independent from the clinical degree  of varicocele (WHO, 1992). 





       The primum movens in varicocele disease is reflux in the internal  sper matic vein, due to either anatomical or functional inadequacy of  its valvular system, or to the presence of collateral circulation  between the renal vein or peri-renal plexus and the internal spermatic  vein (reno-gonadal bypass). Reflux may be enhanced as a result of renal  venous compression between the aorta and the cranial mesenteric artery  (so called nut cracker phenomenon) (Sayfan et al., 1984). Always the  direction of blood circulation is inverted (centrifugal) in the caudal  section of the internal spermatic vein and cranial segment of the  pampiniform plexus, at least when the person stands erect or performs  Valsalva’s maneuver. 

       Refluxing blood has been shown to contain a high concentration of  certain cathecholamines, particularly norepinephrin (Comhaire &  Vermeulen, 1974; Cohen et al., 1975). The increased hydrostatic pressure  in the intrascrotal veins enhances the physiological counter-current  exchange from these veins to the testicular artery that is coiled and  enrolled within the venous plexus. The increased norepinephrin  concentration causes constriction of the (intra)testicular arterioles  (Terquem & Dadoune, 1981; Chakraborty et al., 1985), decreasing  arterial perfusion as evidenced by means of isotope studies (Comhaire et  al., 1983). Long lasting exposure to a high concentration of  cathecholamines and vaso- constriction results in endothelial  hyperplasia of the intratesticular arterioles (Terquem & Dadoune,  1981), rendering the perfusion deficit irreversible in spite of  treatment interrupting reflux. 

       The cells of Sertoli are very sensitive to impaired arterial blood  supply and hypoxemia. They display microscopic alterations and  vacuoles, and become incapable of “sustaining” the spermatogenic cells  (Terquem & Dadoune, 1981). Spermatids, spermatocytes and, finally,  spermatogonia are “sloughed” from the spermatogenic epithelium,  appearing in increased number in the ejaculate as (peroxidase negative)  round cells (Mac Leod, 1965).

       Also, the secretory capacity of the cells of Sertoli is decreased,  with subnormal concentration of Inhibins (A & B) in serum (Mahmoud  et al., 1998). This results in increased serum concentration of FSH,  which stimulates the cells of Sertoli. 

       The latter produce excess amounts of, among other substances,  Interleukin 6 (Comhaire et al., 1998) that, in its turn, inhibits the  production and secretion of Sertoli cell-transferrin. Transferrin is of  pivotal importance in the transportation of iron through the  blood-testis barrier (Sylvester & Griswold, 1994) to the dividing  spermatocytes and the spermatids. These display transferrin receptors on  their membrane. Decreased iron supply, as a consequence of the  transferrin deficit,  results in decreased cell division and  oligozoospermia.

       The ejaculates of subfertile men with varicocele were shown to  contain increased concentrations of IL-6 and decreased transferrin, and  the latter was found to increase after treatment (Comhaire et al.,  1998). Leydig cell function is also impaired in men with varicocele  (Hudson & McKay, 1980; Pasqualini et al., 1980; Pirke et al., 1983),  causing premature “PADAM” (androgen deficiency of the aging male)  (Comhaire & Vermeulen, 1975). However, varicocele patients at  reproductive age usually have normal serum testosterone (Comhaire 1976),  although the secretory reserve of Leydig cells may be decreased (Ando  et al., 1984; Castro-Magana et al., 1991). 

       These findings provide a logical and proven explanation for the pathological changes observed in varicocele patients.

       Intervention Studies 





       Almost all studies report significant improvement of sperm  characteristics  after varicocele treatment interrupting spermatic  venous reflux (Dubin & Amelar, 1975; Brown, 1976; Soffer et al.,  1983; Tinga et al., 1984; Cocket et al., 1984; Burke, 1987; Yavetz et  al., 1992). Increased sperm concentration is associated with enhancement  of testicular volume. The majority of authors report sperm motility and  morphology also to improve. The metabolic capacity of spermatozoa, as  estimated by means of the resazurin reduction test was shown to improve,  even before microscopic changes occur (Fuse et al., 1993). Similarly,  the in vitro hamster oocyte test (Mygatt et al., 1992) and the human in  vitro fertilization capacity (Ashkenazi et al., 1989) improved after  treatment. However, patients with long lasting vasoconstriction causing  endothelial hyperplasia may not restore testicular perfusion, and may  fail to improvement of sperm quality (Comhaire et al., 1983).





       The question whether or not varicocele increases the fertility  potential is still debated by some authors. In fact, this is a false  debate whereby inaccurate or incompetent “authorities” confuse study  results or give incorrect interpretation to study outcomes. Indeed,  there are only few controlled prospective studies on the effect of  varicocele treatment on couple fertility. 

       The commonly cited papers by Vermeulen & Vandeweghe (1984) and  Vermeulen et al. (1986) include twice the same patient material, and  the study design is not randomized. In these publications, as in the one  by Baker et al. (1985), the selection of controls (refusing treatment  or historical controls) favors the possibility of bias. In the study by  Baker et al. no improvement of sperm quality was observed, but the  completeness of spermatic venous occlusion by surgery was not  certified. 

       The only prospective, truly randomized and controlled trial that  gives a negative outcome (no effect of surgery) is that of Nilsson et  al. (1979). In this study, the pregnancy rate of the treated group (51  cases) was only 8%. This is remarkably less than in all other studies,  including the cases and controls of the studies by Vermeulen et al.  (1986) and by Baker et al (1985). It seems, therefore, that selection  bias or inadequate surgery (perhaps even causing testicular damage) may  have been involved in the study by Nilsson et al.

       In fact, all other open and randomized studies report average  pregnancy rates of around 30% after 12 months, and between 45% and 70%  after 24 months among couples with primary infertility (Gerris et al.,  1988; Comhaire & Kunnen, 1985; Kunnen & Comhaire, 1986; for  review see Saypol, 1981). We recorded a one-year pregnancy rate of  around 85% in couples with secondary infertility (Comhaire & Kunnen,  1985), but controlled studies in this type of patients are lacking.

       The question is whether the observed pregnancy rate is better in  treated patients than in randomly assigned, untreated controls. There  are  two recent studies that have addressed this issue. One is the  single center study by Nieschlag et al. (first publication 1995, result  update 1998). The other one is a multicenter study coordinated by WHO,  and of which the results have been published in part by Madgar et al.  (1995) and have been reviewed by Hargreave (1997). The data of the  latter two publications will be added together for further analysis and  will be referred to as WHO study.

       The WHO study included a total of 283 couples, of which 180  (63.6%) completed the 12 months observation period. The study by  Nieschlag et al. included 203 couples, with 125 (61.6%) completing the  12 months follow up. Both studies are equivalent in terms of criteria  for couple selection and rate of protocol completion.

       In the WHO study 50 couples out of 153 couples (32.7%) who  received immediate treatment attained pregnancy within 12 months after  surgery, as compared to 18 out of 128 (14.1%) control couples whose  treatment was postponed during 12 months. The relative risk of attaining  pregnancy is 2.32 (95% Confidence Interval: 1.43-3.77) and odds ratio  is 2.97 (CI: 1.62-5.42).

       The one-year pregnancy rate in the immediately treated couples of  the Nieschlag study was 29.0%, which is similar to the treated cases in  the WHO study. However, the pregnancy rate in the controls was 25.4%,  which is significantly higher than in the controls of the WHO study. As a  result of the high pregnancy rate among controls, the outcome of the  Nieschlag study is considered “negative”, meaning that immediate  varicocele treatment does not seem to generate any therapeutic  advantage. However, sperm concentration increased significantly  (P<0.001) in the treated group, but not in the control group.

       Another interesting aspect concerns the time to pregnancy (TTP).  In the WHO study it took 281 days for 25% of immediately treated couples  to reach pregnancy, as compared to 650 days in the controls with  delayed treatment. What then explains the difference in pregnancy rates  observed in the controls of the WHO as compared to the Nieschlag study?  The response to this question is hidden in Nieschlag’s  paper. It  appears that the latter was not a true controlled study, but an  equivalence study. In actual fact, all couples received “counseling”  treatment, independent of whether or not occlusion of  the internal  spermatic vein was performed. It seems, therefore, that the “counseling”  should give the explanation of the difference between the WHO and the  Nieschlag studies.

       Indeed, counseling included the following: “the gynaecologists  were requested to monitor each partner’s reproductive functions” (cited  from the 1995 paper, but not mentioned in the 1998 update paper).   Apparently, monitoring was performed quite carefully (probably including  laparoscopy), since two female partners where found to have “developed  tubal blockage and endometriosis” during the follow up period. 

       It is well known that an important proportion of female partners  of subfertile men present some degree of reproductive impairment  (Farley, 1986). Improving the female partner’s fertility potential will,  therefore, increase the probability of conception (Steinberger et al.,  1981). Even if “no obvious causes of infertility” were found during the  initial evaluation of the female partner, some (functional) problems may  be present or may occur during follow-up. It seems plausible that  monitoring of the female partner, which probably implied “optimization”  of her reproductive capacity, explains the remarkably high success rate  in the group receiving counseling alone. 

       In order to find out whether counseling was indeed an effective  treatment explaining the high success rate in controls, we have compared  the pregnancy rate in the counseled group of the varicocele study with  that observed in two other controlled studies by Nieschlag’s group  (Kamischke et al., 1998; Rolf et al., 1999). The placebo treated cases  in the latter studies had a pregnancy rate of no more than 0.4% per  month, which is significantly lower (P<0.001) than the 2.6% monthly  pregnancy rate observed in the counseled group of the varicocele study.  In addition, the pregnancies in the varicocele control group occurred  independent of the duration of infertility, and in spite of the absence  of changes in semen quality. This stands in contrast to “treatment  independent pregnancies” which become less frequent as the duration of  infertility is longer (Collins et al., 1983; Comhaire et al., 1992).

       On the basis of the previous arguments, I conclude that the  “equivalence study” by Nieschlag et al. should not be compared to the  WHO study, and that it is a mistake to mix the results of these studies  in meta-analysis (Evers, 1995; Gerris, 1999).





       Epidemiological data and observations on the pathogenic mechanisms  leave no reasonable doubt on the association between varicocele and  male reproductive failure. The proof of causality of this association is  given by intervention studies. These evidence improvement of sperm  production and of fertility after treatment. Considering economical,  ethical and evidence based arguments, varicocele treatment must be  offered to selected subfertile patients. In addition, several recent  publications indicate that treatment of adolescents may prevent sperm  deterioration from occurring later in life (Okuyama et al., 1987; Sayfan  et al., 1987; Haans et al., 1991; Laven et al., 1992). This should  encourage early diagnosis and (non-surgical) treatment of varicocele at  school age.

Ando S, Giacchetto C, Beraldi E, Panno ML, Lombardi A, Sposato G, Golpi G. The influence of age on Leydig cell function in patients with varicocele. Int J Androl, 7, 104-118, 1984.

Ashkenazi J, Shelef M, Dicker D, Goldman GA, Feldberg D, Goldman J. The impact of spermatic vein ligation on the male factor in in vitro fertilization-embryo transfer and its relation to testosterone levels before and after operation. Fertil Steril, 51, 471-474, 1989.

Baker HWG, Burger HG, de Kretser DM, Hudson B, Rennie GC, Straffon WGE. testicular vein ligation and fertility in en with varicoceles. Br Med J, 291, 1678-1980, 1985.

Brown JS. Varicocelectomy in the subfertile male: a ten-year experience with 295 cases. Fertil Steril, 27, 1046-1053, 1976.

Burke RK. Sperm velocity, pre-and post-washing, as a measure of the effects of varicocelectomy and subsequent male fertility. Int J Fertil, 32, 213-216, 1987.

Castro-Magana M, Angulo M, Uy J. Elevated serum estradiol associated with increased androstenedione-testosterone ratio in adolescent males with varicocele and gynecomastia. Fertil Steril, 56, 515-518, 1991.

Chakraborty J, Sinha Hikim AP, Jhunjhunwala JS. Stagnation of blood in the microcirculatory vessels in the testes of men with variaocele. J Androl, 6, 117-126, 1985.

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Cohen MS, Plaine L, Brown JS. The role of internal spermatic vein plasma cathecholamines determination in subfertile men with varicocele. Fertil Steril, 26, 1243-1249, 1975.

Collins JA, Wrixon W, Janes JB, Wilson EH. Treatment-independent pregnancy among infertile couples. New Engl J Med, 309: 1201-1206, 1983.

Comhaire F, Kunnen M. Factors affecting the probability of conception after treatment of subfertile men with varicocele by transcatheter embolization with Bucrylate. Fertil Steril, 43, 781-786, 1985. Comhaire F, Simons M, Kunnen M, Vermeulen L. Testicular arterial perfusion in varicocele: the role of rapid sequence scintigraphy with technetium in varicocele evaluation. J Urol, 130, 923-926, 1983.

Comhaire F, Vermeulen A. Plasma testosterone in patients with varicocele and sexual inadequacy. J Clin Endocrinol Metab, 40, 824-829, 1975.

Comhaire F, Vermeulen A. Varicocele sterility: cortisol and cathecholamines. Fertil Steril, 25, 88-95, 1974.

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Comhaire F. Study of the hypothalamo-pituitary-testicular function in patients with varicocele before and after operation. In: Sperm action. Fifth International Seminar on Reproductive Physiology and Sexual Endocrinology. Progress in Reproductive Biology. Ed. P.O. Hubinont. Publ. Karger, Basel, Vol. 1, 187-191, 1976.

Comhaire FH, Farley TMM, Rowe PJ, on behalf of the World Health Organization Task Force on the Prevention and Management of Infertility. Adenosine triphosphate (ATP) in semen and other sperm characteristics: their relevance for fertility prediction in men with normal sperm concentration. Fertil Steril, 57, 877-881, 1992. 

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Articles

The First World Congress On: Controversies in Obstetrics, Gynecology & InfertilityPrague, Czech Republic - 1999

Author | F. Comhaire

Articles

Treatment of Varicocele: The Best Option for the Management of Subfertile Men