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The First World Congress On: Controversies in Obstetrics, Gynecology & InfertilityPrague, Czech Republic - 1999
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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.
Effects on semen quality
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).
Effects on fertility
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.
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