Hrup451 70.77

Human Reproduction Update, Vol.7, No.1 pp. 70±77, 2001 Sherman J.SilberInfertility Center of St Louis, St Luke's Hospital, 224 South Woods Mill Road, Suite 730, St Louis, MO 63017, USA There is probably no subject that is more controversial in the area of male infertility than varicocele. The overwhelming majority of non-urologist infertility specialists in the world are extremely sceptical of the role of varicocele or varicocelectomy in the treatment of male infertility. Directors of most assisted reproductive technologies (ART) programmes view the enthusiasm with which urologists approach varicocelectomy as a potential impediment to the couple that is getting older and do not have much time left to become pregnant using ART. There are many credible, well-controlled studies which show no effect of varicocelectomy on fertility. There are also a few `controlled' studies that favour varicocelectomy, but all can be criticised on the basis of patient selection bias. Thus the great weight of evidence from controlled studies is against varicocelectomy and the reports supporting varicocelectomy are extremely weak. Finally, the reports that semen parameters are improved by varicocelectomy is ¯awed by uncontrolled observations and the failure to take into account the variability of semen analysis in infertile men and its regression toward the mean. Many control studies have demonstrated that, because of this variability, men with an initially low sperm count tend later to have higher sperm counts in the absence of any treatment Key words: ART/pregnancy rate/semen parameters/varicocelectomy sperm injection (ICSI) as an effective therapy for all cases of male infertility which have failed to respond to conventional treatment has caused a major reassessment and critical analysis of the Lack of effect of varicocele on pregnancy rate following vasova- diagnostic and therapeutic approaches to male infertility (Van Steirteghem et al., 1993). In that light, the varicocelectomy Controlled studies challenging the effectiveness of varicocelectomy Controlled studies supporting varicocelectomy Does varicocele cause a progressive decline in fertility? In May 1998, an azoospermic patient of ours ®nally had twin boys after a fourth cycle of testicular sperm extraction (TESE) and ICSI. He had undergone bilateral varicocelectomy at a major university 2 years earlier, for a sperm count of 19 Q 106 spermatozoa/ml, with a volume of 10 ml, and 60% sperm motility There have been many years of debate over the causes and with normal morphology, and had suffered complete left testicular therapy of male infertility. Many treatments have been strongly infarction and right testicular atrophy. His wife's pregnancy was advocated for male infertility over the past four decades, e.g.
no thanks to her husband's varicocelectomy. A different patient clomiphene citrate, testosterone, human menopausal gonadotro- who had sperm counts that ¯uctuated between 2.8 and 94 Q 106 phin (HMG), human chorionic gonadotrophin (HCG), corticos- spermatozoa/ml had a similar experience several years earlier, teroids (for sperm antibodies), cold wet athletic supports, and also required TESE±ICSI. These occasional complications of vitamins, and even more recently very aggressively marketed varicocelectomy have been known for >20 years (Silber, 1979).
nutritional supplements such as `Proxceed', without any docu- Of course, this is not the usual disastrous result with bilateral mented evidence of effectiveness (Devroey et al., 1998). It is varicocelectomy. In fact, a microsurgical approach to varicoce- becoming clear that many spermatogenic defects in the human are lectomy has been designed to avoid such complications (Silber, genetic in origin, and clearly impervious to improvement with any 1979; Goldstein et al., 1992; Marmar and Kim, 1994; Girardi and current therapy (Reijo et al., 1995; Silber et al., 1995, 1998; Page Goldstein, 1997; Scherr and Goldstein, 1999). Nonetheless, the et al., 1999). Furthermore, the development of intracytoplasmic occasional serious risk of varicocelectomy cannot be disregarded.
Ó European Society of Human Reproduction and Embryology If it were not for this risk, microsurgical approaches to out in the other 37 vasectomy reversal patients who had a varicocelectomy would never have been developed. The more varicocele. There was no statistically signi®cant difference common risk of post-operative hydrocele (5%) is obviously just a between the two groups (although their major point was the nuisance and not as serious as devascularization (Dubin and safety of performing simultaneous varicocelectomy).
Semen analyses are often highly variable, and spontaneous pregnancies without treatment are so common that there is much scepticism about many treatments for male infertility (Baker et In 1995, Nieschlag proposed a basic axiom that needs to be al., 1981, 1984, 1985, 1993; Baker and Kovacs, 1985; Baker and followed in male infertility treatment: `Therapeutic interventions Burger, 1986; Baker, 1986, 1993; Silber, 1989a; Devroey et al., in male infertility should be based on properly controlled clinical 1998; Devroey, 1999). Because no treatment of male infertility is trials' (Nieschlag et al., 1995). Several reports on spontaneous without risk, if for no other reason than simply the delaying of pregnancy rates with no treatment in couples with severe male more effective treatment until the wife is older, I would like to factor justify Nieschlag's axiom. In 1993, Hargreave reported on review in this paper the pitfalls of trying to evaluate either patients with severe oligozoospermia, high serum FSH concen- pregnancy results or sperm count results in patients undergoing trations, and varicocele whose wives became pregnant after an varicocelectomy or, indeed, any other treatment for male initial infertility consultation without any treatment of the male infertility, without properly controlled studies.
(Hargreave and Elton, 1983; Hargreave, 1993). A total of 33% of men in this category had a varicocele, and did not have time to Lack of effect of varicocele on pregnancy rate following undergo varicocelectomy before their wife became pregnant. The point of his study was that, with alarmingly low sperm counts, women can become pregnant without any treatment of the male, In 1989, we reported a 10 year follow-up of men undergoing verifying concepts that have been clear for many years (Smith et vasovasostomy (who had spermatozoa in the vas ¯uid without al., 1977; Zukerman et al., 1977; Steinberger and Rodriguez- secondary epididymal blowouts), and their long-term results (Silber, 1989b). This experience was the origin of my scepticism To understand the importance of a controlled study in regarding the value of varicocelectomy. Out of 282 patients evaluating the validity of varicocelectomy, one has only to look undergoing vasovasostomy ten or more years earlier, who had at the spontaneous conception rates in the wives of men with good sperm in the vas ¯uid (meaning there was no secondary various low sperm counts. Hargreave and Elton's work was not epididymal obstruction), 42 (14.8%) had a discernible (moderate just about varicocelectomy, but also was about the issue of `what or large) varicocele upon physical examination, and 240 (85.2%) is male infertility' (Hargreave and Elton, 1983; Silber, 1989a).
had no such varicocele (Table I). These men had no other medical They found that even in men with sperm counts of `2 Q106 or surgical treatment other than vasovasostomy. The wives of spermatozoa/ml, and with a duration of infertility of as long as 4 78.5% of those men with varicocele (not operated upon), became years, 20% of the wives eventually have a spontaneous pregnant, and the wives of 81.2% of those without varicocele conception without ever having any improvement in the sperm became pregnant. Thus, there was no statistically signi®cant count. In men with sperm counts of 5 Q 106 spermatozoa/ml with difference (78.5 versus 81.2%) in pregnancy rate in those with only 1 year of infertility, 36% of the wives became pregnant varicocele versus those without varicocele for older men under- without any treatment (Table II). Thus, if one had performed a going vasovasostomy. There was also no difference in post- varicocelectomy on such men prior to their wife's conception, operative semen parameters. Our conclusion from this study was without a controlled study, we might have mistakenly concluded that in a group of men with prior fertility who have a varicocele that the operation is what enabled the pregnancy, even though it (who were fertile except for their vasectomy, but many years later was simply a spurious, unrelated event.
decide to have their vasectomy reversed) the presence of a Baker and Burger in 1986, reported life-table pregnancy rates varicocele did not have any discernible effect on their long-term over 3 years in couples with varying categories of semen parameters compared to control groups (Baker and Burger, 1986).
A decade later, essentially the same question was addressed Although lower sperm counts resulted in lower pregnancy rates, a (Mulhall et al., 1997) when varicocelectomy was performed simultaneously with vasovasostomy in 10 vasectomy reversal patients who had varicocele but varicocelectomy was not carried Table II. Percentage chance of conception for the next year (wife with normal results after investigation) (Hargreave and Elton, 1983) Table I. Lack of effect of varicocoele (not operated on) on pregnancy rate following vasovasostomy (taken from Silber, 1989b). Values in parentheses substantial percentage of couples achieved pregnancy sponta- couples would not have become pregnant without the surgery.
neously despite severe oligoasthenozoospermia (Figure 1).
Nieschlag concluded in 1998, as did Mordel in 1990, `Studies In 1983, Schoysman reported an extensive 12 year experience since 1952 advocating varicocelectomy have been uncontrolled following 1291 oligozoospermic men who underwent no and not evidence-based' (Mordel et al., 1990; Nieschlag et al., improvement in semen parameters (Schoysman and Gerris, 1983). They found that for men with sperm counts of 1±5 Q It is easy to become enthusiastic about any treatment of male 106 spermatozoa/ml, 12% of wives became pregnant within 5 infertility that is performed without adequate controls. In a series years and 27% of wives became pregnant within 12 years without of men with either azoospermia or extremely severe oligozoos- any treatment (Table III). Even when the sperm count was <1 permia, the pregnancy rate in 56 severely oligozoospermic men Q106 spermatozoa/ml, 4% of wives conceived spontaneously following varicocelectomy was 23% (13 out of 56), and for within 5 years, and 9% within 12 years without any treatment.
`azoospermic' men was 9% (two out of 22) (Steckel et al., 1993; When sperm counts were 15±20 Q 106 spermatozoa/ml, 69% of Matthews et al., 1998). The problem with these studies again is wives became pregnant within 5 years and 82% within 12 years, that there is no control group, no longitudinal follow-up, and it again with no treatment of the male. These studies demonstrate pays no attention to the concept of `regression toward the mean.' the dif®culty of interpreting whether any treatment of the male More recently a similar study (Kim et al., 1999) resulted in no with oligozoospermia, e.g. varicocelectomy, has any discernible spontaneous pregnancies even in the varicocelectomy group even though these authors maintained that sperm count `improved' In 1975, Amelar and Dubin compiled a summary of all after surgery. Once again there is no control group of similar varicocelectomy studies prior to that time (Dubin and Amelar, patients who did not receive surgery. We all have seen men who 1975). None of the 11 papers on varicocelectomy published by are initially azoospermic, who will eventually, in subsequent 1975 was controlled. Most of them showed ~60±70% of patients semen analyses, have spermatozoa in the ejaculate without any had an improvement in sperm count, and most of the studies treatment (MacLeod and Gold, 1953; Baker and Kovacs, 1985).
showed pregnancy rates from a low of 30% to a high of 55%.
Without a control group to compare with, one should not be None of the studies controlled for the pregnancy rate in couples surprised to see a spontaneous pregnancy rate of 9±23% without not undergoing varicocelectomy, and just assumed that these any treatment of the male partner with severe sperm defects, particularly if the couple has had a short period of infertility, and/ or if the wife is young (Hargreave and Elton, 1983; Schoysman Varicocelectomy and sperm countMacLeod and Gold, as far back as 1951 (MacLeod and Gold, 1951; MacLeod and Gold, 1953), ®rst demonstrated that sperm concentration and motility tend to increase with time with repeated testing in oligozoospermic and asthenozoospermic men despite no treatment. This was a peculiar mathematical quirk related to the highly variable nature of the sperm count. That means that, without any treatment whatsoever, if you continue to get sperm counts and semen analyses longitudinally on men who initially have low sperm counts and poor motility, the low sperm count and the poor motility will routinely tend to increase with repeated tests and no treatment (MacLeod and Gold, 1951, 1953).
Baker et al. were the ®rst to clearly and mathematically explain this phenomenon of `regression toward the mean' (Baker et al., 1981; Baker and Kovacs, 1985; Baker, 1986). `Regression toward Figure 1. Cumulative and life-table pregnancy rates (Baker and Burger, 1986).
the mean' has profound implications for all clinical trials.
Whenever there is a highly variable measurement, if patients have a controlled period followed by a treatment period, there is Table III. Pregnancy rates in 1291 oligozoospermic men (Schoysman and likely to be a signi®cant improvement even if the treatment is ineffective. Baker et al. observed the same phenomenon that McLeod and Gold had observed 30 years earlier, that sperm concentration and motility increased progressively in their study of day-to-day variability of semen analyses in infertile men.
Sperm motility increased equally on both active drug and on placebo treatment in a double-blind controlled trial of erythro- mycin for asthenozoospermia (Baker et al., 1984). Clearly, erythromycin had no impact whatsoever on either sperm count or sperm motility. However, in this double blind control study, it was obvious that the sperm motility increased in an equal manner in patients that were on erythromycin and patients that were on 63 of them underwent counselling. It is important to point out that placebo. `In a similar fashion, sperm motility increased in men it was not just a `treatment versus no treatment' group, but rather with varicoceles whether or not they had testicular vein ligations it was a `surgical varicocelectomy treatment group' versus a performed' (Baker et al., 1985). No matter what the treatment, `psychological counselling group' (Figure 2) shows the survival whether erythromycin, or watchful waiting, clomiphene citrate or curve results of the two different groups. There was no signi®cant varicocelectomy, an initially low sperm count (because of difference in pregnancy rate measured over time between those intrinsic variability) will gravitate higher because of `regression couples that underwent varicocelectomy and those couples that underwent psychological counselling. Furthermore, Nieschlag's Baker and Kovacs also concluded in 1985 that `a group of group found no relationship of pregnancy to semen parameters, subjects selected for low results will on average have higher hormone concentrations, grade of varicocele, or the age of the results on re-measurement' (Baker and Kovacs, 1985). This male. The only relationship to pregnancy rate was the age of the phenomenon of `regression toward the mean' signi®es that wife and that was the only factor that could help predict the whenever you have a phenomenon that is highly variable, and you have a select group of couples on the low end of that Nieschlag's controlled study attempted to put us on a more phenomenon, whether sperm count or sperm motility, because of scienti®c footing in evaluating varicocelectomy, and also helped the intrinsic variability, repeated tests will generally show an us realize how differences in the population characteristics of the increase which has nothing to do with biology but is simply a wives of these infertile men would have potentially a major mathematical event that has to occur. As Baker and Kovacs confounding effect. For example, one might, without proper showed, therefore, a low sperm count will generally improve, control studies, be very enthusiastic about varicocelectomy in a with or without any treatment. Similarly, a very high sperm count practice involving younger couples, and less enthusiastic in a will generally become worse with or without any treatment. Men practice involving older ones. We discovered a similar confound- with an average ®rst sperm count of 28 Q 106 had an average ing phenomenon in the treatment of obstructive azoospermia with second sperm count of 56 Q 106. Men with an average ®rst sperm count of 271 Q 106 had a mean second sperm count of 145 Q 106.
Table IV. Obstructive azoospermia and intracytoplasmic sperm injection Among 216 semen donors whose initial motility averaged 42%, (ICSI): female age-related variation in pregnancy rate the second semen analysis showed a mean of 55% motility. Thus, whenever uncontrolled varicocelectomy studies mention an improvement in motility, or sperm count, this is what one often would expect to ®nd with no treatment whatsoever when you are beginning with oligozoospermic couples (Baker and Kovacs, Controlled studies challenging the effectiveness of varicocelectomyNieschlag's group performed a very meticulously controlled study to attempt to evaluate the effect of varicocelectomy (Nieschlag et al., 1995, 1998). They studied 125 infertile couples with varicocele. Of those couples, 62 underwent varicocelectomy and Figure 3. Life-table curves of pregnancy rates for before ligation (n) and after ligation (s) groups. Number of patients initially and those followed up to the end of each year is shown at top of ®gure. Symbols indicate those months in which the life table changed, i.e. pregnancies occurred. Although some patients were followed up for >5 years (those in before ligation group for Figure 2. Cumulative pregnancy rates over 12 months in couples with male maximum of 92 months, after ligation group for 108 months), the longest varicocele treated by intervention (ligation or embolization) or counselling duration of follow up to pregnancy was 60 months. There was no signi®cant alone (taken from Nieschlag et al., 1998. Previously published in Hum.
difference between the two curves by log rank test (Baker et al., 1985.
Reprinted with permission from British Medical Journal).
sperm retrieval and ICSI. The only factor that signi®cantly spermatozoa/ml. Of patients with sperm counts of >10 Q 106 affected the variation in pregnancy rate in couples undergoing spermatozoa/ml, those who conceived had a mean sperm count of ICSI with retrieved spermatozoa was the age of the wife (Silber et 40 Q 106 spermatozoa/ml, and those who did not conceive had a al., 1997) (Table IV). The delivery rate with ICSI using retrieved mean sperm count of 48 Q 106 spermatozoa/ml.
spermatozoa was 44% in women under aged <30 years; 34% with In 1979, Nilsson et al. questioned the ef®cacy of varicoce- women aged 30±36; 13% with women ages 37±39; and only 4% lectomy with a boldly titled paper: `Improvement of semen and with women aged >40 years the delivery rate per cycle. With pregnancy rate after ligation and division of the internal spermatic women aged <37 years, who also had a good ovarian reserve, the vein: Fact or ®ction?' (Nilsson et al., 1979). They randomized delivery rate was 42%. Thus, it seems that in any kind of their patients to 51 having varicocelectomy and 45 serving as infertility treatment for male factor, regardless of sperm count, controls. All had similar varicocele characteristics and all the and whether for varicocele or obstructive azoospermia, the most patients had suffered 2±8 years of infertility. Varicocelectomy important confounding factor, aside from duration of infertility, is produced no change in semen parameters. Most importantly, the age and ovarian reserve of the wife.
pregnancies were achieved in four out of 51 (8%) patients In the controlled varicocele study performed earlier by Baker's undergoing varicocelectomy, and in eight out of 45 (17%) having group (Baker et al., 1985), 651 infertile couples with varicocele were studied for pregnancy rate per month with or without In 1992, Rageth et al. studied 89 patients with varicocele, poor varicocelectomy. Biases due to any difference in prognostic semen, and duration of infertility of up to 7 years (Rageth et al., factors were allowed for by using the Cox regression analysis. Of 1992). Of the 56 patients undergoing varicocelectomy, the wives the couples, 324 had sperm counts of <20 Q 106 spermatozoa/ml of 23 (41%) became pregnant eventually with treatment. Of the and 327 had sperm counts of >20 Q 106 spermatozoa/ml. There 33 who did not undergo varicocelectomy, the wives of 14 became was no signi®cant difference in the sperm concentration or pregnant (42%) with treatment. Thus, there was no difference at motility after varicocelectomy. There was no difference in all in pregnancy rate between those who had surgery and those pregnancy rate after varicocelectomy. Figure 3 demonstrates the who did not. Rageth et al. observed an improvement in sperm pregnancy rate of these couples over a course of 5 years. Looking count after surgery from 9 to 15 Q 106 spermatozoa/ml, an at the `before ligation' and the `after ligation' groups reveals that improvement in morphology from 22 to 28%, and an improve- the two curves essentially overlap each other. There is no signi®cant difference in log rank test between these curves. In In all fairness, we need to mention the peculiarities of some of fact, in the ®rst few months of the study, the pregnancy rate these control studies in the following critical way. In the study of appeared to be higher before varicocele ligation but eventually Baker et al. (1985), the sperm count did not improve with after 1 or 1/2 years, the curves had completely coalesced (Baker et varicocelectomy, but sperm motility improved equally with or without varicocelectomy. Patients who had a varicocele did have The studies of Nieschlag's group in 1995 and 1998, and the a higher pregnancy rate than those who did not have a varicocele study by Baker et al. a decade earlier, seemed to dampen any whether operated on or not. In Rodriguez-Rigau et al.'s group, the overwhelming enthusiasm for varicocelectomy on the part of sperm count and motility improved after varicocelectomy, but many infertility physicians, even though there is still registered pregnancy rate was not affected (Rodriguez-Rigau et al., 1978). In throughout the urology world a strong defensive posture regarding Nieschlag et al.'s group, the sperm count increased in the this procedure. There were, however, other controlled studies, not varicocelectomy group, but not in the control group. Sperm quite as carefully designed as the aforementioned, that also motility did not change with or without varicocelectomy. Sperm revealed the shaky ground on which the pro-varicocelectomy morphology decreased simply over time in both groups, the forces stood. In 1986, Vermuelen from Belgium reported on 90 patients undergoing varicocelectomy and 25 patients not under- Additional criticisms have been offered on the Nieschlag study.
going varicocelectomy. Both groups were comparable in terms of It does not appear to be well-controlled for varicocele size, and duration of infertility, age, sperm count, and motility. Cumulative the follow-up was limited only to several years. In Vermeulen's pregnancy rates in these two groups were the same over a 12 study (1986), some patients in the non-operated group got month follow-up period. Interestingly, both groups showed pregnant before surgery could be performed. In Nilsson's group `slightly improved sperm characteristics' (Vermeulen et al., (1979), the pregnancy rates were rather low in both groups, though they may not be a valid criticism since they were treating In 1978, Rodriguez-Rigau et al. from Texas reported a large couples with a long duration of infertility in an older age group.
group of patients which was not prospective and not randomized, Despite these possible criticisms, for the most part the control but was controlled, some of whom underwent varicocelectomy studies showing no effect of varicocelectomy have been viewed and others who did not (Rodriguez-Rigau et al., 1978).
by most andrologists to be reliable.
Rodriguez-Rigau et al. noted a slightly increased percentage motility in patients undergoing varicocelectomy. However, there Controlled studies supporting varicocelectomy was no difference in pregnancy rate among those who had varicocelectomy versus those who did not. Furthermore, there was There have been three reported `control' studies that suggest a no relation of improvement in post-operative sperm count to bene®cial effect of varicocelectomy. Marmar and Kim (1994), pregnancy rate. Those patients who conceived after varicocelect- reviewed retrospectively a series of 466 varicocelectomies and omy had a mean sperm count of 28 Q 106 spermatozoa/ml and only 19 controls. Of the 466 couples that underwent those who did not conceive had a mean sperm count of 26 Q 106 varicocelectomy, 186 became pregnant (pregnancy rate 35.6%). The pregnancy rate in the small number of 19 the question of whether or not varicocele really created `stress' `controls' that did not undergo varicocelectomy was 15.8%.
that results eventually in deterioration of testicular function.
The large difference in the size of the varicocelectomy group As far back as 1968, Uehling studied the fertility of 440 and the control group certainly suggests an unwitting selection married men in the military coming in for routine physical bias. This kind of a skewed population would make it very examination, with and without varicoceles. Of this group, 138 had likely that the `controls' were simply people whose semen was no children (31.4%) and 302 did have children (68.6%). To break so poor that there was no desire to undergo surgery, or it down further, of the 75 men with a varicocele, 69% had possibly there may have been a problem with the wife that children and of the 227 men without a varicocele, 68% had made surgery also very problematic. At any rate, being a children. Thus, there was no difference in fatherhood of those retrospective study with such unbalanced varicocelectomy young married military recruits who had varicocele versus those control groups, indicates a probable selection bias.
who did not have varicocele. The presence or absence of a Another `control' study often referred to is that of Girardi and varicocele in these young men had no in¯uence on whether or not Goldstein in which 1500 infertile males underwent varicocelect- their wives were able to get pregnant (Uehling, 1968). At least in omy, and only 47 controls underwent varicocelectomy (Girardi young men, varicocele seemed to have no negative impact on and Goldstein, 1997). This is clearly the same problem of balance between patients undergoing varicocelectomy and patients So what is the prevalence of varicocele in a group of otherwise serving as `controls' that occurred in the study of Marmar and healthy young men? Thomason et al. in a similar study of military Kim. They reported a 43% pregnancy rate in couples in whom the recruits, in 1979, concluded, `It is apparent that the prevalence of husband had a varicocelectomy and a 17% pregnancy rate in those varicoceles in young men occurs with signi®cant frequency and whose husbands did not have a varicocelectomy. They also noted does not interfere with the fertility in all individuals' (Thomason an improvement in sperm count from 40 to 47 Q 106 and Farris, 1979). It was found that 30.7% of all recruits had a left spermatozoa/ml. This is not a very dramatic increase in mean varicocele (14% were small, and 16.7% were moderate or large), sperm count and is most likely simply related to `regression and 29.4% of recruits who had fathered children also had a toward the mean.' This study also suffers from a great likelihood varicocele (15% were moderate or large). This is similar to the of selection bias in that only 3% of the men in the study were frequency of large or moderate left varicocele in older vasectomy `controls' for the other 97% who had surgery.
reversal patients (Silber, 1989b). They concluded, `the prevalence The World Health Organization (WHO) study was an attempt of a left-sided varicocele occurs with such frequency among a to settle the varicocele issue employing thousands of couples in a group of healthy men that one would question the association of a multi-centre trial design (WHO, 1992). This study was never varicocele and poor semen quality.' Although I have observed no published in its original form because of problems with protocol difference in fertility after vasovasostomy in older men with or deviations (Nieschlag et al., 1995, 1998). It is very dif®cult with without varicocele, there are, nonetheless, many other reports multi-centre studies involving a highly controversial subject to be which suggest a deterioration caused by varicocele as one gets certain that all programmes that want to serve their patients in the way they think is best, can stick to a rigid protocol. However, It has been commonly thought that secondary infertility, (i.e.
such a rigid protocol would be necessary in order to give the study the couple gets pregnant without treatment for their ®rst child, and credibility (WHO, 1992). One group that pulled out of the WHO then cannot get pregnant years later when they want another one) study did publish the results of 45 couples out of their 210 who was due to increased age and declining fertility of the female were split off from the original group of 9034 infertile couples (Nieschlag et al., 1995, 1998; Silber et al., 1997). Gorelick and originally entering the study, 1326 of whom had a clinical Goldstein, however, have suggested that a varicocele is found in varicocele. This group maintained that varicocelectomy did have 35% of men with primary infertility, and in 81% of men with a bene®cial effect. However, such a splitting off from the original secondary infertility, implying that secondary infertility is caused study group of ®ve times as many patients as originally started, by declining semen parameters related to the long-term even in their local programme and representing only 3% of the deleterious effect of an uncorrected varicocele (Gorelick and original WHO couples, has a great risk of unwitting selection bias Goldstein, 1993). Out of 1001 men with `primary' infertility, 352 (35%) had a varicocele on routine physical examination, but when couples came for `secondary' infertility,' 79 out of 98 (81%) had Does varicocele cause a progressive decline in fertility? a varicocele present. This is an impressive incidence of ®nding a varicocele in infertile couples. Witt and Lipshultz (1993) have For years, urologists talked about an excess number of `tapered' made a similar claim that 50% of couples with primary infertility forms of spermatozoa, i.e. the `stress pattern,' as a distinctive have a varicocele and 69% of couples with secondary infertility feature of patients with varicocele. It was called a `stress pattern' have a varicocele (Witt and Lipshultz, 1993).
to re¯ect what was thought to be a `stress' on testicular function The authors suggested this meant that over time the presence of created by the varicocele. However, Baker et al. in 1985 a varicocele causes a diminution in sperm quality and indeed is questioned whether there is a `speci®c abnormality of sperm the major cause of secondary infertility. This would suggest a morphology with varicoceles?' In fact, they found no signi®cant need for varicocelectomy in virtually all young men with a difference in the morphological patterns with or without varicocele in order to prevent subsequent decline of testicular varicocele. Contrary to popular myth, there was `no characteristic function. That's a lot of varicocelectomies. Of course, there were morphologic stress pattern in infertile men with large left some problems with these reports. Firstly, there was no varicoceles' (Baker et al., 1981, 1985; Baker, 198). This raised demonstrated decline in sperm count caused by the varicocele, but rather simply an increased incidence of varicocele found in varicocele in adolescents with reduced left testicular size may the older couples. Secondly, the mean FSH concentration in their have a long-term effect on sperm count, if not on fertility, requires patients with primary infertility was 7.9 IU/ml, and in their a carefully controlled longitudinal study. In science, our minds patients with secondary infertility the mean FSH was 17.6 IU/ml.
must always remain open, and not be driven by what we merely These ®ndings are confusing in that one would not expect an FSH to be so elevated in men with mean sperm counts of 30 Q 106 spermatozoa/ml. Thirdly, the group of men de®ned as having primary male infertility had normal mean sperm counts.
Nonetheless, if other centres were able to con®rm that 81% of older couples with secondary infertility have a varicocele, and Baker, G. (1992) The use of the semen analysis in predicting fertility outcome.
only 20% of younger couples with primary infertility have a [Editorial comment.] Aust. N.Z. J. Obstet. Gynecol., 32, 154±155.
Baker, H.W.G. (1986) Requirements for controlled therapeutic trials in male varicocele, the conclusion would be enormous in terms of infertility. Clin. Reprod. Fertil., 4, 13±25.
recommending varicocelectomy for 15±35% of the entire world.
Baker, H.W.G. (1993) Management of immunological infertility. In Berger, On the contrary however, other authors have demonstrated no H.G. and Oshima, H. (eds), An Approach to Clinical Andrology. Serona difference in the incidence of varicocele in men with primary or Symposia Reviews, no. 29, pp. 105±110.
Baker, H.W.G. and Burger, H.G. (1986) Male infertility in reproductive secondary infertility (Jarow et al., 1996). They found the primary medicine. In Steinberger, E., Frajese, G., Steinberger, A. (eds.) determinant of secondary infertility was the age of the wife. We Reproductive Medicine. Raven Press, New York, USA, pp. 187±197.
have also found no such increase in the incidence of varicocele Baker, H.W.G. and Kovacs, G.T. (1985) Spontaneous improvement in semen quality: regression towards the mean. Int. J. Androl., 8, 421±426.
either in secondary infertility or in other men with infertility. So Baker, H.W.G., Burger, H.G., de Kretser, D.M. et al. (1981) Factors affecting this fascinating speculation that in 81% of couples with secondary the variability of semen analysis results in infertile men. Int. J. Androl., 4, infertility, the cause is varicocele, may not turn out to be valid.
Infertility centres see many older couples who did not try to Baker, H.W.G., Straffon, W.G.E., McGowan, M.P. et al. (1984) A controlled trial of the use of erythromycin for men with asthenospermia. Int. J.
have their baby when they were in their 20s. These couples might very well have been couples with `secondary' infertility if it were Baker, H.W.G., Burger, H.G., de Kretser, D.M. et al. (1985) Testicular vein not for the fact that they did not marry until they were 35 and did ligation and fertility in men with varicoceles. Br. Med. J., 291, 1678± not already have children. One would expect in this group of older Baker, H.W.G., Liu, D.Y., Bourne, H. and Lopata, A. (1993) Diagnosis of couples also to see a higher incidence of varicocele if the presence sperm defects in selecting patients for assisted fertilization. Hum. Reprod., of varicocele over the period of time causes a decline in fertility and/or sperm count. However, we do not see a higher incidence of Devroey, P., Vandervorst, M., Nagy, P. and Van Steirteghem, A. (1998) Do varicocele in older couples than in younger couples coming in for we treat the male or his gamete? Hum. Reprod., 13 (Suppl 1), 178±185.
Devroey, P. (1999) The relevance of semen analysis. Presented at Thirty- primary infertility. Furthermore, we have found no difference in Second Annual Postgraduate Program of the American Society for pregnancy rate or semen parameters with long-term follow-up of Reproductive Medicine in Toronto, Canada, September 1999. pp. 15±32.
older vasovasostomy patients who did or did not have a varicocele Dubin, L. and Amelar, R.D. (1975) Varicocelectomy as therapy in male Girardi, S.K. and Goldstein, M. (1997) Varicocele. Curr. Ther. Endocrinol.
However, there are studies which suggest that varicocelectomy may be of bene®t in some selected cases. In 1991, Wensing's Goldstein, M., Gilbert, B.R., Dicker, A.P. et al. (1992) Microsurgical inguinal group in Holland studied testis volumes, semen quality and varicocoelectomy with delivery on the testis: an artery and lymphatic morphological patterns of spermatozoa in adolescents with and sparing technique. J. Urol., 148, 1808±1811.
Gorelick, J.I. and Goldstein, M. (1993) Loss of fertility in men with without varicocele, trying to nail down the issue of whether early varicocele. Fertil. Steril., 59, 613±616.
varicocelectomy could be recommended as a preventative in Haans, L.C.F., Laven, J.S.E., Mali, W.P.Th. M. et al. (1991) Testis volumes, adolescents with left testicular atrophy (Haans et al., 1991; Laven semen quality, and hormonal patterns in adolescents with and without et al., 1992). They showed a small increase in the adolescent's left varicocele. Fertil. Steril., 56, 731±736.
Hargreave, T.B. and Elton, R.A. (1983) Is conventional sperm analysis of any testicular volume after varicocelectomy. They found that `varicocele-related' unilateral or bilateral growth failure is not Hargreave, T.B. (1993) Varicocele ± a clinical enigma. Br. J. Urol., 72, 401± clearly associated with a decrease in sperm counts or semen quality, but could be prevented by adolescent varicocelectomy in Jarow, J.P., Coburn, M. and Sigman, M. (1996) Incidence of varicocoeles in men with primary and secondary infertility. Urology, 47, 73±76.
those young men presenting with a left varicocele and a smaller Kim, E.D., Leibman, B., Grinblat, D. and Lipshultz, L. (1999) Varicocele left testicle. It was not clear, however, whether this `growth repair improves semen parameters in azoospermeric men. J. Urol., 162 failure' continued during adulthood and could lead to future disturbances in infertility. Differences in semen parameters were Laven, J.S.E., Haans, L.C.F., Mali, W.P.T.M. et al. (1992) Effects of varicocele treatment in adolescents: a randomized study. Fertil. Steril., 58, not at all convincing. Furthermore, despite their enthusiasm for studying the early impact of varicocele on testicular atrophy, they MacLeod, J. and Gold, R.Z. (1951) The male factor in fertility and infertility.
could ®nd no evidence to suggest further deterioration of II. Spermatozoon counts in 1000 men of known fertility and in 1000 cases of infertile marriage. J. Urol., 66, 436±449.
MacLeod, J. and Gold, R.Z. (1953) The male factor in fertility and infertility.
I do not wish to conclude on a 100% negative note regarding VI. Semen quality and other factors in relation to ease of conception.
the varicocele issue, because we must always have an open mind in science. It appears fairly conclusive that varicocelectomy does Madjar, I., Weissenberg, R., Lunenfeld, B. et al. (1995) Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil. Steril., not do much, if anything, to help the average infertile couple. That should not be controversial. The speculation that the occasional Marmar, J.L. and Kim, Y. (1994) Subinguinal microsurgical varicocelectomy: A technical critique and statistical analysis of semen and pregnancy data.
Silber, S.J. (1989b) Pregnancy after vasovasostomy for vasectomy reversal: a study of factors affecting long-term return of fertility n 282 patients Matthews, G.J., Matthews, E.D. and Goldstein, M. (1998) Induction of followed for 10 years. Hum. Reprod., 4, 318±322.
spermatogenesis and achievement of pregnancy after microsurgical Silber, S.J., Nagy, Z., Liu, J. et al. (1995) The use of epididymal and testicular spermatozoa for intracytoplasmic sperm injection: the genetic oligoasthenospermia. Fertil. Steril., 70, 71±75.
implications for male infertility. Hum. Reprod., 10, 2031±2043.
Mordel, N., Mor-Yosef, S., Margalioth, E.J. et al. (1990) Spermatic vein Silber, S.J., Nagy, Z., Devroey, P. et al. (1997) The effect of female age and ligation as treatment for male infertility. J. Reprod. Med., 35, 123±127.
ovarian reserve on pregnancy rate in male infertility: treatment of Mulhall, J.P., Stokes, S., Andrawis, R. and Buch, J.P. (1997) Simultaneous azoospermia with sperm retrieval and intracytoplasmic sperm injection.
microsurgical vasal reconstruction and varicocele ligation: Safety pro®le and outcomes. Urology, 50, 438±442.
Silber, S.J., Alagappan, R., Brown, L.G. and Page, D.C. (1998) Y chromosome Nieschlag, E., Hertle, L., Fischedick, A. and Behre, H.M. (1995) Treatment of deletions in azoospermic and severely oligozoospermic men undergoing varicocele: counselling as effective as occlusion of the vena spermatica.
intracytoplasmic sperm injection after testicular sperm extraction. Hum.
Nieschlag, E., Hertle, L., Fischedick, A. et al. (1998) Update on treatment of Smith, K.D., Rodriguez-Rigau, L.J. and Steinberger, E. (1977) Relation varicocele: counselling as effective as occlusion of the vena spermatica, between indices of semen analysis and pregnancy rate in infertile couples.
Nilsson, S., Edvinsson, A. and Nilsson, B. (1979) Improvement of semen and pregnancy rate after ligation and division of the internal spermatic vein: Steckel, J., Dicker, A.P. and Goldstein, M. (1993) Relationship between Fact or ®ction? Br. J. Urol., 51, 591±596.
varicocele size and response to varicocelectomy. J. Urol., 149, 769±771.
Page DC, Silber S, Brown LG. (1999) Men with infertility caused by AZFc Steinberger, E. and Rodriguez-Rigau, L.J. (1983) The infertile couple.
deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum. Reprod., 14, 1722± Thomason, M. and Farris, B.L. (1979) The prevalence of varicocele in a group of healthy young men. Milit. Med., 144, 181±186.
Rageth, J.C., Unger, C., DaRugna, D. et al. (1992) Long-term results of Uehling, D.T. (1968) Fertility in men with varicocele. Int. J. Fertil., 13, 58±60.
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Van Steirteghem, A.C., Nagy, Z., Joris, H. et al. (1993) High fertilization and Reijo, R., Lee, T., Salo, P. et al. (1995) Diverse spermatogenic defects in implantation rates after intracytoplasmic sperm injection. Hum. Reprod., humans caused by Y chromosome deletions encompassing a novel RNA- binding protein gene. Nature Genet., 10, 383±393.
Vermeulen, A., Vandeweghe, M. and Deslypere, J.P. (1986) Prognosis of Rodriguez-Rigau, L.J., Smith, K.D. and Steinberger, E. (1978) Relationship of subfertility in men with corrected or uncorrected varicocele. J. Androl., 7, varicocele to sperm output and fertility of male partners in infertile Witt, M. and Lipshultz, L. (1993) Varicocele: A progressive or static lesion? Scherr, D. and Goldstein, M. (1999) Comparison of bilateral versus unilateral varicocelectomy in men with palpable bilateral varicoceles. J. Urol., 162, World Health Organization (1992) The in¯uence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil.
Schoysman, R.G. and Gerris, J. (1983) Twelve-year follow-up study of pregnancy rates in 1291 couples with idiopathically impathically impaired Zukerman, Z., Rodriguez-Rigau, L.J., Smith, K.D. and Steinberger, E. (1977) male fertility. Acta Eur. Fertil., 14, 51±56.
Frequency distribution of sperm counts in fertile and infertile males.
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