1 Andrology Unit, Department of Obstetrics & Gynecology, 2 Department of Radiology and the Interventional and Vascular Unit, Rabin Medical Center, Beilinson Campus, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 3 Department of Urology, Ghent University Hospital, Ghent, Belgium and 4 Department of Medicine B, Rabin Medical Center, Beilinson Campus, Petah Tiqva, Israel
5 To whom correspondence should be addressed at: Department of Obstetrics & Gynecology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. Email: yigalgat{at}yahoo.com
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Abstract |
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Key words: azoospermia/embolization/oligozoospermia/sperm/varicocele
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Introduction |
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Materials and methods |
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Procedure
Patients were examined in a warm room after standing for 5 min. The volume, position and consistency of the testes and epididymis were checked, and each spermatic cord was palpated in the standing position and during the Valsalva manoeuvre. Findings were graded according to the system of Dubin and Amelar (1971) as follows: grade I, varicocele palpable only during Valsalva manoeuvre; grade II, varicocele palpable in standing position; grade III, varicocele detectable by visual scrutiny alone. All patients underwent contact thermography using a flexible liquid crystal thermostrip Varicoscreen (FertiPro; Beernem, Belgium). ISV sclerotherapy was performed after venography as described in the study of Gat et al. (2004a)
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Evaluation
Semen analysis was performed twice before embolization and at least twice 4, 6, 9 or 12 months after (except for nine patients who agreed to only one analysis before, and one 6 months after, embolization). Patients were instructed to abstain from sexual intercourse for 3 days before semen collection. The samples were assessed within 1 h of collection for sperm concentration, motility and morphology according to the World Health Organization criteria (Aboulghar, 1997). The pre- and post-procedural semen values were averaged separately.
Endocrinological evaluation was performed before embolization and at 6 weeks after, including assays of serum FSH, LH, testosterone and free testosterone. Testosterone was measured in all cases between 08:00 and 10:00. The normal ranges at our laboratory are as follows: FSH, 18 mIU/l; LH, 4.925 IU/l; testosterone 8.538.8 nmol/l; free testosterone, 4.314.9 nmol/l.
Statistical analysis
Two-sample paired Student's t-test was used for statistical analyses. Values were expressed as means±SD. Type I error =0.05 and P<0.05 were considered significant.
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Results |
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Table I shows the changes in sperm parameters for the whole cohort and by group. In the azoospermia group, significant improvement was noted in mean (± SD) sperm concentration, motility and morphology in 18 of the 32 men (56.2%). Mean sperm concentration increased from zero total sperm in the ejaculate to 3.81±1.69 x 106/ml after embolization (P<0.03); mean sperm motility rose to 1.20±3.62% (P<0.001), and mean sperm morphology to 8.30±2.64 (P<0.005). A mean post-embolization sperm count of >1 x 106 was achieved in seven men (22%), and of >5 x 106 in four men (13%).
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In the virtual azoospermia group, significant improvement in sperm parameters was noted in 29 of the 31 men (94%). Mean sperm concentration increased from 0.054±0.007 x 106/ml sperm in the ejaculate to 10.31±1.87 x 106/ml after embolization (P<0.001); mean sperm motility rose from 6.07±2.69 to 35.8±2.76% (P<0.001), and mean sperm morphology from 1.96±0.56 to 15.25±2.10% (P<0.001). A mean post-embolization sperm count of >1 x 106 was achieved in 23 men (74%), and of >5 x 106 in 17 men (55%).
In the extremely severe OTA group (sperm concentration up to 1 x 106), significant improvement was noted in mean (± SD) sperm concentration, motility and morphology in 36 of the 38 men (94.7%). Mean sperm concentration increased from 0.54±0.04 total sperm in the ejaculate to 12.11±1.85 x 106/ml after embolization (P<0.001); mean sperm motility rose from 13.96±3.06 to 33.24±3.13% (P<0.001), and mean sperm morphology from 4.9±1.03 to 15.83±2.28% (P<0.001). A mean post-embolization sperm count of >5 x 106 was documented in 22 men (58%).
Mean serum testosterone concentration for the study group was 9.81±5.67 nmol/l (range 227 nmol/l) pre-operatively and 18.23±8.09 nmol/l (range 337 nmol/l) after ISV embolization (P<0.001), for an increase of 86%. Corresponding values of mean serum free testosterone were 5.10±2.37 nmol/l (range 112 nmol/l) and 10.59±5.13 nmol/l (range 423 nmol/l) (P<0.001), for an increase of 108% (Figure 1). Mean serum FSH concentration for the study group was 10.8±5.27 mIU/ml pre-operatively and 8.7±3.53 mIU/ml after ISV embolization (data not shown).
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Discussion |
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There is growing evidence that patients with varicocele-induced severe OTA and even azoospermia may benefit from varicocele repair (Matthews et al., 1998; Kim et al., 1999
; Kadioglu et al., 2001
; Pasqualotto et al., 2003
), though the findings remain controversial. Tulloch (1952)
was the first to report a spontaneous post-varicocelectomy pregnancy in a couple with an azoospermic male. Since then, varicocelectomy has become the most commonly performed surgery in the treatment of male infertility. Several studies reported that varicolectomy improved serum testosterone level and spermatogenesis (Su et al., 1995
; Cayan et al., 1999
); however, in other studies, these findings were not statistically significant (Evers and Collins, 2003
). In a recent report on IUI, Daitch et al. (2001)
found that varicocele repair improved pregnancy and live birth rates in couples in which the male had varicocele and the woman was healthy. On the other hand, in their systematic review, Evers and Collins (2003)
stated in a comprehensive meta-analysis that Varicocele repair does not seem to be an effective treatment for male subfertility. Their stated findings are not surprising, since nearly all the patients in their meta-analysis were treated according to the usual practice, on the left side only. A recent study demonstated that varicocele is a predominantly bilateral disease (Gat et al., 2004a
) and the diagnosis of bilaterality is missed by physical examination in >90% of the cases (Gat et al., 2004b
). In essence, the patients in Evers' meta-analysis were treated only partially.
The present study agrees with previous reports indicating that men with azoospermia, virtual azoospermia or extremely severe OTA can benefit from varicocele repair. In our series, semen parameters were improved in 83 of 101 patients (82%), (Figure 1) and 34% of the couples achieved pregnancy, 58% of them unassisted. A positive effect of varicocelectomy in this patient population also has important implications for assisted reproduction technologies. First, even modest improvements in sperm motility and quality in the ejaculate can reduce the need for TESE by open or needle biopsy, an invasive and potentially damaging procedure, in ICSI procedures (Aboulghar et al., 1997; Belenky et al., 2001
). Second, in men with spermatogenic failure, freshly ejaculated sperm are easier to use, and fertilization ability in ICSI is higher with normal semen than with sperm retrieved by TESE (Aboulghar et al., 1997
).
In our earlier study, we observed that bilateral varicocele was present in 81% of 255 consecutive infertile men presenting for infertility evaluation (Gat et al., 2004a). In the present series, 90 of the 101 patients had bilateral disease: 28 of 32 men (87.5%) with azoospermia, 26 of 31 men (84%) with virtual azoospermia, and 35 of 38 men (92%) with extremely severe OTA. The difference in rates of bilaterality between the three groups was not statistically significant. Similar findings were noted by Matthews et al. (1998)
, namely, an 82% rate of bilateral varicocele in 78 infertile patients: 77% for those with severe OTA and 84% for those with azoospermia. Accordingly, Kadioglu et al. (2001)
reported that all the azoospermic men in their series with bilateral high-grade (2 or 3) varicocele improved after bilateral surgery, and all the spontaneous pregnancies that occurred were in this subgroup.
In the present study, semen quality improved significantly in 18 patients (56.2%) in the azoospermia group, 29 patients (94%) in the virtual azoospermia group, and 36 patients (94.7%) in the extremely severe OTA group. Mean post-embolization counts of >1 x 106 were achieved in seven azoospermic men (22%) and 23 virtual azoospermic (74%) men, and of >5 x 106 in four men (13%) and 17 men (55%) respectively. In the extremely severe OTA group, a count of >5 x 106 was achieved in 22 men (58%). Thirty-four pregnancies (34% of cases) were documented, including 20 unassisted. Thus, 56.2% of our patients were spared TESE procedures, which is usually the initial therapeutic option in azoospermic men.
Although we had no control group, our results can be compared to those of Madgar et al. (1995), who reported only a 10% spontaneous pregnancy rate at 12 months in partners of men with OTA and untreated unilateral left-side varicocele. Moreover, our results are in agreement with those of Matthews et al. (1998)
who reported that after microsurgical varicocelectomy, 55% of the 78 infertile men in their series had motile sperm in the ejaculate, and the partners of 24 (31%) became pregnant (15 unassisted and nine assisted). Separate analysis of the azoospermia/zero motile sperm group yielded a 69% rate of patients with motile sperm and a 24% pregnancy rate (seven unassisted, five assisted). Among the improved patients, elevated serum FSH level (up to 150% above normal) or smaller testicular volume (but with elastic consistency) did not block the induction of spermatogenesis and varicocele grade was not associated with the outcome. Kim et al. (1999)
demonstrated motile sperm in the ejaculate in 12 of 28 patients (43%) with complete azoospermia after microsurgical inguinal varicocele repair, but no pregnancies by natural intercourse within 24 months. Others reported a 20.8% rate of motile sperm in the ejaculate in 24 men with complete azoospermia treated by microsurgical inguinal varicocele repair (Kadioglu et al., 2001
), and induction of spermatogenesis in seven of 15 azoospermic men (47%) after treatment (Pasqualotto et al., 2003
).
In our study, the large majority of patients responded favourably to ISV embolization in terms of concentrations of serum testosterone (86% increase) and free testosterone (108% increase). Microsurgical techniques for varicocele, such as our procedure, successfully occlude all potential collateral venous channels (Kunnen and Comhaire, 1992) have similarly successful results. Su et al. (1995)
reported a 28% increase in serum testosterone concentrations (from 319±12 to 409±23 ng/dl) in 53 infertile men with varicocele, and Cayan et al. (1999)
reported a 49% increase in serum testosterone (from 5.63 to 8.37 ng/ml) and 42% increase in free testosterone (from 23.1 to 32.8 pg/ml) in 78 infertile patients. Comhaire and Vermeulen (1975)
were the first to demonstrate significant increase in serum testosterone in patients with sexual inadequacy and infertility. These data are further supported by our previous study, demonstrating elevation of testosterone after bilateral embolization of spermatic veins (Gat et al., 2004c
).
It should be noted that once sperm is detected in the semen analysis after varicocele repair, the patient needs to be warned of the possibility of relapse and offered the option of sperm cryopreservation.
Based on our findings, the followng statements can be made. (i) Varicocele may cause any variation of severity in OTA, including azoospermia. (ii) Since male fertility is preserved with only one testis, OTA, azoospermia or virtual azoospermia represent bilateral testicular dysfunction. (i) Treatment of bilateral varicocele may reverse testicular dysfunction and improve spermatognesis and testosterone production in men with extremely severe OTA and induce sperm production in men with azoospermia. (iv) If azoospermia is not too long-standing, the treatment of varicocele may significantly improve spermatogenesis and renew sperm production. (v) Adequate treatment may spare the need for TESE as preparation for ICSI in >50% of azoospermic patients. (vi) Since achievement of pregnancy in IVF units is higher when spermatogenesis is better, the treatment of varicocele (bilateral) is an effective medical adjunct for IVF units prior to the treatment.
We recommend that infertile men with azoospermia or virtual azoospermia or extremely severe OTA be evaluated for varicocele, with special attention to its bilateral nature.
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Submitted on October 11, 2004; resubmitted on November 22, 2004; accepted on November 30, 2004.