Journal of Andrology, Vol. 33, No. 2, March/April 2012Copyright E American Society of Andrology Varicocelectomy Does Not Impact Pregnancy Outcomes FollowingIntracytoplasmic Sperm Injection Procedures FABIO F. PASQUALOTTO, DANIELA P. A. F. BRAGA, RITA C. S. FIGUEIRA, AMANDA S. SETTI,ASSUMPTO IACONELLI JR, AND EDSON BORGES JR From the Fertility-Assisted Fertilization Center, Sao Paulo, and the Institute of Biotechnology, University of Caxias doSul, Rio Grande do Sul, Brazil.
There are many studies in the literature suggesting an and group 2 (33.8 6 0.38 years; P 5 .1872). Semen volume was acquired, apparently progressive infertility due to varicocele. In fact, higher in group 1 (3.3 6 0.3 mL) than it was in group 2 (2.5 6 0.14; P 5 varicocelectomy has become the most commonly performed male .0043). No differences were detected between groups 1 and 2 with infertility surgery. Assisted reproductive technologies such as intra- regard to sperm concentration (30.08 6 4.01 million/mL and 24.1 6 cytoplasmic sperm injection (ICSI) are also important for couples with 2.42 million/mL, respectively; P 5 .138), sperm motility (38.2% 6 male factor infertility associated with varicocele. Therefore, the aim of 2.69% and 38.7% 6 2.08%, respectively; P 5 .881), and morphology this study was to evaluate the effect of varicocelectomy on sperm according to Tygerberg’s strict criteria (2.6% 6 0.44% and 2.4% 6 quality and pregnancy rate with ICSI. Data were analyzed from 248 0.37%, respectively; P 5 .7202). Also, no differences were detected in patients who had varicocele or underwent a previous varicocelectomy the number of oocytes retrieved between group 1 (14.8 6 1.74) and and were treated with ICSI between 2000 and 2008. Patients with group 2 (14.9 6 1.04; P 5 .9515). The fertilization rate was higher in varicocele were divided into two groups: men with clinical varicocele group 1 (73.2%) than it was in group 2 (64.9%; P 5 .0377); however, (group 1, n 5 79) and men who underwent varicocelectomy before no differences were detected in the pregnancy rates (31.1% vs 30.9%; ICSI (group 2, n 5 169). In all cases, female infertility was not P 5 .9806), implantation rates (22.1% vs 17.3%; P 5 .5882), or detected. We evaluated and compared the two groups’ semen miscarriage rates (21.7% vs 23.9%; P 5 .8401) between groups 1 and characteristics as defined by the World Health Organization and 2. Although a varicocelectomy should always be performed before Tygerberg’s strict criteria: the female partner’s age; the number of assisted reproduction is pursued, this surgery does not increase oocytes retrieved; and the fertilization, implantation, pregnancy, and pregnancy rates or decrease miscarriage rates following ICSI.
miscarriage rates. We used the Wilcoxon signed rank test or the Varicocele, ICSI, spermatozoa, male infertility, Mann-Whitney test for these analyses. No differences were detected in the age of the female partners between group 1 (33.0 6 0.46 years) Fertility problems occur in approximately 10% to The decrease in scrotal temperature following varicocele 15% of reproductive-age couples, due to female ligation supports the causative role of increased factor or male factor infertility (Witt and Lipshultz, temperature in varicocele-related infertility (Sofikitis et 1993; Schlesinger et al, 1994; Kamal et al, 2001). Male al, 1992). Additionally, it has been hypothesized that factor infertility is at least partially responsible for 50% varicoceles cause hypoxia, which may play a role in of infertility cases. Varicocele is present in approximate- impairing spermatogenesis in the patient with varico- ly 10% to 20% of the healthy male population, but in cele. Furthermore, infertile men with varicocele have 30% to 40% of the infertile male population (Witt and elevated levels of spermatozoal reactive oxygen species Lipshultz, 1993; Schlesinger et al, 1994; Kamal et al, (Hendin et al, 1999; Pasqualotto et al, 2000, 2008; 2001). A number of theories have been proposed to explain the decreased semen quality detected in infertile The effects of varicocele vary, but they often result in men with varicocele. Semen quality uniformly declines an overall impairment of sperm production character- in animals with induced varicoceles, even when only a ized by abnormal semen quality and a reduced fertilizing left varicocele is present (Sofikitis and Miyagawa, 1994).
capacity of the male gamete (Sofikitis et al, 1996; Gat etal, 2003, 2004). Currently, surgical repair of varicocele isreported to be more cost-effective than intracytoplasmic Correspondence to: Edson Borges Jr, Fertility-Assisted Fertilization sperm injection (ICSI; Garceau et al, 2002; Meng et al, Center, Av Brigadeiro Luı´s Antoˆnio, Sa˜o Paulo, SP 01401-002, Brazil 2005). However, even when varicocele is repaired and all (e-mail: [email protected]).
beneficial improvements in semen quality appear to Received for publication September 15, 2010; accepted for have been obtained, unassisted pregnancy rates vary from 19% to 35% (Marmar and Kim, 1994; Gat et al, 2003, 2004; Pasqualotto et al, 2006), and these rates are according to WHO criteria (Cooper et al, 2010), and significantly lower in patients who had germ cell aplasia morphology according to Tygerberg’s strict criteria (Kruger before surgery (Pasqualotto et al, 2005).
et al, 1986). At least two centrifuged semen samples were Varicocele repair has induced or enhanced spermato- genesis in 40% to 60% of men with azoospermia and severe oligoasthenozoospermia (Matthews et al, 1998;Kim et al, 1999; Kadioglu et al, 2001; Pasqualotto et al, The presence of granulocytes in the semen specimens was 2006; Inci et al, 2009). However, few pregnancies have assessed by a myeloperoxidase test (Kruger et al, 1986). A 20-mL been reported to result after varicocelectomy in men volume of liquefied specimen was placed in a Corning 2.0-mLcryogenic vial (Corning Costar Corp, Cambridge, Massachu- with varicocele and azoospermia. Therefore, ICSI is a setts), to which 20 mL of phosphate-buffered saline (pH 7.0) and valuable tool for couples in which the male partner has 40 mL of benzidine solution were added. The mixture was varicocele and azoospermia, because not all couples vortexed and allowed to sit for 5 minutes. A 5-mL portion of the achieve pregnancy after varicocele repair alone.
specimen was placed on a Makler chamber (Sefi Medical, Haifa, The aim of this study was to evaluate the effect of Israel) and examined for cells that stained dark brown, which varicocelectomy on sperm quality and pregnancy rate indicated that they were positive for neutrophils. Leukocyto- spermia was defined as the presence of at least 1 6 106 whiteblood cells per milliliter. In our study, we excluded patients whohad more than 1.0 6 106 white blood cells per milliliter.
The patients’ female partners completed an infertility workup This study was approved by the University of Caxias do Sul consisting of at least one evaluation assessment and hystero- review board, and the patients involved gave informed salpingography. Female partners’ mean age 6 SD was 30.6 6 consent. A retrospective study of 248 patients who had varicocele or had previously undergone a varicocelectomy, The patients’ female partners underwent a unique controlled and who were treated with ICSI between 2000 and 2008, was ovarian stimulation protocol. Gonadotropin-releasing hor- performed. Only patients presenting varicocele grade III were mone agonist (leuprolide acetate) was administered for at least 14 days. Ovarian stimulation with recombinant follicle- For the purposes of this study, infertility was defined as the stimulating hormone (Gonal F; Merck Serono Laboratories, failure to establish a pregnancy after at least 1 year of Geneva, Switzerland) was initiated in a step-down protocol unprotected intercourse. A basic infertility evaluation, including until a minimum of 2 follicles reached an average diameter of a detailed history and a complete physical examination, was 18 mm. Oocyte retrieval was performed using transvaginal conducted. Only patients who were diagnosed with varicocele ultrasonography 36 hours after the administration of 10 000 IU grade III were submitted to receive assisted reproduction of human chorionic gonadotropin. The oocytes were kept in treatment or varicocelectomy. In addition, semen analyses were human tube fluid medium supplemented with 7.5% synthetic performed in all patients, and only those presenting poor semen serum substitute for approximately 3 to 5 hours before parameters according to World Health Organization (WHO) cumulus cell removal. The cumulus cells were removed from 2010 guidelines were included. All couples participating in the the oocytes by placing them in hyaluronidase at a concentra- study underwent ICSI cycles for the first time.
tion of 80 IU/mL for approximately 30 to 60 seconds. The Patients who had varicocelectomy and recurrence of the oocytes were transferred to fresh medium, and the corona cells varicocele were excluded from the study. Patients who were taking antioxidants, such as vitamins C and E, and those whohad azoospermia or leukocytospermia were also excluded from ICSI was performed with oocytes in metaphase II (MII), Patients with varicocele were divided into two groups: men following the technique described by Palermo et al (1992). The with clinical varicocele (group 1, n 5 79) and men who had microinjection dish was prepared by pipetting seven 4-mL undergone varicocelectomy before ICSI (group 2, n 5 169).
droplets of human tubular fluid medium and adding HEPES All 248 patients underwent a subinguinal varicocelectomy with and 15% synthetic serum substitute to the center of the dish.
magnification, as previously described (Marmar and Kim, The center droplet was removed and replaced with 4 mL of polyvinylpyrrolidone solution. Prepared sperm was added tothe drop of polyvinylpyrrolidone solution and the oocytes, and then placed into the drops of medium. The droplets were Semen samples were obtained by masturbation after at least overlaid with mineral oil. ICSI was performed microscopically 48 hours of abstinence. Samples were collected into sterile on a heated stage. After the oocytes were injected, they were containers and allowed to liquefy at 37uC for 30 minutes and rinsed and placed in equilibrated growing medium (15% then analyzed for sperm concentration, percent motility human tubular fluid–synthetic serum substitute). The micro- Varicocelectomy and Assisted Reproductive Outcomes Table. Parameters evaluated in patients with varicocele (n 5 79) and patients who underwent a previous varicocelectomy (n5 169) Abbreviations: FSH, follicle-stimulating hormone; MII, metaphase II.
manipulated oocytes were incubated in 50- to 100-mL drops in The couples in group 2 had had tried longer to achieve a a culture dish overlaid with mineral oil. The oocytes were pregnancy (6.0 6 0.49 years) than those in group 1 (2.7 observed for fertilization for 16 to 18 hours after the injection procedure. Abnormally fertilized or unfertilized oocytes were Semen volume was higher in group 1 (3.3 6 0.3 mL) removed from the dish. Twenty-four hours later, cleavage of than in group 2 (2.5 6 0.14 mL; P 5 .0043). However, fertilized oocytes was assessed. Embryo transfer was per-formed approximately 72 hours after injection.
no differences were detected between groups 1 and 2 insperm concentration (30.08 6 4.01 million/mL and 24.1 6 2.42 million/mL; P 5 .138), sperm motility (38.2% 62.69% and 38.7% 6 2.08%; P 5 .881), and morphology Clinical pregnancy was determined by the visualization of atleast one gestational sac by ultrasound at 7 weeks.
according to Tygerberg’s strict criteria (2.6% 6 0.44%and 2.4% 6 0.37%; P 5 .7202). The mean volume (in milliliters) of the left testicle did not differ betweengroup 1 (19.4 6 0.71) and group 2 (18.8 6 0.66; P 5 We compared the age of the male patients with their femalepartners, the men’s semen characteristics (according to WHO .4929), nor did the mean volume of the right testicle and Tygerberg’s strict criteria), right and left testicular volume, (20.3 6 0.60 and 19.9 6 0.67 for groups 1 and 2, the women’s follicle-stimulating hormone and estradiol levels, the number of oocytes retrieved, the number of MII oocytes The mean follicle-stimulating hormone levels of the retrieved, the number of cycles canceled, fertilization, implan- female partners in both groups were not different (2371.7 tation, the number of embryos transferred, and pregnancy and 6 100.69 IU and 2249.4 6 63.68 IU for groups 1 and 2, miscarriage rates between the two groups. For this analysis, we respectively; P 5 .2943), nor were mean estradiol levels used the Wilcoxon signed rank test or the Mann-Whitney test.
(1926.8 6 364.73 pg/mL and 2002.4 6 201.33 pg/mL forgroups 1 and 2, respectively; P 5 .8490).
There were no differences in the number of oocytes retrieved in group 1 (14.8 6 1.74) and group 2 (14.9 61.04; P 5 .9515), and there was no difference in the No differences were detected in the age of the men in percentage of oocytes retrieved (65.4% for group 1 and group 1 (36.1 6 0.55 years) and group 2 (37.8 6 67.6% for group 2; P 5 .6401). No differences were 0.47 years; P 5 .1872; Table), and no differences were detected in the mean of number of MII oocytes retrieved detected in the age of the women in group 1 (33.0 6 in group 1 (8.8 6 1.34) and in group 2 (10.4 6 0.79; P 5 0.46 years) and group 2 (33.8 6 0.38 years; P 5 .1872).
.2805). There was no difference in the mean number of oocytes injected per couple in group 1 (10.3 6 1.16) and peutic approach for infertile couples with varicocele is whether to treat this condition before using TESE/ICSI.
The fertilization rate was higher in group 1 (73.2%) Treating varicocele is more cost-effective than other than in group 2 (64.9%; P 5 .0377). However, no infertility treatments, especially if future pregnancies are differences were detected in the pregnancy rates (31.1% planned (Van Steirteghem et al, 1993; Penson et al, vs 30.9%; P 5 .9806), implantation rates (22.1% vs 2002). On the other hand, Lee et al (2009) demonstrated 17.3%; P 5 .5882), and miscarriage rates (21.7% vs that when direct costs are considered, microsurgical 23.9%; P 5 .8401) in groups 1 and 2. No differences TESE appears to be more cost-effective than varicocel- were detected in the mean number of embryos trans- ectomy for treating varicocele-associated nonobstructive ferred in group 1 (2.8 6 0.18) and group 2 (2.4 6 0.13; P azoospermia (Haydardedeoglu et al, 2010). The cost- 5 .0785), or in the number of cycles cancelled per cycle effectiveness of both treatments has improved with time.
(5.1% and 10.1%, respectively; P 5 .2277).
Most importantly, the authors concluded that cost-effectiveness analyses may be tailored to institution-specific data to allow more individualized results.
A retrospective study by Haydardedeoglu et al (2010) evaluated whether a history of varicocele repair in men Varicocelectomy has become the most commonly with nonobstructive azoospermia improved ICSI out- performed male infertility surgery. In fact, according comes. The authors found a significantly higher sperm to Zini et al (2008), men with poorer baseline retrieval rate in the varicocele repair group compared characteristics are more likely to opt for varicocele with the group of men who had not undergone repair. Furthermore, couples electing not to repair the varicocele repair. The clinical pregnancy and live birth varicocele are more likely to undergo ICSI procedures to rates were significantly higher in the varicocelectomy improve their chances of conception.
group. Therefore, varicocele repair might be considered The relationship between varicocele and azoospermia in patients with nonobstructive azoospermia who are is controversial. The main question is whether azoo- spermia is caused by varicocele or by coexisting primary Smit et al (2010) in a very elegant study prospectively testicular failure. Therefore, there is no consensus on evaluated sperm chromatin structure changes in infertile whether to correct varicocele in azoospermic men with patients before and after surgical varicocele repair and maturation arrest or Sertoli cell–only syndrome. Fur- their impact on pregnancy rates. After varicocelectomy, thermore, the question remains whether surgical repair sperm parameters significantly improved and sperm DNA of varicocele should be recommended for the above fragmentation was significantly decreased. Low DNA conditions to avoid the need to obtain sperm by fragmentation index values were associated with a higher testicular sperm extraction (TESE) for ICSI. Motile pregnancy rate (both spontaneous and with assisted sperm from the ejaculate provide better fertilization, reproductive techniques). Therefore, the authors argued cleavage, and pregnancy rates with ICSI than those that varicocelectomy should be considered in infertile men from TESE (Loutradi et al, 2006). It is generally with palpable varicocele, men with abnormal semen accepted that sperm production recovers somewhat analysis, and female partners with no major infertility after varicocele repair, but remains suboptimal. In a factors. However, the study included only 49 men, which recent study, Inci et al (2009) evaluated 96 men with was too small a sample to allow for conclusive results.
complete nonobstructive azoospermia and a history ofclinical unilateral or bilateral varicocele. Their results In our study of 248 patients who had varicocele or suggest that varicocele repair significantly increases the who had previously undergone a varicocelectomy, we sperm retrieval rate in patients with clinical varicocele found that although the fertilization rate was higher in and nonobstructive azoospermia. The authors conclud- the varicocele group, the pregnancy, implantation, and ed that men with clinical varicocele and nonobstructive miscarriage rates did not differ between the groups.
azoospermia who undergo varicocelectomy are not Further studies are needed to confirm our results.
likely to retain sufficient sperm quality to achieve pregnancy either with intercourse, intrauterine insemi-nation, or ICSI without the use of TESE.
We conclude that although past evidence indicates that The development of ICSI as the method of choice in varicocelectomy may be of benefit in some circumstanc- cases of severe male factor infertility has encouraged es and should always be considered before recommend- scientists to modify their diagnostic and therapeutic ing assisted reproductive techniques when appropriate, approaches (Van Steirteghem et al, 1993; Penson et al, this surgical procedure was not shown to have an impact 2002). Thus, a frequent question regarding the thera- on pregnancy or miscarriage rates following ICSI in Varicocelectomy and Assisted Reproductive Outcomes couples where the male partner had an existing or Matthews GJ, Matthews ED, Goldstein M. Induction of spermato- genesis and achievement of pregnancy after microsurgical varico-celectomy in men with azoospermia and severe oligoasthenosper-mia. Fertil Steril. 1998;70:71–75.
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