Male infertility Ashok Agarwal, Fnu Deepinder and Edmund S. Sabanegh Jr Center for Reproductive Medicine, Glickman Urological and Kidney Institute, The Cleveland Clinic, Cleveland, OH, USA The role of varicocelectomy in management of male subfertility Background Varicocele is present in approximately 40% of men pre- senting with infertility [1]. Although varicocele repair is widely used in the management of male-factor infertility, the effectiveness of varicocelectomy has been intensely debated, and there is still no consensus on the topic. Existing literature is conflicting, and very few suffi- ciently large and adequately controlled prospective trials are available evaluating the efficacy of varicocelectomy in improving pregnancy outcomes. Two published meta- analyses evaluating prospective randomized trials came to the same conclusion that varicocele repairs do not improve subfertility [2,3]. A recently updated Cochrane review reco- mmended against varicocele repair for unexplained infer- tility [4]. However, these meta-analyses have been criticized for methodological flaws which may have biased their results [5]. Consequently, they have not resolved the issues surrounding varicocelectomy and subfertility. The development of assisted reproductive techniques (ART) has led to increased use of intracytoplasmic sperm injection (ICSI) for all causes of male infertility including varicoceles. However, these techniques have safety issues, deprive patients of the satisfaction of natural conception, and are less cost-effective [6]. Recent guidelines from the Best Practice Policy Committee of the American Urological Association (AUA) and the American Society for Reproductive Medicine (ASRM) have recommended varicocele repair for infertile men with a clinically palpable varicocele and at least one or Evidence-Based Urology. Edited by Philipp Dahm, Roger R. Dmochowski. 0 2010 Blackwell Publishmg. 146 more abnormal semen parameters with female partner having either normal or potentially treatable fertility [7]. Rationale for the use of varicocelectomy in management of male subfertility The exact mechanism by which varicocelectomy improves fertility in affected men remains unknown. Oxidative stress and DNA damage to sperm, which are well-documented components of varicocele pathophysiology, have shown improvement after varicocele repair. Hurtado de Catalfo and colleagues have demonstrated elevated levels of thio- barbituric acid reactive substances which are markers of oxidative stress in both seminal and peripheral plasma of varicocele patients which returned to normal 1 month post varicocelectomy. Other markers of oxidative stress were also decreased and the total antioxidant capacity was increased 6 months after varicocelectomy in their study [8]. Confirming the increased antioxidant capacity after vari- cocele repair, a more recent study also found a significant decrease in the levels of 8-hydroxy-2-deoxy-guanosine (8-0HdG), another marker of oxidative stress in all post- varicocele repair patients. In this study, investigators also demonstrated a significant decline in the incidence of 4977 bp deletion in mitochondrial DNA, a marker of oxi- dant-mediated DNA damage after varicocele repair [91. Shiraishi & Naito showed that elevated preoperative 4-hydroxy-2-nonenal (4-HNE) modified protein levels in the testis could predict a response to varicocele repair [101. These landmark studies have suggested that varicocele repair decreases the levels of oxidative stress as a mechanism for improving fertility. Literature search We conducted new meta-analyses to assess the effect of varicocelectomy on pregnancy outcomes and semen parameters [11,121. In these analyses, we included both
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Male infertility
Ashok Agarwal, Fnu Deepinder and Edmund S. Sabanegh JrCenter for Reproductive Medicine, Glickman Urological and Kidney Institute, The Cleveland Clinic, Cleveland, OH, USA
The role of varicocelectomy inmanagement of male subfertility
Background
Varicocele is present in approximately 40% of men pre-senting with infertility [1]. Although varicocele repair iswidely used in the management of male-factor infertility,the effectiveness of varicocelectomy has been intenselydebated, and there is still no consensus on the topic.
Existing literature is conflicting, and very few suffi-
ciently large and adequately controlled prospective trials
are available evaluating the efficacy of varicocelectomy
in improving pregnancy outcomes. Two published meta-
analyses evaluating prospective randomized trials came to
the same conclusion that varicocele repairs do not improve
subfertility [2,3]. A recently updated Cochrane review reco-
mmended against varicocele repair for unexplained infer-
tility [4]. However, these meta-analyses have been criticized
for methodological flaws which may have biased their
results [5]. Consequently, they have not resolved the issues
surrounding varicocelectomy and subfertility.
The development of assisted reproductive techniques
(ART) has led to increased use of intracytoplasmic sperm
injection (ICSI) for all causes of male infertility including
varicoceles. However, these techniques have safety issues,
deprive patients of the satisfaction of natural conception,
and are less cost-effective [6].
Recent guidelines from the Best Practice Policy
Committee of the American Urological Association (AUA)
and the American Society for Reproductive Medicine
(ASRM) have recommended varicocele repair for infertile
men with a clinically palpable varicocele and at least one or
Evidence-Based Urology. Edited by Philipp Dahm, Roger R. Dmochowski.
0 2010 Blackwell Publishmg.
146
more abnormal semen parameters with female partnerhaving either normal or potentially treatable fertility [7].
Rationale for the use of varicocelectomyin management of male subfertility
The exact mechanism by which varicocelectomy improvesfertility in affected men remains unknown. Oxidative stressand DNA damage to sperm, which are well-documentedcomponents of varicocele pathophysiology, have shownimprovement after varicocele repair. Hurtado de Catalfoand colleagues have demonstrated elevated levels of thio-barbituric acid reactive substances which are markers ofoxidative stress in both seminal and peripheral plasmaof varicocele patients which returned to normal 1 monthpost varicocelectomy. Other markers of oxidative stresswere also decreased and the total antioxidant capacity was
increased 6 months after varicocelectomy in their study [8].
Confirming the increased antioxidant capacity after vari-
cocele repair, a more recent study also found a significant
decrease in the levels of 8-hydroxy-2-deoxy-guanosine(8-0HdG), another marker of oxidative stress in all post-
varicocele repair patients. In this study, investigators also
demonstrated a significant decline in the incidence of
4977 bp deletion in mitochondrial DNA, a marker of oxi-
dant-mediated DNA damage after varicocele repair [91.
Shiraishi & Naito showed that elevated preoperative
4-hydroxy-2-nonenal (4-HNE) modified protein levels in
the testis could predict a response to varicocele repair [101.
These landmark studies have suggested that varicocele
repair decreases the levels of oxidative stress as a mechanism
for improving fertility.
Literature search
We conducted new meta-analyses to assess the effect
of varicocelectomy on pregnancy outcomes and semen
parameters [11,121. In these analyses, we included both
Although critics may object to inclusion of observationalstudies in a meta-analysis, we adhered to the principlesof the Potsdam guidelines laid down by a group of 20scientists for the conduct and interpretation of meta-analyses [13].
Studies were identified by performing an extensivesearch using BIOSIS, EMBASE, and Medline (from 1985to the present) with the help of a professional librarianas well as by hand-searching review articles and cross-ref-erences. The following keywords were used to search thedatabases: "varicocelectomy," "microsurgery," "high liga-tion," "infertility," "semen parameters," and "pregnancyor outcome." No exclusions were made based on language.Studies were excluded if subclinical varicocele only orsubclinical varicocele combined with clinical varicocelewere examined or if the effect of treatment was examinedonly in an adolescent population.
Types of participantsInfertile males diagnosed with unilateral or bilateral vari-coceles with abnormal semen parameters. The controlgroups were composed of infertile males with varicocelewho declined to undergo surgical repair of varicocele,were randomized to no/ medical treatment or randomized
to receive treatment after the follow-up period.
Types of interventionSurgical ligation (high ligation, inguinal or microsurgery).
Types of outcome measures• Effect of varicocelectomy on semen parameters — change in
semen parameters (count, motility and morphology) after
surgery using before-and-after repeated measures studies.
These studies had semen data from the same individual,
before and after varicocelectomy.
• Effect of varicocelectomy on pregnancy outcome — propor-
tion of couples achieving spontaneous pregnancy during
follow-up of up to 24 months using observational and ran-
domized controlled trials.
Effect of varicocelectomy on semen parameters
Blinding and scoring. All articles and reviewers wereblinded during the evaluation period. Two evaluators
blinded to the concluding results, authors, journal, and year
of the articles evaluated each study on its methodological
merits. Articles with both pre- and postoperative repeated
measures of semen parameters were evaluated for
methodological qual-ity by our new scoring system (Table
16.1). The questions and scores were developed to evaluate four
categories of bias: selection or follow-up bias, confounding
bias, information or detection bias, and other sources of bias
such as misclassification. If the points for more than one
category of bias totaled to below an acceptable range, the
Male infertility CHAPTER 16
study was automatically excluded from the final analysis.
If the points for only one category totaled below theacceptable range, the study was re-examined to determinewhether the overall study was likely to be biased and,if not, whether it could be included in the meta-analysis. If
the follow-up time was more than 2 years after the surgery
or with no follow-up within this time period or if the study
did not account for time-varying confounders, then it waslikely that the study would be excluded. Two reviewers
scored each study independently, and the final decision on
whether or not a study was to be included was determined
by a discussion between the two reviewers.
Data extraction. Data were extracted by one of the investig-
ators on a preformatted data extraction sheet. The outcomes
of interest for continuous variables such as concentration,
motility and morphology data were extracted, and a weighted
mean was calculated. Population information (i.e. primary
versus secondary infertility) and study characteristics such
as the specific intervention (high ligation, microsurgery, and
laparoscopy) were listed.
Data analysis. The data were then entered in the RevMan
software (version 4.2.8) developed by the CochraneCollaboration for the purpose of meta-analysis (www.cochrane.org).The semen data were segregated according
to the type of surgical procedure used on these patients.Studies were included that had at least three semenanalyses per patient. Since sequential semen data oftendemonstrate variability, a random effects model wasused to adjust for the heterogeneity. A p value < 0.05was used as a cut-off point for significance testing in allstatistical tests.
Effect of varicocelectomy on pregnancy outcome To examinethe effect of varicocelectomy on "spontaneous or natural"
pregnancy outcome, cohorts were studied within a 2-yearfollow-up, after a varicocelectomy was performed onone cohort and no/ medical treatment or no surgicaltreatment on another. Studies were retrieved in the samemanner as described above for semen characteristics.They were then graded using a scoring sheet that wasspecifically intended to examine the research question.The development of the scoring criteria was similar tothat described above with the same considerations ofbias, but other questions were developed for cohortstudies rather than pre/ post repeated measures studies.Studies were excluded if they had men with subclinicalvaricoceles. Patients who had undergone ART were notincluded in the analysis, Studies that used embolizationor sclerosis techniques for varicocele corrections werealso excluded.
Extraction of data was performed without a data extrac-tion sheet because there was only one outcome of interest.
147
Selection/follow-up
From what, if any, underlyingcohort is the study populationderived?
(3) From a geographical cohort(3) From a community(2) From a clinic population(1) Unable to answer
How were subjects recruited?
(3) All cases in the populationwere included(2) Cases were recruitedconsecutively over a periodof time
(3) Cases were randomlyselected
(1) Unable to answer
Did the investigators restrict
against participants based on
infection, previous treatment,
and female factor infertility
or conditions related to
ART outcome and sperm
parameters?
(3) Yes
(2) No
(1) Unable to answer
Was there loss of follow-up or
lack of participation greater
than 10% of those sampled
initially?
(1) Yes
(2) No
(1) Unable to answer
Total =
Exclusion criteria
Category
Selection
Confounding
Information
Other
Confounding
Was the time between the two
follow-up periods short enough to
allow for no confounding by age
within subjects (under 2 years)?
(3) Yes
(1) No
(1) Unable to answer
Do they evaluate and account for
potential confounders that may vary
over time, e.g. amount of follow-
up time, season, smoking, alcohol
consumption, original sperm count,
time-varying exposures, etc.?
(2) Yes, but they do not adjust
(3) Yes, and they adjust for them
when necessary(1) Unable to answer
Did the investigators prespecify the
same procedures for analysis for
before and after the intervention?
(2) Yes
(2) Not applicable
(1) No
(1) Unable to answer
Total =
Maximum score
11
8
10
10
Information/detection bias
Was the method of follow-up
the same before and after
treatment?
(3) Yes
(2) No
(1) Unable to answer
Was the measurement of
outcome(s) objective?
Objective meaning medical
records or diagnostic test, not
objective/subjective meaning
recall, etc.
(3) Yes
(2) No
(1) Unable to answer
Was ascertainment of outcome
performed at the same
location both before and after
treatment?
(4) Yes
(2) No
(1) Unable to answer
Total =
Minimum score
4
3
3
3
Any study will be excluded if two or more categories score in the ''exclude" range
Any studies will be re-reviewed if only one category scores in the ''exclude" range
Other
.1
Does the study combine outcomes acrossgroups with very heterogeneous histories/durations of infertility and across differentinterventions?
(2)Yes
(3) No
(1) Unable to answer
Was severity/grade of varicocele
evaluated before the intervention?
(3) Yes
(2) No
(1) Unable to answer
Did investigators use an established
set of guidelines for semen analysis?
(4) Yes
(1) No
(1) Unable to answer
Total =
Include score Exclude score
11-7
8-5
10—8 7-3
10-8 7-3
Pregnancy data were recorded for the 24-month intervalafter surgery and the overall odds were calculated. Thedata were verified by a second investigator, and analysisof the pregnancy data was performed by both random andfixed effects models.
Clinical question 16.1
What is the effect of varicocelectomy on semen parameters?
Trials included
A total of 136 studies were identified, of which only17were included in the meta-analysis that pertained to
semen parameters [14-30].
Outcomes
Of the 17 studies, only 10 examined concentration and
motility of sperm before and after intervention by micro-
randomized controlled study conducted by the WorldHealth Organization and a multicenter prospective ran-domized Scottish trial found no evidence to support thishypothesis [40,431.
Rationale for the use of clomiphene citratein male infertility
Clomiphene indirectly stimulates the secretion of gonado-tropin-releasing hormone (GnRH), FSH and luteinizinghormone (LH) by binding to estrogen receptors in thehypothalamus and pituitary, thereby blocking estrogen
151
CHAPTER 16 Male infertility
Post-varicocelectomy
Study N
Barabalis et al. 1998 22
Dhabuwala et al. 1992 36
Goldstein etal. 1992 271
Grasso et al. 2000
Hsieh et al. 2003
Zini al. 1999
Zini et al. 2005
Pre-varicocelectomyMean (SD)
15.20 (12.00)
36.10 (1.90)
39.62 (38.35)
30.06 (3.01)
62.30 (16.17)
46.40 (14.70)
20.90 (1.90)
Mean (SD)
34
96
30
37
22
36
271
34
96
30
37
28.40 (22.60)
40.30 (1.70)
46.85 (38.35)
28.97 (2.99)
64.68 (16.91)
54.40 (1 1.00)
22.10 (2.60)
WMD (random)
WMD (random) Cl95% Cl
13.20[2.49, 23.911
2.40[3.39, 5.011
7.23[0.77, 13.691
-1.09[-2.52, 0.341
2.38[-2.30, 7.06]
8.00[1.43, 14.571
1.20[0.16, 2.24]
3.16[0.72, 5.601
Total (95% CD 528 528
Test for heterogeneity: Ch2 = 55.85, dt = 9 (p < 0.00001), r = 97.2%
Test for overall effect Z = 8.02 (p < 0.00001) _ 50 o 50 100_ 100
Test for heterogeneity: Ch2 = 8.47, dt = 4 (p < 0.17), r = 38.1%
Test for overall effect Z = 2.68 (p = 0.007)
0.01 0.1
Favors control
0.48[0.04, 5.611
13.50[2.55, 71.401
2.93[0.82, 10.441
1.99[1.02, 3.86]
3.90[0.76, 19.951
2.87[1.33, 6.201
10 100
Favors secure
Figure 16.4 Effect of varicocelectomy on pregnancy rate using random effect model showed significant improvement (p = 0.007). Cl, confidence interval;
n, number of couples achieving pregnancy with male partners diagnosed with clinical varicoceles; N, total number of cases; OR, odds ratio; SD, standarddeviation; WMD, weighed mean difference.
feedback inhibition. The resultant increase in intratesticular
testosterone concentration is believed to boost the game-
togenic function of the testis. Men treated with clomiphene
consistently demonstrate an elevation in serum FSH, LH
and testosterone levels. However, it is essential to maintain
serum testosterone within normal limits because higher
levels may negatively influence spermatogenesis [35,361.
Application of clomiphene citrate in males with non-
obstructive azoospemia may result in sufficient sperm for
152
ICSI, either identified in the ejaculate or by successfulsurgical testicular sperm extraction [481.
Literature search
Studies were identified by performing an extensiveMedline search (from 1975 to the present) with the helpof a professional librarian as well as by hand-searchingreview arücles and cross-references. The following keywords
Male infertility CHAPTER 16
were used to search the databases: "clomiphenecitrate," "antiestrogens," "oligospermia," "infertility,""semen parameters," and "pregnancy rate or outcome."Randomized controlled trials (RCT) of clomiphene therapy
for at least 3 months or more compared to placebo or alter-
native treatment for subfertile males among couples where
subfertility was attributed to male factor were selected.
Couples who failed to achieve pregnancy after at least
12 months of unprotected intercourse were chosen. The
male partners of the couples included were diagnosed
with idiopathic infertility and had oligo- and/or asthe-nozoospermia. Any patient with known cause for infertil-
ity, such as history of toxin or drug exposure, varicocele,
undescended testis, primary germinal infertility or known
endocrine disorder, was excluded. The female partners
had no demonstrable cause for infertility as they hadnormal menstrual and ovulatory pattern and no sig-nificant mechanical abnormalities by laparoscopy or
hysterosalpingography.
Pregnancy data were recorded for 6—12 months after the
clomiphene empiric therapy and the overall odds werecalculated. P values < 0.05 were used as a cut-off point for
significance testing in all statistical tests.
Clinical question 16.3
Is clomiphene citrate effective for male infertility treatment?
Trials included
A total of 21 studies were identified, of which only seven
met our inclusion criteria [38-43,451. Five studies used
placebo as a control group [39,41-43,45] whereas one each
compared antioxidant vitamin C [401 and low-dose cortisone
acetate [38] to clomiphene citrate therapy.
Outcomes
The odds of "spontaneous" pregnancy after at least 3months of clomiphene therapy compared with no oralternative empiric treatment for male subfertility did notdiffer significantly: 1.55 (95% CI 0.66—3.68) by fixed effect
model and 1.35 (95% CI 0.75—2.42) by random effect model
(Table 16.2).
However, some of the trials demonstrated significant
improvement in semen parameters, especially the total
and heterogeneity among these trials precluded us from
conducting a meaningful meta-analysis evaluating the
improved outcomes in semen parameters.
Comment
Empiric clomiphene therapy 25—50 mg/ day for at least 3
months may have a beneficial effect on fertility status in
subfertile men by improving semen parameters which may
allow a downstaging of the required ART procedure, i.e.
utilizing intrauterine insemination (IUI) instead of ICSI.
Recommendations
Empiric trial therapy with clomiphene citrate 25—50 mg/
day for at least 3 months may be offered to subfertile men
with oligo- and/or asthenozoospermia at the clinician's
discretion before proceeding to advanced ART techniques
such as ICSI (Grade 2C). Literature support remains incon-
clusive, awaiting large randomized prospective trials of
empiric therapy.
Table 16.2 Effect of empiric clomiphene citrate therapy on pregnancy outcomes
Study
WHO 1992
Sokol et al, [41]
Micic & Dotlic [451
Wang et al. [421Abel et al.
Ronnberg [39]
Paulson [381
Total
Clomiphene dose Treatment group Control group
(mg/day)
25
25
50
25 or 50
50
50
25
25-50
7/70
1/11
7/56
4/29
15/93
1/14
7/17
42/298
Placebo
Placebo
Placebo
Placebo
Vitamin C 200 mg/day
Placebo
Cortisone 10 mg/day
Control group
6/71
4/9
0/45
0/7
10/86
2/15
23/248
Odds ratio
(95% CD
1.20 (0.39-3.75)
0.17 (0.02-1.21)
6.81 (146-31.69)
3.89 (0.29-51.80)
1.45 (0.62-3.37)
107 (0.06-18.10)
4.55 (0.77-26.83)
1.35 (0.75-2.42)
CHAPTER 16 Male infertility
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