male infertility - cleveland clinic...post varicocelectomy. other markers of oxidative stress were...

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


Was there loss of follow-up or

lack of participation greater

than 10% of those sampled

initially?

(1) Yes

(2) No


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


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


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


Was the measurement of

outcome(s) objective?

Objective meaning medical

records or diagnostic test, not

objective/subjective meaning

recall, etc.

(3) Yes

(2) No


Was ascertainment of outcome

performed at the same

location both before and after

treatment?

(4) Yes

(2) No


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


Was severity/grade of varicocele

evaluated before the intervention?

(3) Yes

(2) No


Did investigators use an established

set of guidelines for semen analysis?

(4) Yes

(1) No


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-

surgery. The sperm concentration was increased by

9.71 >< 106 /mL (95% confidence interval (CI) 7.34—12.08,

p < 0.00001) in all 10 studies (Figure 16.1A). The aver-

age motility was increased by 9.92% (95% CI 4.90—14.95,

p = 0.0001) in the studies that utilized microsurgery

(Figure 16.1B).

The results for high ligation were similar by applying a

weighted average in seven or eight studies (depending on

the outcomes measured). Concentration was increased by

12.03 x 106 /mL (95% Cl 5.71-18.35, p 0.0002) as calcu-

lated from reported results in eight studies (Figure 16.2A).

Motility was increased by 11.72% (95% CI 4.33—19.12,

p = 0.002) as averaged over reported results in seven stud-

ies (Figure 16.2B).

Morphology was only reported in seven of the 17

studies. These studies were analyzed together, but three

utilized microsurgery and three used high ligation.

One study had data on morphology using both of these

techniques. The combined results for both the types of

surgery were included in the analysis. The change in

morphology was statistically significant with an esti-

mated change of 3.16% (95% Cl 0.72-5.60, p = 0.01)

(Figure 16.3).


What is the effect of varicocelectomy on pregnancy rate?


Trials included

Out of the 101 articles retrieved, our meta-analysis was

limited to five surgical studies that had data on "spontane-

ous" pregnancy rates [30-341.

Outcomes

The odds of "spontaneous" pregnancy after varicocelec-

tomy compared with no/medical treatrnent for clinicalvaricocele was significantly different at 2.87 (95% CI 1.33—

6.20, p = 0.007) using random effects model (Figure 16.4).

A fixed effects model also yielded a significant odds ratio

of 2.63 (95% Cl 1.60-4.33, p = 0.00001). The test for the

presence of heterogeneity between study measures was

not significant (p = 0.17).

Comment

Surgical varicocelectomy in selected patients does have

a beneficial effect on fertility status. In infertile men with

palpable lesions and at least one abnormal semen param-

eter, it improves the odds of spontaneous pregnancy in

their female partners. Similarly, varicocelectomy signifi-

cantly improves semen parameters in infertile men with

palpable varicocele and abnormal semen parameters. The

couples who fail to achieve a natural pregnancy after vari-

cocele repair may achieve better results with ART because

of the increase in semen quality.

Recommendations

We support the latest best practice policy guidelines laid

down by the ASRM and the AUA and recommend vari-

cocele repair for infertile men with clinically palpable

varicocele having at least one abnormal semen parameter

(Grade 1B).

Efficacy of clomiphene citrate in maleinfertility treatment

Background

Antiestrogens are used as empiric nonspecific therapy

in the management of idiopathic male infertility. The

two most commonly used nonsteroidal antiestrogens

are clomiphene citrate and tamoxifen. Clomiphene is

a synthetic compound similar in structure to diethyl-

stilbestrol. In spite of its mild estrogenic properties, it

predominantly acts as an antiestrogen. Clomiphene citrate

is usually prescribed in doses of 12.5—50 mg per day

149

Study

Barabalis et al. 1998Cayan et al. 2000

Goldstein et al. 1992

Jungwirth et al. 2000Kamal et al. 2001

Kibar et al. 2002

Schatte et al. 1998

su et al. 1995Zini et al. 1999

Zini et al. 2005

N

22

236

271

272

159

90

61

53

30

37

Pre-varicocelectomyMean (SD)

16.20 (13.80)

29.70 (l .21)

36.97 (38.35)

51.70 (4.20)

22.50 (2.10)

22.10 (4.20)

23.36 (35.45)

34.00 (6.00)

34.60 (41.40)

34.60 (6.00)

Total (95% CD 1231

N

22

236

271

272

159

90

61

53

30

37

1231

Post-varicocelectomyMean (SD)

36.80 (28.20)

36.62 (l .58)

46.85 (38.35)

64.30 (6.60)

28.90 (3.00)

38.30 (6.10)

29.19 (38.48)

34.00 (7.00)

33.60 (55.90)

38.40 (7.60)

Test for heterogeneity: Ch2 = 320.71, dt = 9 (p < 0.00001), r = 97.2%

WMD (random) WMD (random)

20.80[7.48, 33.721

6.92[6.67, 7.17]

9.88[3.42, 16.341

12.60[11.77, 13.43]

6.40[6.83, 6.97]

16.20[14.67, 17.731

5.83 (-7.30, 18.98]

11.00[8.52, 13.481

-1.20[-26.09, 23.691

3.80[0.68, 6.921

9.71 [7.34, 12.081

Test for overall effect Z = 8.02 (p < 0.00001)

-IOO -50 o 50 100

pre- Post-

varicocelectomy varicocelectomy

Study

Barabalis et al. 1998

Cayan et al. 2000

Goldstein et al. 1992

Grober et al. 2004

Kamal et al. 2001

Kibar et al. 2002

Schatte et al. 1998

su et al. 1995

Zini et al. 1999

Zini et al. 2005

Total (95% a)

N

22

236

271

272

159

90

61

53

30

37

1015


16.20 (13.80)

29.70 (1.21)

36.97 (38.35)

51.70 (4.20)

22.50 (2.10)

22.10 (4.20)

23.36 (35.45)

34.00 (6.00)

34.60 (41.40)

34.60 (6.00)

N

22

236

271

272

159

90

61

53

30

37

1015

Post-varicocelectomy

Mean (SD)

36.80 (28.20)

36.62 (1.58)

46.85 (3835)

64.30 (6.60)

28.90 (3.00)

38.30 (6.10)

29.19 (38.48)

34.00 (7.00)

33.60 (55.90)

38.40 (7.60)

WMD (random) WMD (random)Cl

12.00[3.01, 20.99]

17.87[17.62, 18.211

6.04[2.72, 9.361

7.30[5.71, 8.89]

1 1.80 [7.29, 16.311

21.90[21.30, 22.501

5.83 [0.08, 11.581

5.00[4.24, 5.76]

10.30[-2.63, 17.97]

1.20[0.16, 2.24]

9.92[4.90, 12.081

Test for overall effect Z = 3.87 (p = 0.0001)

-100 -50 o 50 100pre- Post-


(b)

Figure 16.1 (a) Postoperative sperm concentration increased significantly following microsurgical varicocelectomy (p < 0.00001). (b) Postoperative sperm

motility increased significantly following microsurgical varicocelectomy (p = 0.0001). Cl, confidence interval; SD, standard deviation; WMD, weighed mean

Test for heterogeneity: Ch2 = 2327.48, dt = 9 (p < 0.00001), r 99.6%

difference.

either continuously or on a 25-day cycle with a 5-day

rest period each month [35,361.

Although numerous investigators have studied the effect

of clomiphene on male infertility, controversy still exists

regarding its efficacy. Many well-designed prospective

150

randomized controlled trials failed to demonstrate any

significant improvement with clomiphene as comparedto placebo [37-43]. However, a few studies have shown

a positive effect of clomiphene on pregnancy outcomes[44,451. The Cochrane systematic review which was

Cayan et al. 2000 232

Dhabuwala et al. 1992 38

Grasso et al. 2000

Hsieh et al. 2003

Khan et al. 2003

Sayfan et al. 1992

34

96

15

55

Segenreich et al. 1997 158

30.97 (2.46)

33.80 (5.60)

16.89 (l .88)

26.20 (18.77)

13.50 (3.50)

(47.00)

7.40 (0.60)

Total (95% CD 650

22

232

38

34

96

15

55

158

650

28.40 (22.60)

34.57 (3.58)

58.60 (10.10)

16.00 (2.27)

42.78 (28.50)

21.90 (5.60)

93.00 (129.00)

21.70 (0.60)

Test for heterogeneity: Ch2 = 2205.10, dt = 9 (p < 0.00001), r - - 97.7%

13.20[2.37, 24.03]

3.60 [3.04, 4.16]

24.80[21.13, 28.471

-0.89[1-1.88, 0.10]

16.58[9.75, 23.411

8.40[5.06, 11.74]

46.00[9.72, 82.28]

14.30[14.17, 14.43]

12.03[5.71, 18.36]


-100 -50 o 50 100pre— Post-


Study N

Barabalis et al. 1998 22

Cayan et al. 2000 236


Grasso et al. 2000

Hsieh et al. 2003

Khan et al. 2003

Sayfan et al. 1992

Total (95% CD

34

96

15

55

496


36.60 (18.00)

2560 (1 .16)

24.90 (1.80)

22.06 (2.83)

31.86 (18.64)

23.60 (6.10)

71.00 (51.00)

N

22

236

38

34

96

15

55

496

Post-varicocelectomy Mean (SD)

49.20 (24.10)

43.47 (1.55)

30.90 (1.80)

22.99 (2.70)

47.62 (21.03)

39.20 (7.60)

88.00 (54.00)

WMD (random)95% Cl

WMD (random)95% Cl

12.60[0.03, 25.17]

17.87[17.62, 18.121

6.00 [5.19, 6.81]

0.93 [-0.38, 2.24]

15.76[10.14, 21.38]

15.60[10.67, 20.53]

17.00[-2.63, 36.631

Test for heterogeneity: Ch 2 = 2205.10, dt = 9 (p < 0.00001), r = 97.7%11.72 [4.33, 19.121

Test for overall effect Z = 3.73 (p 0.0002)

-100 -50 o 50 100pre— Post-

varicocelectomy varicocelectomy(b)

Figure 16.2 (a) Postoperative sperm concentration increased significantly following varicocelectomy by high ligation (p = 0.0002). (b) Postoperative spermmotility increased significantly following varicocelectomy by high ligation (p = 0.002). Cl, confidence interval; SD, standard deviation; WMD, weighed meandifference.

updated more than a decade ago found no significantbenefit with clomiphene in increasing the fertility rates of

men with idiopathic oligospermia [46]. In another meta-

analysis, Kamischke & Nieschlag demonstrated no signi-

ficant therapeutic effect of antiestrogen therapy with

clomiphene and tamoxifen on pregnancy outcomes [47].

Some investigators have found men with normal pre-

treatment follicle-stimulating hormone (FSH) to be more

likely to respond to clomiphene treatment. They sug-

gested utilizing pretreatment serum hormone levelsto differentiate potential responders and nonresponders

However, a large multicenter double-blind

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


Goldstein etal. 1992 271

Grasso et al. 2000

Hsieh et al. 2003

Zini al. 1999

Zini et al. 2005


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 overall effect Z = 8.02 (p < 0.00001) _ 50 o 50 100_ 100

Post-pre—


Figure 16.3 Postoperative sperm morphology increased significantly following varicocelectomy (p = 0.01).

OR (random) OR (random)

Study Varifoefectory

n/N

Control 95% Cln/N

Grasso 2000

Madgar 1995

Marmar 1994

Okuyama 1988

Onozawra 2002

Total (95% Cl)

1/34

15/25

66/186

43/141

6/30

398

Total events 131 (Varicocelectomy) 27 (Control)

2/34

2/20

15/83

6/18



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


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.


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

motile sperm count. Unfortunately, insufficient studies

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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male infertility - cleveland clinic...post varicocelectomy. other markers of oxidative stress were...

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