U J - Spring 2012.pdf

505Vol. 9 | No. 2 | Spring 2012 |U R O LO G Y J O U R N A L

Effects of Varicocele Repair on Spontane-
ous First Trimester Miscarriage
A Randomized Clinical Trial

Mandana Mansour Ghanaie,1 Seyyed Alaeddin Asgari,1 Nassrin Dadrass,1 Aliakbar Allahkhah,1

Elham Iran-Pour,2 2

Purpose: To evaluate the effects of varicocelectomy on semen parameters, preg-

Materials and Methods: One hundred and thirty-six women with recurrent mis-
carriage were recruited into this study. All of the husbands had normal semen
parameters according to World Health Organization criteria and clinical varico-
cele. In order to evaluate the causes of recurrent pregnancy loss, we looked for

diseases. Both groups were well matched according to male/female age, varico-
cele grade, and smoking history. These couples were assigned randomly into two

followed up until delivery. In each 3-month follow-up visits, two semen analyses
were performed.

Results: Mean sperm concentration, sperm progressive motility, and sperm with
-

P
P

P P
P

factors to pregnancy rate by multiple regression analysis.

Conclusion: Varicocelectomy improves semen quality, increases pregnancy rate,

our results seem warranted.

Keywords: varicocele, pregnancy trimesters, abortion, randomized controlled trial

Corresponding Author:

Mohammad Reza Safa-
rinejad, MD

P.O. Box 19395-1849,
Tehran, Iran

Tel: +98 21 2245 4499
Fax: +98 21 2245 6845

E-mail: info@safarinejad.
com

Received June 2011
Accepted September 2011

1Urology Research Center,
Guilan University of Medi-

cal Sciences, Rasht, Iran
2Private Practice of Urology
and Andrology, Tehran, Iran

Sexual Dysfunction and Infertility

506 | Sexual Dysfunction and Infertility

INTRODUCTION

The incidence of varicocele in both men and adolescent boys varies between 10% and
The association of a varicocele with infertility has
been well documented. It has been demonstrated
that testicular development is compromised in
teenagers with varicocele; this impairment can ad-
versely affect sperm quality. It is also important
to note that varicocele can result in sperm DNA
damage, and elevated reactive oxygen species

When ROS are in
excess, they can cause pathological impairment
by inducing oxidative changes in cellular lipids,
proteins, and DNA. Men whose semen contains
increased levels of ROS may have diminished fer-
tility for both invitro and invivo procedures, and
there may be adverse effects on embryo develop-
ment.
In some cases, apoptosis may commence, but ter-
minate prematurely, in a process known as abor-
tive apoptosis, leading to ejaculation of mature
sperm with apoptotic traits, such as fragmented
DNA. Chen and colleagues reported that pa-
tients with varicocele have elevated levels of 8-hy-
droxydeoxyguanosine, a marker of oxidative DNA
damage. Excessive levels of DNA damage have
been associated with a decrease in several fertility
indices, including embryo cleavage rate, implanta-
tion rate, pregnancy rate, and live birth rate.
Furthermore, examination of biopsies obtained
from varicocele-affected testes by atomic force
microscopy reveals structural and morphological

well as changes in head dimensions. Surgical
varicocelectomy improves seminal parameters
and is associated with decreased ROS production
and increased levels of seminal plasma antioxi-
dants.

loss of three or more consecutive pregnancies in

It affects about 1% of all fertile couples trying to
conceive. Despite extensive investigations, no
clear cause is found in more than half of cases and
they are categorized as idiopathic RM.
There is an interaction between the male and fe-
male genomes during the time of both natural and
assisted conception. The paternal genome plays
its role during early embryonic development by

-
sion.
measures increased sperm chromatin susceptibility

in the time from unprotected intercourse to con-
ception in men with high SCSA values. In a
study by Evenson and associates, higher values of
the SCSA were able to predict 39% of the miscar-
riages.
Furthermore, correlations exist between sperm
DNA integrity and outcomes of invitro fertilization
treatment cycles. Another study, investigating
sperm chromosome anomalies, demonstrated a

We therefore designed a prospective randomized,
double blind study to determine pregnancy out-
come after varicocele repair in normozoospermic
men.

MATERIALS AND METHODS
Study Population
In a randomized clinical trial, consecutive women
were recruited from Alzahra Hospital’s gynecolo-

gynecology clinic due to recurrent pregnancy loss

-
riages were included in this study. In order to evalu-
ate the causes of RPL, we looked for chromosomal

-
tory, and infectious diseases. When these women

507Vol. 9 | No. 2 | Spring 2012 |U R O LO G Y J O U R N A L

Varicocelectomy and Miscarriage | Mansour Ghanaie et al

to them for consideration of their participation in
this study. Couples were excluded if their husband
had abnormal semen analysis according to the

-
tive antisperm antibody assay.
Evaluations
Women willing to participate were encouraged to
ring for an appointment. At this appointment, a full
history was taken and the results of previous in-
vestigations were noted to make certain that there
no cause was found for RPL. In all the cases, the
wives had undergone gynecologic workups and
were found to be fertile. The trial was then ex-
plained further and a written informed consent was
obtained.
All the patients underwent karyotype analysis in
order to determine chromosomal abnormalities,
such as balanced translocations. The anatomy of
the uterus was evaluated by transvaginal ultrasound
scan and hysterosalpingography and/or hysteros-
copy in order to diagnose mullerian malformations

All men underwent a basic infertility evaluation,
including history taking, complete physical exami-

of varicocele was diagnosed by physical examina-

parameters, at least two semen analyses were per-
formed at 1 month interval to remove inadvertent
and possible adverse effects of various issues on
spermatogenesis. The normal WHO values in-

6/mL concentration with grade A

of spermatozoa and normal morphology in at least
30% of the spermatozoa. Exclusion criteria includ-

on physical examination, total testicular volume of

or substance abuse, severe general diseases, and
endocrinopathies.

informed consent and Local Medical Ethics Com-
mittee approved the study protocol.
Randomization
Women meeting the inclusion criteria were visited

508 |

after a negative pregnancy test. If the consent was
obtained, couples were given consecutive study
numbers and sent to Department of Urology. A

-
-

number.
We used minimization to ensure comparability be-
tween women with respect to parity, type of mis-
carriage, and gestation. Both groups were well
matched according to male/female age, varicocele

grade, and smoking history. Inguinal standard vari-
cocelectomy was performed using a loupe magni-

Outcome Measures
The primary endpoint was clinical pregnancy and
live birth. The secondary outcome was to deter-

Patients and their husbands were visited every
month during the whole study period. Since be-

Sexual Dysfunction and Infertility

Table 1. Baseline demographic and clinical characteristics of study groups.*
Characteristics Group 1 (n = 68) Group 2 (n = 68) P
Age, y

Male 36.1 ± 4.2 .67
Female 29.1 ± 3.7 .46

Infertility duration, y 5.4 ± 2.6 .52
Prior miscarriage, No. 3.7 ± 1.3 .72
Body mass index, kg/m2

Male 27.3 ± 2.4 27.6 ± 2.2 .72
Female 24.1 ± 2.7 24.3 ± 2.6 .64

Varicocele grade, No. (%)
Grade I 17 (25.0) 15 (22.1)
Grade II 41 (60.3) 42 (61.7) .24
Grade III 10 (14.7) 11 (16.2) .09

Testis volume, mL 23.7 ± 2.6 23.6 ± 2.7 .12
Serum hormones
Male

Testosterone, nmol/L 16.4 ± 4.7 16.2 ± 4.6 .27
FSH, IU/L 12.2 ± 3.6 12.6 ± 4.1 .34

Female
SHBG, nmol/L 63.2 ± 14.4 .47

LH, IU/L .62

FSH, IU/L 9.7 ± 2.4 9.4 ± 2.3 .46

Estradiol, pmol/L 91.2 ± 47.1 .26

Estrone, pmol/L 102 ± 25 .52

PRL, pmol/L

prolactin.

509Vol. 9 | No. 2 | Spring 2012 |U R O LO G Y J O U R N A L

ginning of the study, to assess fertility outcome,
women were visited every month to complete a
questionnaire.
We collected data regarding pregnancy, including
date of last normal menstrual period, serum level

-
mation of clinical pregnancy. Pregnancy testing
was performed by the quantitative measurement of
serum level of hCG in the absence of menstruation.
For every 3-month visit, two semen samples were

time to pregnancy since the start of the trial. All
of the clinical pregnancies were followed up until
delivery.
Statistical Analysis
Univariate analyses were carried out using Stu-
dent’s t test for continuous variables and the Chi-
Square or Fischer’s exact test for dichotomous
variables. A two-sided independent-sample t test
was used for comparison. The Pearson correla-
tion r was used to determine any potential associa-
tions. Cox proportional hazards regression analy-
sis was performed to determine which groups of

Varicocelectomy and Miscarriage | Mansour Ghanaie et al

Table 2. Semen parameters and pregnancy data at various assessment points.£

Assessment points after varicocelectomy Assessment points during expectant therapy

Variables Baseline 3 months 6 months 9 months 12 months Baseline 3 months 6 months 9 months 12 months

Semen parameters, (mean ± SD)

Total sperm

count, ×106
110.6 ±

15.3

114.2 ±

14.4d
159.4 ±

176.2 ±

15.1c c
113.4 ±

12.2

115.2 ±

14.2d 14.2d
114.2 ±

14.7d
115.5 ±

16.7d

Sperm density,

×106/ml

32.2 ±

6.4

33.2 ±

4.4d
55.2 ±

5.2c
56.2 ±

62.6 ±

5.7c
32.4 ±

6.4

36.6 ±

5.3d 6.1d
36.6 ±

6.2d
36.7 ±

6.1b

Sperm motility, %
2.2

41.4 ±

2.5d 4.4a b
54.2 ±

5.7c
37.2 ±

2.1 2.6d
40.4 ±

2.2d
39.6 ±

2.6d
40.6 ±

2.5 d

Normal morphol-
ogy, %

56.7 ±

2.6

59.7 ±

2.6d
64.4 ±

3.4a
67.6 ±

4.6c
66.4 ±

4.2c 2.4

67.7 ±

3.4d 3.5d 3.5 d d

Pregnancy data, No. (%)*

Clinical preg-
nancy rate

NA 0 (0) 20 (29.4) 7 (10.3) 3 (4.4) NA 5 (7.3) 4 (2.6) 3 (2.6)

Live birth rate NA
0 (0)

3 (100.0) NA 0 (0.0) 1 (20.0) 1 (25.0) 2 (66.7)

Miscarriage rate NA
0 (0)

3 (15.0) 1 (14.3) 0 (0.0) NA 1 (100.0) 3 (75.0) 1 (33.3)

aP = .02 to .05, bP = .01, cP = .001 to .005, and dP = not significant.
All P values are versus baseline.
*New cases between previous assessment point and current assessment point.
£

510 |

pregnancy rates. The SPSS software (the Statisti-
cal Package for the Social Sciences, Version 17.0,

statistical analyses and a P value < .05 was consid-

RESULTS
Baseline demographics and clinical characteristics
of study groups are shown in Table 1. Mean total
sperm count, sperm concentration, sperm motility,

in sperm parameters were observed during the

Baseline mean sperm concentration in groups 1

mL, respectively (P
period, the mean sperm concentration increased by

(P -
celectomy, the increases in total sperm counts from

improved sperm motility. Mean sperm motility

months postoperatively (P
underwent varicocelectomy, the normal morpho-
logical sperm level increased from a mean of 56.7

(P
When studying the correlations between the time
elapsed after the varicocelectomy and the semen
analysis parameters, strong positive correlations
were found between elapsed time and sperm con-

P
P -

phology (r = 0.37; P
Forty-three of 138 couples conceived clinically

-
nancies were after the varicocelectomy and 13

P = .003; Table

varicocelectomy group, respectively. These rates

respectively (P
-

tively (P

Table 3. Summary of multiple regression analysis of factors affecting live birth rates in couples.

Variables Univariate Multivariate

Coefficient P Odds ratio (95% CI)* Coefficient P Odds ratio (95% CI)

Male age, y -0.024 .03 -0.026 .03

Female age, y -0.062 .002 -0.064 .002

Varicoceletomy .001 .001

Total sperm count, ×106 0.061 .001 3.6 (2.5 to 5.6) 0.067 .001

Sperm density, ×106/mL 0.072 .001 3.7 (2.7 to 6.4) 0.073 .001 3.2 (2.5 to 5.2)

Normal morphology, % 0.064 .001 2.7 (1.7 to 4.7) 0.061 .01 2.7 (1.7 to 4.7)

*CI indicates confidence interval.

Sexual Dysfunction and Infertility

511Vol. 9 | No. 2 | Spring 2012 |U R O LO G Y J O U R N A L

ended with miscarriage in the expectant group.
Correlations
We also addressed the correlations between some
variables and live birth. We put them in multivari-

-
lated to outcome were the sperm density followed

chance of pregnancy increased with an increase in

P = .001] and decreased with rising age of

to 0.90; P
The time elapsed from varicocelectomy was a con-
tinuous variable that was categorized into two dif-

P
-

nancy within the statistical model. With sperm mo-

was almost 3.5 times more than the chance with

to 5.8; P -
ogy was > 60%, the chance of achieving pregnancy

DISCUSSION
-

celectomy and the rate of clinical pregnancy and
miscarriage. The risk of child loss decreased sig-

-
mained after correction for male/female age and

study for comparison. Our data indicate that even
in healthy men with varicocele, without overt oli-
goasthenoteratozoospermia, there is an increased
risk of miscarriage in their wives. In the present

study, varicocelectomy in normozoospermic men
resulted in improved live birth rate in their wives.
We could not explain this completely.
Men with varicocele have increased oxidative
DNA damage. Seminal antioxidant capacity

Increased oxidative stress production in seminal

membrane and the sperm DNA integrity. Exces-
sive sperm DNA damage is associated with a re-
duction in some fertility indices, such as fertiliza-
tion, embryo cleavage, implantation, and clinical
pregnancy rates.
O’Brien and coworkers studied the outcomes in
infertile men with varicocele who had female part-
ners older than 35 years. They reported that sur-
gical and nonsurgical approaches resulted in simi-
lar pregnancy rates. In this study, we included men
with normal semen parameters.

-
tion and excessive ROS production. It has been
shown that oxidative stress plays a key role in
sperm dysfunction in patients with varicocele.
Spermatozoa are vulnerable to oxidative damage

In
men with varicocele, sperm ROS levels are greater
than those in normal healthy men. It has been
demonstrated that varicocelectomy decreases ROS
levels and increases the antioxidant capacity of
seminal plasma from infertile men with varicocele.

Increased level of ROS in the reproductive tract
disrupts the integrity of DNA in the sperm nucleus.
Spermatozoa containing damaged DNA may result
in paternal transmission of defective genetic mate-
rial with adverse outcomes for embryonic devel-
opment. It has been reported that infertile men
demonstrate improved sperm DNA integrity six
months after varicocele repair.
Varicocele is characterized by increased tempera-
ture of the scrotum. According to one theory, in-

Varicocelectomy and Miscarriage | Mansour Ghanaie et al

512 |

creased temperature can result in thermal dam-
age of the DNA and proteins in the nucleus of
spermatic tubules’ cells and/or Leydig cells.
Furthermore, it has been shown that in men with
varicocele, germ cell apoptosis is a very common
phenomenon. Indeed, germ cell apoptosis can
lead to subsequent oligozoospermia. Varicocele
grades in the treated and untreated groups were
well matched.
Our study is not without limitations. The main lim-
itation is the small sample size. The sample was

-
graphical area, limiting the generalizability of the

-
al sperm parameters, such as seminal antioxidant
capacity, sperm acrosomal reaction, and sperm
DNA integrity.

CONCLUSION
Our results demonstrate that varicocele repair in-
creases the chance for spontaneous pregnancy and
live birth. Varicocelectomy may be offered to cou-
ples who suffer from recurrent miscarriage. None-
theless, further studies with a large number of sub-

CONFLICT OF INTEREST
None declared.

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Varicocelectomy and Miscarriage | Mansour Ghanaie et al