Induction of Spermatogenesis in

Azoospermic Men after Varicocele Repair

Hasan Farsi
K.A. University Hospital
King Faisal Specialist
Hospital
Jeddah
Case Report
 26y male with 1ry infertility of 3y.
 Examination: Bilateral normal testes, Bilateral grade
II varicocele.
 Semen x2 Azooepermia, Volume 2-3cc, normal
semen fructose
 FSH was normal.
 Bilateral inguinal varicocelectomy, testicular biopsy:
– Hypospermatogenisis
 18 months later one child
 Semen:
– Volume: 1.5 cc
– Conc.: 3 m/cc
– Motility: 25%
Varicocele

 10-15% general population

 40% 1ry infertility
 80% 2ry infertility
 Ambroïse Paré (1500–1590): a clinical problem

 Barfield, late 19th century: Relationship to infertility

 Lipshultz, 1979: Relationship to testicular atrophy that is

progressive with age

 Kass and Belman, 1987:significant increase in testicular volume

after varicocele repair in adolescents
Clinical study of varicocele: the results
of long-term follow-up.

 Sixty-four infertile male patients with

varicocele :
– Varicocelectomy 31 cases
– No surgery 30 cases
 The mean follow-up duration was 76.2
months
 The pregnancy rate: (60%) VS (28%)
Int J Urol. 2002 Aug;9(8):455-61.
Surgery Vs Observation

 146 men left varicocelectomy

 62 men refused surgery treated with
tamoxiphene
 Followed up for at least 1 year
 Improvement in semen parameters:
– 83.2% VS 32.3%
 Pregnancy within 1 year:
– 62(46.6%) VS 8 (12.9%) (p<0.001).
Eur Urol. 2001 Mar;39(3):322-5.
Is varicocelectomy really beneficial in
the treatment of male factor infertility?
Efficacy of varicocelectomy in improving
semen parameters: new meta-analytical
approach.

 A meta-analysis was performed to evaluate both

randomized controlled trials and observational studies
using a new scoring system.
 Adjust and quantify for various potential sources of bias,
including selection bias, follow-up bias, confounding bias,
information or detection bias, and other types of bias, such
as misclassification
 Of 136 studies identified through the electronic and hand
search of references, only 17 studies met our inclusion
criteria
…..continue

 Statistically significant improvement in:

– Concentration
– Motility
– Morphology
 CONCLUSIONS: Surgical varicocelectomy
significantly improves semen parameters in
infertile men with palpable varicocele and
abnormal semen parameters.
Agarwal A, Department of Obstetrics Gynecology, Cleveland Clinic
Urology. 2007 Sep;70(3):532-8
Varicocelectomy Improves Intrauterine Insemination
Success Rates in Men with Varicocele.

 24 pts 63 intrauterine insemination cycles without varicocele

treatment.
 34 pts 101 intrauterine insemination cycles following
varicocelectomy.
 No statistically significant difference was noted in the mean post-wash
total motile sperm count in the treated and untreated groups.

 The pregnancy rate per cycle = 6.3 VS 11.8, p = 0.04

 Live birth rate per cycle =1.6 VS 11.8, p = 0.007

 Conclusion: A functional factor not measured on routine semen

analysis may affect pregnancy rates in this setting

Daitch JA. J Urol. 2001 May;165(5):1510-3

Why Does Varicocelectomy Improve
the Abnormal Semen Parameters?

 68 infertile men
 Seminal plasma levels of two ROS and six antioxidants on the
day prior to varicocelectomy
 Same parameters were measured again 3 and 6 months post-
operatively.
 concluded that varicocelectomy reduces ROS levels and
increases antioxidant activity of seminal plasma from infertile
men with varicocele.
 Conclusion: Varicocelectomy reduces ROS levels and
increases antioxidant activity of seminal plasma from infertile
men with varicocele.

Mostafa T, Department of Andrology, Faculty of Medicine, Cairo

University Int J Androl. 2001 Oct;24(5):261-5.
Varicocele: a bilateral disease
 286 infertile men
 Physical examination, contact thermography, Doppler sonography, and
venography of both testes.
 88.8% bilateral
 Mean sperm concentration increased from 6.12 +/- 1.02 to 21.3 +/-
1.69 million/mL
 mean sperm motility from 16.81 +/- 1.51 to 35.90 +/- 1.41%
 mean sperm morphology from 9.75 +/- 0.85 to 16.92 +/- 1.17%.
 Pregnancy rate was 43.5%

 This may suggest that we should consider varicocele a bilateral

disease

Gat Y. Fertil Steril. 2004 Feb;81(2):424-9.

Is assisted reproduction the optimal
treatment for varicocele-associated male
infertility? A cost-effectiveness analysis.

 The cost per delivery with ICSI was found to be

$89,091
 The cost per delivery after varicocelectomy was only
$26,268
 The average published U.S. delivery rate after one
attempt of ICSI was only 28%. whereas a 30%
delivery rate was obtained after varicocelectomy.
 CONCLUSIONS: Specific treatment of varicocele-
associated male factor infertility with surgical
varicocelectomy is more cost-effective than primary
treatment with assisted reproduction.
Schlegel PN. Urology. 1997 Jan;49(1):83-90
Varicocele & Azoospermia

 4.3-13.3%
Consideration of sterility; subfertility in
the male

 Interestingly, the first study on the

importance of varicocelectomy to male
infertility (Tulloch, 1952 ) reported
spontaneous pregnancy after varicocele
repair in an azoospermic man

Tulloch, W.S Edinb. Med. J. 1952 , 59, 29–34.

Results of ligation of internal spermatic vein
in the treatment of infertility in azoospermic
patients.

 10 azoospermic patients
 2 pregnancies

Mehan DJ. Fertil Steril. 1976 Jan;27(1):110-4.

Inguinal Varcocelectomy in
Azoospermic patients

 13 azo inguinal varicocelectomy

 Induction of spermatogenesis was achieved
in 3 (23%) patients
 Two of them had hypospermatogenesis and
one had maturation arrest at spermatid stage
 No pregnancies by natural intercourse

Cakan M. Arch Androl. 2004 May-Jun;50(3):145-50

Sclerotherapy for Varicocele in
Azoospermic patients

 14 Azo sclerotherapy
– 7/14 produced sperms
 Sperm con 3.1 ± 1.2 × 106/mL
 Mean sperm: 2.2 ± 1.9%
 mean sperm normal morphology:
7.8 ± 2.2%
 2 pregnancies
Poulakis V. Asian J Androl. 2006 Sep;8(5):613-9.
Embolization of Varicocele

 32 men with azoospermia

 Improved in 18/32:
– sperm concentration in the ejaculate 3.81±1.69 x
106/ml
– mean sperm motility: 1.20±3.62%
– mean sperm morphology: 8.30±2.64
 Nine pregnancies (26%)
– Four (12%) unassisted
– Five (15%) by ICSI
Gat Y. Human Reproduction 2005 20(4):1013-1017
 Is the Effect Durable?

 27 azoospermia microsurgical varicocelectomy

 Induction of spermatogenesis was achieved in nine
men (33.3%)
 Sperm conc 1.2 x 10(6)/mL to 8.9 x 10(6)/mL
 Motility 24% to 75.7%,
 One patient with maturation arrest established
pregnancy
 Five relapsed into azoospermia 6 months after the
recovery of spermatogenesis
Pasqualotto FF, Fertil Steril. 2006 Mar;85(3):635-9.
How long does it take for the sperms to
appear?

 17 azo microsur
 Spermatozoa in the ejacultae 47% (8/17)
 Only 35% (6/17) of them had motile sperm
 Mean time for appearance of spermatozoa in
the ejaculates was 5 months (3 to 9 months).

Esteves SC. Int Braz J Urol. 2005 Nov-Dec;31(6):541-8.

Predictors of Success
Response to varicocelectomy in oligospermic men
with and without defined genetic infertility.

 33 men with infertility & varicocele

– 7 has coexisting genetic infertility:
 Abnormal karyotype in 4
 Y chromosome microdeletion in 3

– 26 No defect
 Same semen parameters
 All had varicocelectomy
 54% VS 0% improvement
 CONCLUSIONS: From this early experience, men with
varicocele and genetic lesions appear to have a poorer
response to varicocele repair than men without coexisting
genetic lesions.
Paternity after varicocelectomy: preoperative
sonographic parameters of success.

 What are the sonographic findings that could predict the outcome of
varicocele repair in the treatment of male infertility?
 107 patients with varicocele.

 CONCLUSIONS: The best preoperative sonographic parameters of

success of varicocele repair are:

– The presence of normal-sized testes

– Clinically palpable veins
– Bilateral varicocele

Donkol RH. J Ultrasound Med. 2007 May;26(5):593-9.

Relationship between varicocele size
and response to varicocelectomy.

 grade 1--small (22 patients)

 grade 2--medium (44)
 grade 3--large (20)
 Sperm count, per cent motility, per cent tapered
forms were measured preoperatively and
postoperatively.
 Conclusion: infertile men with a large varicocele
have poorer preoperative semen quality but repair of
the large varicocele in those men results in greater
improvement than repair of a small or medium sized
varicocele.
Goldstein M.J Urol. 1993 Apr;149(4):769-71
Azoospermia: Predictors of Success

 FSH

 Histology
FSH

 Preoperative FSH levels between men who

did (14.8 ± 3.1 IU/L) and did not
(19.4 ± 3.8 IU/L) show improvement in
semen parameters after sclerotherapy were
not significantly different

Czplick M. Arch Androl. 1979;3(1):51-5

Histology

 Germinal Aplasia
 Maturation arrest at spermatocyte stage

 Hypospermatogenisis
 Maturation arrest at spermatid stage
….continue: predectors of success

 13 Azoospermic patients
– Age
– Preoperative sex hormones
No association
– Unilaterl VS Bilateral
– Varicocele grade

– Hypospermatogenesis and late maturation arrest

Arch Androl. 2004 May-Jun;50(3):145-50

 Author Year No. of pts Tech. % of pts with sperms Pregnancy(%)

Czaplicki 1979 33 Micro 12(34%) 3 patients

Matthews 1998 22 Micro 12(55%) 3PTS

Kadioglu 2001 24 Micro 5(20.8%) ?

Kim 1999 28 Micro 12(43%) 2

Schlegel 2004 31 Micro 7(22%) Nil

Cakan 2004 13 Inguin 3(23%) Nil

Pasqualotto 2006 27 Micro 9(33.3) 1

Lee 2007 19 Micro 7(36.4%) 1

Esteves 2005 17 Micro 8(47%) 1 Spontan

4 ICSI
Gat 2005 32 Embo. 18(56.2%) 9(26%)

Poulakis 2006 14 Sclero 7(50) 2

Osmonov 2006 15 sclerot 8(53) all <0.1m/cc Nil

TOTAL 275 108 (39.27%)

Subclinical Varicocele

 subclinical in 73 patients
 Clinical in 66 patients, based on palpation in
addition to ultrasonography.
 Conclusion: ligation of varicoceles detected
using Doppler ultrasonography, whether
palpable or not, results in an increase in
sperm concentration and motility.
Pierik FH, Rotterdam, The Netherlands. Int J Androl. 1998 Oct;21(5):256-60.
 76 underwent varicocele repair
 Improvement: Clinical VS subclinical:67% VS 41%
 But: Equal number were worse postoperatively and,
thus, mean sperm count was unchanged for the
group with subclinical varicocele
 Conclusion: The results of our study suggest that
subclinical varicocelectomy is of questionable
benefit.

Jarow JP North Carolina, USA. J Urol. 1996 Apr;155(4):1287-90

Fertilization and pregnancy rates after
intracytoplasmic sperm injection using ejaculate
semen and surgically retrieved sperm.

 350 patients:
– Ejaculated sperm
– Epididymal
– Testicular

CONCLUSION: The fertilizing ability of sperm in ICSI is highest with

normal ejaculated semen and lowest with sperm extracted from a
testicular biopsy in non-obstructive azoospermia.

Aboulghar M. Fertil Steril. 1997 Jul;68(1):108-11

Conclusion
 Varicocele may cause any variation of severity in spermogram including
azoospermia.

 The treatment of varicocele may significantly improve spermatogenesis and

renew sperm production.

 Adequate treatment may spare the need for TESE as preparation for ICSI in
>30% of azoospermic patients.

 Since achievement of pregnancy in IVF units is higher when spermatogenesis

is better, the treatment of varicocele is an effective medical adjunct for IVF
units prior to the treatment.

 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
 Y o u
h an k
T