Induction of Spermatogenesis in Azoospermic Men after Varicocele Repair

Hasan FarsiK.A. University HospitalKing Faisal Specialist HospitalJeddah

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.STulloch, 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. 19761976 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

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.

Sclerotherapy for Varicocele in Azoospermic patients

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

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., Fertil Steril. 2006 Mar;85(3):635-9.

Is the Effect Durable?

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. 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 – Unilaterl VS Bilateral– Varicocele grade

– Hypospermatogenesis and late maturation arrest

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

No association

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):108-11Aboulghar 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

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