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

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

Statistically significant improvement in: …..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

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

Donkol RH. J Ultrasound Med. 2007 May;26(5):593-9. 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 Unilaterl VS Bilateral Varicocele grade Hypospermatogenesis and late maturation arrest No association Arch Androl. 2004 May-Jun;50(3):145-50

TOTAL 275 108 (39.27%) Author Year No. of pts Tech. % of pts with sperms Pregnancy(%) Czaplicki 1979 33 Micro 12(34%) 3 patients Matthews 1998 22 12(55%) 3PTS Kadioglu 2001 24 5(20.8%) ? Kim 1999 28 12(43%) 2 Schlegel 2004 31 7(22%) Nil Cakan 13 Inguin 3(23%) Pasqualotto 2006 27 9(33.3) 1 Lee 2007 19 7(36.4%) Esteves 2005 17 8(47%) 1 Spontan 4 ICSI Gat 32 Embo. 18(56.2%) 9(26%) Poulakis 14 Sclero 7(50) Osmonov 15 sclerot 8(53) all <0.1m/cc 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

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

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