Cornell University

NEW YORK
CORNELL
Cornell University
Weill Medical College

Cornell Institute for Reproductive Medicine

Center for Male Reproductive Medicine and Microsurgery

"State-of-the-Art Compassionate Care for the Infertile Couple"

What's New at 2002 AUA Meeting (Orlando, Florida, May 2002)

  • Take Home Message for Male Infertility Topics
  • The 2002 AUA First Prize of the Best Video Award

  • Take Home Message for Male Infertility Topics at 2002 AUA

    (The following sessions on male infertility were orginally prepared by Dr. Edward Kim, Associate Professor of Surgery/Urology at the University of Tennessee, Knoxville. Source: AUANews, June/July 2002, Volume 7, Isseue 4)

    1.
    Introduction
    2. Pathophysiology and Basic Science
    3. Treatment Advances
    4. Summary

    1. Introduction:

    Presentations at the 97th annual meeting of the AUA are establishing the foundations for the future of male infertility, which include elucidation of the genetic regulation of spermatogenesis and identification of potential new treatments based on this enhanced understanding of sperm production. Having rapidly integrated intracytoplasmic sperm injection (ICSI) into clinical practice in less than a decade, solutions to our future clinical challenges will be based on this enhanced knowledge of the pathophysiology of impaired spermatogenesis, potentially leading towards gene therapy.

    2. Pathophysiology/Basic Science:

    Apoptosis, a form of programmed cell death in contrast to necrosis, which represents "accidental cell death," plays an important role in spermatogenesis. Apoptosis represents the end point of a complex process controlled by specific extrinsic and intrinsic testicular regulators. The challenge is the identification and elucidation of the mechanism of action of these regulators. A number of extrinsic causes of testicular apoptosis were identified. In rat models excessive alcohol intake resulted in Leydig cell apoptosis (AUA Abstract #1266, #1272), while cocaine resulted in mitochondrial apoptosis (AUA Abstract #1268). Similarly cyclosporine A, a powerful immunosuppressant in widespread use, resulted in Sertoli cell apoptosis (AUA Abstract # 1267). Building upon work pioneered by Meistrich et al,1 Endo et al reported that luteinizing hormone releasing hormone agonists, by inducing testosterone withdrawal, may protect against doxorubicin induced spermatogonial damage in rats by inducing apoptosis during chemotherapy (AUA Abstract #1233).

    Current screening for genetic abnormalities consists of Y chromosome microdeletion assay and karyotype analysis for men with severe oligozoospermia (less than 1 to 5 x 106 sperm/ml) and cystic fibrosis transmembrane conductance regulator (CFTR) gene analysis for men with vasal and epididymal abnormalities. Consistent with an increasingly large body of evidence regarding the prevalence of these gene abnormalities, Y chromosome microdeletion abnormalities were identified in 6.7% of Brazilian men with less than 5 x 106 sperm/ml (AUA Abstract #1278). Kolettis et al found that 2 of 14 men (14%) with unilateral vasal agenesis had CFTR gene mutations (AUA Abstract #1401).

    Unfortunately, the vast majority of men with severe oligozoospermia do not have an identifiable cause. For this reason an increasing number of translational research projects have focused on identification of autosomal gene regulators of spermatogenesis. While these studies are important as initial investigations, their significance needs further definition. Hopps et al from Cornell focused on PIASx, which has been implicated as being essential for spermatogenesis, but found no deletions in the genomic DNA of men with severe infertility (AUA Abstract #1245). When Kojima et al examined DAX-1 expression in testis biopsies of men with non-obstructive azoospermia (NOA), immunohistochemical identification was positive in all of these men (AUA Abstract #1246). Similarly, HLA-DRB1 and –DQB1 segments of the HLA class II regions may be critical in the development of NOA (AUA Abstract #1248). Focusing on the androgen receptor (AR), a number of centers have identified that longer CAG repeat lengths within the first exon of the AR may be associated with spermatogenic failure (AUA Abstract #1249).

    Several studies have addressed the significance of sperm DNA damage. Shayegan et al reported that 22% of infertile men had an abnormal sperm DNA denaturation assay (AUA Abstract #1390). Using a sperm chromatin structure assay, no pregnancies with intrauterine insemination were observed when greater than 28% DNA damaged sperm were present (AUA Abstract #1231). This DNA damage does not appear to be related to smoking (AUA Abstract #1234) or to seminal antioxidants (AUA Abstract #1238).

    3. Treatment Advances:

    Relatively few studies have examined the natural history of varicoceles in younger and older populations. Using serial scrotal ultrasonography in a prospective series of Polish adolescents, Paduch et al defined an adolescent varicocele as greater than 1.7 min (AUA Abstract # 1229). When testicular atrophy was present, varicocelectomy restored testicular volume, whereas observation did not. At the other extreme of age Zapzalk et al identified a left varicocele in 42% of older men and a right varicocele in 21% (AUA Abstract # 1384). While larger lesions correlated with softening of the testis, bilateral testicular softening was necessary for a decrease in serum testosterone level.

    The end-to-side vasoepididymovasostomy (VE) using interrupted sutures was developed by Thomas in 1987.2 Berger introduced the increasingly popular 3-suture intussusception modification in 1998.3 Using this technique, Chan et al from Cornell reported an excellent patency rate of 84% (32 of 38 men) and a natural intercourse pregnancy rate of 30% (8 of 27) (AUA Abstract #1224). In an effort to simplify this technique further, Marmar introduced the 2-suture intussusception VE technique in 2000.4 Chan et al from Cornell compared intussusception techniques (AUA Abstract# 1225). Their newly described modified longitudinal 2-suture technique produced patency rates (93% vs. 64%) superior to the 3 and 2-suture techniques in a rat model, while shortening operative time.

    In an effort to improve sperm retrieval rates from men with NOA Schlegel and Li described testicular microdissection as a form of testicular sperm extraction (TESE) in 1998.5 This technique uses an operative microscope to identify individual seminiferous tubules that might contain sperm. Okada et al found that microdissection significantly improved (45% vs. 24%) sperm retrieval rates (AUA Abstract #1222). However, at the University of Illinois sperm were retrieved in 41.7% with microdissection and 37.5% with conventional TESE (AUA Abstract #1223). Microdissection added 50 minutes and increased costs. While TESE complications are low, a significant decrease in serum testosterone levels may persist for more than 1 year, especially if more than 2 TESE procedures have been performed (AUA Abstract #1221). In an experimental rat model Teloken et al observed a decrease in testis size and spermatogenesis after testicular sperm aspiration (AUA Abstract #1264).

    Medical therapies for male infertility are continuing a slow evolution. Given its accessible location and rapidly dividing cell population, the testis may be amenable to gene therapeutic approaches. Studies on gene transfer by intratubular or interstitial injection and electroporation in rats provide encouraging results regarding methods of gene therapy delivery. Two separate studies demonstrate that this method can result in gene expression (AUA Abstract #1235) and that testis function may recover (AUA Abstract #1276). Finally, we were reminded that sperm cryopreservation should be offered to younger men undergoing treatments for cancer, as many of these younger cancer patients will have good semen quality (AUA Abstract #1397). Rofeim et al reported a mean sperm density of 61 x 106 in younger cancer patients cryopreserving sperm (AUA Abstract #1395). TESE before chemotherapy in azoospermic patients can successfully retrieve sperm for potential use in future intracytoplasmic sperm injection cycles (AUA Abstract #1396).

    4. Summary

    Studies on male infertility presented at this year's annual meeting have further advanced our understanding of the role of apoptosis and genetic regulation of spermatogenesis, potentially opening the door for treatment advances for improving spermatogenesis. Newer techniques of sperm retrieval and VE modifications are promising and becoming increasingly popular. The next decade of advances in male infertility will be exciting, especially as the complex puzzle of spermatogenesis is pieced together at the molecular genetic level.

    Reference:

    1 Meistrich, M. L., Wilson, G., Ye, W. S. et al: Relationship among hormonal treatments, suppression of spermatogenesis, and testicular protection from chemotherapy-induced damage. Endocrinology, 137: 823, 1996.

    2 Thomas, A. J., Jr.: Vasoepididymostomy. Urol Clin North Am, 14: 527, 1987.

    3 Berger, R. E.: Triangulation end-to-side vasoepididymostomy. J Urol, 159: 1951, 1998.

    4 Marmar, J. L.: Modified vasoepididymostomy with simultaneous double needle placement, tubulotomy and tubular invagination. J Urol, 163: 483, 2000.

    5 Schlegel, P. N. and Li, P. S.: Microdissection TESE: sperm retrieval in non-obstructive azoospermia. Hum Reprod Update, 4: 439, 1998

    (Source: AUANews, June/July 2002, Volume 7, Issue 4)


    2002 AUA First Prize Winner of the Best Video Award

    1. Marc Goldstein,M.D., Peter TK, Chan, M.D. and Philip S. Li, M.D.: Ultra-precise Multi-layer microsurgical Vasovasostomy: Tricks of the Trade (2002 AUA Abstract # V641)

    2. DVD Video presentation ( 45 minutes) with extended surgical edition (Never-before-seen footage and bonus materials) of “ Microsurgical Vasovasostomy” are available.


    1. ULTRA-PRECISE MULTI-LAYER MICROSURGICAL VASOVASOSTOMY: TRICKS OF THE TRADE

    Marc Goldstein, M.D., Peter TK, Chan, M.D. and Philip S. Li, M.D.
    Center for Male Reproductive Medicine and Microsurgery
    Cornell Institute for Reproductive Medicine
    &
    Department of Urology
    Weill Medical College of Cornell University
    The New York Presbyterian Hospital
    New York, NY 10065
    (2002 AUA Abstract # V641)

    INTRODUCTION AND OBJECTIVES: Vasovasostomy most often requires anastomosis of two lumina with markedly discrepant diameters. We present a 4-layer microsurgical vasovasostomy technique that allows precise mucosal approximation and an atraumatic, leak-proof anastomosis.

    METHODS: The testicular and abdominal ends of the vasa are transected using a slotted-never-cutting clamp and an ultra-sharp micro-knife to provide a perfect transverse cut. Prior to performing the anastomosis, the vasal ends are freshened by progressive trisection until healthy mucosa and muscularis with good blood supply are obtained. Minimal instrumentation of the mucosa is performed. The microdot-mapping technique is used by placing 6 evenly distributed microdots on the cut surface of the vas deferens, indicating the exit points of the mucosal sutures. This allows perfect approximation of very discrepant lumina. The mucosal layer employs inside-out placement of six 10-0 monofilament nylon sutures double-armed with 70 um diameter fishhook shaped tapered needles. The muscularis is approximated with 6 sutures of 9-0 nylon placed exactly in-between each pair of mucosal sutures. The vasal adventitia is approximated with 6 interrupted sutures of 9-0 nylon placed exactly in between each pair of muscularis sutures. The vasal sheath, the fourth layer, is approximated with 6 sutures of 7-0 PDS.

    RESULTS: The average operating time per anastomosis was 2 hours. The outcomes of the surgery is 297 consecutive men with obstructive azoospermia revealed a patency rate (sperm count > 10,000/ml) at one year post-op of 99.7% (296/297), with a crude pregnancy rate of 55%. If couples with female-factor infertility were excluded, the pregnancy rate was 65%.

    CONCLUSIONS: This multi-layer technique allows a precise, leak-proof approximation of vasa with markedly discrepant luminal diameters. Although a relative longer operating time and more meticulous techniques are required, close to 100% patency rates and high naturally conceived pregnancy rate are possible.



    2. DVD Video presentation (45 minutes) of “ Microsurgical Vasovasostomy “ and extended surgical edition (Never-before-seen footage and bonus materials: Special lecture by Dr. Marc Goldstein “Infertility—It’s about more than getting pregnant”) are available.

    In this DVD presentation, we will illustrate the technique of microsurgical multi-layer vasovasostomy. We will also share with you tricks of the trade on how to increase your success rates in achieving a patent and durable microanastomosis.

    2002 AUA First Prize Winner of the Best Video Award

    “This presentation is extremely well done with excellent visual presentation of the procedure. Congratulations on the production of this material. It is a first rate presentation!”
    Arnold Belker, M.D.
    Clinical Professor of Urology
    Division of Urology
    University of Louisville School of Medicine
    Louisville, Kentucky


    “These beautifully produced film are as close as you can get to being there, without actually sitting next to an experienced microsurgeon in the operating room.”
    Zev Rosenwaks, M.D.
    Revlon Distinguished Professor of Reproductive Medicine
    Director of the Center for Reproductive Medicine and Infertility
    The Weill Medical College of Cornell University


    “This is the ideal way to illustrate how this operation is performed. Any experienced urologists or urologists in training can benefit greatly from this teaching series.”
    E. Darracott Vaughan, M.D.
    James J. Colt Professor of Urology and Chairman Emeritus of Urology
    The Weill Medical College of Cornell University



    For more information, please contact us at
    psli@med.cornell.edu.


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