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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 1999 AUA Meeting (Infertility Topics)
1999 American Uologic Association Meeting Dallas, TX, May 1999
(The following sessions on infertility were reviewed and abstracted by Drs. Dale McClure, Dana Ohl, Mark Sigman, and Randall Meacham,. Source: SSMR Newsletter September, 1999)
Infertility: Therapy, Poster Session
Infertility: Evaluation, Podium Session
Infertility: Physiology and Pathophysiology, Poster Session
Summary: Infertility Topics
1. Infertility: Therapy Poster Session ( May 4,1999)
Fujisawa et al (Abstract 1081) induced overexpression of the tumor suppressor protein p53 in testes of Sprauge-Dawley rats. This tumor suppressor gene plays a role in pro-grammed cell death and has been localized to spermatocytes. By using recombinant adenoviral vectors, virus containing wild type p53 and the cytomegalovirus promoter (to induce overexpression of p53) were infused into the right testis of the rats. Overexpression of p53 was noted in the testes. Testicular weight and spermatogenesis were significantly reduced with an almost complete disappearance of germ cells by day 14. Testis infected with control adenovirus without p53 were unchanged.These data suggest a significant role of p53 in normal spermatogenesis.
Varicocele is a common contributor to male infertility. Caruso et al (Abstract 1083) demonstrated that creation of experimental varicocele in the rat leads to increase in germ cell apoptosis. These results suggest that programmed cell death may be one mechanism by which varico-cele induces testicular failure in subfertile men.
Fertility in spinal cord-injured men is clearly reduced, however, the mechanisms for this reduction are largely unknown. Ohl et al (Abstract 1085) have developed a canine model to study fertility following spinal cord injury. Electroejaculation was effective in obtaining ejaculates. Decreased motility was not noted until 3 weeks following injury. This model will allow for more detailed studies of fertility changes following spinal cord injury.
Cigarette smoking has long been implicated as a gonotoxin. Rajpurkar et al (Abstract 1086) further developed this concept by evaluating the effect of cigarette smoke exposure using a smoking chamber for periods ranging from 15 to 45 days. They noted a reduction in sperm cell count and seminiferous tubule diameter in smoke-exposed rats. In another poster presented in the same session, these investigators demon-strated that such exposure to cigarette smoke leads to an increase in germ cell apoptosis. (Rajpurkar et al , Abstract 1097)
In many instances, it is more convenient to perform MESA at a scheduled date and freeze the specimen for use in conjunction with IVF/ICSI at a future time Spitz et al (Abstract 1087) demonstrated that similar fertilization and implantation rates were obtained when using fresh versus frozen epididymal sperm.
Micro-deletions in the Y chromosome are found in a sub population of severely oligospermic and azoospermic men. Most studies are performed on DNA from leukocytes in the peripheral blood. Nudel et al (Abstract 1089), using a single cell PCR, developed a technique to examine single sperm for the presence of specific Y chromosome markers. This will allow for the detection of deletions that may be limited to germ cells.
2. Infertility: Evaluation, Podium Session ( May 4, 1999)
Wolter et al (Abstract 1201) comparing vasovasostomy to MESAIIVF undertook a cost-benefit analysis. Vasovasostomy was performed in 157 men and MESA/IVF in 103. They examined actual costs and cost per delivery. Patency rate for vasovasostomy was 75% and pregnancy rate was 52% per couple. The pregnancy rate for MESA/IVF was 26% per cycle. The cost per pregnancy was 5,500 DM for vasovasostomy as compared to 28,000 DM. Thus, there were considerable cost savings with vasovasostomy for obstructive azoospermia as compared to MESA/IVF.
Epididymovasostoirly is the most technically demanding microsurgical procedure performed by urologists. Several years ago, Dr. Berger described a new technique for epididymovasostomy suing three sutures that are placed ma triangulation pattern to facilitate the end-to-side epididymovasostomy. McCallum et al (Abstract 1196) compared the triangulation epididymovasostomy to the standard end-to-side epididymovasostomy in a rat model. They observed a 11% significant improvement in potency rate, 92% versus 54%, and a reduction in sperm granola rate, 21% versus 58%, when using this new technique. A more recent modification that even simplifies Berger's technique further employing just two sutures was also discussed.
A study of genomic instability using microsatellite analysis of 4 loci was performed in infertile men was discussed by Kim at el (Abstract 1197). Testicular microsatellite analysis revealed testicular gene alterations as compared to blood in approximately 40% of men with abnormal sperm production.
One of the most novel presentations of the meeting was by Macbluf et al (Abstract 1198) describing a new method of testosterone replacement therapy by purification in the rat and were able to culture these cells in vitro. Cultured cells in CaCI2 and then poly-L-lysine and injected them into the peritoneum of recipient castrate animals. They then docu-mented continued in vivo function by normalization of serum testosterone levels in the castrated rats.
Two separate studies assessed the role of varicocelectomy in azoospermic men. Both Lipshultz et al (Abstract 1200) and Esteves et al (Abstract 1199) demonstrated restoration of sperm to the ejaculate of azoospermic men following repair of clinical varicoceles. Sperm counts remained very low and spontaneous pregnancies were rare. However, removal of testicular tissue was avoided for those couples who proceeded to IVF. Patients with Sertoli cell only did not respond favorably. Thus, testicular biopsy may be considered prior to varicocele repair in the azoospermic patient. A very interesting study carried out by questionnaire Sharma et al (Abstract 1207) found that infertile couples were in favor of post-mortem sperm retrieval and against government intervention on this issue.
3. Infertility: Physiology and Pathophysiology, Poster Session ( May 5, 1999)
Nigham et al (Abstract 1320) found that pregnancy rates achieved with epididymal sperm extracted either by percutaneous or microsurgical routes were similar whether using fresh or frozen samples. On the contrary, Maier et al (Abstract 1339) found that the take-home baby rate was significantly higher when fresh sperm were used.
An important study by Samli et al (Abstract 1329) demonstrated heterogeneity of spermatogenesis in nonobstructed azoospermia. In 29.7% of patients, there was a difference in the histopathological findings between a right and left testes biopsy. This stresses the Importance of doing bilateral testes biopsies in searching for sperm in individuals with nonobstructed azoospermia.
In studying the physiological advances that occurred during electroejaculation (EEJ) in men with spinal cord injuries, Sonksen et al (Abstract 1325) found that EEJ induces ejaculation by stimulation of a complex neurological pathway. The sustained nature of the response in EEJ patients suggests that the electro-stimulation should be stopped -during ejaculation to allow more relaxation of external sphincter, thus preventing decrease in retrograde ejaculation.
In a comparison study between Kruger's strict morphology and the optimized sperm penetration assay, Lucena et al (Abstract 1328) found there is a disparity between the results of the strict morphology and SPA in predicting IVF outcome. This supports the theory that different functional aspect of sperm are being evaluated by two these tests.
Johnsen et al (Abstract 1342) and Kunne et al ( Abstract 1343) reviewed two nonoperative forms of treatment for varicocele. Johnsen evaluated 10 years of experience with antegrade scrotal sclerotherapy (ASA) in 4,666 patients.They found ASA has equivalent persistence rate,complication rate, pregnancy rate, and results of semen analysis to the conventional surgical approach. Kunnen et al found transfemoralcoaxial embolization of the internal spermatic vein with tissue adhesive to be both highly effective and safe.
Brandell et al (Abstract 1355) gave further verification of the efficacy of the Berger triangulated end-to-side vasoepididymostomy, with an 83% patency rate at 6 months in 18 patients, comparing favorably to a published series from the same center utilizing a previous technique.
McCullough et al (Abstract 1366) compared ICSI outcomes between frozen epididymal sperm and fresh testicular sperm. Interestingly, despite comparable fertilization and chemical pregnancy rates, fresh testicular sperm yielded higher implantation and clinical pregnancy rates, leading the investigators to hypothesize that the use of frozen epididymal sperm may negatively impact implantation and/or early embryo development.
Lamb et al (Abstract 1351) reported results form electroejaculation (EEJ) with ICSI in a group of 17 couples who had failed EEJ/IUI. Pregnancy rates were 15% per cycle and 29% per couples (more than one attempt in some) which were significantly lower than ICSI rates seen in non-EEJ male factor patients.
Okada et al (Abstract 1350), from Japan, reported an association between the 9 +0 sperm flagellar defect and autosomal dominant polycystic kidney disease. All four patients with the specific sperm defect were found to have PCKD. Low fertilization and pregnancy rates from ICSI were seen in these patients.
4. Summary of 1999 SSMR (SOCIETY FOR THE STUDY OF MALE REPRODUCTION) Annual Meeting
( The following sessions was submitted by Stanton C. Honig, M.D. Source: SSMR Newsletter, September 1999)
The 1999 SSMR meeting was attended by 138 people. The focus of the meeting was to allow audience participation in complicated, but relatively common cases in male infertility.
The cases relating to obstructive azoospermia discussed the role of source of sperm retrieval, timing and surgical approach. The audience response to these issues were as follows:
Source of sperm retrieval
71% epididymis or vas (if possible)
Timing of procedure
68% timed with wife's cycle
32% intentional cryopreservation prior to ICSI cycle
71% local with sedation
29% only local anesthesia
Drs. Arnold Belker and Paul Turek discussed their biases on these issues.
The main take-home points were as follows:
Each case is unique and therapy needs to be individualized.
Listen to, as well as guide your embryology laboratory.
Discussion of the need for multiple IVF cycles may guide your approach.
The urologist needs to be at the forefront of development of these minimally invasive. techniques.
Good fertilization and pregnancy rates have been obtained with frozen-thawed testis sperm.
Cases of non obstructive azoospermia were discussed by Drs. Oates and Schlegel. The overwhelming majority of the audience approached these cases with an open testis biopsy/ extraction (90%). 74% would proceed with a pre-ICSI diagnostic/TESE with cryopreservation. Of the audience responding, 64% perform genetic testing with both karyotyping and Y chromosome microdeletions. Both speakers agreed that genetic testing and counseling is essential prior to TESE/ICSI cycles. Dr. Oates prefers intentional cryopreservation of sperm with a pre-ICSI procedure, because his experience has been a 90% sperm recovery rate. Although the data suggests that no preoperative parameters can predict sperm retrieval, he will do a fresh "TESE" timed with the ICSI cycle in patients with severely atrophic testes, low testosterone or Klinefelter's syndrome. Dr. Schlegel will do most TESE procedures timed with the wife's cycle and recommends a wide incision in the tunica albuginea to possibly isolate tubules with sperm that may be seen under microscope evaluation in patients with heterogeneous testis parenchyma. The majority of the audience polled (58%) favored a viability assessment of the cryopreserved sperm and if few viable sperm were identified, to proceed with a fresh TESE timed with the wife's cycle. 24% favored a repeat fresh TESE without viability testing of the frozen specimen.
Significant differences of opinion were shared by Drs. Mullhall and Zini regarding the patient with only immotile sperm in the ejaculate. Both agreed that these patients should have a urologic work up that might eventually include electron microscopy of the sperm. They both emphasized that this was potentially a genetically transmittable problem. 50% of the audience responded that they would do viability testing on the sperm, and if a high percentage were viable, would use the immotile ejaculated sperm. 24% would proceed directly to TESE without viability testing. Dr. Zini discussed his experience with using viable irnmotile ejaculated sperm identified by the hypoosmotic swelling test (HOST). He feels that pregnancy rates are equal when using either motile ejaculated sperm, viable (using HOST) immotile ejaculated sperm or testicular sperm. Dr. Mulhall cautioned that we do not know the dangers of HOST on sperm and using testicular sperm will allow for a higher percentage of viable sperm, with minimal morbidity to the patient. When performing viability testing, the audience responded that they would use the HOST test (36%) and vital staining (46%). Finally, Drs. Kim and Sandlow discussed two very different cases of male infertility related to varicoceles. The issues for discussion involved whether sophisticated testing might influence your decision making process for treatment of the varicocele. Dr. Kim argued that sophisticated testing was valuable because in certain cases it might suggest that varicoceles may be incidental to the infertility, i.e. associated Y chromosome microdeletion, high WBC count, etc. He also summarized the data with varicoceles in azoospermic men and stressed that repairing the varicocele in these cases might restore some sperm to the ejaculate and obviate the need for multiple testicular sperm aspirations. Dr. Sandlow focused his attention on the data evaluating varicocele success rates and certain sophisticated tests such as sperm penetration the hemizona assay and strict morphology. He emphasized that there are a few small studies that have valuated this topic and the data were not convincing. Although sophisticated testing gives some information, his perspective was that they should not influence your decision to proceed with a varicocele repair vs. ART.
This year's meeting was well attended. Plans for next year's meeting are underway. An audiotape was made of the meeting and may be available as needed Thanks again for the support of Weiser and associates for their coordination efforts and to Doug Watford of Merck Pharmaceuticals for coordination of audience response system.
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