Center for Male Reproductive Medicine & Microsurgery

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Results

We have treated over 2,500 men at our center using IVF with simultaneous sperm retrieval surgery for non-obstructive azoospermia.  Results with ICSI are primarily dependent on the availability of viable sperm and age of the female member of the couple being treated.  Although many couples we now see have had failed sperm retrieval (often several times) at other centers, our initial experience with sperm retrieval (in men who were predominantly treated here first) is illustrative.  In the first 1,414 attempted treatment cycles for couples in whom the man had NOA. The mean age of patients entering treatment was 35.5 years for men and 30.4 years for women.  In men, the initial mean serum FSH level was 25.3 IU/L (normal, 1 to 8 IU/L), and average testicular volume 13 ml.  During the initial 1,414 attempted TESE-ICSI cycles, sperm were retrieved for injection in 794 (56%) cycles (52% (607/1176) retrieval rate per-patient). For those cycles in which sperm were retrieved, the fertilization rate per injected oocyte was 51% (4,423 of 8,705). Our embryo transfer rate was 94 %. Clinical pregnancies were established in 48% of the cycles, and live deliveries occurred in ­­­­­41% of couples. With multiple gestations were seen in 10% of pregnancies.

No etiology of azoospermia provided an absolute predictor for the presence or absence of sperm within the testes, except for AZFa and AZFb deletions.  Testicular volume and serum FSH levels did not predict sperm retrieval because these features reflect overall function of the testis, not the best area of sperm production - the focus of the search with microTESE. 

The results for treatment of 127 men with classic and mosiac KS (47,XXY, or mosaic patterns that do not include 46,XY) who underwent attempted sperm retrieval during simultaneous 155 ICSI cycles at our institution are presented herein. Sperm were found in 65% (100/155) of the fresh retrieval attempts.  Our per-patient success rate of sperm retrieval for these 127 men was (77/127) 61%.  Embryo transfer occurred in 83% cases, with clinical pregnancy and fertility of 40% and 40 children born to-date. A multiple gestation rate of 31% has been seen in these pregnancies. Results did not differ for mosaic or non-mosaic patients.  All children have been healthy (46,XX girls and 46,XY boys.). These findings illustrate the potential for TESE-ICSI to provide fertility despite underlying genetic abnormalities.  Pre-treatment testicular biopsy histology was not helpful in distinguishing who would succeed with microdissection TESE for patients with Klinefelter syndrome.  Although a majority of men had Sertoli cell-only on diagnostic biopsy, 70% of these patients had sperm found on subsequent microdissection TESE.  Even though two of the patients treated had previously undergone multiple random biopsy TESE with no sperm found, sperm were retrieved in a subsequent procedure using the microdissection TESE technique. These findings illustrate the potential for TESE-ICSI to provide fertility despite underlying genetic abnormalities.  

Another treated subset of men with nonobstructive azoospermia includes the cohort of men with a history of chemotherapy administered for a variety of diagnoses who underwent sperm retrieval attempts with TESE for persistent nonobstructive azoospermia. All men were azoospermic and at least six years post-chemotherapy at the time of treatment.  In a cohort of 93 men with a history of chemotherapy administered for a variety of diagnoses underwent 114 sperm retrieval attempts for persistent NOA. Thirty of the 93 (32%) patients had also received extragonadal radiation. Sperm were successfully retrieved in 48% (55/114) of micro-TESE attempts, with clinical pregnancy occurring in 40% of couples. Per-patient sperm retrieval rate was 42% (39/93).  Men treated for lymphoma had a sperm retrieval rate per cycle of 44%, whereas after treatment for germ cell tumor the retrieval rate was 70%.  Diagnostic biopsy was not helpful in determining the prognosis for sperm retrieval.  Most patients had predominantly Sertoli cell-only pattern, even if germ cells were present in some seminiferous tubules.  No correlation was noted between the outcome of TESE-ICSI and the specific chemotherapeutic agents used.

Several case reports have described successful pregnancies after TESE with ICSI for men with NOA associated with cryptorchidism. While the undescended testicle results in a loss of germ cells, including spermatogonia with subsequent NOA. The treatment with an orchiopexy, have multiple risk factors and might cause ischemic insult to the testicle. It is believed that orchiopexy has no benefit for seminiferous tubules that have undergone irreversible degeneration. However, it serves to preserve the foci of germ cells capable of normal spermatogenesis. Micro-TESE allows for the harvesting of such foci that may have otherwise gone undetected.  In 152 men, 181 micro-TESE procedures were performed.  At Weill Cornell, spermatozoa were successfully retrieved in 116/181 (64%) attempts at sperm retrieval, pregnancy rate was 50%, and the delivery rate was 38% with 8 spontaneous abortions.  In this subgroup, the per-patient sperm retrieval rate was 62% (94/152).   In our cohort, 39% had bilateral cryptorchidism, and 4 patients with history of other genetic abnormality. The sperm retrieval rate in men with a history of bilateral cryptorchidism was 62%. 

            Genetic testing for Y chromosome microdeletions is of prognostic significance for TESE procedures.  For men with complete deletions of the AZFb region the chance of sperm retrieval during TESE is severely impaired.  In our experience, 0 of 23 men with Y chromosome partial deletions involving all of AZFb had sperm retrieved with TESE, whereas the sperm retrieval rate in a contemporary series of men with non-obstructive azoospermia but no AZFb deletions was 67% (85/126).  The presence of a complete deletion of AZFa appears consistently associated with Sertoli cell-only and a poor chance of sperm retrieval (Kamp et al., 2001).  Of the men with complete deletions of the AZFa region, who had diagnostic biopsies or TESE at our institution, zero out of ten had sperm found.  Therefore, for men with complete AZFa or AZFb deletions, we do not recommend proceeding with TESE (Hopps et al., 2003). 

            Pregnancy rates for ICSI using sperm from men with Y microdeletions appear to be very similar to those obtained for couples with similar sperm production.  For men with AZFc deletions alone (the only Y-deleted patients who have had sperm in our experience), most (75%) men will have at least rare sperm in the ejaculate.  For those men who are AZFc-deleted and azoospermic, most (50-75%) will have sperm found with biopsy or microTESE (Hopps et al., 2003).  We recently reviewed a series of 27 IVF cycles involving men with AZFc microdeletions who were azoospermic (12 cycles) or severely oligospermic (15 cycles.)  The clinical pregnancy rates per cycle were comparable to that obtained for non-affected men from azoospermic (TESE cycles) and  oligospermic men (ejaculated sperm.)  All children born were phenotypically normal, but we expect all boys to have deletions involving the AZFc region, with resulting impairments in spermatogenesis (Choi et al., Fertil Steril 81:337, 2004).

Results with ICSI are primarily dependent on the availability of viable sperm and age of the female member of the couple being treated.  Encouraging experience has been obtained at Weill-Cornell with TESE-ICSI in the past 1,414 attempted treatment cycles for couples in whom the man had NOA. The mean age of patients entering treatment was 35.5 years for men and 30.4 years for women.  In men, the initial mean serum FSH level was 25.3 IU/L (normal, 1 to 8 IU/L), and average testicular volume 13 ml.  During the past 1,414 attempted TESE-ICSI cycles, sperm were retrieved for injection in 794 (56%) cycles (52% (607/1176) retrieval rate per-patient). For those cycles in which sperm were retrieved, the fertilization rate per injected oocyte was 51% (4,423 of 8,705). Our embryo transfer rate was 94 %. Clinical pregnancies were established in 48% of the cycles, and live deliveries occurred in ­­­­­41% of couples. With multiple gestations were seen in 10% of pregnancies.

No etiology of azoospermia provided an absolute predictor for the presence or absence of sperm within the testes, except for AZFa and AZFb deletions.  Testicular volume and serum FSH levels did not predict sperm retrieval. 

The results for treatment of 127 men with classic and mosiac KS (47,XXY, or mosaic patterns that do not include 46,XY) who underwent attempted sperm retrieval during simultaneous 155 ICSI cycles at our institution are presented herein. Sperm were found in 65% (100/155) of the fresh retrieval attempts.  Our per-patient success rate of sperm retrieval for these 127 men was (77/127) 61%.  Embryo transfer occurred in 83% cases, with clinical pregnancy and fertility of 40% and 40 children born to-date. A multiple gestation rate of 31% has been seen in these pregnancies. Results did not differ for mosaic or non-mosaic patients.  All children have been healthy (46,XX girls and 46,XY boys.). These findings illustrate the potential for TESE-ICSI to provide fertility despite underlying genetic abnormalities.  Pre-treatment testicular biopsy histology was not helpful in distinguishing who would succeed with microdissection TESE for patients with Klinefelter syndrome.  Although a majority of men had Sertoli cell-only on diagnostic biopsy, 70% of these patients had sperm found on subsequent microdissection TESE.  Even though two of the patients treated had previously undergone multiple random biopsy TESE with no sperm found, sperm were retrieved in a subsequent procedure using the microdissection TESE technique. These findings illustrate the potential for TESE-ICSI to provide fertility despite underlying genetic abnormalities. 

Another treated subset of men with nonobstructive azoospermia includes the cohort of men with a history of chemotherapy administered for a variety of diagnoses who underwent sperm retrieval attempts with TESE for persistent nonobstructive azoospermia. All men were azoospermic and at least six years post-chemotherapy at the time of treatment.  In a cohort of 93 men with a history of chemotherapy administered for a variety of diagnoses underwent 114 sperm retrieval attempts for persistent NOA. Thirty of the 93 (32%) patients had also received extragonadal radiation. Sperm were successfully retrieved in 48% (55/114) of micro-TESE attempts, with clinical pregnancy occurring in 40% of couples. Per-patient sperm retrieval rate was 42% (39/93).  Men treated for lymphoma had a sperm retrieval rate per cycle of 44%, whereas after treatment for germ cell tumor the retrieval rate was 70%.  Diagnostic biopsy was not helpful in determining the prognosis for sperm retrieval.  Most patients had predominantly Sertoli cell-only pattern, even if germ cells were present in some seminiferous tubules.  No correlation was noted between the outcome of TESE-ICSI and the specific chemotherapeutic agents used.

Several case reports have described successful pregnancies after TESE with ICSI for men with NOA associated with cryptorchidism. While the undescended testicle results in a loss of germ cells, including spermatogonia with subsequent NOA. The treatment with an orchiopexy, have multiple risk factors and might cause ischemic insult to the testicle. It is believed that orchiopexy has no benefit for seminiferous tubules that have undergone irreversible degeneration. However, it serves to preserve the foci of germ cells capable of normal spermatogenesis. Micro-TESE allows for the harvesting of such foci that may have otherwise gone undetected.  In 152 men, 181 micro-TESE procedures were performed.  At Weill Cornell, spermatozoa were successfully retrieved in 116/181 (64%) attempts at sperm retrieval, pregnancy rate was 50%, and the delivery rate was 38% with 8 spontaneous abortions.  In this subgroup, the per-patient sperm retrieval rate was 62% (94/152).   In our cohort, 39% had bilateral cryptorchidism, and 4 patients with history of other genetic abnormality. The sperm retrieval rate in men with a history of bilateral cryptorchidism was 62%. 

            Genetic testing for Y chromosome microdeletions is of prognostic significance for TESE procedures.  For men with complete deletions of the AZFb region the chance of sperm retrieval during TESE is severely impaired.  In our experience, 0 of 23 men with Y chromosome partial deletions involving all of AZFb had sperm retrieved with TESE, whereas the sperm retrieval rate in a contemporary series of men with non-obstructive azoospermia but no AZFb deletions was 67% (85/126).  The presence of a complete deletion of AZFa appears consistently associated with Sertoli cell-only and a poor chance of sperm retrieval (Kamp et al., 2001).  Of the men with complete deletions of the AZFa region, who had diagnostic biopsies or TESE at our institution, zero out of ten had sperm found.  Therefore, for men with complete AZFa or AZFb deletions, we do not recommend proceeding with TESE (Hopps et al., 2003). 

            Pregnancy rates for ICSI using sperm from men with Y microdeletions appear to be very similar to those obtained for couples with similar sperm production.  For men with AZFc deletions alone (the only Y-deleted patients who have had sperm in our experience), most (75%) men will have at least rare sperm in the ejaculate.  For those men who are AZFc-deleted and azoospermic, most (50-75%) will have sperm found with biopsy or microTESE (Hopps et al., 2003).  We recently reviewed a series of 27 IVF cycles involving men with AZFc microdeletions who were azoospermic (12 cycles) or severely oligospermic (15 cycles.)  The clinical pregnancy rates per cycle were comparable to that obtained for non-affected men from azoospermic (TESE cycles) and  oligospermic men (ejaculated sperm.)  All children born were phenotypically normal, but we expect all boys to have deletions involving the AZFc region, with resulting impairments in spermatogenesis (Choi et al., Fertil Steril 81:337, 2004).

The normal fertilization rate per metaphase II oocyte injected was 4,603/9,280(45%). Clinical pregnancies (fetal heart seen on ultrasound) were established for 369/816 (45%*) couples with retrieved sperm. 

Data extended from Palermo, Schlegel, et al. Human Reprod 14:741, 1999. Updated 04/2013.

TESE-ICSI Non-Obstructive Azoospermia

Retrieval AttemptsN=1,540
Sperm Retrieval 54% (830/1,540)
Fertilization Rate45% (4,603/9,280)
Clinical Pregnancy45%*(369/816)

The most advanced spermatogenic pattern (but not the predominant pattern) appears to affect the results of sperm retrieval. For men who had at least one area of hypospermatogenesis present on diagnostic testis biopsy, retrieval of spermatozoa was achieved in 79% (31/39) of attempts, whereas for men with maturation arrest as the most advanced pattern, only 47% (9/19) of men had sperm retrieved by TESE. If the entire diagnostic biopsy had a Sertoli cell-only pattern, then sperm were retrieved in 24% (5/21) TESE attempts. Although no finding absolutely determined sperm retrieval or negated the possibility of successful TESE, the findings of diagnostic biopsy were helpful in evaluating the chance of success with TESE. In addition to the role of diagnostic biopsy in identifying the rare cases of intratubular germ cell neoplasia (carcinoma-in-situ) and confirming the diagnosis of non-obstructive azoospermia, diagnostic biopsy helps to provide prognostic information regarding the chance of a successful TESE procedure to obtain sperm.

Seven TESE-ICSI cycles involved men with classic Klinefelter's syndrome(47,XXY karyotype, or mosaic patterns that do not include 46,XY). Three of seven cycles resulted in ongoing pregnancies or deliveries, despite the appearance of Sertoli cell-only in one man on diagnostic biopsy prior to attempted sperm retrieval. The delivery of a healthy, normal boy for one couple, twins (boy and girl) and an ongoing pregnancy with two normal fetal karyotypes for a third couple have been achieved for these men with Klinefelter's syndrome. These findings illustrate the importance of genetic evaluation prior to treatment and the potential of TESE-ICSI to provide fertility for couples despite underlying genetic abnormalities. Spermatid retrieval and injection provides some hope for treatment of couples where no sperm can be retrieved with TESE.

Center for Male Reproductive Medicine & Microsurgery Weill Cornell Medicine
525 E 68th Street
New York, NY 10065