Guiding a couple with nonobstructive azoospermia requires an integrated approach to care by the urologist and the reproductive endocrinologist. After informing the couple of the implications of the diagnosis, care must be taken to outline the options of parenthood. Most experts agree that sperm retrieval in men can be challenging. This article describes various options of sperm retrieval, historic and contemporary, and highlights the advantages and disadvantages of each. The authors find that using a testicular map can invariably help guide sperm retrieval and overall fertility care. The right approach is one that involves a shared decision with the couple.
Key points
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Men with nonobstructive azoospermia (NOA) should undergo complete genetic testing before discussion of surgical sperm retrieval.
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Offered treatment pathways may involve testicular mapping followed by sperm retrieval or upfront sperm retrieval and should include discussion of both advantages and disadvantages.
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The couple should be encouraged to help guide the decision.
Setting the stage
The diagnosis of azoospermia must be confirmed with 2 separate semen analyses demonstrating complete absence of sperm using high-powered microscopy. Once the diagnosis of nonobstructive azoospermia (NOA) has been confirmed with thorough history, physical examination, and hormonal testing, important considerations must then be made in order to guide a couple through their journey to parenthood. The couple should be made aware that assisted reproduction, whether through partner or donor sperm, traditional adoption, and embryo adoption, is the pathway forward. Foremost, genetic testing in the form of karyotype and Y-chromosome microdeletion (YCMD) should be obtained for the purposes of counseling and prognostication. Both Klinefelter syndrome (KS) and YCMD have a prevalence of approximately 10% in men with NOA. Guiding the couple on the probability of finding sperm may start with a discussion of genetic evaluation in patients who accept this testing. In patients without an identifiable cause of NOA, the natural follow-up questions are: what are my chances of finding sperm? and what is the best approach to finding sperm ?
Several studies have investigated noninvasive predictors of sperm retrieval. Colpi and colleagues and Ghalayini and colleagues have shown that increased follicle stimulating hormone (FSH) levels are associated with decreased retrieval success regardless of the type of retrieval procedure. In the same studies, Colpi could not show a significant relation between testicular volume and sperm retrieval; however, Ghalayini demonstrated a positive correlation between testicular volume and retrieval success. On the contrary, Ramasamy and colleagues in their large cohort did not show a correlation between high FSH levels and sperm-retrieval failure via microdissection testicular sperm extraction (microTESE). A composite analysis of sperm-retrieval data suggests that testicular volume and hormonal values alone do not exhibit reliable predictive value in retrieval success.
Testicular histology is the most reliable predictor of sperm-retrieval success. Men with the least severe form of spermatogenic dysfunction (ie, hypospermatogenesis) demonstrate a retrieval rate of 80% to 98%, whereas those with the most severe form of spermatogenic dysfunction (ie, sertoli cell only syndrome [SCOS] or germ cell aplasia) have a success rate of 5% to 24%. Most notably, those with less severe forms of spermatogenic dysfunction demonstrate a high retrieval rate even with the least invasive techniques of sperm retrieval. There are several limitations of testicular histology, however. First, the performance of biopsy introduces the risk associated with a diagnostic procedure. As it is known, an open biopsy may then lead to a second invasive procedure for sperm retrieval. Second, and perhaps even more important, there is evidence of high discordance in histologic diagnosis among pathologists. In 2003, Cooperberg and colleagues reported significant intraobserver variability between initial histologic diagnosis and subsequent review diagnosis from 1 institution to another that resulted in clinically significant changes to management of 27% of patients. Last, it is well established that spermatogenesis can be focal and sporadic, and therefore, limited sampling via a single or multiple “random” biopsies may still lead to incomplete information on spermatogenesis while introducing additional risk to patients.
Sousa and colleagues reported significant histologic variability in patients with previously diagnosed “sertoli cell only syndrome,” because nearly 40% of the men had a combination of maturation arrest, early, or late spermiogenesis in the study cohort. As a result, sperm retrieval in their patients ranged from 5% to 98% via conventional testicular sperm extraction (cTESE). Thus, it has been suggested that focal spermatogenesis in patients with histologically diagnosed “SCOS” cannot be reliably predicted even in the setting of multiple random biopsies. Ramasamy and Schlegel have described sperm-retrieval rates (SRR) as high as 51% with microTESE in patients with prior biopsies, albeit demonstrating lower retrieval rates and poorer outcomes in cases with increasing negative prior biopsies. Furthermore, the same group reported a retrieval rate of 37% in patients with “SCOS” and at least 1 prior negative biopsy. Therefore, when evaluating predictive factors for sperm retrieval, it is apparent that although histology can guide sperm retrieval in many patients with less severe forms of spermatogenic failure, it does not reliably predict absence of spermatogenesis in those with “SCOS” diagnosed from a traditional, focal or multifocal, biopsy.
A provider may then ask: How do I guide my patients with NOA toward their treatment goals? Because of the historically poor predictive tools for successful sperm retrieval, 2 care pathways have emerged: Upfront testicular sperm retrieval versus testicular mapping guided sperm retrieval.
Upfront testicular sperm retrieval
There are 2 accepted forms of sperm-retrieval techniques: percutaneous and open.
Percutaneous Retrieval
During a percutaneous procedure for NOA, sperm is aspirated with a moderately large-gauge needle or angiocatheter that is inserted percutaneously after an adequate spermatic cord block. It may also be performed with adjunctive sedation. Using a standard Luer-Lock or Cameco piston syringe to generate suction, the needle is oscillated in the same plane to release a substantial conglomerate of testicular tubules. These tubules are released at the skin and transferred into buffer media for morcellation, analysis, and storage. Patients with NOA are generally reported to have lower success rates with upfront percutaneous techniques (11%–47%) compared with open techniques (16%–63%). Mercan and colleagues reported an SRR of 14% with percutaneous aspiration in their cohort of 452 men with NOA. Those who had a failed aspiration (testicular sperm aspiration [TESA]) went on to have a cTESE in the same setting with an overall SRR of 64.4%. Men with a successful aspiration in their cohort had a much higher likelihood of hypospermatogenesis as the predominant histopathology and were much less likely to have maturation arrest or germ cell aplasia. Vicari and colleagues described a much higher rate of SRR with aspiration at 47.3%, albeit with a smaller cohort of NOA. Similar to the prior study, their results showed that aspiration was successful in 100% of men who had diagnostic biopsies demonstrating hypospermatogenesis or maturation arrest with focal spermatogenesis, but the success rates with this technique were lower in complete maturation arrest (42.3%), SCOS (14.3%), and SCOS with focal spermatogenesis (0%).
Table 1 outlines outcomes observed through percutaneous procedures.
| Author, Year | Case (n) | SRR (%) |
|---|---|---|
| Friedler et al, 1997 | 37 | 11 |
| Ezeh et al, 1998 | 35 | 14 |
| Mercan et al, 2000 | 452 | 14 |
| Vicari et al, 2001 | 55 | 47.3 |
Open Retrieval
Open testicular sperm extraction (TESE) can be accomplished using 2 main methods: conventional TESE (via single or multiple random/directed biopsies) and microTESE.
Conventional testicular sperm extraction
cTESE is distinct from a percutaneous procedure in that it involves incision of the tunica albuginea in order to obtain tissue. It is distinct from microTESE in that it does not involve the use of high-powered microscopy and testicular bivalving (see later discussion) in order to guide retrieval. As a result, testicular tissue is retrieved via a single incision or multiple incisions based on surgeon preference. Tubular characteristics are not factored in tissue retrieval, as is the case with microTESE. SRRs from various studies are outlined in Table 2 . In a 2006 study, Vernaeve and colleagues reported an overall SRR of 49% with 41% success on first attempt. This study showed high SRR in those men who underwent repeat cTESE with a second attempt resulting in 75% SRR (n = 77), third attempt resulting in 82% SRR (n = 28), and fourth attempt resulting in 100% SRR (n = 11). On pathology review, they found a 98.9% SRR in men with hypospermatogenesis, of which all 57 men undergoing their first cTESE had successful retrieval. On the contrary, in men with “SCOS,” the SSR was 38.7% on first attempt and 77.6% on second attempt. As before, SCOS is placed in quotes, because clearly, if sperm are retrieved, this is not the true diagnosis. From this study, and across all studies with available pathology, it is once again clear that men with hypospermatogenesis have reliably and reproducibly high SRRs using conventional methods of retrieval. However, the efficacy of these methods decreases substantially in cases of severe spermatogenic dysfunction.
| Author, Year | Case (n) | SRR (%) |
|---|---|---|
| Schlegel, 1999 | 22 | 45 |
| Amer et al, 2000 | 100 | 30 |
| Mercan et al, 2000 | 389 | 59 |
| Okada et al, 2002 | 24 | 16.7 |
| Tsujimura et al, 2002 | 37 | 35.1 |
| Ramasamy et al, 2005 | 83 | 32 |
| Vernaeve et al, 2006 | 628 | 49 |
| Ghalayini et al, 2011 | 68 | 38.2 |
Microdissection testicular sperm extraction
First described in 1999 by Schlegel, microTESE has suggested promising results in men with NOA when compared with cTESE. In most scenarios, microTESE is performed under general anesthesia. The testes are examined one at a time, with most surgeons preferring to initiate exploration in the larger of the two. After delivery of the testis, the tunica albuginea is incised equatorially toward the mediastinum testis bilaterally, thereby avoiding the traverse of areas rich in vascularity. Upon completing the “bivalving” of the testis, high-powered microscopy enables the systematic examination of the seminiferous tubules in each of the testicular lobules. Dilated opaque tubules are sought in a sea of collapsed or obliterated tubular architecture. Once promising tubules are harvested, they are placed in a buffer, morcellated, and examined by an andrologist or embryologist in real time for the presence of sperm. A decision regarding exploration of the contralateral testis is made based on quantity and quality of obtained sperm. Hemostasis is attained with bipolar electrocautery; the tunica albuginea is securely closed, and the testis is returned to the tunica vaginalis ( Fig. 1 ).
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