Global Practice Patterns and Variations in the Medical and Surgical Management of Non-Obstructive Azoospermia: Results of a World-Wide Survey, Guidelines and Expert Recommendations

Contributors: Eric Chung (Australia), Koji Chiba (Japan), Hisanori
Taniguchi (Japan), and Akira Tsujimura (Japan)

Commentary:

There is a lack of societal guidelines and ongoing controversies regarding non obstructive azoospermia (NOA) management. The experts from the Global Andrology Forum (GAF) have conducted the largest survey on the real-world medical and surgical management of NOA by reproductive experts. This global survey provides a valuable and comprehensive perspective on global practices in NOA and highlights the diverse practice patterns and the need for evidence-based international consensus guidelines.
A total of 367 participants from 49 countries completed the 56-question online survey. Specifically of interest are the questionnaires and expert recommendations relating to surgical sperm retrieval (SSR) in the settings of hormonal therapy and those with genetic conditions as well as the role of testicular biopsy and varicocele repair (VR).

There is no international consensus on the treatment regimen for NOA cases secondary to exogenous testosterone therapy. Exogenous testosterone should not be used for men with NOA who are still interested in testicular sperm retrieval and future fertility. Instead, selective estrogen receptor modulators, aromatase inhibitors, or human chronic gonadotropins can be used to raise testosterone levels without compromising spermatogenesis although the exact dose and formulation remain debatable. Hormonal therapy for 3 to 6 months was suggested before SSR with the SSR rate reported as high as 50.0% by the respondents. While microdissection testicular sperm extraction (mTESE) is the most efficient procedure for sperm retrieval in men with NOA, the proportion of surgeons performing mTESE is relatively low. The wide range of SSR rates reported by the survey participants can be explained by the heterogeneous nature of patients with NOA (age, location, testicular size, hormonal levels, etiology), and variations in surgeon experience and techniques. In patients with Klinefelter syndrome, the SSR rates were quoted between 20%–60% and it has been shown that surgeons’ expertise and high volume mTESE centers may have better success rates.

The presence of AZF deletions can significantly impact SSR and the chance of finding sperm in men with Y chromosome AZFc microdeletion remains reasonable although proper counseling should be undertaken regarding the transmission of the AZF deletion to the male offspring. On the other hand, it is advisable not to consider sperm retrieval in the settings of a complete deletion of AZFa and AZFb given the likelihood of severe spermatogenesis impairment. To date, testicular biopsy and mapping remain controversial. While this approach can be more cost-effective since the histopathological outcome can guide subsequent fertility management, testicular biopsy is not considered standard of care by most guidelines. Nonetheless, sending a testicular biopsy for histopathology during SSR may be reasonable to determine the subsequent prognosis if no sperm is identified in the sample or in men with risk factors for testicular malignancy such as cryptorchidism or intratesticular microlithiasis. Similarly, the role of VR in men with NOA remains controversial as is reflected in the divergent practice patterns and the limited concrete evidence. The decision to perform VR in cases of NOA is a shared decision between the physician and the couple after a detailed discussion of the risks and benefits, likely guided by parameters such as testicular volume, FSH level,female partner’s age, testicular

histology if available, and overall fertility status.

To our knowledge, this is the first global survey for NOA and addresses important issues for clinicians. The results demonstrate a diverse range of practices in the medical an surgical management of NOA and underscore the need for evidence-based international consensus guidelines to ensure the highest standard of care for all patients. It is important to acknowledge the great variations in the findings among the respondents which reflect the locoregional expertise, access to technology, and financial aspects in NOA management. Comparing contemporary expert global practices against available international practice guidelines, the “expert recommendation” section can clarify the current best practices of NOA management based on global practices, society guidelines, and available evidence from the literature.

Take Home Message
Contributing author: Ashok Agarwal, Director, Global Andrology Forum, Moreland Hills, OH, USA

1. Microdissection Testicular Sperm Extraction (mTESE) as the Preferred Technique: mTESE remains the superior technique for sperm retrieval in men with NOA, particularly in those with small testicular volume, high FSH levels, or a history of testicular injury. Most guidelines and expert opinions recommend mTESE as the first-line approach when available.

2. Significance of Testicular Biopsy: Performing a testicular biopsy during surgical sperm retrieval (SSR) is essential for establishing a histological diagnosis, assessing the prognosis for future sperm retrieval attempts, and detecting conditions like intratubular germ cell neoplasia in situ (GCNIS), which could pose a high risk for testicular cancer.

3. Gene Therapy and CRISPR/Cas9 as Emerging Therapies: Gene therapy, particularly using CRISPR/Cas9 technology, shows potential for treating NOA caused by genetic defects. However, its clinical application requires further research to determine safety and efficacy.

4. Controversy in Varicocele Repair: While varicocele repair (VR) is considered for improving sperm retrieval in NOA patients, the evidence supporting its efficacy is limited. Specialists should counsel patients that while VR might increase the chances of sperm appearance in the ejaculate, the quality of evidence remains poor, and results may take up to 12 months.

5. Heterogeneity in Global Practices: There is significant variability in the global management of NOA, with practices often differing from established guidelines. This underscores the need for evidence-based international consensus guidelines to standardize care and improve outcomes.

Eric Chung, MBBS, FRACS: Short Biography

My Viewpoint on the GAF Global Survey on Medical and Surgical Management of NOA
Dr. Koji Chiba responds to questions from Ashok

Q1. What factors influence the decision to perform mTESE simultaneously with oocyte retrieval versus performing it with cryopreservation?

Dr. Chiba: Considering the sperm retrieval rate in mTESE, there are not a few cases where ICSI cannot be performed even when oocytes are retrieved, and performing mTESE simultaneously with oocyte retrieval may impose unnecessary invasion on the wife. On the other hand, fresh sperm may have a better effect on ICSI results, since sperm can receive a certain amount of damage from freezing and thawing. In cases planning to use donor sperm if sperm could not be retrieved, or with a strong expectation of sperm retrieval (e.g. in cases of AZFc deletion), mTESE simultaneously with oocyte retrieval is more likely to be proposed.

Q2. What are the current global practices regarding the use of preimplantation genetic testing in NOA patients?

Dr. Chiba: In cases where fertilization is achieved with sperm from NOA patients with a background of Klinefelter syndrome or AZF microdeletion, PGT may be suggested. In the majority of Klinefelter syndrome, chromosomal aneuploidy is not a concern when sperm is retrieved. On the other hand, in cases of AZFc deletion, there is a very high possibility that the trait will be inherited if a male child is born. Counseling is strongly recommended, and whether to perform PGT largely depends on the social background and the preferences of the couple.

Q3. How does the use of ultrasound to identify the most vascularized areas in the testis impact the success rates of sperm retrieval in NOA?

Dr. Chiba: There is currently no firm evidence supporting the use of imaging techniques to improve the success of sperm retrieval. However, in a situation where the sperm retrieval rate for mTESE is not satisfactory, it is hoped that new techniques to be developed to identify the foci where sperm is present.

Q4. How does the use of ultrasound to identify the most vascularized areas in the testis impact the success rates of sperm retrieval in NOA?

Dr. Chiba: There is currently no firm evidence supporting the use of imaging techniques to improve the success of sperm retrieval. However, in a situation where the sperm retrieval rate for mTESE is not satisfactory, it is hoped that new techniques to be developed to identify the foci where sperm is present.

Q5. What are the recommended waiting periods before proceeding to mTESE after a failed conventional TESE?

Dr. Chiba: Depending on the extent of the invasion to the testes caused by cTESE, tissue damage due to subcapsular hematomas and other factors may persist for around six months. On the other hand, a prolonged waiting period can impact the age factors of the couple. Therefore, it is reasonable to propose mTESE after about 6 months. However, if the initial cTESE was minimally invasive, it might be acceptable to perform mTESE after approximately three months.

Q6. How do the practices of using fine-needle aspiration (FNA) before mTESE vary among clinicians?

Dr. Chiba: Performing FNA before mTESE may provide the possibility of obtaining sperm that can be used for ICSI and may provide helpful information on the location to be explored for mTESE. However, FNA is not a completely non-invasive procedure and there are concerns about certain damage to the testicular parenchyma, such as hematoma or inflammation. Only a few doctors perform FNA before mTESE, and some question its usefulness, while others even argue that it harms later mTESE. At present, there is a lack of enough evidence to suggest that FNA should be recommended in many NOA cases before mTESE.

Q7. What are the challenges in establishing evidence-based international consensus guidelines for the management of NOA?

Dr. Chiba: Management of NOA is complex because of the variety of its pathologies. In addition, there may be differences due to racial biological differences and differences in the social structure surrounding healthcare. If the management of NOA can be viewed from a global perspective through surveys, as was done in this study, it should be useful to establish evidence-based international consensus guidelines for the management of NOA.

Q8. How does the geographical distribution of respondents impact the reported practice patterns in NOA management?

Dr. Chiba: There are certain differences in testicular pathology between races, accessibility to healthcare, and the costs covered by healthcare insurance from country to country. These factors could have a significant impact on the management of NOA. Due to these factors, the geographical distribution of respondents may influence the outcome of the NOA practice pattern.

Q9. What are the expert recommendations for hormonal therapy before SSR in NOA patients based on the Delphi process?

Dr. Chiba: The evidence in favor of hormonal therapy to increase SSR in patients with NOA is still low and it is not a routine treatment. However, some patients may benefit from hormonal therapy as it may increase SSR. Further detailed research to determine which patients and which treatments may increase SSR is expected to advance and be applied clinically in the future.

Koji Chiba, MD, PhD: Short Biography

My Viewpoint on the GAF Global Survey on Medical and Surgical Management of NOA
Dr. Hisanori Taniguchi responds to questions from Ashok

Q1. What are the cutoff levels for FSH that predict positive SSR outcomes?

Dr. Taniguchi: At this time, there is no definitive cutoff value of FSH that predicts a positive SSR outcome for NOA patients. In other words, there is no evidence that FSH levels are not appropriate for mTESE for NOA patients. If a NOA patient shows an FSH level of around 8-9 IU/L, the physician should consider hypospermatogenesis or late spermatocyte arrest before TESE.

Q2. How does the management of NOA differ in patients with Klinefelter syndrome?

Dr. Taniguchi: The difference in management between patients with Klinefelter syndrome (KS) and those without KS is the management after TESE. Testicular volume in patients with KS often tends to be smaller and tends to have lower testosterone levels before TESE. Therefore, the physician should pay close attention to testosterone levels after TESE. However, there are no definitive criteria for testosterone levels during this period. Because low testosterone levels are associated with anemia, osteoporosis, and diabetes, the physician should explain to patients with KS preoperatively the possible complications that low testosteronemia can cause. It should also be explained that in some cases, testosterone replacement therapy may be recommended postoperatively.

Q3. What are the benefits and limitations of microsurgical varicocelectomy in improving sperm retrieval rates in NOA patients?

Dr. Taniguchi: As discussed in the main manuscript, there is limited evidence to support varicocelectomy in patients with NOA. Most varicocelectomy is undergone for cases that expect sperm appearance in the ejaculate and improve sperm retrieval such as a relatively normal FSH level (<10 IU/L) or relatively smaller ipsilateral testis. However, the appearance of sperm in the ejaculate may avoid surgery (mTESE), and improvement in sperm quality after varicocelectomy may improve fertility rates. In the case of varicocelectomy, the physician should explain the side effects of the surgery and the extended duration of treatment, especially in older couples.

Q4. What are the current recommendations for managing NOA due to exogenous testosterone use?

Dr. Taniguchi: Discontinuation of exogenous testosterone is strongly recommended. Alternatives include oral clomiphene citrate or hCG injections. Some patients present with NOA due to testosterone administration. There are cases in which discontinuation of
testosterone administration alone can be expected to restore spermatogenesis 3 months or later after discontinuation.

Hisanori Taniguchi, MD, PhD: Short Biography

My Viewpoint on the GAF Global Survey on Medical and Surgical Management of NOA
Prof. Akira Tsujimura responds to questions from Ashok

Q1. How do different global practices approach the treatment of normogonadotropic, hypogonadotropic, and hypergonadotropic hypogonadism in NOA patients?

Dr. Tsujimura: The most ideal case for hormonal treatment before performing TESE for NOA is hypogonadotropic hypogonadism. Normal gonadotropism should be considered next, while hypergonadotropic hypogonadism, which is most common in NOA, is performed the least frequently. Recently, there have been reports that when sperm cannot be extracted after the first mTESE, hormone therapy can be used before the second mTESE attempt even for hypergonadotropic hypogonadism, and hormone therapy can be considered if the patient wishes. In any case, the most important factor to consider should be FSH.

Q2. What is the impact of varicocele repair on the appearance of sperm in the ejaculate in NOA patients?

Dr. Tsujimura: There is no uniformity in the response to NOA patients with varicocele. The EAU guideline suggests that the ejaculated sperm emergence rate with varicocele repair is 20.8% to 55.0% for NOA patients with varicocele, but in actual clinical practice, the rate seems to be a little lower. Even if varicocele repair does not result in the appearance of ejaculated sperm, the fact that the sperm retrieval rate by TESE is improved by varicocele repair is also supportive of recommending varicocele before TESE.

Q3. How does the variability in hormonal therapy recommendations reflect the quality of evidence available for treating NOA?

Dr. Tsujimura: The unequivocal evidence is the avoidance of testosterone administration. There is uniformity in the notion that the benefit of hormonal therapy is limited, at least not routinely. No one strongly recommends hormonal treatment, although there are differences in the recommendations. It is desirable to establish what should be recommended through analysis of a large number of cases in the future.

Q4. What are the common predictors of successful sperm retrieval in NOA patients undergoing SSR?

Dr. Tsujimura: Various factors have been analyzed, including testicular size, FSH, age, and others, but the factors that predict successful sperm retrieval are not clear. Some centers have attempted to improve sperm retrieval rates by performing preoperative ultrasound examinations, but their usefulness is skeptical. The most significant predictive factor is probably the preoperative examination of testicular tissue. In this sense, some centers perform preoperative FNA. However, it is not yet a standard procedure, and its usefulness is not yet sufficient.

Q5. What are the key differences between obstructive and non-obstructive azoospermia in terms of etiology and management?

Dr. Tsujimura: The most common congenital form of obstructive azoospermia is congenital bilateral absence of the vas deferens (CBAVD), while the most common acquired form is infection of the epididymis or prostate gland. Many cases of non-obstructive azoospermia are congenital, including chromosomal and genetic abnormalities such as Klinefelter syndrome and Y-chromosome microdeletions. However, some cases are acquired as a result of chemotherapy or radiation therapy as well as post-mumps orchitis. In obstructive cases, reproductive tract surgical reconstruction is the treatment of choice; however, considering the wife's age and other factors, the patient may proceed to TESE-ICSI. In non-obstructive cases, there is no alternative but to hope for sperm retrieval with TESE-ICSI.

Q6. How does the lack of clear guidelines affect the management of NOA across different regions?

Dr. Tsujimura: In NOA, the only way to have a baby in any region is TESE-ICSI. However, there is still no certainty about the technical procedure of TESE. There is also no uniform treatment strategy for NOA associated with varicocele. In addition, the usefulness of hormonal therapy before TESE is also unclear, and its implementation varies from region to region. Accumulation of evidence and enhancement of treatment are desirable.

Q7. What is the role of hormonal therapy in the management of NOA, and how do different guidelines view its efficacy?

Dr. Tsujimura: Regarding hormone therapy before TESE for NOA, the EAU guidelines are negative, and the AUA/ASRM guidelines recommend that patients be informed that there are some effective cases of hormone therapy before TESE. Although the guidelines are not clear and recent meta-analyses have not always confirmed the benefit, many cases are treated with hormone therapy before TESE.

Q8. How effective is mTESE compared to cTESE for sperm retrieval in NOA?

Dr. Tsujimura: It is generally believed that mTESE increases the sperm retrieval rate compared to cTESE. However, there are no reliable comparative studies of the two techniques, and mTESE is not always the only technique used. mTESE is given only a weak
recommendation in the EAU guidelines, as the sperm retrieval rates of mTESE and cTESE are similar in several reports. Some centers continue to perform mTESE if no sperm is identified after cTESE. Nevertheless, mTESE is most commonly performed from the beginning in a real-world setting.

Akira Tsujimura, MD, PhD: Short Biography