Global Practice Patterns in the Evaluation of Non-Obstructive Azoospermia: Results of a World-Wide Survey and Expert Recommendations

Commentary:

Non-obstructive azoospermia (NOA)is the most challenging diagnosis for the andrologist and the infertile male patient. Medical treatment is often disappointing, because there is no established diagnosis (idiopathic) in many cases, and assisted reproduction techniques are expensive and not always universally accessible. Furthermore, many diagnostic and treatment modalities remain a matter of debate and there is a lack of guidelines among academic societies. 

In this comprehensive survey, the authors examined global practices in managing NOA patients, comparing them against professional society guidelines (AUA/ASRM, EAU, EAA) and expert recommendations from Global Andrology Forum (GAF) members. Conducted between July and September 2022, the survey utilized a 56-item questionnaire to assess NOA diagnosis and management practices among 367 participants from 49 countries, 3analyzed through a Delphi process. The current paper presents findings from the initial 21 questions, focusing on survey demographics and NOA evaluation approaches. The 336 responses came from 49 countries, providing an expanded view of the practices used by doctors (mostly responders) in the diagnosis and treatment of NOA. 

Most azoospermia cases were non-obstructive and linked to primary hypogonadism (hypergonadotropic hypogonadism or testicular failure). Various congenital, environmental, iatrogenic, and acquired conditions can cause testicular failure and NOA, though the clinical relevance of a varicocele associated with NOA remains unclear. 

The majority of respondents’ practices aligned with guidelines recommending a second semen sample if the initial examination shows an absence of spermatozoa. Most considered an interval of 11 to 29 days between semen analyses ideal, with 22.9% citing three months, reflecting a full cycle of spermatogenesis. 

Serum FSH, LH, and total testosterone were the most commonly evaluated hormones in NOA patients. Studies have shown significant differences in these hormone levels between men with NOA and OA. However, serum total testosterone levels may not accurately reflect functional testosterone availability due to variations in serum sexhormone binding globulin (SHBG) levels, influenced by conditions like metabolic syndrome, thyroid disorders, pituitary disease, chronic liver disease, prostate cancer, nephrotic syndrome, estrogen use, anticonvulsants, and steroids. In such cases, calculating free testosterone after SHBG assay is recommended. Additionally, serum estradiol should be measured in obese men, and serum prolactin should be tested if decreased sexual desire and erectile dysfunction are present. 

Patients with azoospermia or severe oligospermia have a higher likelihood of genetic abnormalities. The survey indicated the need for karyotyping and Y chromosome microdeletion testing in NOA patients, aligning with guidelines and common practices among respondents. Notably, 27% of respondents recommended Kal1 gene testing for X-linked Kallmann Syndrome, a common cause of congenital hypogonadotropic hypogonadism often associated with anosmia or severe hyposmia. Genetic counseling is crucial, and a significant proportion of respondents offer it. However, there is probably a need of a better understanding among the attending physicians of how and when some genetic testing should be performed because almost 1/5 of the respondents routinely perform CFTR gene mutation testing in patients with NOA although CFTR gene 4mutation does not cause NOA. According to GAF expert members, CFTR gene mutation testing should be performed only in cases of vas aplasia or congenital obstruction, particularly in regions with high CFTR mutation carrier prevalence.

Categorizing azoospermia into OA or NOA is vital due to differing management strategies. In most cases, clinical and laboratory results suffice for diagnosis. In this survey, 45.1% of participants did not perform diagnostic testicular biopsy routinely. GAF experts suggest that testicular biopsy should not precede therapeutic testicular sperm extraction (TESE) and should be recommended only in specific cases where serum FSH and LH levels and testicular volumes are normal, combined with surgical sperm retrieval. However, it is important to consider that obstructive azoospermia caused by an epididymal obstruction occurs with normal testis volume, normal FSH, and testosterone levels and that a definitive diagnosis that allows reconstruction through vaso-epididymal anastomosis is only possible during scrotal surgical exploration. Imaging plays a minor diagnostic role.

The survey revealed that 66.4% of respondents agreed that normal serum FSH predicts a higher chance of sperm retrieval by conventional TESE (cTESE) or microdissection TESE (mTESE).

Shah et al. concluded that global clinical practices, literature evidence, and recommended guidelines for NOA diagnosis were generally congruent. However, significant disparities in practices highlighted the need for evidence-based, international consensus guidelines to standardize NOA evaluation and address gaps in professional recommendations.

Take Home Message
Accurate diagnosis of NOA necessitates a comprehensive clinical and laboratory evaluation, including genetic testing and hormonal profiling. While definitive preoperative predictors for successful sperm retrieval are lacking, normal FSH levels, testicular volume, and specific histopathological findings suggest higher success rates. Genetic counseling with karyotype and Y microdeletion testing is advised for all NOA patients. Diagnostic testicular biopsy is not routinely required for differentiating NOA from OA. Personalized patient management plans, advanced diagnostic techniques, interdisciplinary collaboration, and ongoing research are essential for optimizing care and improving outcomes for NOA patients.

Sidney Glina, MD: Short Biography

Q1. What are the expert recommendations for preoperative biochemical or clinical variables that predict positive sperm retrieval in NOA patients?

Dr. Glina: There are no preoperative biochemical or clinical variables that definitively predict positive sperm retrieval in patients with NOA. However, normal FSH, normal testicular volume, a history of sperm in the ejaculate, and favorable histopathology predict higher chances of sperm retrieval.

Q2. Which histopathological findings are associated with higher chances of sperm retrieval in NOA?

Dr. Glina: Testicular histopathology with hypospermatogenesis predicts higher chances of sperm retrieval in patients with NOA.

Q3. What are the common practices regarding the use of diagnostic testicular biopsy in NOA patients?

Dr. Glina: Although testicular histology is a good, maybe the best, predictor of successful surgical sperm retrieval in NOA patients it should not be done routinely as a diagnostic test, but only combined with therapeutic TESE.

Q4. How do expert recommendations derived through a Delphi consensus compare to international practice guidelines for NOA?

Dr. Glina: Although the Delphi consensus presents limitations, such as a limited number of physicians and countries participants, it provides a comprehensive perspective of real-life global practices. Also, this survey showed that although there is a congruity between global clinical practices, evidence in the literature, and professional society recommendations, there are several areas where guidelines are not available and clinical practices differ from the recommendations.

Q5. What are the limitations of current guidelines for the evaluation and management of NOA?

Dr. Glina: There are several topics on the diagnosis and management of NOA where there are no available guidelines.

Q6. What are the main predictors of successful sperm retrieval during conventional and microdissection TESE?

Dr. Glina: Normal FSH, normal testicular volume, a history of sperm in the ejaculate, and favorable histopathology predict higher chances of sperm retrieval.

Q7. What are the identified gaps in knowledge and areas needing further research in the evaluation and management of NOA?

Dr. Glina: Besides a better understanding of the etiology of idiopathic NOA, further research is needed on the possible medical treatment of NOA and the identification of predictors of sperm finding on surgical testicular retrieval.

Rafael Ambar, MD: Short Biography

Q1. What are the most common hormone tests ordered for diagnosing NOA?

Dr. Ambar: The most commonly ordered hormones are FSH, LH, and testosterone. Prolactin and estradiol might be useful in selected cases.

Q2. How do physical examination findings contribute to differentiating between obstructive azoospermia (OA) and NOA?

Dr. Ambar: During the physical examination, the reproductive urologist should determine if the patient has vas deferens agenesia, evaluate testes size, as well as secondary sexual characteristics.

Q3. What genetic tests are most frequently requested for patients suspected of having NOA?

Dr. Ambar: Karyotype and Y chromosome microdeletions should be requested in NOA

cases.

Q4. How is a definitive diagnosis of azoospermia typically confirmed?

Dr. Ambar: The definitive diagnosis is obtained by a testicular biopsy. However, in clinical practice, serum FSH levels higher than 7.6 mIU/mL and a testicular long axis less than 4.6 cm suggest NOA

Q5. What is the role of testicular histology in predicting the success of testicular sperm extraction (TESE) in NOA patients?

Dr. Ambar: Although there are conflicting results in medical literature, it is commonly accepted that histopathology with hypospermatogenesis predicts higher chances of sperm retrieval. On the other hand, histopathology showing SCO is related to an unsuccessful sperm extraction.

Q6. How do serum testosterone levels impact the diagnosis and management of NOA?

Dr. Ambar: Isolated serum testosterone level is not significant to diagnosis, as it may be impacted by several conditions. Concerning clinical management, testosterone levels are of importance to determine, together with gonadotropin levels, if hormonal stimulation therapy is needed.

Q7. What are the common criteria used to differentiate between OA and NOA based on semen tests?

Dr. Ambar: The volume and the presence of fructose are the most important parameters to differentiate between OA and NOA.

Edson Borges Junior, MD, PhD: Short Biography

Q1. How does the serum FSH level influence the management of NOA?

Dr. Borges: Elevated serum FSH levels indicate testicular failure and impaired spermatogenesis. However, there is no direct relationship between serum FSH levels and the possibility of obtaining testicular sperm.

Q2. What are the global trends in the use of karyotype analysis and Y chromosome microdeletions testing for NOA?

Dr. Borges: Despite these tests being considered mandatory in the investigation of non-obstructive azoospermia, they are still not adequately requested by urologists and physicians who treat male infertility. We need to increase the knowledge of these professionals so that these tests are more widely ordered.

Q3. How do clinical practices differ from professional society recommendations in the management of NOA?

Dr. Borges: Limited knowledge of the causes and treatment options for NOA leads to limitations in the clinical investigation, including both andrological examination and laboratory and hormonal tests. This simplification in the approach often hinders or delays the proper guidance of these patients.

Q4. How does the history of sperm in the ejaculate influence the approach to sperm retrieval in NOA patients?

Dr. Borges: A history of the presence of sperm in the ejaculate indicates a better prognosis for the recovery of testicular sperm. This suggests that spermatogenesis was present at some point.

Q5. How does the testis volume correlate with the likelihood of successful sperm retrieval in NOA?

Dr. Borges: Testicular volume has no direct correlation with the possibility of sperm recovery, regardless of the etiology of NOA.