Testicular Sperm Extraction for Men with Cryptozoospermia – Are We Jumping the Gun

Contributors: Logan Hubbard, MD (USA), Sindhuja Srinivasan, MBBS,vMSc, PhD (India), and Omer Raheem, MD (USA)

Commentary:
The short review by Japari et al elegantly addresses the challenging issue of managing and treating men with cryptozoospermia, specifically exploring whether ICSI outcomes differ between using ejaculated sperm and testicular sperm.

Traditionally, cryptozoospermia is often characterized by the absence of sperm in the ejaculate on routine testing, with sperm being detected only after centrifugation. This condition, which affects over 8% of men with infertility, shares many causes with azoospermia, such as varicoceles, hormonal imbalances, genetic issues, gonadotoxic or testosterone exposure, environmental factors, and even testicular damage. When cryptozoospermia is diagnosed, addressing modifiable factors like lifestyle changes, weight management, varicocele repair, and hormonal corrections should be considered as an initial treatment option. If these measures prove ineffective, ICSI can be a valuable treatment option.

Men with cryptozoospermia often face challenges with sperm collection, quality, and quantity in the ejaculate, ultimately leading to the common recommendation of combining surgical sperm retrieval (SSR) with ICSI. Contemporary research studies, including well-conducted meta-analyses, have often debated whether ejaculated sperm or testicular sperm leads to better fertilization, clinical pregnancy rates, and overall outcomes. Ejaculated sperm might be preferred due to its maturity and ease of collection. However, using ejaculated sperm presents potential drawbacks such as difficulties in sample collection, increased oxidative stress (resulting in higher sperm DNA fragmentation), and the need for centrifugation, all of which can negatively impact fertilization and clinical pregnancy rates. Conversely, SSR has emerged as an effective method, by directly obtaining testicular sperm that helps avoid these abovementioned issues. Nonetheless, potential surgical complications such as testicular damage leading to subsequent hypogonadism, psychological stress, an increased chance of being unable to retrieve sufficient sperm, and significant costs necessitate adequate counseling, discussion, and documentation before SSR.

To address these uncertainties, Japari et al. conducted a narrative review analyzing nine high-quality studies from 2013 to 2023. The review finds that there is no clear evidence conclusively favoring either testicular or ejaculated sperm. Some studies suggest the benefits of testicular sperm, such as lower sperm DNA fragmentation, better implantation rates, improved embryo quality, and fewer canceled ART cycles. However, findings are often unclear on critical outcomes like live birth and pregnancy rates.

Variability in results may be attributed to limitations in the studies, such as unaccounted female factor infertility, differences in ovarian stimulation protocols, and insufficient sperm for morphological selection in performing ICSI.

Given these gaps in the literature, future research should include a well-designed randomized trial comparing ejaculated versus testicular sperm with fertilization, live birth, and clinical pregnancy rates as endpoints, with a special focus on controlling for other factors such as female factor infertility. These additions would provide clearer guidance on this issue and inform current clinical practice.

Main Takeaways:
1. Address modifiable risk factors and lifestyle changes for cryptozoospermia before resorting to costly and invasive ART options.
2. There is no definitive consensus on whether testicular or ejaculated sperm is superior for pregnancy and live birth rates.
3. SSR may be considered in cases where:
❖ The patient cannot provide a specimen
❖ Cryopreservation is not possible
❖ Suitable sperm is not available on the day of egg retrieval

❖ There has been a prior ICSI failure with ejaculated sperm

❖ Elevated sperm DNA fragmentation is present

My Viewpoint on the TESE for Men with Cryptozoospermia
Dr. Logan Hubbard responds to questions from Ashok

Q1. What are the primary etiological factors associated with cryptozoospermia?

Dr. Hubbard: The etiologic drivers of cryptozoospermia are numerous and can share many features with causes of azoospermia. These causative factors can often be subcategorized into hormonal (hypo- and hypergonadotropic hypogonadism), genetic (Klinefelter syndrome, and Y chromosomal abnormalities), and factors causing direct damage to the testicles (varicoceles, surgery, trauma, chemoradiation, endocrine disrupting chemicals).

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

Dr. Hubbard: 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. What are the benefits and risks associated with surgical sperm retrieval (SSR) in cryptozoospermic patients?

Dr. Hubbard: Surgical sperm retrieval (SSR) has demonstrated benefits in situations of elevated sperm DNA Fragmentation (SDF), and situations where obtaining ejaculated specimens is unreliable (the patient is unable to produce a specimen, or suitable sperm is
unable to be found on the day of egg retrieval). Certain benefits to assisted reproductive techniques (ART) exist – such as lower canceled cycle rates, and implantation rates – while other metrics such as live birth rates and pregnancy rates remain controversial. Despite these benefits, there are clear risks to SSR including surgical and anesthetic complications, tubular damage with consequent fibrosis hypogonadism, psychological duress from undergoing a procedure, and a significant financial burden to some patients.

Q4. What are the psychological and financial implications for patients undergoing SSR?

Dr. Hubbard: Male factor infertility in general carries with it a known psychological burden. A study of 300 men with disaggregated infertility found men undergoing urologic procedures were seven times more likely to experience significant infertility-related stress. Failed TESE procedures were found to lower patient self-esteem, add to familial stress, and even precipitate affective symptoms. These drawbacks are all compartmentalized from the financial burden of infertility treatment where studies have shown 47% of those surveyed reported financial strain due to infertility treatments, and 46% had management options limited due to expense. Both percentages are likely underestimations.

Q5. Why is it important to analyze multiple semen samples before deciding on SSR for cryptozoospermic patient?

Dr. Hubbard: ICSI is often the treatment of choice for men with crypotozoospermia. However, in instances when rare and motile ejaculated sperm can be identified, ICSI can be performed using these samples and surgery can potentially be avoided. Analyzing multiple samples can improve the likelihood of finding rare motile sperm suitable for ICSI. Furthermore, a recent study found that the use of multiple ejaculated samples over a short period had no adverse effect on sperm concentration and improved motility on the day of planned mTESE with a live birth rate of 36%.

Q6. What are the potential complications of SSR, and how can they be minimized?

Dr. Hubbard: The complications of SSR include standard surgical risks such as bleeding, infection, and damaging local structures. Although rates of complications vary somewhat by SSR procedure, each carries a risk of intratesticular hematoma formation, tubular damage, microcalcifications, hyalinosis, testicular atrophy, and hypogonadism. In addition to proper patient counseling and selection, the use of mTESE may help reduce complications versus other surgical techniques. mTESE has lower intratesticular hematoma rates, and fibrosis rates, though with similar rates of testosterone recovery on long-term follow-up.

Q7. How can lifestyle modifications and medical treatments improve sperm quality in cryptozoospermic patients?

Dr. Hubbard: Many lifestyle factors are directly correlated with decreased semen parameters and sperm integrity. Correction of obesity, excessive drinking, smoking, and drug use can generate improvements in ejaculate volume, SDF, and hormonal parameters. Similarly, an improved diet can decrease SDF and positively affect sperm parameters. Electromagnetic radiation (in the form of cellular devices and computers) can increase SDF and reduce anti-oxidative activities. Stress can affect sperm motility and viability, in addition to suppressing the hypogonadal pituitary-gonadal axis. Couples should try to minimize their exposure to these factors, which could help improve their chances of conceiving, and reduce the need for costly and invasive therapies.

Q8. What are the key considerations for reproductive specialists when counseling cryptozoospermic patients about their treatment options?

Dr. Hubbard: First and foremost, patients should be counseled regarding the correction of modifiable risk factors and lifestyle changes that can be made to improve their fertility before discussing ART. Their options of using either ejaculated sperm or SSR with ICSI should be thoroughly discussed including the risks and benefits of both choices. Patients who cannot provide a specimen, or suitable sperm is not available at the time of egg retrieval, instances where cryopreservation is not possible, there is elevated SDF or couples with prior ICSI failures should be considered for and counseled on SSR. Otherwise, patients can be advised that there is no definitive consensus as to whether testicular or ejaculated sperm is superior for pregnancy and live birth rates.

Q9. What future research is needed to better understand and manage cryptozoospermia in infertile men?

Dr. Hubbard: The field at large is lacking a well-designed randomized trial comparing ejaculated versus testicular sperm including measuring fertilization outcomes, live birthrates, and clinical pregnancy rates. Accounting for the etiology of patients with cryptozoospermia, and consideration of female factor fertility (age, ovarian reserve, ovarian stimulation protocols) is vital to providing clearer evidence that can ultimately answer unresolved questions in this ongoing debate.

Logan C. Hubbard MD, MS: Short Biography

My Viewpoint on the TESE for Men with Cryptozoospermia
Dr. Srinivasan responds to questions from Ashok

Q1. What is cryptozoospermia and how is it diagnosed?

Dr. Srinivasan: Cryptozoospermia is a term applied when there is no sperm seen on a wet mount of a semen sample, but sperm are identified in the pellet of a semen sample centrifuged at 3000g for 15 minutes. Centrifugation is the key step in differentiating
between azoospermia and cryptozoospermia when no sperms are seen in a fresh wet mount preparation. Interestingly, the term cryptozoospermia is not mentioned in the sixth edition of the WHO manual for Semen analysis and we use the definition of it as mentioned in the fifth edition.

Q2. How does intracytoplasmic sperm injection (ICSI) help in managing infertility in cryptozoospermic patients?

Dr. Srinivasan: In infertile patients with cryptozoospermia, ICSI is the only choice for fertilization. Since the overall number of sperm is low in cryptozoospermic patients, it is important to cryopreserve multiple samples before the ovum pick-up procedure to have a sufficient number of morphologically normal sperm for ICSI.

Q3. What are the advantages and disadvantages of using ejaculated sperm for ICSI in cryptozoospermic patients?

Dr. Srinivasan: The main advantage of using ejaculated sperm for ICSI is its availability without an invasive procedure. Depending on the number of oocytes retrieved, if more sperm is required, a second sample can be requested from the male partner. The major disadvantage of ejaculated sperm is the non-availability of morphologically normal sperm for selection and high DNA fragmentation.

Q4. How does sperm DNA fragmentation (SDF) impact the outcomes of ICSI in cryptozoospermic patients?

Dr. Srinivasan: Patients with cryptozoospermia often have higher levels of DNA fragmentation. However, there may not always be enough sperm to accurately diagnose high DNA fragmentation using tests like Sperm Chromatin Dispersion (SCD) or TUNEL in patients with cryptozoospermia. In these cases, several groups have tried using testicular sperm in the place of or in addition to using ejaculated sperm to overcome the effect of high DNA fragmentation, although there is not enough evidence to support this. In my experience, when performing ICSI in cryptozoospermic patients, other factors like morphology of available sperm, and number of expected oocytes have to be borne in mind to adequately counsel patients before performing testicular biopsy for use in ICSI.

Q6. How do the outcomes of ICSI with ejaculated sperm compare to those with testicular sperm in terms of fertilization, pregnancy, and live birth rates?

Dr. Srinivasan: Several individual studies have shown contradictory evidence for the use of testicular sperms over ejaculated sperms and vice versa in terms of fertilization, pregnancy, and live birth. However, two meta-analyses have confirmed that using testicular sperms over ejaculated sperms does not increase the fertilization rate but increases the pregnancy and live birth rates when DNA fragmentation is high in ejaculated sperms.

Sindhuja Srinivasan, MBBS, MSc (Clinical Embryol), PhD: Short Biography

Omer Raheem MD, MSc, MCh Urol, MRCSI, FACS: Short Biography