Challenges in the Management of Nonobstructive Azoospermia

Commentary:

Infertility nearly affects 1 in 6 North American couples, with male factor infertility seen in half of cases. It is known that several factors play a role in male infertility. Azoospermia which is defined as the absence of mature sperm in the ejaculate, is estimated to affect 1.9% of the general population and 10-20% of men with fertility problems. Two types of azoospermia have been identified. In nonobstructive azoospermia (NOA), it occurs due to deterioration in spermatogenesis. But, in obstructive azoospermia (OA) there are occlusions in the ductal system or ejaculatory system.
Numerous factors are implicated in NOA. It is mainly classified as pre-testicular (hypogonadotropic hypogonadism) or testicular (spermatogenic failure). Hypogonadotropic hypogonadism (HH) may be congenital (Kallmann syndrome, Prader Willi syndrome, and Laurence-Moon syndrome) or acquired (trauma, tumors, or radiation of hypothalamus/pituitary gland, exogenous steroids or androgens, including testosterone replacement therapy, anabolic steroids, and certain pituitary, adrenal, or testicu­lar tumors). Spermatogenic failure (SF) may occur because of some genetic abnormalities such as Klinefelter syndrome, Y chromosome microdeletions or cryptorchidism, varicocele, prior infection (e.g., mumps orchitis), gonadotoxic exposures (chemotherapy agents, radiation exposure), and testicular trauma or ischemia (e.g., testicular torsion, injury from prior surgery).
In the initial evaluation, the patient should be questioned about his fertility history and a thorough physical exam must be performed. Azoospermia is diagnosed via a semen analysis, preferably with two con­cordant semen analyses obtained at least 1 month apart, showing a total absence of spermatozoa, even in the centrifuged pellet. Semen volume, FSH and LH levels, and physical exam findings should aid in differentiating between OA and NOA. Men with OA can have low semen volume (<0.5–1 mL) and normal FSH levels, while men with NOA will have normal semen volume and may have an abnormal FSH level. Small testis volume may be a sign of NOA, while the absence of vasa deferentia or enlarged proximal epididymis would indicate underlying OA. After the diagnosis of NOA is made, hormonal evaluation should be obtained to differentiate between HH and SF. Low FSH, low LH, and low testosterone levels are seen in HH. In contrast, SF is characterized by high/normal FSH and LH and low/ normal testosterone. Treatment of NOA varies according to the cause. HH can often be managed successfully
with hormonal therapy. This condition is characterized by impaired spermatogenesis due to decreased pituitary LH production causing decreased testicular testosterone production. Therefore, management focuses on stimulating ITT production. hCG is the primary medication used in this setting, as it directly stimulates LH receptors on Leydig cells to increase testosterone production. After testosterone levels have normalized, FSH supple­mentation is commonly added to the hCG regimen to further stimulate spermato­genesis. In men on anabolic steroids or testosterone replacement therapy, the first step is discontinuation of all such hormones. Spermatogenic recovery after discontinuation of exogenous testosterone is variable.
In spermatogenic failure, hormonal therapy is controversial. The use of hormonal therapy before testicular sperm extraction (TESE) in men with SF is commonly utilized despite a lack of supporting evidence, particularly in men with idiopathic SF.
In patients with NOA and clinically significant varicocele, varicocelectomy can be considered. 43.9% of patients with NOA were found to have sperm in postoperative semen analysis after varicocelectomy, and this was signifi­cantly higher in patients with hypospermatogenesis compared to maturation arrest and Sertoli cell-only syndrome. Varicocelectomy has also a positive effect on sperm retrieval and pregnancy rates, but this difference is not statistically significant.
In NOA patients, There are several techniques were described for sperm extraction includ­ing testicular sperm aspiration (TESA), conventional testicular sperm extraction (cTESE), and microdissection testicular sperm extraction (micro-TESE or mTESE). It was shown that cTESE was 2.0 times more likely to have successful sperm retrieval compared to TESA. Compared to cTESE, mTESE is generally believed to have improved the SRR in men with NOA. SRRs increased from 45% with cTESE to 63% with mTESE and found that mTESE was 1.5 times more likely to have successful sperm retrieval compared to cTESE.
There are several areas of investigation that may aid in the diagnosis and management of NOA in the future. Detailed genetic evaluation such as karyotyping for chromo­somal translocations and next-generation sequencing may be useful in delineating the etiology of azoospermia. Predictive modeling and artificial intelligence may be used to help predict successful sperm retrieval in men with NOA.

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Baris Altay, MD, FECSM, FEBU: Short Biography

Q1. What is the definition of non-obstructive azoospermia (NOA)?
Dr. Bakırcıoğlu: The definition of non-obstructive azoospermia is simply testicular sperm
production failure and, depending on semen analysis, the total absence of spermatozoa
after the search of centrifuged pellet. However, the accurate diagnosis of azoospermia can
be problematic according to WHO recommendations and almost 24% of cryptozoospermic
men are misdiagnosed as azoospermia.
Q2. How does NOA differ from obstructive azoospermia (OA)?
Dr. Bakırcıoğlu: The medical history and physical examination (the normal volume of testis,
epidydimal enlargement, absence of vas deferens) are the essentials to differentiate
obstructive azoospermia from NOA. In semen analysis, decreased ejaculate volume and
normal serum levels of FSH and total testosterone are the signs of obstructive azoospermia.
However, in rare cases, testis biopsy is the only way to differentiate NOA from OA ( Normal
testis volume, Normal FSH (<7 IU/mL), and normal ejaculate volume (>1.5 mL).
Q3. What are the two main classifications of NOA based on the anatomical location of
the underlying problem?
Dr. Bakırcıoğlu: The two main classifications of non-obstructive azoospermia (NOA) based
on the anatomical location of the underlying problem are:
a. Pre-testicular NOA (Hypogonadotropic Hypogonadism - HH): This refers to a
hormonal abnormality from the hypophysis gland that prevents the stimulation of
spermatogenesis.

b. Testicular NOA (Spermatogenic Failure): This occurs when the testes themselves
have an issue with producing sperm despite proper hormonal stimulation.
Q4. What are the common causes of hypogonadotropic hypogonadism (HH) leading to
NOA?
Dr. Bakırcıoğlu: Common causes of hypogonadotropic hypogonadism (HH) leading to nonobstructive azoospermia (NOA) include congenital conditions such as Kallmann syndrome,
Prader-Willi syndrome, and Laurence-Moon syndrome, as well as acquired factors like
trauma to the pituitary or hypothalamus, tumors affecting these areas, radiation exposure,
the use of exogenous steroids or androgens (e.g., testosterone replacement therapy,
anabolic steroids), and tumors of the pituitary, adrenal, or testicular glands.
Q5. List some genetic conditions associated with spermatogenic failure (SF) in NOA.
Dr. Bakırcıoğlu: Genetic conditions associated with spermatogenic failure (SF) in nonobstructive azoospermia (NOA) include Klinefelter syndrome, XYY syndrome and Y
chromosome microdeletions, the most common form is AZFc deletions. These genetic
abnormalities can disrupt normal sperm production, leading to spermatogenic failure.
Q6. How is NOA managed in men with Klinefelter syndrome?
Dr. Bakırcıoğlu: Men with Klinefelter syndrome (KS) have a chance to become genetically
father with sperm recovery from testis by MicroTESE operation and using testicular sperm
intracytoplasmic sperm injection technique. Some studies showed the benefit of hormonal
therapy in men with KS who have low serum testosterone levels. In a study, sperm recovery
success was significantly higher in men with KS who had a better response to hormonal
therapy compared to no response to hormone treatment and remained with low
testosterone levels.
Q7. What predictors are associated with successful TESE in Klinefelter syndrome?
Dr. Bakircioğlu: Aging is negatively affected in men with KS. However, hormonal levels of
FSH, LH, and total testosterone levels did not predict successful sperm recovery. Although
the total testis volume of the men with KS did not show any difference between sperm
positive and negative groups, the patients who have decreased left testis volume have poor
prognosis. Q3. What roles do machine learning algorithms play in predicting the success
of therapeutic procedures in andrology?
Q8. What is the recommended management approach for men with NOA and androgen
excess due to anabolic steroid use?
Dr. Bakircioğlu: The duration of anabolic steroid use negatively affects spermatogenic
recovery in men with NOA. Longer use of steroids is associated with a decreased probability
of recovery, as prolonged suppression of spermatogenesis can lead to irreversible damage
in some cases. The longer the duration of use, the less likely full spermatogenic recovery
will occur.
Q9. How does the duration of anabolic steroid use affect spermatogenic recovery in
NOA?
Dr. Bakircioğlu: The duration of anabolic steroid use negatively affects spermatogenic
recovery in men with NOA. Longer use of steroids is associated with a decreased probability
of recovery, as prolonged suppression of spermatogenesis can lead to irreversible damage
in some cases. The longer the duration of use, the less likely full spermatogenic recovery
will occur.

Mustafa Emre Bakircioğlu, MD: Short Biography

Q1. How is azoospermia diagnosed through semen analysis?

Dr. Kalkanli: Azoospermia is the condition in which no spermatozoa are found in semen analysis. For a definitive diagnosis, spermatozoa should not be detected in a semen analysis performed at least one month apart. The recommended method to distinguish absolute azoospermia from cryptozoospermia is to centrifuge the semen at 3,000 rpm for 15 minutes and perform a comprehensive pellet microscopic examination with phase contrast optics at ×200 magnification. In this method, a small amount of sperm that can potentially be used for intracytoplasmic sperm injection can be detected.

Q2. What are the key physical exam findings that help differentiate between OA and NOA?

Dr. Kalkanlı: In men with azoospermia, small testicular volume, abnormal secondary sexual characteristics, testicular masses, unilateral or bilateral absence of testicles, gynecomastia, and varicocele may support non-obstructive azoospermia. Absence of vas deferens or enlarged proximal epididymis may indicate underlying obstructive azoospermia.

Q3. What hormonal levels are indicative of hypogonadotropic hypogonadism in NOA?

Dr. Kalkanli: Assessing levels of four hormones is indispensable in the diagnosis of hypogonadotropic hypogonadism, which occurs as a result of inadequate stimulation of the testicles by the hypothalamic-pituitary-gonadal axis. These include low LH, low FSH, and low testosterone levels, as well as prolactin levels within normal limits.

Q4. When is karyotyping and Y chromosome microdeletion analysis recommended in the evaluation of NOA?

Dr. Kalkanli: Chromosomal abnormalities show a 10-fold higher incidence in men with severe oligozoospermia (spermatozoa <5 million/mL) or azoospermia compared to the general population. Men with azoospermia are at highest risk. Karyotype analysis and Y chromosome microdeletion analysis should be performed on all azoospermia patients.

Q5. What is the significance of the azoospermia factor (AZF) microdeletions on the Y chromosome in NOA?

Dr. Kalkanli: Y deletions are detected in 8-12% of azoospermic patients. AZFc deletions are most common (65-70%). AZFb, AZFb+c, and AZFa+b+c deletions are less common (25-30%).
AZFa deletions are the rarest type (<5%). Complete deletion of the AZFa region is associated with Sertoli Cell Only Syndrome, and complete deletion of the AZFb region is associated with spermatogenic arrest. In complete deletions of the AZFa and AZFb regions, the sperm retrieval rate with mTESE is close to zero. Therefore, TESE is not recommended in these patients. AZFc region deletions may result in a phenotypic spectrum ranging from azoospermia to oligozoospermia. In cases of AZFc microdeletions, 50-75% sperm can be obtained with mTESE.

Q6. What is the role of hormonal therapy in the management of men with hypogonadotropic hypogonadism (HH)?

Dr. Kalkanli: Since the insufficiency of the hypothalamo-pituitary-testicular axis reduces adequate testosterone secretion from the testicles, all stages of spermatogenesis and spermiogenesis are disrupted in HH patients. The use of analogues of gonadotropins expected to be released from the pituitary can increase the levels of intratesticular testosterone and restart spermatogenesis. The high success rate after treatment indicates that hormonal therapy has a critical role in hypogonadotropic hypogonadism patients.

Q7. What medications are commonly used in hormonal therapy for HH, and how do they work?

Dr. Kalkanli: Gonadotropins (LH and FSH) are missing in HH patients; therefore the goal of treatment is to replace these hormones. hCG (an LH analogue) can stimulate Leydig cells and increase testosterone levels. Adding FSH analogues to the treatment after increasing testosterone levels will initiate spermatogenesis. Various formulations of FSH are available, including menopausal (hMG), urinary FSH (uFSH), highly purified FSH (FSH-HP), and recombinant FSH (rFSH).

Q8. What is the expected success rate of spermatogenesis after hormonal therapy in men with HH?

Dr. Kalkanlı: After hormonal therapy, 63% to 95% of patients with HH have sperm in their ejaculate. The pregnancy rate after hormone therapy is between 51 - 83%. Also, the duration of gonadotropin therapy is an important factor in the success rate.

Q9. How does testicular volume impact the response to hormonal therapy in men with HH?

Dr. Kalkanlı: Larger initial testicular volume is a good prognostic indicator for response to gonadotropin therapy in men with hypogonadotropic hypogonadism.

Q10. Why might hormonal therapy be controversial in the management of spermatogenic failure (SF) in NOA?

Dr. Kalkanlı: Hormonal therapy in men with NOA is controversial. There is no high level of evidence that either gonadotropin therapy or other hormonal treatments (estrogen receptor modulators or aromatase inhibitors) can improve spermatogenesis. Also, the use of a combination of these therapies in men with NOA has no strong evidence.

Arif Kalkanli, MD: Short Biography

Q1. What is the role of testicular sperm extraction (TESE) in the management of NOA?

Dr. Kaya: The majority of patients with NOA require the retrieval of testicular sperms for intracytoplasmic sperm injection (ICSI) as the only necessary treatment. The introduction of sperm retrieval techniques, especially TESE, and assisted reproductive technologies, such as ICSI, has provided many men with the chance of fathering a child that is genetically theirs and techniques like TESE have also significantly changed how NOA is managed.

Q2. What are the different techniques of sperm extraction mentioned in the chapter?

Dr. Kaya: Both approaches are based on a similar set of principles. The main difference is that the urologist operates with a microscope in a micro-TESE procedure, which enables the surgeon to enhance the probability of identifying spermatozoa. An experienced urologist can easily differentiate the tubules that are larger or “healthier looking” than the atretic and thin tubules via this microscope technique.

Q3. How does microdissection testicular sperm extraction (micro-TESE) differ from conventional TESE?

Dr. Kaya: MRI is nowadays used upfront for prostate biopsies. AI makes risk stratification possible; this implies that MRI images can be interpreted better making the need for prostate biopsies lower. Even with the nowadays performed transperineal prostate biopsies; it remains an invasive diagnostic test that comes with certain risks. By using AI and more accurately picking the patients that need to be biopsied, this potential risk of biopsy will be minimized.

Q4. What are the potential histopathologic findings in testicular biopsy of men with NOA?

Dr. Kaya: Biopsies carry the risk of bleeding and infection. Therefore, fully utilizing the biopsied tissue is critical in relieving the patient’s burden, avoiding a second biopsy, and assisting in clinical diagnosis. Furthermore, even after a testicular biopsy, the histopathologist may offer no conclusion because of the disrupted cell structure in the tissue, due to tissue quality, or other reasons. Following the collection of testicular samples in line with the specified methodology; the histological features of NOA are mainly classified into hypospermatogenesis, maturation arrest, and Sertoli cell only. In hypospermatogenesis, germ cells of all stages of spermatogenesis are present but with a relative paucity in numbers. In maturation arrest, spermatogenesis is incomplete and halts at primary or secondary spermatocyte (early) or spermatid (late) stages. Therefore, mature spermatozoa are usually absent. Sertoli cell-only Syndrome is characterized by a complete loss of germinal epithelium. It should be noted that it is common for men with NOA to present mixed histological patterns. Interstitial fibrosis, inflammation, testicular dysgenesis, and/or atrophy could be reported as histopathologic findings in testicular biopsy.

Q5. What factors may predict the success of sperm retrieval during TESE?

Dr. Kaya: The success rates of these procedures vary depending on the underlying cause. A thorough diagnostic workup is crucial in identifying the underlying cause of NOA. In addition, some factors affect fertility in men with NOA. The etiology of NOA, history of orchidopexy or previous failed TESE attempts, having Y-chromosome microdeletions and the type of deletions, type of the testicular pathology, the FSH-Inhibin B-testosterone levels, and the surgeon’s experience could all have a role in the prediction of the success of TESE. By contrast, the predictive role of age, obesity, and testicular volume is very limited.

Q6. What is the likelihood of spontaneous sperm recovery in men with NOA after varicocelectomy?

Dr. Kaya: The current evidence regarding the effectiveness of a varicocelectomy for men with NOA and clinical varicocele is limited and of very low certainty. The likelihood of spontaneous sperm recovery in men with NOA after varicocelectomy varies depending on several factors, including the presence and severity of the varicocele, testicular histopathology, and baseline hormonal levels. Men who have these conditions should be counseled carefully. The success of the operation should lead to the expectation of a spontaneous pregnancy. For realistic expectations, it should be made very clear that thisvoperation aims to find sperm in the ejaculate or during TESE.

Q7. What are the potential adverse effects of hormonal therapy in the treatment of NOA?

Dr. Kaya: The alteration of hormonal balance, the conversion of testosterone to estrogen, the systemic distribution of exogenous hormones to the whole body, water and salt retention, immune responses, and skin reactions are the main underlying mechanisms resulting from the adverse effects of hormonal therapy in men with NOA. A man who will begin to use hormonal treatment should be well-counseled before the treatment about the possible adverse effects and these should be monitored during the pre-and post-treatment period.

Q8. How might the timing of hypogonadism onset influence the outcome of hormonal therapy?

Dr. Kaya: If hypogonadism occurs before puberty, it can interfere with the development of the hypothalamic-pituitary-gonadal (HPG) axis, leading to more severe impairments in testicular function. In such cases, the response to hormonal therapy might be less favorable because the foundational development of the testicular and reproductive systems has been compromised. If hypogonadism develops after puberty, the HPG axis and testicular function have usually matured, so the impairment might be less severe. Hormonal therapy in these men might be more successful in restoring spermatogenesis because the foundational
development was already complete, and the testicular environment may be more responsive to hormonal stimulation. So, in cases of early-onset hypogonadism, more aggressive or combined treatment strategies might be necessary, while in late-onset cases, standard hormonal therapy may suffice.

Q9. What are the recommendations for ART in men with NOA who have completed hormonal therapy?

Dr. Kaya: Sperm retrieval combined with ICSI is the only option for men with NOA to impregnate their partner. However, given the uncertainty of sperm acquisition and the suboptimal sperm retrieval success rates in NOA males, the ideal position would be to optimize spermatogenesis and hence increase the chances of successful sperm recovery.
Although it is generally believed that empirical medical treatment is ineffective in men with spermatogenic failure, there might be a potential role for pharmacotherapy for men with NOA. The goals are to induce the recovery of sperm in the ejaculate or improve surgical sperm retrieval rates. During the treatment, hormone measurements (serum FSH, LH, estradiol, total testosterone, free testosterone, SHBG, and 17-hydroxy-progesterone levels) and liver enzymes (patients taking aromatase inhibitors) should be performed every three to four weeks. Semen analysis is carried out three months after the treatment commences and then every four weeks for over three months in patients who continue the therapy. Also, infertile men should try to conceive spontaneously during treatment. In the first year of treatment, a semen analysis should be performed and, depending on the results, ART should be started if the sperm concentration is <1 × 106/mL or wait until the second year of treatment to achieve spontaneous pregnancy if the sperm concentration is >5 × 106/Ml. In the absence of a pregnancy within two years, regardless of sperm count, the use of ART is recommended.

Q10. What is the role of salvage hormonal therapy in men with NOA who failed initial TESE?

Dr. Kaya: The testicular biopsy pathology of the first TESE may be important in determining the indication for salvage hormone therapy. This treatment modality could be used in men with NOA except those who have Sertoli cell-only syndrome. However, the type or administration method of this has not been defined in the literature. Typically, salvage hormonal therapy is administered for several months before a repeat TESE is attempted. This allows sufficient time for the hormonal modulation to potentially improve spermatogenesis. In addition, a micro-TESE should be preferred after the failure of any type of TESE.

Coşkun Kaya, MD, FEBU: Short Biography

Q1. What is the overall success rate of achieving pregnancy after hormonal therapy in men with HH?

Dr. Yenice: Different hormonal treatments, especially gonadotropins, can be preferred in the treatment of patients with HH. When different predictive factors are taken into account, pregnancy rates have been determined as 50%-85%.

Q2. How does the presence of a clinically apparent varicocele impact the success of varicocelectomy in men with NOA?

Dr. Yenice: Varicocele can be observed in men with NOA and varicocele at rates up to 44%. It has been observed that the rate of sperm detection is higher in postoperative semen analysis after varicocelectomy, especially in those with hypospermatogenesis. Pregnancy can be achieved in these patients using spontaneous or assisted reproductive techniques at different rates. While higher SRR rates are detected after surgery, there is no clear statistical data regarding pregnancy rates. Therefore, it would be appropriate to make a patient-based decision on this controversial issue, taking into account partner-related factors.

Q3. What is the role of brain MRI in the evaluation of NOA, particularly in men with suspected hypothalamic-pituitary axis abnormalities?

Dr. Yenice: Although brain MRI is not routine, it can be performed especially in men with hyperprolactinemia and to exclude the diagnosis of cranial tumors.

Q4. How do SERMs and aromatase inhibitors play a role in the management of idiopathic SF in NOA?

Dr. Yenice: Aromatase inhibitors prevent the negative feedback on gonadotropin release by preventing the conversion of testosterone to estradiol in peripheral tissues. SERMs downregulate negative feedback on the hypothalamic-pituitary-gonadal axis by competitively inhibiting estrogen receptors in the hypothalamo-pituitary region, thereby increasing the secretion of LH and FSH.

Q5. What are the potential outcomes of TESE in men with different histopathologic findings (e.g., Sertoli cell-only syndrome, maturation arrest)?

Dr. Yenice: Testicular histopathology has the most important role in predicting the success rates of mTESE. SRR rates are 70-100% in hypospermatogenesis, 25-85% in late maturation arrest, 25-40% in early maturation arrest, and 20-40% in Sertoli cell-only syndrome. Salvage TESE and surgical experience have effects on these rates.

Q6. What is the current evidence supporting the use of aromatase inhibitors in men with idiopathic SF in NOA?

Dr. Yenice: Aromatase inhibitors are quite safe drugs that improve hormonal and semen parameters by increasing endogenous testosterone production. However, prospective randomized controlled trials are lacking in this regard. Existing studies are contradictory and there are no definitive protocols regarding the duration, dose, or type of treatment.

Q7. Why might GnRH therapy be considered impractical for some patients with NOA?

Dr. Yenice: GnRH can be administered in a pulsatile manner, but it is expensive, and administered every 2 hours is impractical for most patients. Another factor that makes it not preferred is that the success rates are similar to those of HCG +/- FSH therapy.

Q8. What are the challenges in establishing definitive protocols for hormonal therapy in men with idiopathic NOA?

Dr. Yenice: In general, there is limited evidence regarding the use of hormone therapy before sperm retrieval in patients with idiopathic NOA. When the literature is reviewed, studies show different treatment protocols and durations, different follow-up periods, and TESE surgeons with different experiences. In addition, idiopathic NOA patients have unique and multifactorial problems (age, partner, comorbidities, etc.) that cause difficulties in establishing definitive protocols for hormonal therapy.

Q9. How do the 2020 American Urological Association (AUA) guidelines approach the use of hormonal therapies in NOA?

Dr. Yenice: The 2020 American Urological Association (AUA) guidelines recommend informing men with NOA that there is limited data on SERMS, aromatase inhibitors, and gonadotropin therapies.

Q10. What are the limitations of current research on the hormonal management of NOA?

Dr. Yenice: Despite the physiological rationale for hormonal therapy, there is a lack of convincing evidence and no definitive protocols regarding the duration, dose, or type of hormonal therapy. When looking at studies investigating the effect of hormone therapy on SRR, most studies are not randomized or prospective. SRR results are influenced by surgical and embryological factors, type of surgery, and experience. In addition, another prognostic factor for sperm retrieval surgery is the histopathological subtype, but most studies did not report data on this confounding variable or compare markers of testicular function.

Coşkun Kaya, MD, FEBU: Short Biography