madman
Super Moderator
Abstract
The differential diagnosis between obstructive and nonobstructive azoospermia is the first step in the clinical management of azoospermic patients with infertility. It includes a detailed medical history and physical examination, semen analysis, hormonal assessment, genetic tests, and imaging studies. A testicular biopsy is reserved for the cases of doubt, mainly in patients whose history, physical examination, and endocrine analysis are inconclusive. The latter should be combined with sperm extraction for possible sperm cryopreservation. We present a detailed analysis on how to make the azoospermia differential diagnosis and discuss three clinical cases where the differential diagnosis was challenging. A coordinated effort involving reproductive urologists/andrologists, geneticists, pathologists, and embryologists will offer the best diagnostic path for men with azoospermia.
1. Introduction
Azoospermia (a-, without + –zoo– » Greek zôion, animal + –spermia– » Greek sperma, sperm/seed) is defined by the absence of sperm in the ejaculate. Although the term does not imply an underlying etiology, azoospermia inevitably provokes infertility [1]. According to global estimates, 1 out of 100 men at reproductive age and up to 10% of men with infertility are azoospermic [2–4].
Azoospermia is broadly classified into obstructive and nonobstructive. This differentiation is clinically meaningful because it affects patient management and treatment outcomes [4]. Notably, nonobstructive azoospermia (NOA) relates to an intrinsic testicular defect caused by various conditions that ultimately affect sperm production profoundly.
The severe spermatogenic deficiency observed in NOA patients is often a consequence of primary testicular failure affecting mainly spermatogenic cells (spermatogenic failure (STF)) or related to a dysfunction of the hypothalamus-pituitary-gonadal axis (hypogonadotropic hypogonadism (HH)). From this point on, the acronyms STF and HH will distinguish these types of NOA, as appropriate [5]. The above-proposed terminology might be more intuitive for the clinician. It not only indicates the site of the problem (central or local) explicitly but also makes it clear that the testicular disorder refers primarily to a spermatogenic defect, unlike the indistinct term ‘testicular failure’ that may relate to an isolated spermatogenic defect or such a defect combined with Leydig cell failure.
The differential diagnosis between STF and HH is also essential because the former is linked with severe and untreatable conditions, whereas the latter can be effectively treated with gonadotropin therapy [5,6]. By contrast, obstructive azoospermia (OA) originates from a mechanical block along the reproductive tract, namely, vas deferens, epididymis, or ejaculatory duct [7,8]. Unlike NOA, spermatogenesis is preserved, and both reconstructive procedures and sperm retrieval are typically highly successful in OA patients [7–10].
Nonobstructive azoospermia can be distinguished from OA using history, physical examination, semen analysis, hormonal assessment, and genetic testing in most patients [4,5,11]. However, in some instances, this distinction is not straightforward, and a testis biopsy is required. In this article, we first provide readers an overview of the azoospermia differential diagnosis. Secondly, we discuss the differential diagnosis in cases of doubt, including a workable clinical algorithm. Lastly, we present exemplary clinical cases to illustrate a difficult diagnosis and its outcomes.
2. Azoospermia Differential Diagnosis: An Overview
The primary goals of the differential diagnosis are the identification of:
• Potentially correctable forms of azoospermia (e.g., by surgery or medication).
• Irreversible types of azoospermia suitable for sperm retrieval and intracytoplasmic sperm injection (ICSI), using own sperm.
• Types of azoospermia in which donor insemination or adoption are the only possibilities.
• Health-threatening illness associated with azoospermia requiring medical attention.
• Genetic causes of azoospermia that may affect the patient or offspring’s health, mainly if assisted reproductive technology is used.
It is critical to evaluate the azoospermic patient using a standardized workup to achieve these goals, as discussed in the next sections.
2.1. Medical History
A thorough medical history is pivotal to help determine the type of azoospermia. It must cover eight critical elements (Table 1), which are:
1. Infertility history
2. Sexual history
3. Childhood and development history
4. Personal medical history
5. Previous surgery/treatments
6. Gonadotoxic exposure
7. Family history
8. Current health status and lifestyle
2.2. Physical Examination
2.3. Semen Analysis
2.4. Hormonal Evaluation
2.5. Genetic Analysis
2.6. Imaging Studies
3. Differential Diagnosis in Cases of Doubt: Testis Biopsy
4. Clinical Cases: Difficult Differential Diagnosis
4.1. Case 1
4.2. Case 2
4.3. Case 3
5. Discussion
The clinical assessment and management of infertile men with azoospermia should consider the (i) differential diagnosis of azoospermia, (ii) identification of patients eligible for reconstructive procedures (e.g., OA), gonadotropin therapy (e.g., NOA-HH), or sperm retrieval, (iii) identification of patients with NOA-STF that might benefit from interventions (e.g., varicocele repair, hormonal modulation) before a sperm retrieval attempt, (iv) use of an optimal surgical method to harvest sperm, and (v) utilization of state-of-the-art IVF techniques when applicable. A detailed discussion of these aspects is outside the scope of this article and can be found elsewhere [5,9,10].
Nevertheless, the most challenging azoospermic patient to manage clinically is probably that with NOA-STF. Table 2 outlines the essential aspects to be considered under this scenario. Among several critical factors, a sensitive matter relates to hormonal modulation for men with NOA, as briefly described in clinical cases 1 and 2. The reason stems from the fact that it is generally believed that empirical medical treatment for men with NOA-STF is ineffective because gonadotropins’ plasma levels are usually high. Yet, many patients with NOA-STF present with hypogonadism and might thus lack adequate levels of intratesticular testosterone, which are essential for spermatogenesis in combination with adequate Sertoli cell stimulation by FSH [80–82]. Furthermore, gonadotropin action is determined by the frequency, amplitude, and duration of its secretory pulses. Due to the high baseline levels of endogenous gonadotropins commonly seen in patients with NOA-STF, the relative amplitudes of FSH and LH are low, leading to a paradoxically weak stimulation of Leydig and Sertoli cells [35,83]. Therefore, there may be a potential role for pharmacotherapy in men with NOA [84,85].
Selective estrogen receptor modulators, aromatase inhibitors, human chorionic gonadotropin (hCG), and FSH have been used off-label to manipulate male reproductive hormones and optimize intratesticular testosterone production [5,84,86–88]. The goals are to induce recovery of sperm to the ejaculate or improve surgical sperm retrieval rates. Case series and a few cohort studies suggested that these treatments might increase sperm retrieval rates, and in some cases, treatment was associated with the return of minimal numbers of sperm to the ejaculate [5,84–88]. Despite that, no randomized controlled trial exists, making it difficult to make clear recommendations on this matter.
Notwithstanding these observations, limited data indicate that treatment with hCG and recombinant FSH could lead to 10–15% higher sperm retrieval rates than sperm retrieval with no previous treatment [35]. Furthermore, hCG treatment was shown to improve intratesticular testosterone production remarkably in men with NOA [89]. Based on these concepts and with the goals of inducing return of sperm to the ejaculate or improving surgical sperm retrieval rates, we have used hCG alone or in combination with recombinant FSH off-label to optimize intratesticular testosterone production and FSH action, as previously described [5]. Our treatment protocol, utilized in clinical cases 1 and 2, relies primarily on hCG to boost intratesticular production. Additionally, hCG treatment was shown to decrease FSH levels, which are typically elevated in most of these patients [51]. Based on limited data from animal and human studies, it has been speculated that FSH reset to normal levels might reduce Sertoli cell desensitization caused by excessive circulating endogenous gonadotropins [90–95]. Consequently, an increased Sertoli cell function and expression of FSH receptors could be obtained. Our patients are followed with a monthly hormonal assessment, and we add an aromatase inhibitor in the course of treatment when the testosterone (ng/dL) to estradiol (pg/mL) ratio becomes less than 10. We also prescribe recombinant FSH when, after hCG treatment, the FSH levels drop below 1.5 IU/L [4,51]. The ultimate goal is to increase intratesticular testosterone to optimal levels through hCG stimulation while securing adequate FSH levels within normal ranges. Although we need more data in this area, hormone stimulation for men with NOA may be worth considering in selected cases.
6. Conclusions
The differential diagnosis between OA and the two forms of NOA, namely NOA-STF and NOA-HH can be effectively established in most patients based on a standardized male infertility workup. This is the first and critical step in the clinical decision-making process and it will guide the physician on how to optimally manage these patients, thus providing the couples with an optimal path for parenthood.
A testicular biopsy should be reserved for the cases of doubt, mainly in patients whose history, physical examination, semen analysis, hormonal evaluation, genetic tests, and imaging studies are inconclusive. Histopathology findings will indicate if spermatogenesis is preserved or disrupted, confirming whether azoospermia is obstructive or nonobstructive. Besides providing specimens for a formal histopathology examination, a diagnostic testis biopsy allows for a concomitant fresh examination of one or more extracted specimens; in the presence of viable sperm, cryopreservation should be offered. Alternatively, a formal surgical scrotal exploration may be utilized in cases of doubt, provided the surgeon is prepared to fix an obstruction at the level of epididymis or vas deferens or perform epididymal or testicular sperm retrieval as appropriate. Therefore, these procedures should be carried out at properly equipped facilities
A coordinated multidisciplinary effort involving reproductive urologists/andrologists, reproductive gynecologists, geneticists, and embryologists are vital to offer infertility patients with azoospermia the best chance of achieving biological parenthood.
The differential diagnosis between obstructive and nonobstructive azoospermia is the first step in the clinical management of azoospermic patients with infertility. It includes a detailed medical history and physical examination, semen analysis, hormonal assessment, genetic tests, and imaging studies. A testicular biopsy is reserved for the cases of doubt, mainly in patients whose history, physical examination, and endocrine analysis are inconclusive. The latter should be combined with sperm extraction for possible sperm cryopreservation. We present a detailed analysis on how to make the azoospermia differential diagnosis and discuss three clinical cases where the differential diagnosis was challenging. A coordinated effort involving reproductive urologists/andrologists, geneticists, pathologists, and embryologists will offer the best diagnostic path for men with azoospermia.
1. Introduction
Azoospermia (a-, without + –zoo– » Greek zôion, animal + –spermia– » Greek sperma, sperm/seed) is defined by the absence of sperm in the ejaculate. Although the term does not imply an underlying etiology, azoospermia inevitably provokes infertility [1]. According to global estimates, 1 out of 100 men at reproductive age and up to 10% of men with infertility are azoospermic [2–4].
Azoospermia is broadly classified into obstructive and nonobstructive. This differentiation is clinically meaningful because it affects patient management and treatment outcomes [4]. Notably, nonobstructive azoospermia (NOA) relates to an intrinsic testicular defect caused by various conditions that ultimately affect sperm production profoundly.
The severe spermatogenic deficiency observed in NOA patients is often a consequence of primary testicular failure affecting mainly spermatogenic cells (spermatogenic failure (STF)) or related to a dysfunction of the hypothalamus-pituitary-gonadal axis (hypogonadotropic hypogonadism (HH)). From this point on, the acronyms STF and HH will distinguish these types of NOA, as appropriate [5]. The above-proposed terminology might be more intuitive for the clinician. It not only indicates the site of the problem (central or local) explicitly but also makes it clear that the testicular disorder refers primarily to a spermatogenic defect, unlike the indistinct term ‘testicular failure’ that may relate to an isolated spermatogenic defect or such a defect combined with Leydig cell failure.
The differential diagnosis between STF and HH is also essential because the former is linked with severe and untreatable conditions, whereas the latter can be effectively treated with gonadotropin therapy [5,6]. By contrast, obstructive azoospermia (OA) originates from a mechanical block along the reproductive tract, namely, vas deferens, epididymis, or ejaculatory duct [7,8]. Unlike NOA, spermatogenesis is preserved, and both reconstructive procedures and sperm retrieval are typically highly successful in OA patients [7–10].
Nonobstructive azoospermia can be distinguished from OA using history, physical examination, semen analysis, hormonal assessment, and genetic testing in most patients [4,5,11]. However, in some instances, this distinction is not straightforward, and a testis biopsy is required. In this article, we first provide readers an overview of the azoospermia differential diagnosis. Secondly, we discuss the differential diagnosis in cases of doubt, including a workable clinical algorithm. Lastly, we present exemplary clinical cases to illustrate a difficult diagnosis and its outcomes.
2. Azoospermia Differential Diagnosis: An Overview
The primary goals of the differential diagnosis are the identification of:
• Potentially correctable forms of azoospermia (e.g., by surgery or medication).
• Irreversible types of azoospermia suitable for sperm retrieval and intracytoplasmic sperm injection (ICSI), using own sperm.
• Types of azoospermia in which donor insemination or adoption are the only possibilities.
• Health-threatening illness associated with azoospermia requiring medical attention.
• Genetic causes of azoospermia that may affect the patient or offspring’s health, mainly if assisted reproductive technology is used.
It is critical to evaluate the azoospermic patient using a standardized workup to achieve these goals, as discussed in the next sections.
2.1. Medical History
A thorough medical history is pivotal to help determine the type of azoospermia. It must cover eight critical elements (Table 1), which are:
1. Infertility history
2. Sexual history
3. Childhood and development history
4. Personal medical history
5. Previous surgery/treatments
6. Gonadotoxic exposure
7. Family history
8. Current health status and lifestyle
2.2. Physical Examination
2.3. Semen Analysis
2.4. Hormonal Evaluation
2.5. Genetic Analysis
2.6. Imaging Studies
3. Differential Diagnosis in Cases of Doubt: Testis Biopsy
4. Clinical Cases: Difficult Differential Diagnosis
4.1. Case 1
4.2. Case 2
4.3. Case 3
5. Discussion
The clinical assessment and management of infertile men with azoospermia should consider the (i) differential diagnosis of azoospermia, (ii) identification of patients eligible for reconstructive procedures (e.g., OA), gonadotropin therapy (e.g., NOA-HH), or sperm retrieval, (iii) identification of patients with NOA-STF that might benefit from interventions (e.g., varicocele repair, hormonal modulation) before a sperm retrieval attempt, (iv) use of an optimal surgical method to harvest sperm, and (v) utilization of state-of-the-art IVF techniques when applicable. A detailed discussion of these aspects is outside the scope of this article and can be found elsewhere [5,9,10].
Nevertheless, the most challenging azoospermic patient to manage clinically is probably that with NOA-STF. Table 2 outlines the essential aspects to be considered under this scenario. Among several critical factors, a sensitive matter relates to hormonal modulation for men with NOA, as briefly described in clinical cases 1 and 2. The reason stems from the fact that it is generally believed that empirical medical treatment for men with NOA-STF is ineffective because gonadotropins’ plasma levels are usually high. Yet, many patients with NOA-STF present with hypogonadism and might thus lack adequate levels of intratesticular testosterone, which are essential for spermatogenesis in combination with adequate Sertoli cell stimulation by FSH [80–82]. Furthermore, gonadotropin action is determined by the frequency, amplitude, and duration of its secretory pulses. Due to the high baseline levels of endogenous gonadotropins commonly seen in patients with NOA-STF, the relative amplitudes of FSH and LH are low, leading to a paradoxically weak stimulation of Leydig and Sertoli cells [35,83]. Therefore, there may be a potential role for pharmacotherapy in men with NOA [84,85].
Selective estrogen receptor modulators, aromatase inhibitors, human chorionic gonadotropin (hCG), and FSH have been used off-label to manipulate male reproductive hormones and optimize intratesticular testosterone production [5,84,86–88]. The goals are to induce recovery of sperm to the ejaculate or improve surgical sperm retrieval rates. Case series and a few cohort studies suggested that these treatments might increase sperm retrieval rates, and in some cases, treatment was associated with the return of minimal numbers of sperm to the ejaculate [5,84–88]. Despite that, no randomized controlled trial exists, making it difficult to make clear recommendations on this matter.
Notwithstanding these observations, limited data indicate that treatment with hCG and recombinant FSH could lead to 10–15% higher sperm retrieval rates than sperm retrieval with no previous treatment [35]. Furthermore, hCG treatment was shown to improve intratesticular testosterone production remarkably in men with NOA [89]. Based on these concepts and with the goals of inducing return of sperm to the ejaculate or improving surgical sperm retrieval rates, we have used hCG alone or in combination with recombinant FSH off-label to optimize intratesticular testosterone production and FSH action, as previously described [5]. Our treatment protocol, utilized in clinical cases 1 and 2, relies primarily on hCG to boost intratesticular production. Additionally, hCG treatment was shown to decrease FSH levels, which are typically elevated in most of these patients [51]. Based on limited data from animal and human studies, it has been speculated that FSH reset to normal levels might reduce Sertoli cell desensitization caused by excessive circulating endogenous gonadotropins [90–95]. Consequently, an increased Sertoli cell function and expression of FSH receptors could be obtained. Our patients are followed with a monthly hormonal assessment, and we add an aromatase inhibitor in the course of treatment when the testosterone (ng/dL) to estradiol (pg/mL) ratio becomes less than 10. We also prescribe recombinant FSH when, after hCG treatment, the FSH levels drop below 1.5 IU/L [4,51]. The ultimate goal is to increase intratesticular testosterone to optimal levels through hCG stimulation while securing adequate FSH levels within normal ranges. Although we need more data in this area, hormone stimulation for men with NOA may be worth considering in selected cases.
6. Conclusions
The differential diagnosis between OA and the two forms of NOA, namely NOA-STF and NOA-HH can be effectively established in most patients based on a standardized male infertility workup. This is the first and critical step in the clinical decision-making process and it will guide the physician on how to optimally manage these patients, thus providing the couples with an optimal path for parenthood.
A testicular biopsy should be reserved for the cases of doubt, mainly in patients whose history, physical examination, semen analysis, hormonal evaluation, genetic tests, and imaging studies are inconclusive. Histopathology findings will indicate if spermatogenesis is preserved or disrupted, confirming whether azoospermia is obstructive or nonobstructive. Besides providing specimens for a formal histopathology examination, a diagnostic testis biopsy allows for a concomitant fresh examination of one or more extracted specimens; in the presence of viable sperm, cryopreservation should be offered. Alternatively, a formal surgical scrotal exploration may be utilized in cases of doubt, provided the surgeon is prepared to fix an obstruction at the level of epididymis or vas deferens or perform epididymal or testicular sperm retrieval as appropriate. Therefore, these procedures should be carried out at properly equipped facilities
A coordinated multidisciplinary effort involving reproductive urologists/andrologists, reproductive gynecologists, geneticists, and embryologists are vital to offer infertility patients with azoospermia the best chance of achieving biological parenthood.
