Continuing Education Activity

Azoospermia is the complete absence of spermatozoa in the ejaculate. It is the most severe and one of the leading causes of male infertility. The exact pathophysiology of azoospermia is not always known. Azoospermia can be due to pre-testicular, testicular, and post-testicular causes. It is also classified as obstructive azoospermia (OA) or non-obstructive azoospermia (NOA). Recent advances in evaluating and managing patients with decreased or absent sperm in the ejaculate have progressed significantly. In addition, the management of azoospermia has been drastically improved as assisted reproductive technology offers potentially successful treatments in couples having male factor infertility. This activity reviews the interprofessional team's role in managing males with azoospermia.

Objectives:

• Describe the appropriate tests for assessing extremely low or absent sperm counts in males.
• Identify the etiology of azoospermia.
• Explain the differential diagnosis of azoospermia.
• Summarize the importance of coordination among the interprofessional team in providing positive pregnancy outcomes to couples with male azoospermia-related infertility.

Introduction

Factors affecting the male are crucial contributors to infertility amongst infertile couples. The overall incidence of infertility accounts for nearly 15% of the total population. Male infertility in its most severe form is known as azoospermia. Azoospermia is defined as the complete absence of spermatozoa in two separate centrifuged semen specimens. It affects nearly 1% of the male population and about 10%-15% of all males with infertility.[1][2] Many untreatable testicular disorders result in azoospermia, the most severe form of male infertility.[3] (Aspermia is the total lack of ejaculate.)

Azoospermia can be subdivided into pre-testicular, testicular, or post-testicular causes. Based on the presence or absence of obstruction of the ducts or vas deferens, azoospermia can be classified into obstructive azoospermia (OA) and nonobstructive azoospermia (NOA). It is important to differentiate between obstructive and nonobstructive azoospermia, i.e., primary testicular failure. With the advanced assisted reproductive technologies, various fertility options are available for couples having difficulties in conception due to male infertility, even with azoospermia. 

Amongst azoospermic males, 40% will have obstructive azoospermia.[4][5] Obstructive azoospermia may be due to the following reasons: congenital bilateral absence of the vas deferens, obstruction of ejaculatory and epididymal ducts, atresia of the seminal vesicles, various infections of the genitourinary tract resulting in obstruction or pelvic and inguinal procedures leading to a complete blockage such as a bilateral vasectomy.[6][7]

In obstructive azoospermia, spermatogenesis is often normal. Therefore, treatment options for obstructive azoospermia often include the surgical correction of the blockage in addition to other assisted reproductive techniques. 

The majority of azoospermic men, about 60%, will have nonobstructive azoospermia making it the most common type of azoospermia. Nonobstructive azoospermia is most often due to severe defects in spermatogenesis, which are frequently due to primary testicular failure or dysfunction. It can also result from dysfunction of the pituitary or hypothalamus. The exact pathology of nonobstructive azoospermia is often idiopathic. Advanced assisted reproductive techniques can often treat nonobstructive azoospermia (primary testicular failure).[8] 

Testicular biopsies of patients suffering from severe spermatogenic failure often show various areas of normal spermatogenesis.[9] These sperm can be retrieved using testicular sperm extraction (TESE) or testicular sperm aspiration (TESA) techniques and used in advanced assisted reproductive techniques such as intracytoplasmic sperm injection (ICSI). Sperm retrieved from the testes in these ways and used for in-vitro fertilization with ICSI generally result in healthy offspring.[10][11] 

Health care professionals face many challenges in providing care to infertile men with spermatic failure. Diagnostic modalities used for patients with azoospermia are hormonal assessment, biomarkers in semen, ultrasonography, testicular biopsy, and vasography. The best tool for diagnosing distal male reproductive system obstruction is transrectal ultrasound.[12][13]

Etiology

In obstructive azoospermia, spermatogenesis is often normal. However, the exact pathology of non-obstructive azoospermia is often idiopathic.

Non-obstructive azoospermia may be due to several causes.[14] These include:

• Androgen insensitivity
• Chemotherapy
• Congenital absence of germ cells (Sertoli cell-only syndrome)
• Heavy metal exposure
• Hyperprolactinemia
• Hypogonadotropic hypogonadism, as in Kallmann syndrome 
• Impaired sperm production due to chromosomal abnormalities as in Klinefelter syndrome or Y chromosome microdeletions of subregions AZFa, AZFb, or AZFc [15]
• Infections such as mumps and orchitis
• Radiation therapy (Experimentally, epsilon aminocaproic acid has been shown to protect sperm DNA from radiation damage, but this has not yet been approved for clinical practice.)[16][17])
• Spermatogenic (maturation) arrest
• Testicular torsion
• Translocation or inversion of azoospermia factor cryptorchidism
• Varicoceles

Etiological classification according to pretesticular, testicular, and post-testicular causes:

Epidemiology

The overall incidence of infertility accounts for nearly 15% of all couples. Male azoospermia affects nearly 1% of the male population and about 10 to 15% of all infertile men.[18] At any given time, there are about 600,000 azoospermic men of reproductive age in the US, most of whom will have non-obstructive azoospermia.[19] 

Azoospermic men are also at increased risk of developing cancer compared to the general population. For example, between 5% and 8% of men with testicular cancer will be azoospermic.[20][21] The exact incidence is unknown as infertility is not a reportable disease, is usually managed in physicians' offices, and is probably underreported in developing nations where advanced treatment is either too costly or unavailable.[22]

Pathophysiology

The types of azoospermia can be classified as either testicular/post-testicular or obstructive/non-obstructive; both appear in the table below. We find the classification based on obstruction to be more useful and practical. 

The exact pathophysiology of azoospermia is not always known. However, in such cases, azoospermia mainly occurs due to abnormal ciliary function and poor mucus quality.

Pretesticular causes are endocrinal abnormalities related to the hypothalamus, pituitary, and male gonads (testis). In addition, testicular causes usually involve disorders related to spermatogenesis. Posttesticular causes of azoospermia include any ductal obstruction at any site in the entire male reproductive tract.

Pretesticular Causes

Pretesticular causes, also called secondary testicular failure, usually result from pathological endocrine conditions. Although relatively uncommon, up to 3% of infertile men with subfertility will have underlying endocrinopathies.[23]

Pretesticular azoospermia can be congenital or acquired. Pretesticular azoospermia may be seen in association with the following:

1. Kallmann syndrome: These are defects seen at the level of the hypothalamus where there is a failure of GnRH hormone secretion (hypogonadotropic hypogonadism). In Kallmann syndrome, it occurs due to failure in the migration of GnRH-releasing neurons to the olfactory lobe, which explains the presence of a decreased sense of smell in affected individuals.[24]
2. Hyperprolactinemia: Hyperprolactinemia is the excessive production of prolactin hormone.[25] Hyperprolactinemia results in sexual dysfunction due to inhibition of secretion of GnRH from the hypothalamus, which leads to impaired fertility.[26] In these patients, there is decreased spermatogenesis due to testicular abnormalities on both sides.[27]
3. Mumps orchitis: It may lead to testicular atrophy on both sides and may lead to infertility in 13% of cases.
4. Klinefelter Syndrome: It is characterized by a tall eunuchoid phenotype, decreased facial and pubertal hair, decreased penis size, hard testicles, decreased cognitive abilities, and decreased testosterone levels.[27] These patients have azoospermia. During testicular sperm extraction, spermatozoa are seen in almost 69% of men having Klinefelter syndrome.[28]

 Post-testicular Causes of Azoospermia

1. Congenital bilateral absence of the vas deferens (CBAVD): Its incidence is 1% amongst infertile men. It mainly occurs due to mutations in the cystic fibrosis transmembrane regulator gene (CFTR) and defective mesonephric duct differentiation.[29]
2. Vasal obstruction: Incidences of unintended vasal obstruction are usually seen after corrective surgeries for inguinal canal hernias.[30] The testicular size remains normal on examination, but the epididymis feels firm.
3. Obstruction of epididymis: Obstruction of the epididymis is present in Young syndrome, which is a triad of chronic sinusitis, bronchiectasis, and obstructive azoospermia.
4. Obstruction of the ejaculatory ducts: Obstruction of the ejaculatory ducts of unilateral or bilateral.[31][32][33]

Types of Azoospermia and Causes

History and Physical

A detailed evaluation should be done in patients with azoospermia. The evaluation includes a complete medical, sexual, and surgical history of the patients. A detailed history regarding trauma to the genital organs, drug allergies, medication history (gonadotropins, toxins), chemotherapy, pesticide, and radiation exposure must be taken. The history of genitourinary infections and sexually transmitted diseases must be evaluated in detail.[25] 

Physical examination of the patient of azoospermia is also essential. The patient should be examined in both the supine and standing positions. The room temperature should ideally be 36 to 37 degrees Celsius (96.8 to 100.4 F) which is quite warm.

The patient should be examined for varicocele. The grading of varicoceles is related to the progression of the disease and helps in determining the further treatment plan for the disease.[34][35] The development of secondary sexual characters must be evaluated. Body, axillary and pubertal hair distribution is decreased in low androgen levels. The thyroid gland should be palpated. Auscultation of the heart and lungs should be done. Breast and abdominal examinations should also be performed. 

Examination of the male genitalia is particularly important. Testes must be palpated, and their length, width, and volume should be noted. A decrease in the size of the testes is associated with impaired spermatogenesis.[36] Normal testicular size is generally 20 cc or more. Testicular length is generally considered to be normal at 4 cm, but the actual "normal" limit is 31 mm in White race individuals and 34 mm in African Americans. Patients with obstructive azoospermia usually have a normal hormonal profile and unremarkable testicular size, although some men with a late maturational arrest can present similarly.[37][38] Bilateral atrophic or hypotrophic testes, along with high FSH levels, are usually associated with primary testicular failure. They tend to have worse fertility outcomes, although ICSI may still be possible in some.

The vas deferens and epididymis need to be palpated bilaterally, and their consistency noted. The absence of one or both vas deferens should be carefully noted. (Such an absence is often associated with a cystic fibrosis gene mutation.) A digital rectal examination is essential to rule out any mass and further evaluate the prostate gland's size and consistency. The seminal vesicles may be prominent and felt in ejaculatory duct obstruction.

Evaluation

Semen Analysis

At least two separate analyses should be done with three days of sexual abstinence preceding each specimen. In patients with azoospermia who have normal ejaculate volume, there is either spermatogenic failure or obstruction between the testes and the seminal vesicles. Patients with azoospermia having low semen volume and normal-sized testicles may either have ejaculatory duct obstruction or ejaculatory dysfunction. Therefore, all patients displaying absent ejaculate (aspermia) or low-volume ejaculation (1.5 ml<) should be requested to redo the semen investigations and also give a post-ejaculation urine example. 

Hormonal Evaluation

In evaluating azoospermia, especially with normal testicle size and consistency on physical examination, a detailed endocrinological evaluation is necessary to make a specific diagnosis and strategize the treatment protocol.[39] Hormonal profiles, including testosterone level (total and free), follicle-stimulating hormone, luteinizing hormone, prolactin, and estradiol levels, should be obtained in addition to a thyroid profile. There is usually a decreased or normal FSH level in patients with obstructive azoospermia. In contrast, FSH levels are typically high in nonobstructive azoospermia, especially if the testes are below normal size. However, there is some overlap, so FSH levels alone may not be sufficient for differentiation. (As a general rule, the higher the FSH, the more likely a significant spermatogenic failure will be.) Thus, a testicular biopsy may need to be done to differentiate the two, which will be definitive. Fortunately, this is necessary for diagnosis only infrequently.[40]

Hypogonadotropic hypogonadism is a relatively uncommon cause of nonobstructive azoospermia. It accounts for no more than 2% of all infertile males. Possible causes include Kallmann syndrome, androgen-induced hypogonadism (from testosterone supplementation), brain neoplasms, radiation, trauma, radiation, etc.[41] 

Imaging (Scrotal Ultrasonography)

The role of scrotal ultrasound in evaluating male infertility is evolving and becoming more routine. It allows for a more precise measurement of testis size and can identify cysts, varicoceles, spermatoceles, and lesions that might not otherwise be detectable by other means. It can also help differentiate obstructive from nonobstructive azoospermia. Scrotal ultrasonography will tend to show ectasia of the epididymal tubules and/or the rete testis, abnormal epididymal echogenicity, or dilated proximal vas deferens in obstructive azoospermia. Testicular volume, epididymal head size, and the resistive index of intratesticular vessels will all tend to be increased compared to patients with nonobstructive azoospermia.[42] In addition, transrectal ultrasonography can be used to evaluate the seminal vesicles and to screen for ejaculatory duct cysts. The absence of the seminal vesicles suggests a possible cystic fibrosis genetic mutation (CFTR)

If the seminal vesicles are absent or dilated/enlarged, an obstructive etiology of azoospermia can be diagnosed. The presence or absence of an ejaculatory duct cyst can also be determined using transrectal ultrasonography. Ultrasound examinations are painless and inexpensive, but a discussion with the diagnostic radiologist on which factors to look for and evaluate when a scrotal ultrasound is ordered for a male infertility patient will be very helpful. Therefore, the recommendation is for routine use of a comprehensive sonographic evaluation to help diagnose azoospermia and the differentiation of obstructive from nonobstructive etiologies.  

Genetic Testing

Klinefelter Syndrome

Cytogenic abnormalities will be found in approximately 5% of men with nonobstructive azoospermia.[43] The most common sex chromosomal abnormality is Klinefelter syndrome which is the presence of an extra X chromosome (XXY). Patients are phenotypically male, and there is a highly variable clinical presentation. Many patients are unaware they have the condition until they present with infertility. It is believed that about 50% of all patients are never diagnosed. The overall incidence is about one in every 500 to 800 men, accounting for 3% of all infertile men. Klinefelter patients typically exhibit Sertoli cell-only syndrome on histological examination. Some of the symptoms of Klinefelter syndrome include the following:[44]

• Taller than average stature
• Longer legs, shorter torso, and broader hips compared to other boys
• Poor muscle tone
• Poor fine motor skills, dexterity, and coordination
• Absent, delayed, or incomplete puberty
• After puberty, less muscle as well as less facial and body hair compared with other teens
• Small, firm testicles
• Small penis
• Enlarged breast tissue (gynecomastia)
• Infertility

The presence of germ cells and sperm is highly variable in these individuals. Microscopic testicular sperm extraction (micro-TESE) can retrieve viable sperm in 50% of men with Klinefelter syndrome.[45] The data is conflicting on the use of age or testosterone levels to help predict successful sperm retrieval in men with this disorder.[46][47][48] Therefore, sperm retrieval surgical procedures should be limited to adults and are not currently recommended in boys and adolescents with Klinefelter.[37][49] 

Adult men with the syndrome also have high rates of hypogonadism, diabetes, thromboses, metabolic syndrome, various cancers (breast, hematological, and extragonadal germ cell tumors), and cardiovascular disease and should receive appropriate counseling and referrals.[50]

Other Genetic Disorders

The overall incidence of chromosomal abnormalities in infertile men is about 6%.[51] The highest risk is found in nonobstructive azoospermic men.[52][53] The absence of one or both vas deferens and/or the seminal vesicles on transrectal ultrasound is highly suggestive of a genetic interaction associated with cystic fibrosis, which will be present about 80% of the time.[54] It is recommended that both the patient and his partner be tested for the cystic fibrosis gene (CFTR). Other abnormalities include Robertsonian and reciprocal translocations as well as chromosomal inversions. 

All men with primary testicular failure should be given karyotype and Y chromosome microdeletion testing. About 6% of men with nonobstructive azoospermia will have microdeletions of the Y chromosome involving the AZFa and/or AZFb subregions. Men with such microdeletions typically have extremely poor sperm retrieval rates and should be counseled to consider using donor sperm for ICSI or adoption.[55] 

Four percent will have a microdeletion of the AZFc subregion, which is not quite as severe a problem with infertility but will be inherited by male offspring. Up to 30% of nonobstructive azoospermic men will have Y chromosome microdeletions.[6] Complete deletions of the AZFa, AZFb, or AZFc subregions generally result in nonobstructive azoospermia. Histologically, about 46% of men with AZFc microdeletions will demonstrate Sertoli cell-only syndrome, and 38% will have maturational arrest.[56] There are also rare cases where atypical Y chromosome microdeletions will be found. Individualized counseling and treatment should be offered to such patients.

Men with hypogonadotropic hypogonadism should also be considered for genetic testing. About a third will demonstrate a genetic lesion with variable inheritance. For example, 13 genes have been identified to date that contribute to maturational arrest resulting in nonobstructive azoospermia.[57]

Differentiating Obstructive Azoospermia from Non-Obstructive 

Obstructive azoospermia will tend to have normal FSH and LH levels along with normal-sized testes. Testicular ultrasound may demonstrate an increased intratesticular resistive index or some dilated ducts in the testes, epididymis, or proximal vas. Nonobstructive azoospermia may have normal FSH and LH levels but will often show elevated levels. The size of the testes may be normal, hypotrophic, or atrophic. If the differentiation is still unclear, a testis biopsy may be required.

Further Evaluation of Low Semen Volume Azoospermia

Azoospermia patients with semen volumes consistently below 1.5 ml are likely to have retrograde ejaculation, an ejaculatory duct cyst, or congenital absence of the vas or seminal vesicle. Examination of the post-ejaculation urine sample can identify patients with retrograde ejaculation. The physical examination can determine if there is an absent vas deferens. Transrectal ultrasonography or cystoscopy can be used to identify an ejaculatory duct cyst. The seminal vesicles can be evaluated with transrectal ultrasonography. 

Further Evaluation of Nonobstructive Azoospermia

Azoospermia is diagnosed with at least two separate semen samples for detailed analysis. In nonobstructive azoospermia, the abnormal hormonal profile suggests a significant spermatogenic abnormality as evidenced by an elevated FSH level. In cases of a normal hormonal profile, a testicular biopsy can be used to further evaluate spermatogenesis as it would be the definitive way to diagnose azoospermia from causes like maturational arrest and Sertoli cell-only syndrome. A karyotype analysis, genetic testing, and Y chromosome microdeletion test should be performed to assess genetic abnormalities. Endocrinological abnormalities are diagnosed and then managed accordingly.

Further Evaluation for Obstructive Azoospermia

In cases of obstructive azoospermia, the hormonal profile and testicular volume measurements are generally normal.

Dilation of the epididymis, presence of a hydrocele, or absence of the vas deferens suggest obstruction. Azoospermia due to vassal obstruction or epididymal obstruction has a normal biochemical profile in the seminal fluid. Testicular biopsy is indicated in azoospermic men with normal testicular examinations and hormonal profiles. These patients do not require a karyotype evaluation. However, an assessment for the CFTR gene mutation should be done to rule out cystic fibrosis.

Diagnostic Testicular Biopsy

The design of the testicular tissue is heterogeneous, and spermatogenesis occurs in the foci; hence, a biopsy is infrequently utilized as a diagnostic tool.[58] As a rule, testicular characteristics and diagnostic lab findings are good but not perfect indicators of nonobstructive azoospermia. Hence, testicular sperm extraction (TESE) can be done in a specialized assisted reproduction center which permits cryopreservation of sperm and avoids testicular biopsy. A normal testicular biopsy is suggestive of obstruction, and vasography is required to identify the precise location of the blockage. A formal surgical repair can then be done or sperm retrieval as appropriate. Depending on the severity of the defect, serum testosterone levels can be low, normal, or high. Only a single testis needs to be biopsied for a histological diagnosis. The larger of the two testes should be selected for the procedure.

Testicular Etiologies

Direct testicular pathology may infer from varicocele-induced testicular damage, undescended testes, testicular torsion, mumps orchitis, toxic effects of medications, radiation, hereditary variations from normal, and idiopathic causes. Essential testicular failure in conjunction with azoospermia, commonly named nonobstructive azoospermia, is best managed by collecting testicular sperm, if possible, for ICSI. Higher serum FSH levels and smaller testicular volumes are suggestive of a more severe degree of spermatogenic disruption and poorer outcomes in men with nonobstructive azoospermia.[59] 

In general, maturational arrest, Sertoli cell-only syndrome, and Y chromosome microdeletions of AZFa, AZFb, or AZFc subregions are permanent and untreatable forms of nonobstructive azoospermia. However, micro-TESE may allow sperm retrieval in about 50% of cases.

Other causes of azoospermia include XYY syndrome, myotonic dystrophy, Noonan syndrome, 5 alpha-reductase deficiency, androgen insensitivity syndrome, and vanishing testis syndrome. There is sufficient evidence to confirm that varicoceles have a deleterious impact on the semen and testes, while varicocelectomy has been shown to improve sperm parameters and testicular function.[60][61][62] However, only a small percentage of men with azoospermia due to testicular failure will benefit from surgical treatment of their clinical varicocele.[63]

Undescended Testes

Undescended testicles are the most common genital mutation in boys and young males. They are noted in 2.7% of newborns and up to 0.8% of 1-year-olds.[64] It is important to distinguish cryptorchid from retractile testicles, a circumstance involving hyperactive cremasteric muscles that cause the testes to intermittently dwell within the inguinal canal or high in the scrotum. Although most men with a history of one-sided undescended testicles are capable of paternity, testicular volume and age at orchiopexy are autonomous, independent predictors of fertility potential and potential sperm retrieval in men with a history of cryptorchidism.[65][66]

Testicular Torsion

Testicular torsion happens in about 1:4,000 males before the age of 25 years.[67] This disorder requires prompt surgical exploration with corrective detorsion and bilateral orchidopexy, as the dangers of nonoperative management are well documented.[68] Testicular conservation is usually accomplished if the surgical procedure is performed within 6 hours. Usually, non-absorbable sutures are used for orchidopexy (at least 3 points of fixation on each side), and it is customary to perform a prophylactic orchidopexy on the contralateral testis at the time of the surgery.

Treatment / Management

Azoospermia Management

In this era of advanced assisted reproductive techniques, infertile couples have several options to complete their family biologically.

Obstructive Azoospermia

The main aim of managing obstructive azoospermia is to correct the site of obstruction by using reconstructive surgical techniques, e.g., vasoepididymostomy and vasovasostomy. Assisted reproductive techniques are useful in patients suffering from congenital absence of vas deferens, as surgical reconstruction in these patients is not feasible. In cases of ejaculatory ductal obstruction, surgical correction with transurethral resection is done to achieve the patency of the ejaculatory ducts. Intraoperative vasography gives better results than vasoepididymostomy. Transurethral resection improves semen parameters in about 50 to 70% of cases.

Sperm retrieval for assisted reproduction is an excellent option for managing obstructive azoospermia, as successful sperm recovery is close to 100%. ICSI has increased pregnancy rates as the sperm obtained are motile, and samples can also be cryopreserved.[69][70] In patients suffering from obstructive azoospermia, if surgical repair is not possible or the female factor is a major contributor to infertility in couples, sperm retrieval for assisted reproduction is an excellent option for managing the infertile state. Surgical bypass or repair of sperm obstructions is generally possible in less than 50% of men with obstructive azoospermia.[71] 

The area of obstruction most commonly found is in the epididymis. Current success rates for vasoepididymostomies are 85% patency rates with a 50% spontaneous pregnancy rate. Collecting and cryopreserving sperm at the time of surgery is recommended if the outcome is unsuccessful. Inguinal approaches for microscopic vasovasostomy have been described, and laparoscopic and robotic techniques for vas isolation before a microsurgical anastomosis.[72] 

In obstructive azoospermia, microsurgical epididymal sperm aspiration (MESA) is optimally used for sperm retrieval when possible. This is almost always successful for extra-testicular obstructions. If the blockage is intratesticular, then TESE or TESA will be required. Post-vasectomy obstructions can be treated with microscopic vasectomy reversals, which currently achieve a reported post-operative patency rate of 90 to 97%.[37] These surgeries may also be done robotically with similar success rates.[73] 

Obstruction from scarring, inflammation, or ejaculatory duct cysts is typically treated with transurethral resection of the duct. Reported pregnancy rates following such procedures are 12.5% to 31%, while side effects include failure, incontinence, reflux into the seminal vesicles and ejaculatory ducts, as well as epididymitis. Intraoperative transrectal ultrasound and the use of methylene blue to verify patency can help reduce complications and increase the safety of the procedure.[74] The procedure can also be done with a transurethral laser incision of the ejaculatory duct along with seminal vesiculoscopy. Still, it is unclear if this offers any significant advantages over the standard procedure.[75]

Percutaneous procedures, including TESE, percutaneous epididymal aspiration of sperm, and percutaneous testicular biopsy, can be performed to obtain sperm in couples desiring fertility. However, the highest rates of successful sperm retrieval are reported with microdissection testicular sperm extraction techniques.

Non-Obstructive Azoospermia

Advanced assisted reproductive techniques are required for most patients with non-obstructive azoospermia. Both ICSI and microscopic testicular sperm extraction (micro-TESE) are potentially beneficial to these patients. In testicular sperm aspiration (TESA), a needle is inserted into the testicular parenchyma percutaneously. The failure rate of sperm retrieval in non-obstructive azoospermia is high and varies with the underlying etiology. Overall success in sperm retrieval in these patients is reportedly as high as 75% but averages about 50%. There is also a significant risk of vascular injury. In addition, it has been observed that the incidence of chromosomal abnormalities and DNA damage in the sperm is relatively high in patients with non-obstructive azoospermia, and potentially inheritable infertility-related genes may be passed on to male offspring. Repeat micro-TESE procedures can be performed successfully, if necessary, to retrieve sperm.[76]

To stimulate spermatogenesis in cases of hypogonadotropic hypogonadism or pre-testicular azoospermia (secondary hypogonadism), gonadotropin analogs or FSH and HCG are preferred. This therapy has demonstrated success in achieving at least some sperm in the ejaculate of 75% to 77% of men with non-obstructive azoospermia due to hypogonadotropic hypogonadism, but treatment may require as long as six months.[77] Pulsed GnRH is an option but is usually more expensive and does not offer any substantial benefit over standard treatment. Testosterone therapy is specifically not recommended.

While up to about 11% of azoospermic men who received hormone therapy (usually clomiphene) have shown improvement with the presence of sperm in the ejaculate, there is no standardization of this therapy and no good-quality randomized trials. Therefore, many experts and the European Association of Urology (EAU) do not recommend the general use of hormone therapy in men with non-obstructive azoospermia and primary hypogonadism.[37] The main treatment for these men is microscopic testicular sperm extraction when feasible and ICSI. Overall success with these techniques resulting in a pregnancy is no more than 25%, and they are costly.

The role of estrogen receptor modulators, gonadotropins, and aromatase inhibitors in men with primary hypogonadism and non-obstructive azoospermia is much more controversial. These are frequently used to improve sperm parameters in infertile oligozoospermic men, and some evidence supports their use.[78][79][80] However, their effectiveness in improving sperm retrieval rates through TESE or TESA is somewhat uncertain and has not been definitively proven.[37] Additionally, the optimal protocol and dosing schedule have not yet been determined, although a progressive protocol starting with clomiphene and escalating to HCG has been proposed.[80] There are also potential side effects from the therapy. However, despite these limitations, and since no other treatment is available, the use of hormone stimulation therapy remains a common clinical practice.[81]

Treatment of hypogonadotropic hypogonadism is relatively effective. One regimen for azoospermic men due to hypogonadotropic hypogonadism is the pulsatile administration of 5 to 20 micrograms of GnRH every two hours using a portable infusion pump. The return of sperm in the semen was generally noted after six months of therapy, and 77% of initially azoospermic men were found to have spermatogenesis after 12 to 24 months of treatment.[82] 

FSH stimulation before GnRH therapy seems to improve the outcomes. GnRH is only effective in men with normal pituitary activity. Gonadotropin treatment with HCG (with or without FSH) is preferred in patients with decreased or absent pituitary function. The suggested dosage is 1,000 to 3,000 IU two to three times weekly. This typically leads to sperm production after 3 - 6 months. If unsuccessful, FSH is added at a 75 to 150 IU dose twice a week.[83] The overall success rate of spermatogenesis from medical therapy of hypogonadotropic hypogonadism is about 75%. If medical treatment is unsuccessful, assisted reproductive techniques are recommended.[81][84]

Men with non-obstructive azoospermia tend to have a higher incidence of other health-related disorders, including pituitary prolactinomas, various neoplasms (including Sertoli cell, Leydig cell, and germ-cell tumors) and have three times the overall risk of developing a future malignancy compared to infertile men without azoospermia.[20] About 30% of men with non-obstructive azoospermia also have testosterone deficiency, usually due to Leydig cell dysfunction.[85][86]

The only absolute contraindications for an attempt at sperm retrieval in male non-obstructive azoospermic patients are Y chromosomal microdeletions of the AZFa or AZFb subregions and post bilateral orchiectomy as the sperm retrieval rates will be zero! Even in cases of Sertoli cell-only syndrome, there is a reported sperm retrieval success rate with micro-TESE of at least 24%, with a mean average rate of about 50%.[40][87] No degree of testicular atrophy or FSH elevation can determine the success or failure of a sperm retrieval procedure.

Good predictive indicators of successful sperm retrieval with micro-TESE in non-obstructive azoospermic men include focal type Sertoli cell-only syndrome, late-stage maturation arrest (compared to early maturation arrest), hypospermatogenesis (as opposed to maturation arrest or Sertoli cell-only syndrome), and viable sperm visible in the seminiferous tubules on testis biopsy. With micro-TESE, the successful sperm retrieval rate is about 50%, while ICSI also has approximately a 50% success rate giving an overall pregnancy rate of only 25%. Given the associated costs and potential genetic consequences, couples should seriously consider artificial insemination or ICSI using donor sperm or adoption before starting advanced reproduction treatments.

Differential Diagnosis

• Congenital unilateral absence of the vas deferens (CUAVD) or congenital bilateral absence of the vas deferens (CBAVD)
• Congenital adrenal hyperplasia
• Congenital varicocele
• Cryptorchidism
• Ejaculatory duct obstruction or cysts
• Epididimitis and prostatitis
• Erectile/sexual dysfunction
• Hyperprolactinemia,
• Hypogonadotropic hypogonadism
• Kallmann syndrome
• Long-term testosterone supplementation
• Medication side effects (tamsulosin)
• Mumps orchitis
• Pituitary tumors
• Post bilateral orchiectomy
• Post bilateral vasectomy
• Post TURP
• Retrograde ejaculation
• Spermatoceles

Prognosis

Prognosis mainly depends on the type of azoospermia. In obstructive azoospermia, the prognosis for a successful biological pregnancy using sperm retrieval procedures and intracytoplasmic sperm injections is better than in non-obstructive azoospermia, where spermatogenesis may be so disrupted that no viable sperm can be collected. Advancements in surgical techniques and procedures over the last 20 years have greatly improved the chances of a successful pregnancy with advanced assisted reproductive techniques.

Complications

1. Hematoma formation due to surgery
2. Infection
3. Parenchymal fibrosis of testis
4. Testicular atrophy

Deterrence and Patient Education

Proper counseling, testing, and treatment can offer most male infertility patients, including those with azoospermia, the chance to biologically father children. It is largely possible to make the patient aware of the type, cause, evaluation, possible treatment, and prognosis of azoospermia.

Pearls and Other Issues

Summary

It is best to provide patients with reasonable expectations of ultimate success at the initial visit, as the general public often has a somewhat exaggerated view of the true capabilities of modern medicine in treating azoospermia and male infertility. 

Two properly collected separate semen samples showing no sperm are required to establish the initial diagnosis of azoospermia. Even with azoospermia, most patients can be helped with sperm retrieval procedures and ICSI. 

A detailed history and careful physical and initial hormonal screening (testosterone, FSH, LH, prolactin, and estradiol) are necessary to classify the type of azoospermia as obstructive vs. non-obstructive. Karyotype analysis and genetic testing for Y chromosome microdeletions should be offered to azoospermic men without an apparent cause of their disorder. Genetic testing is recommended before sperm retrieval procedures or testis biopsies. Only

Selective scrotal ultrasonography and transrectal ultrasound examinations may also be helpful in further diagnosing and classifying azoospermia.  

Karyotype testing and genetic screening are recommended before sperm retrieval procedures to avoid unnecessary surgeries.

• A missing vas deferens or seminal vesicle suggests a cystic fibrosis gene mutation—test for CFTR.
• Bilateral small, firm testes are suggestive of Klinefelter syndrome. Perform karyotype.
• Small or normal testicular size and elevated FSH levels suggest non-obstructive azoospermia from a primary testicular disorder of spermatogeneses such as maturational arrest, Sertoli cell-only syndrome, Y chromosome microdeletions, or similar. Consider genetic testing and testis biopsy.
• Normal testicular size with low or micro-TESE, TESA, or MESA is reasonable for ICSI in most cases of azoospermia EXCEPT for primary testicular failure due to Y chromosome microdeletions of the AZFa, AZFb, or AZFc subregions, in which case donor sperm or adoption should be considered.
• Maturational arrest and Sertoli cell-only syndrome will have substantially lower rates of successful sperm retrieval than most other causes of non-obstructive azoospermia.
• No elevation of FSH levels or degree of testicular atrophy is sufficient to guarantee that no sperm will be found on sperm retrieval.
• The role of FSH stimulation in increasing sperm numbers before a testis biopsy and sperm retrieval procedures is controversial and not currently recommended.
• Testosterone supplementation has no role in male infertility or azoospermia treatment. 
• The overall success rate of sperm retrieval in non-obstructive azoospermia is about 50%.
• The overall successful pregnancy rate with ICSI is about 50%.

Obstructive azoospermia can be effectively treated with either surgical reconstruction or sperm retrieval and ICSI. In ideal situations, reconstruction is preferred, but sperm retrieval with ICSI is the better choice if secondary male infertility factors, concomitant female factors, or poor results are expected from the surgery for some other reason.[72]

Most men with azoospermia will have the non-obstructive type, where sperm retrieval followed by ICSI is often their best option. Most of these men will still provide viable sperm for assisted reproduction, with only a few exceptions.

Enhancing Healthcare Team Outcomes

Azoospermia is considered a severe and important cause of male infertility amongst childless couples attempting pregnancy. Classifying and diagnosing the type of azoospermia includes taking a detailed history and physical examination, hormonal investigations, ultrasonography, and genetic testing. Strategizing the medications, treatments, procedures, and protocols is the key to treating couples with infertility.

Physical and emotional support is also essential. These will help enhance the physician's ability to recommend reasonable treatments with appropriate counseling and patient expectations. Collaboration with radiologists, urologists, reproductive endocrinologists, OB-GYN specialists, and their respective nursing care teams is imperative for providing the best possible outcomes for these couples. Trained and competent nurses are an integral part of the interprofessional healthcare team.