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Azoospermia

Author: Stephen W. Leslie Editor: Elsa S. Vadakekut Updated: 8/20/2026 4:10:25 PM

Introduction

Male factors play a crucial role in the evaluation and treatment of infertile couples, contributing to 50% of all infertility cases.[1] The overall incidence of infertility approaches 15% of the total population. See "Male Infertility" for further information.[2] The most severe form of male infertility, azoospermia, often results from a range of potentially untreatable testicular disorders.[3] Azoospermia refers to the complete absence of spermatozoa in 2 separate centrifuged semen specimens, whereas aspermia refers to the complete absence of ejaculate.[4] Azoospermia affects nearly 1% of the overall male population and approximately 10% to 15% of males with infertility.[5][6]

Azoospermia can be categorized according to pretesticular, testicular, or posttesticular causes (see Table 1. Etiologic Classification According to Pretesticular, Testicular, and Posttesticular Causes). Based on the presence or absence of obstruction involving the ducts or vas deferens, clinicians can further classify azoospermia as obstructive azoospermia or nonobstructive azoospermia. Differentiating between these categories remains essential because the underlying classification directly influences treatment selection.[4] Advances in assisted reproductive technologies, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), have greatly expanded fertility options for couples experiencing difficulty conceiving because of male infertility, including couples affected by azoospermia.

Obstructive Azoospermia

Obstructive azoospermia occurs in about 30% of azoospermic men.[7] Causes include congenital bilateral absence of the vas deferens, obstruction of the ejaculatory or epididymal ducts, atresia of the seminal vesicles, genitourinary infections that produce obstruction, and scrotal, pelvic, or inguinal procedures that result in complete blockage, such as bilateral vasectomy.[8][9] In obstructive azoospermia, spermatogenesis is often normal. Therefore, treatment options for obstructive azoospermia frequently include the surgical correction of the blockage in addition to sperm retrieval from the testis or epididymis for use with assisted reproductive techniques. 

Nonobstructive Azoospermia

Nonobstructive azoospermia (NOA) represents the most common form of azoospermia, accounting for approximately 70% of affected men.[7] It describes the condition where sperm production is so impaired that no sperm appear in the ejaculate. Nonobstructive azoospermia is most often due to severe defects in spermatogenesis, frequently caused by primary testicular failure or dysfunction, but it can also result from pituitary or hypothalamic dysfunction.[10] 

The exact pathology of nonobstructive azoospermia is often idiopathic. Advanced assisted reproductive techniques can often be used with sperm retrieval procedures to treat patients with nonobstructive azoospermia.[11]

Diagnostic and Reproductive Considerations

Healthcare professionals encounter substantial challenges when caring for infertile men with complete spermatic failure and azoospermia. Diagnostic evaluation may include hormonal assessment, semen biomarkers, genetic testing, ultrasonography, testicular biopsy, and vasography. Transrectal ultrasound represents the best diagnostic tool for identifying distal obstruction of the male reproductive system.[12][13]

Testicular biopsies from patients with severe spermatogenic failure often demonstrate limited areas of normal spermatogenesis, even though overall spermatogenesis is very abnormal.[14] Clinicians can retrieve sperm from these areas using testicular sperm extraction (TESE) or testicular sperm aspiration (TESA), followed by use in advanced assisted reproductive procedures, e.g., intracytoplasmic sperm injection (ICSI). Sperm retrieved from the testes through these techniques and subsequently used for in vitro fertilization with ICSI generally results in healthy offspring.[15][16]

Etiology

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Etiology

In obstructive azoospermia, spermatogenesis often remains normal, with the underlying causes generally categorized as congenital or acquired. Congenital causes include ejaculatory duct obstruction, idiopathic epididymal obstruction, and congenital bilateral absence of the vas deferens associated with CFTR gene mutations, which account for up to 80% of cases.[17][18][19] See "Male Infertility" for further information.[2]

Acquired etiologies include postinfectious scarring following Chlamydia trachomatis and Neisseria gonorrhoeae infections, with tuberculosis representing an important cause in endemic regions. Surgical and iatrogenic causes include bilateral vasectomy, inguinal hernia repair (particularly procedures performed during childhood), orchidopexy, hydrocelectomy, spermatocelectomy, and other scrotal procedures. Additional acquired causes include calcification involving the vas deferens or epididymis and postinflammatory scarring that produces strictures.[17][18][19] See "Male Infertility" and "Genitourinary Tuberculosis" for further information.[2][20]

Nonobstructive azoospermia may be due to several causes, including: 

  • Anabolic steroid administration
  • Androgen insensitivity
  • Chemotherapy
  • Congenital absence of germ cells (Sertoli cell-only syndrome)
  • Cranial trauma
  • Genetic disorders, eg, chromosomal abnormalities, single-gene (monogenic) defects, and Y-chromosome microdeletions [21] 
  • Heavy metal exposure
  • Hyperprolactinemia
  • Hypogonadotropic hypogonadism, as in Kallmann syndrome
  • Idiopathic
  • Impaired sperm production due to chromosomal abnormalities, as in Klinefelter syndrome or Y-chromosome microdeletions of subregions AZFa, AZFb, or AZFc [22]
  • Infections, eg, mumps, orchitis, and HPV
  • Klinefelters syndrome.
  • Medications (dopaminergic and psychotropic)
  • Prader-Willi syndrome
  • Radiation therapy 
  • Spermatogenic (maturation) arrest
  • Testicular torsion
  • Testosterone supplementation therapy
  • Toxic exposure
  • Translocation or inversion of azoospermia factor cryptorchidism
  • Varicoceles 
  • [10][23][24]

Table 1. Etiological Classification According to Pretesticular, Testicular, and Posttesticular Causes

Classification Etiologies Fertility Outcomes 

Pretesticular Causes (secondary testicular failure). 

 Includes endocrine abnormalities related to the hypothalamus, pituitary, and male gonads (testes) Treatment generally provides effective fertility outcomes.
Testicular Causes Usually involve disorders related to spermatogenesis. Treatment does not generally provide substantive improvement in fertility outcomes, as the disorders are typically irreversible.
Posttesticular Causes Includes causes leading to ductal obstruction at any site in the male reproductive tract. Treatment generally improves fertility outcomes.

Epidemiology

The overall incidence of infertility approaches 15% of all couples. Male azoospermia affects nearly 1% of the male population and approximately 10% to 15% of all infertile men.[25] At any given time, approximately 600,000 azoospermic men of reproductive age reside in the United States, with most affected men having nonobstructive azoospermia.[26]

Azoospermic men are also at lifelong increased risk of developing cancer compared to the general population, as between 5% and 8% of men with testicular cancer will be azoospermic.[27][28] The exact incidence of infertility remains uncertain because infertility does not qualify as a reportable disease and typically receives management in physicians' offices. Underreporting also likely contributes to uncertainty in developing nations, where advanced infertility treatments may remain financially inaccessible or unavailable.[29]

Pathophysiology

Azoospermia can be classified according to a testicular or posttesticular framework or as obstructive or nonobstructive.  The obstruction-based classification is generally more useful and practical because it guides further (genetic) testing, prognosis, and the approach to sperm retrieval. approach (see Table 2. Types of Azoospermia and Causes). The exact pathophysiology of azoospermia is not always known and may be idiopathic. In some isolated cases, azoospermia may be primarily due to abnormal ciliary function and poor-quality mucus affecting sperm transit despite quantitatively normal sperm production.[30][31][32][33]

  • Pretesticular causes, also called secondary testicular failure, usually result from pathological endocrine conditions or abnormalities related to the hypothalamus, pituitary, or male gonads (testes).
  • 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 of Azoospermia

Although relatively uncommon, up to 3% of infertile men with subfertility will have underlying endocrinopathies.[34] Pretesticular azoospermia can be congenital or acquired. Pretesticular azoospermia may be seen in association with the following:

  • Hyperprolactinemia involves excessive prolactin production, usually due to a pituitary microadenoma.[35] Hyperprolactinemia results in sexual dysfunction due to the inhibition of the secretion of GnRH from the hypothalamus, which leads to impaired fertility.[36] In these patients, there is decreased spermatogenesis due to testicular abnormalities on both sides.[37] 
  • Hypogonadotropic hypogonadism is a condition in which the hypothalamus or pituitary gland fails to produce adequate levels of reproductive hormones (GnRH, LH, and FSH) to stimulate the testes. Kallmann syndrome is a genetic form of hypogonadotropic hypogonadism characterized by anosmia. See "Male Infertility" for further information.[2]
  • Kallmann syndrome describes a genetic form of hypogonadotropic hypogonadism characterized by anosmia. It is caused by a defect at the level of the hypothalamus characterized by failure of GnRH secretion (hypogonadotropic hypogonadism). This occurs because GnRH-releasing neurons fail to migrate to the olfactory lobe, which explains the decreased sense of smell in most affected individuals.[38][39] See "Kallmann Syndrome" for further information.[39]
  • Klinefelter syndrome is a genetic disorder characterized by a tall eunuchoid phenotype, decreased facial and pubertal hair, small, firm testicles, variable cognitive disabilities, and typically decreased testosterone levels.[37][40] These patients typically have azoospermia, but during testicular sperm extraction, spermatozoa are seen in up to 69% of men with Klinefelter syndrome.[40] See "Klinefelter Syndrome" for further information.[40]
  • Mumps orchitis is a testicular disease that may lead to azoospermia in 15% of cases after a unilateral infection and in 60% if both testicles are involved.[41][42]
  • Testosterone supplementation therapy and anabolic steroid administration may cause patients to develop azoospermia. Fortunately, sperm production will recover once supplementation stops, or hCG is given to induce intratesticular testosterone production, in most cases, over a number of months of treatment.[43][44][45]

Posttesticular Causes of Azoospermia

Posttesticular conditions associated with azoospermia include:  

  • Congenital bilateral absence of the vas deferens (CBAVD) has an incidence of 1% amongst infertile men. It most commonly results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and defective mesonephric duct differentiation, although it may also be associated with mesonephric anomalies including renal agenesis or defects in renal ascent.[46]
  • Obstruction of the ejaculatory ducts may be unilateral or bilateral.[47][48][49] It may be caused by cysts, ((typically midline Mullerian cysts), ductal abnormalities, infections, stones, surgery, or trauma may cause obstruction of the ejaculatory ducts.
  • Obstruction of the epididymis is caused by congenital genetic abnormalities (e.g., cystic fibrosis gene mutations), infections (chlamydia, gonorrhea, tuberculosis, and UTIs), and previous scrotal surgery. Obstruction of the epididymis is also associated with Young syndrome, which is a triad of chronic sinusitis, bronchiectasis, and obstructive azoospermia. See "Young Syndrome" for further information.[32]
  • Unintended vasal obstruction is usually seen after surgeries for inguinal canal hernias, particularly in pediatrics.[50] Testicular size typically remains normal on physical examination, but the epididymis will tend to be enlarged and feel firm. Infections from Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycobacterium tuberculosis may also cause vasal obstruction.[51] See "Chlamydia," "Gonorrhea," "Sexually Transmitted Infections," and "Genitourinary Tuberculosis" for further information.[20][52][53][54]

 Table 2. Types of Azoospermia and Causes

Obstructive Azoospermia

Nonobstructive Azoospermia

A. Congenital

  • Congenital unilateral absence of the vas deferens (CUAVD) or congenital bilateral absence of the vas deferens (CBAVD) 
  • Karyotype abnormalities
  • Partial or complete absence of the epididymis
  • Young syndrome

B. Endocrinological

  • Androgen insensitivity
  • Excess of androgens, estrogen, prolactin, glucocorticoids
  • GnRH, LH, FSH deficiency
  • Thyroid disorders

C. Acquired

  • Chemotherapy and toxic exposure
  • Iatrogenic: vasectomy; injury following inguinal hernia repair; vasography; post-hydrocelectomy; percutaneous epididymal sperm aspiration (PESA); microsurgical epididymal sperm aspiration (MESA); epididymal biopsy, spermatocelectomy.
  • Radiation exposure
  • Surgeries performed for hernia repair, bilateral vasectomies, spermatoceles, epididymal resections

D. Infections and Inflammatory Conditions

  • Epididymitis and orchitis
  • Lower genitourinary infections
  • Prostatitis

A. Congenital

  • Congenital absence of vas deferens
  • Congenital varicocele
  • Cryptorchidism
  • Ejaculatory duct obstruction or cysts
  • Klinefelter syndrome
  • Malformation of the excurrent ductal system
  • Microdeletions of the Y chromosome (AZFa, AZFb, and AZFc subregions)
  • Obstruction at the prostatic utricle

B. Endocrinological Causes

  • Congenital adrenal hyperplasia (with or without testicular adrenal rest tumors)
  • Hyperprolactinemia
  • Hypogonadotropic hypogonadism: congenital (Kallmann syndrome); acquired (pituitary tumors)
  • Hypothyroidism

C. Inflammatory Conditions

  • Epididymo-orchitis
  • Prostatitis

D. Iatrogenic

  • Chemotherapy
  • Drugs or medical therapy
  • Prior toxic exposures (chemotherapy, radiation)
  • Radiation therapy
  • Testosterone or anabolic steroid administration

History and Physical

Clinical History

Perform a detailed evaluation for every patient with azoospermia. The assessment should include a comprehensive medical, sexual, and surgical history, including previous fertility concerns, treatments already attempted, sexual history, and recent efforts to achieve pregnancy. Clinicians should document any relevant issues affecting the female partner and obtain a family history of infertility or genetic disorders.[55]

The clinical history should specifically address trauma involving the genital organs, drug allergies, medication exposure, including gonadotropins, anabolic steroids, and testosterone supplementation, as well as exposure to toxins, chemotherapy, pesticides, and radiation.[55][56] Obtain a detailed history of genitourinary infections and sexually transmitted diseases. Pay particular attention to childhood illnesses, including mumps, viral orchitis, and cryptorchidism.[35][55][56]

Physical Examination

A comprehensive physical examination also plays an essential role in evaluating azoospermia. The patient should be examined in both supine and standing positions, with careful attention to the testes, epididymis, and vas deferens. The examination room should ideally be maintained at 36 to 37 °C (96.8 to 100.4 °F) to provide a relatively warm environment, which facilitates the examination.

The examination should assess for a varicocele, with varicocele grading providing information about its size to help guide treatment planning.[57][58] Evaluation of secondary sexual characteristics should include assessment of body, axillary, and pubic hair distribution, which may decrease in individuals with low androgen levels. Palpate the thyroid gland, and auscultate the heart and lungs. Also perform breast and abdominal examinations.

Examination of the male genitalia requires particular attention. Palpate both testes carefully, and document testicular length, width, and volume, as reduced testicular size correlates with impaired spermatogenesis.[59] Normal testicular volume generally measures 20 cc or more. Testicular length generally measures 4 cm, although the reported actual “normal” measurement measures 31 mm in White individuals and 34 mm in Black individuals.

The size and consistency of the epididymis should be assessed, as obstructive azoospermia almost always results in an enlarged epididymis, at least in the caput (head) region. Carefully note the absence of one or both vas deferens, as this finding is often associated with a cystic fibrosis gene mutation. A digital rectal examination may help suggest the presence of cysts or masses. The seminal vesicles are usually not palpable but may be prominent in cases of ejaculatory duct obstruction.

Patients with obstructive azoospermia typically have a normal hormonal profile with FSH <7.6 and unremarkable testicular size (testicular length >4.5 cm or volume >15 mL), although some men with late maturational arrest can present with similar findings.[60][61]

Bilateral atrophic or hypotrophic testes, along with high FSH levels, are associated with primary testicular failure in over 95% of cases of azoospermia.[6] These patients tend to have worse fertility outcomes, although sperm retrieval and ICSI may still be possible in some individuals.

Men with nonobstructive azoospermia may have a history of gonadotoxic chemotherapy, cryptorchidism with orchiopexy, or known genetic abnormalities.

Evaluation

Healthcare professionals face many challenges in providing care to infertile men with complete spermatic failure and azoospermia. Diagnostic modalities used for patients with azoospermia include a focused history and physical examination, at least two semen analyses (including pH, volume, and sperm count), a hormonal assessment (FSH and testosterone initially, with a repeat testosterone as well as estradiol, LH, and prolactin, if initial testing is abnormal), semen volume (should be >1.5 mL),  genetic testing (karyotype, examination for Y-chromosome microdeletions including complete AZF sequencing, screening for the CFTR gene as appropriate), and ultrasonography (transrectal ultrasound if low semen volume is present in a man with evidence of obstructive azoospermia and palpable vasa), but testis biopsies and/or vasography are not routinely required for diagnosis, as testicular volume and FSH measurements provide sufficient information in most cases to distinguish obstructive from non-obstructive azoospermia.[2][18][19][55][62][63][64][65]

Semen Analysis

At least two separate semen analyses should be performed with three days of sexual abstinence preceding each examination. It has been suggested that the optimal timing for the second semen analysis should be at least a month after the first, since a complete spermatogenesis cycle takes several months.[55][56][66] American Urological Association (AUA) and American Society for Reproductive Medicine (ASRM) guidelines recommend performing these carefully and including appropriate centrifugation, repeat pellet analysis, staining, volume and pH measurements, and more advanced techniques, including genetic testing (karyotype and Y-chromosome microdeletion analysis).[19][62][63] Centrifugation of the semen is critically important as this procedure increases the sperm detection rate in the ejaculate by as much as 35%.[55][67][68]

 Seminal fructose and neutral α-glucosidase are not part of routine semen analyses but may occasionally help localize suspected blockages in selected cases of obstructive azoospermia.[69][70][71][72][73][72] 

The absence of fructose in the semen suggests ejaculatory duct obstruction or congenital absence of the vas deferens,  while low seminal levels of neutral α-glucosidase are associated with sperm blockage within the epididymis.[74][75][76][77][70][77]

In patients with azoospermia who have normal ejaculate volume, either spermatogenic failure or obstruction between the testes and the seminal vesicles is present. 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 repeat the semen investigations and also give a postejaculation urine sample. 

Some patients initially diagnosed as azoospermic may actually have some sperm in the semen.[78] After thorough and careful semen analyses, almost 16% of 209 patients initially diagnosed as azoospermic were found to have identifiable sperm in the ejaculate.[78] Low FSH levels were associated with a positive finding of sperm, indicating that more careful semen analyses should be performed in men diagnosed with azoospermia and low FSH levels.[78][79]

Hormonal Evaluation

In evaluating azoospermia, especially when testicular size and consistency are normal on physical examination, a detailed endocrinological evaluation is necessary to make a specific diagnosis and to strategize the treatment protocol.[80] Hormonal profiles, including total testosterone (free testosterone is not required), FSH, luteinizing hormone (LH), prolactin, and estradiol, should be obtained in addition to a thyroid profile.[55][81]

High serum estradiol levels in nonobstructive azoospermic men suggest an abnormally low testosterone: estradiol ratio (<10) that may be caused by obesity or aromatase overactivity.[45][82][83][84] High estradiol, as evidenced by a low testosterone: estradiol ratio, can impair spermatogenesis, but such men may be amenable to aromatase inhibitor therapy with anastrozole and similar agents.[82][85][86]

Hyperprolactinemia, often due to a pituitary adenoma, is associated with male infertility.[87] Abnormally high prolactin levels have been shown to adversely affect spermatogenesis, even causing azoospermia, by blocking the rhythmic, intermittent release of gonadotropins from the anterior pituitary.[2][87] Limited, spuriously elevated prolactin levels can occur from stress and other causes that are not clinically relevant, but men with significant, consistent hyperprolactinemia should have a full evaluation for this condition.[87][88] See "Hyperprolactinemia" and "Male Infertility" for further information.[2][87]

Hypogonadotropic hypogonadism accounts for no more than 2% of all infertile males and is a relatively uncommon cause of nonobstructive azoospermia, but one of the few that is medically treatable.[89][90] See "Kallmann Syndrome" and "Male Infertility" for further information.[2][39] Possible causes include Kallmann syndrome, androgen-induced hypogonadism (from testosterone supplementation), brain neoplasms, radiation, and trauma.[90][91] The incidence of azoospermia from testosterone supplementation therapy is increasing as anabolic steroid abuse is growing worldwide, and most patients and even many physicians are unaware or uninformed about the significantly negative effects of testosterone supplementation on sperm counts and spermatogenesis.[92][93][94][95]

In obstructive azoospermia, FSH levels are usually decreased or normal, while in nonobstructive azoospermia, FSH levels are typically high, especially if the testes are below normal size.[96] However, some overlap exists, so FSH levels alone may not be sufficient for reliable differentiation.[97] Other factors to consider include semen volume and pH, seminal plasma neutral α-glucosidase activity, and testicular volume.[98]

In nonobstructive azoospermia, normal serum FSH levels are strongly correlated with high sperm retrieval rates (~100%) and successful ICSI, but these drop rapidly as FSH titers reach double the normal levels or more.[99] As a general rule, the higher the FSH level, the more likely the patient has significant spermatogenic failure.[99][100][101] In some cases, a testicular biopsy may need to be performed to make a definitive diagnosis. Fortunately, this is infrequently necessary for diagnosis.[102]

Ultrasonography and Magnetic Resonance Imaging

The role of scrotal ultrasound in evaluating male infertility is evolving and becoming more routine. This modality allows for a more precise measurement of testicular size and can identify cysts, varicoceles, spermatoceles, and lesions that might not otherwise be detectable by other means.[11][103][104] Ultrasonography can also help differentiate obstructive from nonobstructive azoospermia.[103][104] Scrotal ultrasonography will tend to show ectasia of the epididymal tubules and the rete testis, abnormal epididymal echogenicity, or dilated proximal vas deferens in obstructive azoospermia.[103][104] Testicular volume, epididymal head size, and the resistive index of intratesticular vessels tend to be higher than in patients with nonobstructive azoospermia.[103][104]

Scrotal ultrasound examinations are painless and inexpensive, but a discussion with the diagnostic radiologist about which factors to look for and evaluate when a scrotal ultrasound is ordered for a male patient with azoospermia will be very helpful. Therefore, the recommendation is for the routine use of a comprehensive sonographic evaluation to help differentiate obstructive from nonobstructive etiologies. Additionally, transrectal ultrasonography is the best tool to evaluate the seminal vesicles for dilation and to screen for ejaculatory duct cysts or distal obstruction of the male reproductive tract.[12][13][55][105][106] This examination is typically performed when ejaculatory duct obstruction is suspected.[55][106] The absence of the seminal vesicles suggests a possible cystic fibrosis genetic mutation (CFTR).[107] If the seminal vesicles are absent or dilated/enlarged, an obstructive etiology of azoospermia is demonstrated.

While not routinely used, magnetic resonance imaging (MRI) is emerging as a tool in selected cases to assist in differentiating obstructive from nonobstructive azoospermia and helping identify focal areas of spermatogenesis.[108][109][110]

Genetic Testing

In nonobstructive azoospermia, genetic causes that demonstrate chromosomal defects account for up to 20% of cases.[22][111] About 5% will have Y-chromosome microdeletions, and between 50% and 70% will remain idiopathic even after testing.[3][22][112][113] 

Klinefelter Syndrome

Cytogenetic abnormalities occur in approximately 5% of men with nonobstructive azoospermia.[114] The most common sex chromosomal abnormality involves Klinefelter syndrome, characterized by the presence of an extra X chromosome (XXY). See "Klinefelter Syndrome," for further information. The overall incidence of Klinefelter syndrome ranges from approximately 1 in 500 to 800 men and accounts for 3% of all infertile adult males. Affected patients have a male phenotype, although the clinical presentation can vary substantially among individuals.

Many patients remain unaware of their condition until an infertility evaluation leads to the diagnosis, and approximately 50% of affected patients may never receive a diagnosis. Histological examination of the testes in patients with Klinefelter syndrome typically demonstrates Sertoli cell-only syndrome. Although most men with Klinefelter syndrome are azoospermic, approximately 8% have detectable sperm in the ejaculate.[55]

Common characteristics of Klinefelter syndrome include the following:

  • Absent, delayed, or incomplete puberty
  • After puberty, less muscle as well as less facial and body hair compared with other teens
  • Enlarged breast tissue (gynecomastia)
  • Infertility
  • Longer legs, shorter torso, and broader hips compared to other boys
  • Poor muscle tone
  • Poor fine motor skills, dexterity, and coordination
  • Small, firm testicles
  • Small penis
  • Taller than average stature [115]

The presence of germ cells and sperm varies widely among these individuals. Microscopic testicular sperm extraction (micro-TESE) can retrieve viable sperm in 50% of men with Klinefelter syndrome.[55][116][117] The data are conflicting on the use of age or testosterone levels to help predict successful sperm retrieval in men with this disorder.[118][119][120] Sperm retrieval surgical procedures should be limited to adults and are not currently recommended in boys and adolescents with Klinefelter syndrome.[60][121] 

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.[122] See "Klinefelter Syndrome," for further information. They should receive appropriate counseling and referrals.[123]

Other Genetic Disorders

The overall incidence of chromosomal abnormalities in infertile men is about 6%, with the highest risk found in those with nonobstructive azoospermia.[124][125][126][127] The absence of 1 or both vas deferens or the seminal vesicles on transrectal ultrasound is highly suggestive of a genetic interaction associated with cystic fibrosis (the CFTR gene), which will be present about 80% of the time.[128] Testing both the patient and his partner for cystic fibrosis via the CFTR gene is recommended. Other abnormalities include Robertsonian and reciprocal translocations as well as chromosomal inversions. 

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 that contribute to maturational arrest, resulting in nonobstructive azoospermia, have been identified.[129]

All men with primary testicular failure should have karyotype and Y-chromosome microdeletion testing.[130] About 6% of men with nonobstructive azoospermia will have microdeletions of the Y-chromosome involving the AZFa and/or AZFb subregions.[131] Men with such microdeletions typically have extremely poor sperm retrieval rates and should be counseled to consider using donor sperm for ICSI or adoption.[132] 

Approximately 4% 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.[8] 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% of the men will have maturational arrest.[133] Additionally, rare cases in which atypical Y-chromosome microdeletions are present have been found. Individualized counseling and treatment should be offered to such patients.

Multiple guidelines, including the AUA, the ASRM, the European Academy of Andrology, and the European Association of Urology (EAU), all recommend genetic sequencing of the entire AZF region for all patients with nonobstructive azoospermia since this will affect the likelihood of successful sperm retrieval.[19][134][135][136][137][138] Whole-genome/exome sequencing can be helpful in patients with idiopathic nonobstructive azoospermia when standard genetic tests (AZF analysis, CTFR, karyotype, and Y-chromosome microdeletion analysis) are all negative. This will provide a specific genetic diagnosis in about 20% of such patients.[139][140][141][142] Typical genetic defects are found in genes involved in meiotic recombination and chromosomal synapsis, the piRNA biogenesis pathway, DNA repair, and postmeiotic maturation.[139][143]

Differentiating Obstructive From Nonobstructive Azoospermia

Patients with obstructive azoospermia typically have normal FSH and LH levels and normal-sized testes.[144] See "Male Infertility" for further information. These patients may have clinical features suggestive of an obstruction within the reproductive tract and tend to have specific semen and imaging findings that help distinguish obstructive from nonobstructive causes.

Men with obstructive azoospermia are more likely to report painful ejaculation and hematospermia and may have pancreatic insufficiency.[96] A history may suggest an obstructive etiology, and semen analysis commonly demonstrates a smaller ejaculate volume (<1.4 mL), reduced fructose levels, and a low semen pH (<7).[96] More than 96% of men with obstructive azoospermia have an FSH level of less than 7.6 mIU/mL and a testicular length of greater than 4.6 cm.[96][102] Testicular ultrasonography may demonstrate an increased intratesticular resistive index, dilated ducts within the testes, epididymis, or proximal vas deferens, spermatoceles, or seminal vesicle dilation of greater than 1.5 cm.[96]

Patients with nonobstructive azoospermia may have normal FSH and LH levels, although elevated concentrations occur frequently.[8][97][145] Serum estradiol may also be elevated, while testosterone may remain within the low-normal range because of primary testicular failure.[8][97][145] Testicular size may remain normal but commonly appears hypotrophic or atrophic.[96] In contrast to obstructive azoospermia, the ejaculate volume generally remains normal, with a semen pH of greater than 7.[96] Men with nonobstructive azoospermia tend to have higher FSH levels and smaller testicular size compared with men who have an obstructive etiology.[96][102] Imaging findings generally remain normal, although pituitary abnormalities may appear on MRI scanning.[96] See "Imaging of the Pituitary Gland" for further information. Patients with nonobstructive azoospermia also have a greater likelihood of obesity.[146]

When clinical findings do not clearly distinguish between obstructive and nonobstructive azoospermia, a testicular biopsy may be required to further evaluate testicular histology and clarify the underlying cause.

Further Evaluation of Low Semen Volume Azoospermia

Azoospermia patients with semen volumes consistently below 1.4 mL are likely to have retrograde ejaculation, an ejaculatory duct cyst, or congenital absence of the vas or seminal vesicle (typically also associated with a low acidic semen pH of <7).[19] Examination of the post-ejaculation urine sample can identify patients with retrograde ejaculation, and the physical exam can determine if the vas deferens is absent. Transrectal ultrasonography or cystoscopy can be used to identify an ejaculatory duct cyst. Transrectal ultrasound can be used to specifically examine the seminal vesicles. 

Further Evaluation for Obstructive Azoospermia

In cases of obstructive azoospermia, the hormonal profile and testicular volume measurements are generally normal. Dilation of the epididymis, hydrocele presence, or vas deferens' absence suggest obstruction. Azoospermia due to vasal 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 performed to rule out cystic fibrosis.

Further Evaluation of Nonobstructive Azoospermia

Azoospermia is diagnosed with at least 2 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 biopsy is the definitive way to diagnose azoospermia due to causes, eg, maturational arrest and Sertoli cell-only syndrome. A karyotype analysis, genetic sequencing including the AZF region, and a Y-chromosome microdeletion test should be performed to assess genetic abnormalities.[130][137][138][147][148] 

Genomic profiling of retrieved sperm through DNA sequencing can provide critical information on the etiology of azoospermia and can identify other genetic causes of impaired fertility.[62][149] Similarly, RNA sequencing of seminal fluid from men with nonobstructive azoospermia can help predict the likelihood of successful sperm retrieval with TESA and micro-TESE.[62][149][150][151] Endocrinological abnormalities are diagnosed and then managed accordingly.

Diagnostic Testicular Biopsy

The design of testicular tissue is heterogeneous, and spermatogenesis occurs in foci; hence, while valuable, a biopsy is infrequently needed as a diagnostic tool.[152][153] As a rule, testicular characteristics and diagnostic laboratory findings are good but imperfect indicators of nonobstructive azoospermia. Hence, TESE can be performed in a specialized assisted reproduction center, which permits cryopreservation of sperm and avoids a testicular biopsy. A normal testicular biopsy result is suggestive of obstruction, and vasography is then required to identify the precise location of the blockage.

Following diagnostic evaluation, formal surgical repair or sperm retrieval can be performed as clinically appropriate. The location of the biopsy within the testis does not appear to affect the diagnostic yield, and tissue can be obtained from the upper, middle, or lower pole.[154] Depending on the severity of the underlying defect, serum testosterone levels may be low, normal, or high. Histological diagnosis requires biopsy of only 1 testis. When selecting the testis for biopsy, the larger of the 2 testes should be chosen for the procedure.

Testicular Etiologies

Direct testicular pathology may be inferred 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 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.[155] 

In general, maturational arrest, Sertoli cell-only syndrome, and Y-chromosome microdeletions of the 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.[156][157]

Varicoceles have a clearly deleterious effect on semen quality and testicular function, whereas varicocelectomy has demonstrated the potential to improve sperm parameters and overall testicular function.[158][159][160][161] However, only a small percentage of men with azoospermia resulting from testicular failure derive benefit from surgical treatment of a clinically apparent varicocele.[162] Reports also suggest that 6 months of human chorionic gonadotropin (hCG) therapy may benefit azoospermic men with varicoceles when varicocelectomy alone has failed to improve semen quality and sperm characteristics.[163]

Other causes of azoospermia include XYY syndrome, myotonic dystrophy, Noonan syndrome, 5-alpha-reductase deficiency, androgen insensitivity syndrome, and vanishing testis syndrome.

Undescended Testes

Undescended testicles represent the most common genital condition affecting boys and young males. Cryptorchidism occurs in approximately 2.7% of newborns and up to 0.8% of 1-year-olds.[164] Clinicians should distinguish cryptorchid testes from retractile testes, which result from hyperactive cremasteric muscles that cause the testes to intermittently reside within the inguinal canal or in a high scrotal position. Most men with a history of unilateral undescended testicles retain the capacity for paternity. Testicular volume and age at orchiopexy serve as independent predictors of fertility potential and the likelihood of successful sperm retrieval in men with a history of cryptorchidism.[165][166]

Testicular Torsion

Testicular torsion occurs in approximately 1 in 4,000 males before age 25.[167] The condition requires prompt surgical exploration, corrective detorsion, and bilateral orchidopexy because the risks associated with nonoperative management remain well documented.[168] Testicular preservation can usually be achieved when surgical intervention occurs within 6 hours of symptom onset. Surgeons typically use nonabsorbable sutures for orchidopexy, with at least 3 fixation points placed on each side. Prophylactic orchidopexy of the contralateral testis also remains customary during the same surgical procedure to reduce the risk of subsequent torsion on the unaffected side.

Summary of Evaluation 

Diagnostic evaluation for azoospermia is summarized as follows:

  • Physical examination with particular attention to testicular size, epididymal fullness, any varicoceles or spermatoceles, and confirm the presence of the vas deferens bilaterally.
    • Screen for possible Klinefelter's (small, firm testes, gynecomastia, and tall stature with long limbs). See "Klinefelter Syndrome," for further information.
  • Detailed history to identify any prior scrotal trauma, testicular or pelvic surgery, radiation therapy, or toxic exposure. Also, to document any history of prior pregnancies, delayed puberty, testicular infections, or undescended testes.
  • Laboratory studies
    • Semen analysis testing should include pH, volume, seminal biomarkers (fructose, neutral α-glucosidase (NAG), and zinc levels.
    • Genetic analysis for karyotype and Y-chromosome microdeletions for all men with nonobstructive azoospermia, and CFTR mutation testing if congenital absence of the vas is identified or suspected on physical examination.
    • All men with primary testicular failure (confirmed azoospermia on 2 separate semen samples, elevated FSH with normal or low testosterone, and typically with small (<10 mL) testes) should be given karyotype and Y-chromosome microdeletion testing.[130][147][148] 
    • Postejaculate urinalysis should be performed to evaluate for possible retrograde ejaculation.
    • Semen analysis, with particular attention to volume and pH. (Low semen volume and acidic pH suggest ejaculatory duct obstruction or congenital bilateral absence of the vas deferens. Low volume alone suggests retrograde ejaculation.)
    • Serum FSH levels can be helpful. Elevated FSH suggests primary testicular failure, while normal levels imply obstructive azoospermia.
    • Serum total testosterone level to identify hypogonadism.
  • Scrotal and transrectal ultrasound helps differentiate obstructive from nonobstructive azoospermia and identify ejaculatory duct cysts as well as epididymal abnormalities.[11][169][170][171][172]
  • If the diagnosis remains uncertain between obstructive and nonobstructive azoospermia (for example, when normal-sized testes are found with normal serum FSH levels), a testis biopsy can be used to establish the correct diagnosis.[18]

Treatment / Management

In this era of advanced assisted reproductive techniques, infertile couples due to male factor azoospermia 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, such as 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 performed to achieve patency of the ejaculatory ducts. Intraoperative vasography gives better results than vasoepididyostomy. Transurethral resection improves semen parameters in about 50% to 70% of cases.

Surgical sperm retrieval is almost always successful for extratesticular obstructions, with the most common site of obstruction being the epididymis. Current success rates for vasoepididymostomies are 85% patency rates with up to a 50% spontaneous pregnancy rate.[173][174] Collecting and cryopreserving sperm at the time of surgery is recommended if the outcome is unsuccessful. Inguinal approaches for microscopic vasovasostomy have been described, as have laparoscopic and robotic techniques for vas isolation before microsurgical anastomosis.[175] (B3)

In obstructive azoospermia not amenable to surgical reconstruction, microsurgical epididymal sperm aspiration (MESA) is optimally used for sperm retrieval when possible.[176][177][178] Compared with testicular sperm aspiration (TESA) and microscopic testicular sperm extraction (micro-TESE), MESA provides higher rates of fertilization, clinical pregnancy, and delivery; the retrieved sperm have undergone some degree of epididymal sperm maturation as epididymosomes transfer lipids and proteins to the passing spermatozoa after they leave the testis, thereby optimizing and increasing their quality and fertilization potential; a larger number of sperm are collected, the patient experiences reduced postoperative pain, and the incidence of TESE-related complications, eg, possible testicular atrophy and hypogonadism, is lower.[176][177][178][179][180][181][182][183](B3)

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 adverse effects include failure, incontinence, reflux into the seminal vesicles and ejaculatory ducts, as well as epididymitis. Intraoperative transrectal ultrasound, along with methylene blue to verify patency, can help reduce complications and improve procedural safety.[17] 

In cases of ejaculatory ductal obstruction, surgical correction with transurethral resection is performed to achieve patency of the ejaculatory ducts. Intraoperative vasography gives better results than vasoepididyostomy. Transurethral resection improves semen parameters in about 50% to 70% of cases. The procedure can also be performed with a transurethral laser incision of the ejaculatory duct along with seminal vesiculoscopy. Still, whether this offers any significant advantages over the standard procedure is unclear.[184]

If the blockage is intratesticular, then TESE, micro-TESE, or TESA will be required. Postvasectomy obstructions can be treated with microscopic vasectomy reversals, which currently achieve a reported postoperative patency rate of 90% to 97%.[60] These surgeries may also be performed robotically with similar success rates.[185] 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 epididymal sperm extraction techniques.

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.[186][187] 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 usually preferred, but generally possible in less than 50% of men with obstructive azoospermia.[68] 

Nonobstructive Azoospermia

Advanced assisted reproductive techniques are required for most patients with nonobstructive azoospermia. Micro-TESE together with ICSI is potentially extremely beneficial to these patients. In TESA, a needle is inserted into the testicular parenchyma percutaneously. The failure rate of sperm retrieval in nonobstructive 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%.[188] A significant risk of vascular injury is also present.

In addition, the incidence of chromosomal abnormalities and DNA damage in the sperm has been observed to be relatively high in patients with nonobstructive 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.[189] Men who become azoospermic as a result of testosterone supplementation therapy have an excellent chance of recovery of spermatogenesis just by stopping the hormonal treatment and waiting.[43][45] Most men will recover 85% of their pretreatment sperm counts after 1 year and almost all by 2 years after stopping testosterone supplementation.[45][190][191] (A1)

To stimulate spermatogenesis in cases of hypogonadotropic hypogonadism or pretesticular azoospermia (secondary hypogonadism, testosterone therapy), gonadotropin analogs or FSH and HCG are used. The preferred therapy includes HCG (3,000-10,000 IU, injected 2-3 times per week) plus either anastrozole, clomiphene, FSH, or tamoxifen.[43] This therapy has demonstrated success in achieving at least some sperm in the ejaculate of 75% to 77% of men with nonobstructive azoospermia due to hypogonadotropic hypogonadism, but treatment may require as long as 6 months.[192][193][194][195] See "Male Hypogonadism" for further information.(A1)

Treatment of hypogonadotropic hypogonadism is relatively effective in nonobstructive azoospermia.[193][194][195][196] One regimen for azoospermic men due to hypogonadotropic hypogonadism is the pulsatile administration of 5 µg to 20 µg of GnRH every 2 hours using a portable infusion pump. The return of sperm in the semen was generally noted after 6 months of therapy, and 77% of initially azoospermic men were found to have active spermatogenesis after 12 to 24 months of treatment.[197] (A1)

If medical treatment is unsuccessful, assisted reproductive techniques are recommended.[198][199] Pulsed GnRH is an option but is usually more expensive and does not offer any substantial benefit over standard therapy. Testosterone supplementation is specifically not recommended.(B2)

Male patients with marginal hypogonadism without elevated LH may benefit from clomiphene, which can boost natural testosterone production without affecting sperm production. See "Clomiphene," and "Androgen Replacement" for further information. 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, no standardization of this therapy has been established, and no good-quality randomized trials exist. Therefore, many experts and the European Association of Urology (EAU) do not recommend the general use of hormone therapy in men with nonobstructive azoospermia and primary hypogonadism.[60] 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 nonobstructive azoospermia is much more controversial. These are frequently used to improve sperm parameters in infertile oligozoospermic men, and some evidence supports their use.[200][201][202] However, their effectiveness in improving sperm retrieval rates through TESE or TESA is somewhat uncertain and has not been definitively proven.[60] Aromatase inhibitor therapy (eg, anastrozole) may be most useful in men where the total testosterone to 17β-estradiol (E2) ratio is less than 10. However, its clinical effectiveness is much reduced compared to oligospermic hypogonadal men with infertility.[203][204][205][206](A1)

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.[202] Potential adverse effects from the therapy are also present. However, despite these limitations, and since no other treatment is available, the use of hormone stimulation therapy remains a common clinical practice.[198]

FSH stimulation before GnRH therapy seems to improve the outcomes with better surgical sperm retrieval rates and an increased number of sperm in the ejaculate.[201][207][208][209] 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 of hCG is 1,000 to 3,000 IU, 2 to 3 times weekly. This typically leads to sperm production after 3 to 6 months. If unsuccessful, FSH is added at a 75 IU to 150 IU dose twice a week.[210] (B2)

In general, patients with nonobstructive azoospermia who have FSH levels of 8.4 IU/L or less may benefit from supplemental FSH therapy.[211] Typical therapy would be 150 IU daily or 200 to 300 IU every other day for 3 months.[211][212] High FSH levels generally indicate primary testicular failure, and supplemental FSH would not be helpful.[211] Overall, about one-third of all male patients with nonobstructive azoospermia may be amenable to a clinical trial of medical therapy with aromatase inhibitors, clomiphene, and hCG.[82](A1)

Repair of clinically significant varicoceles can improve semen and sperm characteristics in nonobstructive azoospermic men, but the benefit to pregnancy or live birth rates is marginal and problematic, may be of limited duration, and may not be cost-effective compared with micro-TESE and ICSI.[207][213][214][215][216][217] Still, about 10% of nonobstructive azoospermic men with clinically significant varicoceles will develop sufficient motile sperm in their semen for ICSI with micro-TESE after varicocelectomy surgery.[162](A1)

The only absolute contraindications for an attempt at sperm retrieval in male nonobstructive azoospermic patients are Y-chromosomal microdeletions of the AZFa or AZFb subregions and postbilateral 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 rate of about 50%.[102][207][218] No degree of testicular atrophy or FSH elevation can definitively determine the success or failure of sperm retrieval surgery.(B2)

Positive predictive indicators of successful sperm retrieval with micro-TESE in nonobstructive 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), the presence of a varicocele, low anti-Müllerian hormone and estradiol levels, testosterone: FSH >20, and viable sperm visible in the seminiferous tubules on testis biopsy.[161][219][220][221][222][223][224][225] Smoking history does not appear to have any significant effect on sperm retrieval surgery, but the sperm may exhibit reduced motility.[226](A1)

If surgical sperm retrieval is not successful initially on 1 side, the contralateral testis should undergo micro-TESE at the same session.[64] A bilateral micro-TESE will generally be required in about 50% of cases of nonobstructive azoospermia.[188] While the reported success rate for contralateral micro-TESE is only 8%, this represents a significant benefit in this group of azoospermic men who otherwise would not be able to father biological children.[227] Hypospermatogenesis, Klinefelter syndrome, small testes, and Y-chromosome microdeletions strongly suggest that successful sperm retrieval from the contralateral testis is feasible if micro-TESE initially fails to retrieve sperm.[207] When even bilateral micro-TESE fails to retrieve sperm, a repeat surgery after 6 months can still provide sperm in about 10% to 21% of cases.[64][228][229](B2)

With micro-TESE, the successful sperm retrieval rate is approximately 50%, while ICSI also has approximately a 50% success rate, giving an overall pregnancy rate of only 25% per attempt.[156][157][207][230][231] In one French series, patients with nonobstructive azoospermia who underwent micro-TESE combined with advanced sperm processing and enhanced assisted reproductive techniques reported an ongoing pregnancy or a live birth in 27.3% of couples without the need for a sperm donor.[157] (In this series, elevated FSH, familial infertility, and abnormal karyotypes were associated with unsuccessful sperm retrieval.)[157] 

Given the associated costs and potential genetic consequences, couples should seriously consider artificial insemination, ICSI using donor sperm, or adoption before starting expensive advanced reproduction treatments.

Medical comorbidities are increased in men with nonobstructive azoospermia, as they 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 3 times the overall risk of developing a future malignancy compared to infertile men without azoospermia.[27] About 30% of men with nonobstructive azoospermia also have testosterone deficiency, usually due to Leydig cell dysfunction.[232][233](B2)

Summary of Treatment

Obstructive azoospermia

Obstructive azoospermia should be treated by relieving the obstruction through surgical reconstruction whenever technically feasible. When surgical reconstruction cannot be performed or fails to restore sperm passage, MESA followed by ICSI represents the recommended approach. For patients with intratesticular obstruction, micro-TESE followed by ICSI can provide an alternative method for sperm retrieval and assisted reproduction.

Nonobstructive Azoospermia

Nonobstructive azoospermia associated with hypogonadotropic hypogonadism may respond to hormone therapy. However, most other patients with nonobstructive azoospermia will likely require surgical sperm retrieval through TESA or micro-TESE, followed by ICSI. Patients with a testosterone to 17β-estradiol ratio of less than 10 may be candidates for aromatase inhibitor therapy, eg, anastrozole.[82][85][86] Additional hormonal and surgical interventions may also provide benefit in selected patients. FSH supplementation may be considered when the FSH level remains less than 8.4 IU/L, while varicocelectomy and clomiphene therapy may also improve reproductive outcomes in appropriately selected patients.[234](A1)

Pause and Reflect

A 32-year-old man presents with his partner for evaluation of infertility after 12 months of unsuccessful attempts to conceive. He has no significant medical history and reports no prior scrotal surgery or trauma. Physical examination reveals bilaterally normal-sized testes without palpable abnormalities. Two properly collected, separate semen samples demonstrate azoospermia. Initial laboratory testing shows normal testosterone and LH levels with an elevated FSH level. The clinician is considering whether the patient has obstructive or nonobstructive azoospermia and is determining the appropriate next steps in the evaluation.

  • What is the most appropriate diagnostic protocol for distinguishing obstructive from nonobstructive azoospermia in this patient?
  • Which additional laboratory and genetic evaluations should the clinician consider before proceeding with sperm retrieval or testicular biopsy?
  • How should the clinician counsel the patient regarding the likelihood of successful sperm retrieval and the potential role of assisted reproductive techniques such as ICSI?

Differential Diagnosis

The differential diagnosis for azoospermia includes the following:

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

Prognosis

In general, infertile men have a greater risk of death, along with a higher incidence of autoimmune disorders (rheumatoid arthritis, systemic lupus erythematosus, and thyroiditis), cardiovascular disease, diabetes, erectile dysfunction, hypertension, hypogonadism, metabolic syndrome, and various malignancies, particularly prostate and testicular cancer.[235][236][237][238][239][240][241][242][243][244] Male infertility increases the overall risk of early mortality by 26%, and this is even higher in azoospermic men.[238][245][246] Therefore, conducting complete and comprehensive health screenings periodically for men diagnosed with azoospermia is crucial.[235][238]

The prognosis for producing biological offspring in men with azoospermia depends on the underlying cause. Obstructive azoospermia, often resulting from surgically correctable conditions, eg, congenital absence of the vas deferens or postsurgical blockages, generally offers a favorable prognosis. Surgical interventions or assisted reproductive techniques can be effective in achieving conception for individuals with obstructive azoospermia.

In contrast, nonobstructive azoospermia, primarily due to testicular failure, presents a more challenging prognosis. While advanced reproductive technologies, eg, TESE and ICSI, may enable conception, success rates can vary, and the condition may remain untreatable in some cases. Spermatogenesis may be so disrupted that no viable sperm can be collected. Accurate diagnosis, tailored treatment plans, and ongoing support are crucial factors influencing the prognosis, underscoring the importance of a comprehensive, individualized approach to azoospermia management.

Successful sperm retrieval rates in nonobstructive azoospermia are approximately 50% overall, with the highest retrieval rates reported in men with a history of cryptorchidism and mumps orchitis (75%–81%).[64][247][248] Early maturation arrest and complete Sertoli cell-only syndrome tended to have fewer successful sperm retrieval results, but the lowest rates were reported in men with idiopathic nonobstructive azoospermia (~31%).[219][247][248][249] When taken together with the pregnancy rate of roughly 50% with ICSI, the overall successful pregnancy rate is only about 25%.[230][231][249] Patients with Y-chromosome AZFc microdeletions had the poorest overall outcomes with a live birth rate of only about 19%.[249]

A meta-analysis demonstrated that improved outcomes are associated with younger patient age, smaller testicular volumes, lower serum FSH and LH levels, use of fresh unfrozen spermatozoa, and testicular histology showing at least some viable mature sperm.[219][250] Early maturation arrest and complete Sertoli cell-only syndrome tended to have fewer successful sperm retrieval results.[219]

Better sperm retrieval and pregnancy rates are generally associated with the following:

  • Finding viable sperm on a testis biopsy, even in very small numbers, is considered a very good prognostic sign.[251][252]
  • Focal Sertoli cell-only syndrome may provide some viable sperm from spared patches of normal spermatogenesis compared to complete Sertoli cell-only syndrome, where no viable sperm can be found.[253][254] See "Male Infertility" and "Sertoli Cell–Only Syndrome" for further information.
  • Oligospermia and hypospermatogenesis are associated with significantly higher sperm retrieval rates than true azoospermia, at 90% or more.[64]
  • Patients with late-stage maturation arrest have better sperm retrieval rates than those with early arrest.[253][255]

Complications

Complications of azoospermia or associated surgical treatment include the following:

  • Failure to produce a pregnancy; prolonged or continuing infertility
  • Hematoma formation due to surgery
  • Infection
  • Parenchymal fibrosis of the testis
  • Testicular atrophy

Additionally, azoospermia can lead to significant emotional distress, impacting the mental health of affected individuals and straining relationships. The pursuit of fertility treatments, while offering hope for conception, may also entail financial burdens and emotional stress. The psychological toll of grappling with infertility and potential societal stigmas surrounding male reproductive health further compounds the challenges and complications associated with azoospermia.

Deterrence and Patient Education

Deterrence and patient education play pivotal roles in azoospermia, aiming to prevent and manage this condition effectively. Deterrence involves raising awareness about lifestyle factors that may contribute to azoospermia, eg, smoking, excessive alcohol consumption, testosterone supplementation, and exposure to environmental toxins. Educating patients about the importance of a healthy lifestyle, including maintaining a balanced diet and managing stress, can contribute to overall reproductive well-being.

Patient education is also crucial in fostering an understanding of the various causes and classifications of azoospermia, empowering individuals to make informed decisions about their reproductive health. Proper counseling, testing, and treatment can offer most male infertility patients, including those with azoospermia, the chance to biologically father children. By promoting awareness and providing comprehensive information, healthcare professionals can contribute to the deterrence of modifiable risk factors and equip patients with the knowledge needed to navigate the complexities of azoospermia, ultimately enhancing their proactive involvement in reproductive health management.

Pearls and Other Issues

Clinicians should establish realistic expectations regarding the likelihood of treatment success during the initial visit. Members of the general public often maintain an exaggerated perception of the capabilities of modern medicine for treating azoospermia and male infertility. Clear counseling regarding available treatment options, expected outcomes, and potential limitations can help patients develop an accurate understanding of their prognosis and reproductive options.

The initial diagnosis of azoospermia requires 2 properly collected, separate semen samples demonstrating no sperm. Despite the diagnosis, most patients can receive meaningful assistance through appropriate sperm retrieval procedures followed by ICSI. These approaches can provide viable reproductive options for many men who otherwise would have limited opportunities for biological paternity.

A detailed medical and reproductive history, thorough physical examination, and initial hormonal evaluation are necessary to classify azoospermia as obstructive or nonobstructive. The initial hormonal screening should include testosterone and FSH levels.[256] If morning testosterone is low (<300 ng/dL), the American Urological Association/American Society for Reproductive Medicine (AUA/ASRM) guideline recommends repeating serum testosterone and measuring free testosterone, LH, prolactin, and estradiol.[256]

Karyotype analysis and genetic testing for Y-chromosome microdeletions should be offered to azoospermic men when the evaluation does not identify an apparent cause of the disorder. Genetic testing should precede sperm retrieval procedures or testicular biopsies when indicated, allowing clinicians to identify relevant genetic abnormalities and incorporate those findings into treatment planning and counseling.

Selective scrotal ultrasonography and transrectal ultrasonography may provide additional diagnostic information and assist with further classification of azoospermia. These imaging studies can complement the history, physical examination, hormonal assessment, and genetic evaluation when clinicians require additional information to clarify the underlying etiology and guide management.

Karyotype testing and genetic screening are recommended before sperm retrieval procedures to avoid unnecessary surgeries. The following testing is recommended based on clinical findings:

  • A missing vas deferens or seminal vesicle suggests a cystic fibrosis gene mutation. Clinicians should test for CFTR.
  • Anti-Müllerian hormone levels are generally an indicator of Sertoli cell function. However, low levels do not necessarily correlate well with spermatogenesis, but tend to be associated with overall poor gonadal function, lower semen quality, and men with nonobstructive azoospermia.[257][258]
    • Paradoxically, low serum levels of anti-Müllerian hormone (<4 ng/mL) are associated with a higher rate of successful sperm retrieval with micro-TESE in men with nonobstructive azoospermia.[221][223][257][259][260][261]
  • Bilateral small, firm testes are suggestive of Klinefelter syndrome; a karyotype should be performed.
  • Careful, repeat semen analyses should be performed in men with azoospermia and low FSH levels, as they may actually have some sperm in the semen.[78]
  • Epsilon aminocaproic acid has been shown to protect sperm DNA from radiation damage, but this finding is still investigational and has not yet been approved for clinical practice) [262][263]
  • Hypogonadotropic hypogonadism, utilizing a combined approach of hormonal induction, micro-TESE, and assisted reproduction, can be expected to produce biological fatherhood in about half of initially azoospermic men with this condition, depending on initial severity and partner factors.[234]
  • In experimental studies, isotretinoin (a powerful derivative of vitamin A, also known as Accutane, originally used to treat severe acne) has been shown to increase sperm production in some men with nonobstructive azoospermia.[264][265][266][267][268]
  • Lower levels of anti-Müllerian hormone are associated with a higher rate of positive sperm retrieval from micro-TESE.[221][222][223]
  • Maturational arrest and Sertoli cell-only syndrome will have substantially lower rates of successful sperm retrieval than most other causes of nonobstructive azoospermia.
  • No elevation of FSH levels or degree of testicular atrophy is sufficient to absolutely determine that no sperm will be found on sperm retrieval procedures.
  • Rare causes of azoospermia not mentioned in this review, eg, persistent Mullerian duct syndrome, may also occur.[269][270]
  • Screen for possible Klinefelter's (small, firm testes, gynecomastia, and tall stature with long limbs).
  • Small or normal testicular size and elevated FSH levels suggest nonobstructive azoospermia due to a primary testicular disorder of spermatogenesis, eg, maturational arrest, Sertoli cell-only syndrome, Y-chromosome microdeletions, or similar; genetic testing and testis biopsy should be considered.
  • TESA, micro-TESE, or MESA (obstructive azoospermia only) 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.
  • Testosterone supplementation has no role in male infertility or azoospermia treatment.
  • The role of FSH stimulation in increasing sperm numbers before testis biopsies and sperm retrieval procedures is controversial and not currently recommended.
  • The semen analysis is crucial, so clinicians should ensure analysis is competently performed and includes all the recommended procedures and parameters, including centrifugation, repeat pellet analysis, staining, volume, pH, and genetic testing (karyotype and Y-chromosome microdeletion analysis), as well as seminal biomarkers (fructose, neutral α-glucosidase, and zinc).[19][62][63]

Obstructive azoospermia can be effectively treated with either surgical reconstruction or sperm retrieval with MESA and ICSI. In ideal situations, reconstruction is preferred, but MESA sperm retrieval with ICSI is the better choice if secondary male infertility factors, concomitant female disorders, or poor results are expected from the surgery for some other reason.[175]

Patients who present with infertility and azoospermia after testosterone supplementation therapy are a growing problem. All male patients in the reproductive age group should be informed about the potential deleterious effects of testosterone supplementation on their sperm counts, testicular shrinkage, and infertility.[276] This can often be offset by adding clomiphene to their testosterone replacement therapy.[277] See "Male Infertility" for further information.

Most men with azoospermia will have the nonobstructive type, where sperm retrieval with micro-TESE followed by ICSI is often their best option, as the majority can still provide sufficient viable sperm for assisted reproduction. Patients with idiopathic nonobstructive azoospermia may benefit from empiric hormonal therapy with aromatase inhibitors, FSH, and hCG before micro-TESE.[278][279][280][281][281]

Enhancing Healthcare Team Outcomes

Azoospermia is considered a severe and important cause of male infertility amongst childless couples attempting pregnancy. A collaborative approach among healthcare professionals is essential to deliver patient-centered care and optimize outcomes. Physicians, advanced care practitioners, nurses, pharmacists, and other health professionals must possess a comprehensive skill set to effectively address the multifaceted aspects of azoospermia. Classifying and diagnosing the type of azoospermia includes taking a detailed history and physical examination, hormonal investigations, ultrasonography, and genetic testing. Strategizing medications, treatments, procedures, and protocols is the key to treating couples with infertility. Genetic counseling may be needed in some families and should be available.

Emphasizing evidence-based practices, continuous learning, and adapting to evolving medical advancements is crucial. Physical and emotional support is also essential. This will help enhance the physician's ability to recommend reasonable treatments, provide appropriate counseling, and align with patient expectations. Collaboration with radiologists, urologists, genetic counselors, reproductive endocrinologists, obstetrics/gynecology specialists, and their respective nursing care teams is imperative for providing the best possible outcomes for these couples. Trained and proficient nurses are an integral part of the interprofessional healthcare team.

Care coordination ensures seamless transitions between diagnostic, therapeutic, and follow-up phases. This coordination optimizes resource utilization, streamlines processes, and fosters a continuum of care addressing both the medical and emotional dimensions of azoospermia. The interprofessional team can collectively enhance patient-centered care, improve outcomes, prioritize patient safety, and elevate overall team performance in the management of azoospermia.

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