What is azoospermia

Azoospermia defined as the total absence of spermatozoa (sperm) in a man ejaculates (semen) in two successive semen examinations ¹. If no spermatozoa are observed in the wet preparation, the World Health Organization (WHO) recommends an examination of the centrifuged sample (3000 X g or greater for 15 minutes) ². If no sperm are observed in the centrifuged sample, the semen analysis should be repeated. The presence of a small number of spermatozoa in either of the centrifuged samples is defined as cryptozoospermia, and the complete absence of spermatozoa is defined as azoospermia ². Azoospermia accounts for around 10% of cases of male infertility, and affects about 1% of the men in the general population ³. This may be because the man does not make sperm or because the sperm is blocked from entering the semen. Azoospermia can be classified as non-obstructive azoospermia associated with spermatogenesis failure and obstructive azoospermia characterized by an obstruction in the seminal tract and normal spermatogenesis. Whereas non-obstructive azoospermia accounts for 60% of azoospermic patients, obstructive azoospermia accounts for around 40% ⁴.

Azoospermia may be caused by hormone problems, certain genetic conditions, previous vasectomy or other surgery, or other conditions. Azoospermia may also be caused by certain cancer treatments. Azoospermia can cause infertility (the inability to produce children).

Of the men presenting for fertility investigation, up to 20% are found to be azoospermic. These men can be categorized as having either ⁵:

1. Pre-testicular azoospermia (2% of men with azoospermia, due to a hypothalamic or pituitary abnormality diagnosed with hypo-gonadotropic-hypogonadism),
2. Testicular failure or non-obstructive azoospermia (49% to 93%, while the term testicular failure would seem to indicate a complete absence of spermatogenesis, actually men with testicular failure have either reduced spermatogenesis [hypospermatogenesis], maturation arrest at either an early or late stage of spermatogenesis or a complete failure of spermatogenesis noted with Sertoli-cell only syndrome),1–5
3. Post-testicular obstruction or retrograde ejaculation (7% to 51%, normal spermatogenesis but obstructive azoospermia or retrograde ejaculation) ⁶.

A further group of men have a failure to ejaculate. These may be men with spinal cord injury, psychogenic failure to ejaculate or neurological damage (sympathetic nerve damage from a retroperitoneal lymph node dissection for example).

To understand the management of azoospermia, it is important to also understand the assisted reproductive technologies (ARTs) (e.g., in-vitro fertilization [IVF]). Since the 1970s, breakthroughs in the assisted reproductive technologies (ARTs) have allowed us to offer potentially successful treatments for up to 98% of couples with male factor infertility ⁷. These significant advances had little to do with techniques to improve the sperm quality but relied on ARTs. These programs used techniques to increase the number of mature eggs produced by the women by manipulating the hormonal environment in the women using exogenous hormones (ovulation induction) followed by:

1. Timed insemination: timed to optimize the pregnancy rates: either through intercourse or intra-uterine insemination of the partners washed sperm; or
2. In-vitro fertilization (IVF): oocytes are retrieved from the ovaries then are either incubated with the sperm in a dish; or
3. Intra-cytoplasmic sperm injection (ICSI): injecting the sperm directly into the cytoplasm of the oocyte.

All of the above techniques are widely used to treat couples with male factor infertility.

Using intra-cytoplasmic sperm injection (ICSI), it is now possible to produce a pregnancy with any live sperm (moving or not), from either the semen or any site within the male reproductive tract. Even men with azoospermia can now be offered sperm retrieval with ICSI. Sperm could be retrieved from any site in the reproductive tract and used for ICSI. These are the men who previously had very limited chances to ever have biologically related children. Pregnancy rates of close to 50% per cycle of ICSI (women under 35 years old) are expected, with the pregnancy rates independent of the site of the origin of the sperm ⁷.

Azoospermia key facts

• a) Azoospermia is defined as the absence of sperm in at least two different ejaculate samples (including the centrifuged sediment) ⁸. Ten to fifteen percent of couples in the general population suffer from infertility issues ⁹. Approximately 50% of these cases can be attributable to a male issue. Ten to twenty percent of these men (or 1% of men in the general population) suffer from azoospermia-induced infertility ⁹.
• b) A complete medical history, physical examination and hormonal investigation are the principal components of the initial evaluation of the azoospermic male ¹⁰.
• c) Sperm production is controlled by the hypothalamo-pituitary-gonadal axis.
• d) Scrotal ultrasonography, transrectal ultrasound (TRUS), TRUS-guided seminal vesiculography, seminal tract washout, vasography, endorectal magnetic resonance imaging, abdominal ultrasound and cranial imaging studies can be performed when evaluating the azoospermic male.
• e) In the evaluation of azoospermic patients who have normal-sized testes and a normal hormone profile, testicular biopsy has a critical role in distinguishing between obstructive azoospermia and non-obstructive azoospermia. It is best to plan for the cryopreservation of sperm at the time of the biopsy, if feasible.
• f) Diagnostic testicular biopsies are of limited value in men with small testes and elevated FSH levels (greater than twice the upper limit), which support a diagnosis of non-obstructive azoospermia. It is recommended that such patients undergo a microTESE (testicular sperm extraction) combined with cryopreservation and subsequent in vitro fertilization via intracytoplasmic sperm injection (ICSI); this procedure would enable several samples to be taken ¹⁰.
• g) Genetic factors are important in the evaluation and management of azoospermic males. These factors can be pretesticular (Kallmann syndrome), testicular (Klinefelter’s syndrome or Y chromosome microdeletions) or post-testicular (CBAVD). Genetic counseling provides couples with information about the nature, inheritance patterns, and implications of genetic disorders to help them make informed medical and personal decisions.

Azoospermia causes

The many causes of azoospermia is divided into three primary categories: pretesticular, testicular and post-testicular categories. Although the pretesticular and post-testicular causes of azoospermia are generally curable, the testicular causes of azoospermia are generally not.

Pretesticular (central) causes of azoospermia are endocrine abnormalities that are characterized by low levels of sex steroids and abnormal gonadotropin levels and include hypogonadotropic hypogonadism, hyperprolactinemia, and androgen resistance. These abnormalities can be congenital (e.g., Kallmann syndrome), acquired (e.g., hypothalamic or pituitary disorders) or secondary (e.g., an adverse effect from a medication).

In contrast, testicular causes are characterized by disorders of spermatogenesis inside the testes, such as varicocele-induced testicular damage, undescended testes, testicular torsion, mumps orchitis, gonadotoxic effects of medications, genetic abnormalities, and idiopathic causes. Most cases of non-obstructive azoospermia have a pretesticular or testicular cause. Lastly, post-testicular etiologies (due to ejaculatory dysfunction or genital tract outflow obstruction) are the major contributors to obstructive azoospermia ¹¹. De novo or familial chromosomal or gene abnormalities constitute well-established genetic causes of azoospermia. Congenital testicular causes consist of anorchia, testicular dysgenesis (cryptorchidism), genetic abnormalities (Y chromosome deletions), germ cell aplasia (Sertoli cell-only syndrome) and spermatogenic arrest (maturation arrest). Acquired testicular causes include trauma, torsion, infection (mumps orchitis), testicular tumors, medications, irradiation, surgery (compromising vascularization of testis), systemic diseases (cirrhosis, renal failure) and varicocele ¹².

Post-testicular causes include ejaculatory disorders or obstructions, which impair the transport of spermatozoa from the testis. These obstructions can also be congenital, caused by a congenital bilateral absence of the vas deferens (CBAVD), or acquired because of infection or surgery (vasectomy or an iatrogenic injury). Obstructive azoospermia (OA) is also classified according to the localization of the obstruction: epididymal (postinfection), vasal (vasectomy, congenital bilateral absence of the vas deferens) or ductal (Müllerian cysts) ¹².

Azoospermia may also be clinically classified as obstructive (post-testicular) and nonobstructive (pretesticular or testicular). Obstructive azoospermia is less common than nonobstructive azoospermia and occurs in 15 to 20% of men with azoospermia ¹². Although nonobstructive azoospermia indicates impaired sperm production of the entire testis by definition, it has been observed that focal normal spermatogenesis can be observed in 50 to 60% of men with nonobstructive azoospermia ¹³.

Genetic testing in human azoospermia was initially restricted to karyotype analyses ¹⁴]. With technical progress, genetic screening has been broadened to the analysis of the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR) in patients with obstructive azoospermia ¹⁵ and Y chromosome microdeletions in patients with non-obstructive azoospermia ¹⁶. Over the last 5 years, emergence of whole-genome techniques has led to the identification of many other supposedly causal genetic defects. Table 1 provides an up-to-date overview of all the types of genetic defects known to be linked to human azoospermia, including (i) chromosome abnormalities, (ii) causative gene mutations in obstructive azoospermia, (iii) causative gene mutations in non-obstructive azoospermia, (iv) polymorphisms and (v) epigenetic alterations.

Table 1. Genetic abnormalities observed in cases of obstructive or non-obstructive azoospermia

Genetic abnormality	Type of azoospermia	Sterility phenotype
Chromosome abnormalities
Klinefelter syndrome	Non-obstructive azoospermia	Variable
47,XYY		Variable
46,XX		SCOS
Chromosome rearrangements		Variable
Y chromosome microdeletions
AZFa	Non-obstructive azoospermia	SCOS
AZFb		Meiotic arrest
AZFc		Variable
Gene mutations
CFTR	Obstructive azoospermia	CBAVD
ADGRG2		CBAVD
PANK2		CBAVD
SLC9A3		CBAVD
TEX11	Non-obstructive azoospermia	Meiotic arrest
DMC1		Meiotic arrest
DNAH6		Meiotic arrest
MAGEB4		SCOS
MCM8		Unknown
MEIOB		Meiotic arrest
MEI1		Meiotic arrest
NPAS2		Unknown
PSMC3IP		Unknown
SPINK2		Post-meiotic arrest
STX2		Meiotic arrest
SYCE1		Meiotic arrest
TAF4B		Unknown
TDRD7		Post-meiotic arrest
TDRD9		Meiotic arrest
TEX14		Meiotic arrest
TEX15		Meiotic arrest
XRCC2		Meiotic arrest
ZMYND15		Meiotic arrest

Abbreviations: CBAVD = congenital bilateral absence of the vas deferens; SCOS = Sertoli-cell-only syndrome

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Azoospermia symptoms

Azoospermia accounts for around 10% of cases of male infertility, and affects about 1% of the men in the general population ³.

Azoospermia diagnosis

After at least 2 semen analyses have confirmed azoospermia, men should be investigated with a history, physical examination and laboratory and imaging studies. The history should include information about:

1. the infertility history, such as duration of infertility, whether the infertility is primary or secondary, any treatments to date, libido and sexual activity for both partners;
2. the general health of the men, with particular emphasis on the presence of diabetes, respiratory issues;
3. the history of proven or suspected genito-urinary infections;
4. the exposure to agents which might have an adverse impact on spermatogenesis, including but not limited to:
5. medical agents like hormone/steroid therapy, antibiotics (sulphasalazine), alpha-blockers, 5 alpha-reductase inhibitors, chemotherapeutic agents,
6. environmental factors like pesticides, excessive heat on the testicles;
7. recreational drugs (marijuana, excessive alcohol);
8. the surgery of the reproductive tract (hydrocelectomies, varicocelectomies etc); and
9. the history of any genetic abnormalities in the patient or his family.

If the man has had exposure to any of the above agents, the agents should be discontinued and the semen retested in 3 to 6 months. If the man has had a recent serious medical illness or injury or he has evidence of a recent reproductive tract infection, semen testing should be repeated at least 3 months following recovery from the illness.

Physical examination should include a thorough general examination with particular attention paid to the scrotal exam (size and consistency of the testis, presence and grade of varicoceles and palpable vas deferens). The initial testing will depend on these findings.

Reduced semen volume

If the semen volume is reduced (<1.5 mL) and documented on repeat testing, careful questioning should elicit whether this is an artifact (missed the container, difficulty providing specimen, etc.) or truly a low semen volume. Low semen volume could be due to:

1. absence/abnormalities of the vas deferens/seminal vesicles,
2. retrograde ejaculation, or
3. failure of emission.

Testing the post-ejaculate urine should help determine if there is retrograde ejaculation.

Occasionally, an alpha agonist (use pseudoephedrine or other just before the semen testing) will convert retrograde into antegrade ejaculation. Diabetic men often have retrograde ejaculation or failure of emission.

Physical examination will help determine if the vas deferens is present in the scrotum and a transrectal ultrasound (TRUS) will determine if the seminal vesicles and vas deferens close to the prostate are normal. If absence of the vas deferens and/or the seminal vesicle is identified, the man has about an 80% chance to carry a genetic alteration associated with cystic fibrosis ¹⁷. Cystic fibrosis testing should be performed on all men with absence of the vas deferens/seminal vesicles.

Obstruction of the ejaculatory duct is detected by transrectal ultrasound (TRUS) and is usually accompanied by dilation of the seminal vesicles (typically >1.5 cm). Vasography is not required and should be discouraged for men with an ejaculatory duct obstruction. If an ejaculatory duct obstruction is identified, the man has about a 25% chance to carry a genetic alteration associated with cystic fibrosis ¹⁷. Cystic fibrosis testing should be performed on all men with ejaculatory duct cysts.

As mentioned above, the categories of the causes of azoospermia are:

1. Pre-testicular azoospermia (2%: hypothalamic or pituitary etiology)
2. Testicular failure or non-obstructive azoospermia (49% to 93%)
3. Post-testicular obstruction (7% to 51%: normal spermatogenesis but obstructive azoospermia).

The category of azoospermia can often be determined by the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. The diagnosis of pre-testicular azoospermia is relatively uncomplicated: LH and FSH levels will be low and the testosterone levels will be either low or normal. Men with elevated FSH and LH and small testis bilaterally have non-obstructive azoospermia. However, men with normal levels of FSH and LH could have either non-obstructive or obstructive azoospermia ¹⁸. Unfortunately, there is no non-invasive method to differentiate obstructive from non-obstructive azoospermia in this group of men. A testicular biopsy is usually required to provide a definitive diagnosis.

There have been several recent publications about the use of biomarkers in the semen and serum to differentiate obstructive from non-obstructive azoospermia ¹⁹. A number of authors report on the use of inhibin B serum levels to determine testicular function ⁵. While inhibin B levels are generally lower in those men with more severe testicular dysfunction and is undetectable in those with a Sertoli cell only pattern on testis biopsy, inhibin B levels in men with maturation arrest or hyopospermatogenesis patterns on testis biopsies may be identical to those found in men with full spermatogenesis. At present, serum inhibin B levels do not provide significant clinical benefit: with high FSH the inhibin B levels are generally low (both indicating testicular failure), while with normal FSH the inhibin B levels are generally normal (both indicating either obstructive or non-obstructive azoospermia).

At present, for most men, there are no non-invasive methods to differentiate obstructive from non-obstructive azoospermia. As noted above, about 60% of men with azoospermia will require a testicular biopsy to provide a definitive diagnosis.

When should the azoospermic man have a testis biopsy?

As mentioned above, close to 60% of the men would need a testicular biopsy to document whether the azoospermia is post-testicular (normal spermatogenesis) or testicular (testicular failure with either Sertoli cell only syndrome, Maturation arrest pattern or hypospermatogenesis). However, a testis biopsy should only be offered to men in whom this diagnosis would alter management. As an example, we would discourage a man from having a testis biopsy if the couple is not interested in any of the potential management options that follow (e.g., things like sperm aspiration plus ICSI, vaso-epididymostomy). If the couple is interested in considering the other fertility treatments mentioned above, then the biopsy could be performed by either of these 2 procedures.

The biopsy can be performed as a diagnostic procedure alone (either a percutaneous or an open biopsy are acceptable methods of testicular biopsies). The biopsy results then guide the next treatments.

The biopsy can be the initial part of the larger fertility treatment. Once the biopsy results are available as a quick section, the surgery would then proceed with a reconstruction and/or sperm retrieval (if active spermatogenesis is detected) or a testicular sperm extraction (if a pattern of testicular failure is detected).

A bilateral diagnostic testicular biopsy is generally not required. If there is a discrepancy in testicular size, the larger of the 2 testes should be biopsied.

Failure to ejaculate

In men with a clear neurological cause (spinal cord injury, retroperitoneal lymph node surgery, etc.), no further investigations are required prior to treatment. Men with idiopathic failure to ejaculate (particularly those with a failure to orgasm) should be seen by a sex therapist.

Genetic investigations for men with azoospermia

Genetic factors occupy an important place in the evaluation and management of the azoospermic male. Such factors can be pretesticular (e.g., Kallmann syndrome), testicular (e.g., Klinefelter’s syndrome or Y chromosome microdeletions) or post-testicular (congenital bilateral absence of vas deference [CBAVD]). Genetic counseling provides couples with information about the nature, inheritance pattern, and implications of genetic disorders to help them make informed medical and personal decisions. The common genetic disorders that are associated with azoospermia are reviewed below.

All men with hypogonadotropic hypogonadism should be referred for genetics counseling as almost all of the congenital abnormalities of the hypothalamus are due to a genetic alteration.

All men with absence (absence of the vas deferens) or obstruction (epididymal or ejaculatory duct) of the reproductive tract ductal structures are at an elevated risk to carry a genetic alteration associated with cystic fibrosis. Experts recommend that not only the man but his partner should be offered cystic fibrosis testing in this situation. If a genetic alteration is identified, then genetic counselling is suggested.

All men with testicular failure should be offered karyotype and Y-micro-deletion testing then referred for genetics counselling if an abnormality is identified ²⁰.

Kallmann syndrome

Kallmann syndrome is an X chromosome-linked disorder characterized by isolated gonadotropin releasing hormone (GnRH) deficiency accompanied by complete or partial anosmia. Six X chromosome-linked autosomal dominant and recessive genes have been identified; of these, KAL1 is the gene that is most commonly associated with Kallmann syndrome. Kallmann syndrome is essentially a hormonal disorder in which the lack of GnRH secretion leads to testicular insufficiency (i.e., hypogonadotropic hypogonadism) ²¹.

Kallmann syndrome is diagnosed clinically in the presence of anosmia, micropenis, cryptorchidism, diminished libido, erectile dysfunction and the absence of secondary sex characters. While serum testosterone level is low (<100 ng/ml) in patients with Kallmann syndrome, pituitary and hypothalamus imaging studies are normal. Adult males with Kallmann syndrome tend to exhibit prepubertal testicular volume (<4 ml) and have eunuchoid body habitus caused by delayed skeletal maturation ²¹. One study recently demonstrated that testicular morphology in patients with Kallmann syndrome can vary ²². However, spermatogenesis can be easily induced by hormonal stimulation ²³. Depending on the type of gene mutation, nonreproductive phenotypes in men with Kallmann syndrome can include unilateral renal agenesis, dyskinesia and/or skeletal abnormalities, cleft lip/palate, ear/hearing defects, coloboma (eye defect) and hyperlaxity of the joints.

Klinefelter’s syndrome

Klinefelter’s syndrome has a wide spectrum of clinical presentations. Klinefelter’s syndrome is a chromosomal disorder in which at least one additional X chromosome is observed in the male karyotype. Although there are several mosaic forms of Klinefelter’s syndrome, most cases are of the nonmosaic form, 47, XXY. Klinefelter’s syndrome is the most common chromosome aneuploidy in human beings and the most common form of male hypogonadism, with a prevalence of 0.1 to 0.2% in the general population and up to 3.1% in the infertile population. The presence of the extra X chromosome sets in motion several undefined events that lead to spermatogenic and androgenic failure, gynecomastia, and learning difficulties ²⁴. The extra X chromosome may originate from either the maternal or paternal side.

The clinical presentation of Klinefelter’s syndrome varies according to the age at diagnosis and the severity of the mosaicism. It is difficult to differentiate prepubertal boys with Klinefelter’s syndrome from normal boys based solely on their phenotype. Small, firm testes and varying symptoms of androgen deficiency characterize Klinefelter’s syndrome in adolescence and after puberty ²⁵. On one end of the spectrum are boys who are identified as having Klinefelter’s syndrome because they have failed to undergo puberty and virilization as a result of nearly complete androgenic malfunction. These boys exhibit a eunuchoid appearance. On the opposite end of the spectrum are phenotypically normal boys who are diagnosed with Klinefelter’s syndrome during an evaluation for azoospermia ²⁶.

Although the exact mechanism of androgen deficiency is unknown, most patients with Klinefelter’s syndrome exhibit low serum testosterone concentrations and elevated FSH levels. This reflects spermatogenic compromise and the compensatory elevation of LH levels that results because the Leydig cells are being maximally stimulated and have a small reserve capacity ²⁶. The majority of these patients also suffer from decreased libido and erectile dysfunction. Generally, the patients’ ejaculate presents with azoospermia. A testis biopsy reveals extensive fibrosis, hyalinization of seminiferous tubules and hyperplasia of the interstitium. However, the tubules may exhibit residual foci of spermatogenesis ²⁷.

Congenital bilateral absence of vas deference

Congenital bilateral absence of vas deference (CBAVD) is observed in 2 to 6% of men with obstructive azoospermia and is responsible for infertility in approximately 1% of infertile men ²⁸. A strong association between congenital bilateral absence of vas deference (CBAVD) and the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been demonstrated ²⁹. This gene is located on the short arm of chromosome 7 and encodes the CFTR protein, which is crucial for maintaining proper sodium/chloride balance in epithelial secretions. This balance is necessary to optimize the viscosity and fluidity of these secretions. Approximately 1,500 different mutations of the CFTR gene have been described. Nearly all male patients with clinically diagnosed cystic fibrosis have CBAVD, and approximately 80% of patients with CBAVD have mutations in at least one CFTR allele. The inability to identify a second mutation is presumed to result from the fact that these mutations are located elsewhere in the noncoding regions of the CFTR gene ³⁰.

Cystic fibrosis (CF) is characterized by elevated concentrations of electrolytes in the sweat, chronic pulmonary disease resulting from thickened respiratory epithelial secretions and pancreatic exocrine insufficiency secondary to thickened and occlusive ductal secretions. Both maternal and paternal mutant alleles must be present to cause clinical cystic fibrosis. However, the clinical presentation of cystic fibrosis depends on the severity of the mutations in each CFTR allele and/or in the noncoding regions of the genes (e.g., the 5T alleles). Thus, whereas a subset of patients with CFTR mutations suffer from severe pulmonary disease and pancreatic dysfunctions, the bilateral absence of the vas deferens may be the only observable effect in other patients ³⁰.

The physical examination of the patients with CBAVD reveals normal-sized and full testes, a full and firm caput epididymis caused by efferent ducts that are distended with sperm, a present or absent distal two-thirds of the epididymis and a bilateral absence of the vas deferens. Semen analysis reveals a low-volume (0.5 ml), acidic ejaculate that is devoid of fructose and seminal vesicle fluid because of atrophic, dysfunctional or absent seminal vesicles. The seminal vesicle anomalies can be confirmed with TRUS imaging ²⁶. Most men with CBAVD exhibit normal spermatogenesis, but it has been observed that a large proportion exhibit impaired spermatogenesis. Prior to sperm harvesting, other potential coexisting causes of impaired spermatogenesis should be investigated ³¹. A careful abdominal US should be performed because as many as 10% of patients with CBAVD may also exhibit renal agenesis ³².

Y chromosome microdeletions

The relationship between deletions on the Y chromosome and azoospermia was first recognized in 1976. With the elucidation of the molecular anatomy of the Y chromosome, specific microdeletions that are associated with azoospermia or severe oligospermia were discovered in the 1990s ³³. Since this time, several case series have been published. A study with a large number of participants demonstrated that the prevalence of microdeletions was approximately 3% in unselected infertile men, 8% in men with non-obstructive azoospermia and 5.5% in men with severe obstructive azoospermia ³⁴. Although rare, these microdeletions have also been reported to occur in fertile men ³⁵.

Three microdeletions have been mapped to three different regions on the long arm of the Y chromosome. These regions are referred to as azoospermia factors (AZF)a, AZFb and AZFc and are observed proximally, centrally and distally on Yq11, respectively ³⁶. Multiple genes are distributed throughout these regions; most are involved in spermatogenesis but are still poorly characterized. For example, the deleted-in-azoospermia (DAZ) gene is located in the AZFc region. This gene encodes a transcription factor that is generally present in men with normal fertility ³⁷. The most frequently deleted region is AZFc (65-70%), and the least frequently deleted region is AZFa (5%). AZFb, AZFb+c and AZFa+b+c deletions are responsible for approximately 25 to 30% of Y microdeletions. It has been reported that Y microdeletions are observed nearly exclusively in patients with severe oligospermia (<1 million spermatozoa/ml) and are extremely rare in patients with sperm concentrations >5 million spermatozoa/ml ³⁸.

Genetic testing for Y microdeletions may predict the outcome of sperm retrieval techniques. One study has reported that sperm retrieval is possible in approximately 50% of patients with AZFc and partial AZFb deletions. The same study reported that the possibility of detecting mature spermatozoa in patients with complete AZFb deletions is virtually zero ³⁹. In another study, Kamp et al. demonstrated a strong association between AZFa deletions and Sertoli cell-only syndrome ⁴⁰.

It is also important to know whether AZFc microdeletions are present in patients with oligospermia given the evidence of a progressive decrease in sperm count over time in such men. The cryopreservation of spermatozoa in these cases may avoid invasive sperm retrieval procedures in the future ³⁹.

Hormonal analysis (FSH and inhibin B levels) studies have not been reliable in discriminating between patients with idiopathic and microdeletion-associated oligospermia and azoospermia ³⁸.

The male offspring of men with Y chromosome microdeletions are likely to inherit the same abnormality and may also be infertile. It is unclear whether Y chromosome microdeletions can cause additional health risks or affect the results of assisted reproductive techniques.

Genetic counseling may be offered whenever a genetic abnormality is suspected in either the male or the female partner. Men with non-obstructive azoospermia should receive genetic counseling and should be offered karyotyping and Y chromosome microdeletion analysis before their sperm is used in assisted reproductive techniques ⁴¹.

Azoospermia treatment

Couples have many ways to achieve their goal of completing their family. The options of adoption, donor sperm and child-free living should always be discussed with the couple. The treatment options discussed below are those which allow a couple to have children biologically related to the man. These options depend on the diagnosis.

Hypogonadotropic-hypogonadism or pre-testicular azoospermia

This is best treated with the use of FSH/LH or GnRH analogues to stimulate spermatogenesis. In over 90% of the cases, spermatogenesis is induced and the men have ejaculated sperm. However, therapy may take more than 6 months to be effective.

Retrograde ejaculation

Use of pseudoephedrine or a similar alpha agonist may convert retrograde ejaculation into antegrade ejaculation. If this is not successful, it is often possible to retrieve sperm from the bladder (either using a post-ejaculatory voided or catherized urine specimen). This sperm could then be used for one of the assisted reproductive technologies (ARTs). To optimize the sperm quality, it is often necessary to ask the men to alkalinize (pH of 6.5 – 8) the urine using standard medications.

Obstructive azoospermia

Obstructive azoospermia may be managed with:

1. Sperm retrieved from the reproductive tract (close to 100% chance of finding sperm) then the sperm is used in an intra-cytoplasmic sperm injection (ICSI) program. The type of sperm retrieval used could be a percutaneous or an open microscopic aspiration of sperm from the epididymis or a percutaneous or open biopsy of the testis. Any of the types of retrievals listed above are acceptable.
2. Bypass/repair of the obstructed area of the reproductive tract is possible in less than half of the men with obstructive azoospermia ²⁰. The most common area of obstruction is within the epididymis. With the present micro-surgical techniques, centres with expertise in performing vaso-epididymostomies report over 85% patency of the anastomosis (sperm in the ejaculate is the measure of patency) with over a 50% spontaneous pregnancy rate. However, this is surgery requiring micro-surgical expertise and experience and should only be performed in centres with this kind of expertise. We recommend that all men be offered the option to cryo-bank sperm retrieved during the course of the operation in case the surgery is not successful.
3. Men with an ejaculatory duct obstruction may be candidates for a transurethral resection (TUR) ejaculatory duct. This is best performed using a transrectal ultrasound guidance to allow the transurethral resection to precisely unroof the ejaculatory duct cyst. It is important to warn men of the potential complications associated with a transurethral resection of the prostate.

Non-obstructive azoospermia

Testicular sperm extraction may be used to identify sperm (reported success up to 75%, mean 52%) which could then be processed for use in an ICSI program ⁴². At present, the optimum way to identify these pockets of sperm is to perform an extensive, surgical dissection of the seminiferous tubules (a testicular sperm extraction). Large sections of the seminiferous tubules of the testis are examined with an operating microscope. Those tubules which are larger in size are more likely to have spermatogenesis than smaller diameter tubules. The advantage of this technique over the regular random biopsy method is the ability to identify areas of the seminiferous tubules, which are more likely to contain sperm before the tissue is removed from the testicle. Using this technique the chance of finding sperm is higher than the older technique of taking random testicular biopsies alone (in one series 63% compared to 45%), and while the procedure is laborious (surgical time may exceed 3 hours) the damage to the testicle is minimal due to the minimal amount of testis tissue eventually taken ⁴³. ICSI pregnancy rates using sperm from a testicular sperm extraction program are reported to be between 19% to 50% ²⁰. The testicular sperm extraction procedure should be offered to all men with nonobstructive azoospermia but should only be undertaken in a centre where ICSI is available.

Failure to ejaculate

Men with a neurological cause for a failure to ejaculate should be offered either vibro-stimulation or electro-ejaculation. Both of these procedures may cause autonomic dysreflexia in men with high spinal cord injuries. The semen specimen may be used for one of the ARTs. It is common that multiple (2 to 3) procedures several weeks apart may be needed to optimize the semen quality. These men may also have a concomitant obstruction in the epididymis, so occasionally sperm aspiration is required.

What is the role of varicocelectomy in men with azoospermia?

This remains controversial. There is some evidence that a small percentage of men with azoospermia due to testicular failure may benefit from treatment of a clinical varicocele ⁴⁴. It is considered reasonable to offer men with clinical varicoceles and testicular failure a varicocele repair, but it is important to warn men that there is a low probability that this will result in any improvement in his semen parameters.

What is the role of hormone therapy for men with azoospermia?

Apart from the management of men with hypogonadotropic hypogonadism, the use of hormones to treat men with azoospermia should be discouraged. The use of androgens is contra-indicated.

References

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