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A committee was established at the request of the CUA to determine guidelines for the investigation and management of azoospermia. Members of the committee, all of whom have special expertise in the investigation and management of male infertility, were chosen from different communities across Canada. The members represent different practices in different communities.
Infertility or subfertility affects 15% of couples in Canada, with a male factor contributing to the fertility problem in close to 50% of these couples. Of the men presenting for fertility investigation, up to 20% are found to be azoospermic. These men can be categorized as having either:
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 ARTs have allowed us to offer potentially successful treatments for up to 98% of couples with male factor infertility.6 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:
All of the above techniques are widely used to treat couples with male factor infertility.
In the United States in 2003, 122 872 IVF/ICSI cycles were performed and over 35 785 IVF babies were delivered.6 Also in the United States in 2003, it was estimated that more than 1.0% of all newborns are IVF or ICSI babies. In Denmark, 5% of newborns are IVF/ICSI babies.
Using 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.6
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:
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.
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:
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.7 Cystic fibrosis testing should be performed on all men with absence of the vas deferens/seminal vesicles (Grade A recommendation) (Fig. 1).
Obstruction of the ejaculatory duct is detected by 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 (Level of evidence 3, Grade C Recommendation). If an ejaculatory duct obstruction is identified, the man has about a 25% chance to carry a genetic alteration associated with cystic fibrosis.7 Cystic fibrosis testing should be performed on all men with ejaculatory duct cysts.
As mentioned above, the categories of the etiology of azoospermia are:
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.8 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 (Fig. 2).
There have been several recent publications about the use of biomarkers in the semen and serum to differentiate obstructive from non-obstructive azoospermia.8–20 A number of authors report on the use of inhibin B serum levels to determine testicular function.8,11–14,16,17,21 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) (Level of evidence 3, Grade C recommendation).
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.
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.
All men with hypogonadotropic hypogonadism should be referred for genetics counselling 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. We 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 (Level of evidence 2, Grade B recommendation).
All men with testicular failure should be offered karyotype and Y-micro-deletion testing then referred for genetics counselling if an abnormality is identified (Level of evidence 1, Grade A recommendation).22
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.
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.
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 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 may be managed with:
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.22–29 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) (Level of evidence 2, Grade B recommendation). 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.28 ICSI pregnancy rates using sperm from a testicular sperm extraction program are reported to be between 19% to 50%.22,25–27,30 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.
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.
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.
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.31 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 (Level of evidence 4, Grade D recommendation).
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 (Level of evidence 1, Grade A recommendation).
Competing Interests: None declared.
This paper has been peer-reviewed.