Azoospermia: Absence of Sperm in the Ejaculate

Pre-testicular causes generally encompass causes related to hormone control of reproduction. It includes things such as use of testosterone, general illnesses (esp. anything that causes a fever), kidney failure, hypothalamic or pituitary disease.

All of these fall under the category of non-obstructive azoospermia.

Clinical features: Usually associated with elevated gonadotropins (FSH and LH) and often low testosterone and small testes.

Genetic testing is required unless the cause is obvious (e.g. use of anabolic steroids).

This category includes anything that directly interferes with the testes ability to produce sperm. This is also called primary testicular failure.

Testicular injury generally needs to be bilateral (happens to both sides) for this to be possible. In some cases, a condition in one testis can affect the remaining testis in ways that may not be readily apparent (e.g. testis cancer).

Varicocele is a very common cause of primary testicular failure but only causes azoospermia in a small number.

Causes include testicular trauma (generally rupture or hematoma - being struck has happened to every man and doesn’t count), undescended testes, testicular torsion, radiation, cancer, infection and some drugs.

Drugs implicated in infertility include many types of chemotherapy, steroids, cimetidine and sulfasalazine.

Clinical features: Typically associated with elevated gonadotropins (FSH and LH), often with reduced testosterone and small testes.

Genetic testing is required unless the cause is obvious (e.g. chemotherapy or radiation).

This category includes anything that prevents sperm from getting from the testis itself into the vagina.

Obstructive azoospermia is a major post-testicular cause but there are other causes including erectile dysfunction and retrograde ejaculation.

Obstructive causes include vasectomy, absence of the vas deferens (CBAVD), scarring of the epididymis or vas deferens by infection (e.g. Chlamydia) and surgical injury to the vas deferens (e.g. hernia or scrotal surgery).

Clinical features: Usually completely normal hormone evaluation and normal sized testicles. There is usually a strong history to suggest obstruction when present. Other causes, such as retrograde ejaculation, are usually associated with symptoms that are difficult to miss.

Management: The optimal outcome is to restore sperm to the ejaculate. Treatment depends on the cause. In the cases where this cannot be achieved, sperm can be reliably retrieved to be used for assisted reproduction (IUI or IVF depending on the circumstances).

Idiopathic Non-Obstructive Azoospermia

When the cause of a medical condition cannot be identified, the patient is said to have an idiopathic condition. A very important caveat is that a condition can only be called idiopathic after a complete evaluation has been performed - an idiopathic diagnosis is sometimes called a diagnosis of exclusion since all other causes need to have been excluded by testing.

Patients are often surprised to learn that in a majority of cases of NOA that a cause cannot be identified. Idiopathic NOA is the most common diagnosis. It is frustrating for patients since they often assume that medical science has progressed to the point where there is always an answer.

Once a diagnosis of idiopathic NOA is established, the couple has 2 primary options to start their family:

1. Genetically unrelated/partially related offspring. These options do not pursue retrieval of sperm from the male and as such the offspring are not genetically related to them. However, the egg from the female may be used. These options include use of donor sperm for assisted reproduction utilized for intrauterine insemination or in-vitro fertilization. Adoption is also an option. The fertility centre can assist with counselling and selection of donor sperm. All questions should be directed to them regarding logistics and costs.

2. Genetically related offspring. This approach recognizes that some patients with idiopathic NOA are making sperm but in such small numbers that they do not survive long enough to reach the ejaculate. See below on combined microTESE and IVF approaches. Only 30-50% of men with idiopathic NOA will have sperm found at microTESE and only about half of these will result in a pregnancy.

This is the less common outcome of the diagnostic process for azoospermia. Treatment is highly dependent on the underlying cause and may vary from straightforward with a high chance of success (e.g. anabolic steroid or testosterone use) to complex and challenging (e.g. some genetic causes such as Klinefelter’s or Y-chromosome microdeletion).

Some cases may be amenable to medication treatments (e.g. hCG, stopping testosterone, Clomid) or surgery (e.g. varicocele correction) and we will inform you if that is the case. In other cases, the options are very similar to that for idiopathic NOA.

For couples where there is no path to restoring fertility via medication or surgery, there are 2 primary options to start their family:

1. Genetically unrelated/partially related offspring. These options do not pursue retrieval of sperm from the male and as such the offspring are not genetically related to them. These options include use of donor sperm for assisted reproduction (intrauterine insemination or in-vitro fertilization) or adoption. The fertility centre can assist with counselling and selection of donor sperm. All questions should be directed to them regarding logistics and costs.

2. Genetically related offspring. This approach recognizes that some patients with a specific cause for NOA are making sperm but in such small numbers that they do not survive long enough to reach the ejaculate. See below on combined microTESE and IVF approaches. The chance of successful sperm retrieval will be dependent on the specific cause (this will range form <5% to 70% depending on the cause) and only about half of these will result in a pregnancy.

There is usually a strong history to suggest that obstruction is present. Examples include vasectomy, bilateral hernia or scrotal surgery or an infectious process such as a sexually transmitted infection. Just as in cases of NOA, a cause may not be identified. In general, surgical correction is only possible in cases where a specific cause has been identified and the obstruction is focal (limited to a short, specific area). These include vasectomy or other injuries that have below the level of the inguinal canal. Injuries in the pelvis are not repairable.

When reconstruction is possible (for example, after vasectomy) the costs are generally not covered by the Medical Services Plan.

Reconstruction is rarely possible where the length of injury is very long or where the injury has occurred within the pelvis. Idiopathic obstructive azoospermia typically fits into this category. It is simply to possible to reconstruct these sorts of defects and in many cases, proceeding with surgical retrieval of sperm and IVF is the way to go. Patients often ask if surgically retrieved sperm can be used with insemination (IUI) and the answer is no - surgically retrieved sperm are not found in adequate numbers nor are they mature enough to fertilize an egg without assistance (IVF). Fortunately, the chances of sperm retrieval approaches 100%.

Occasionally there are features which do not permit easy categorization. These are typically idiopathic and often the clinical findings are ‘borderline’ - for example, maybe there is something in the story that suggest that an injury to the vas deferens or epididymis might have occurred (such as Chlamydia) and the epididymis feels a bit firm - but the testes are a little small and the FSH is high normal. In such situation, one must decide if they should proceed with a diagnostic biopsy and coordinate an attempt at cryopreservation of sperm which is an additional cost or conversely proceed with the microTESE and concurrent IVF plus donor sperm backup - or something else in-between.

Speak to your urologist about your individual circumstance.

TESE is short for testicular sperm extraction. It’s essentially a testis biopsy with the goal of using the sperm for reproduction. Microdissection testicular sperm extraction is basically a more accurate TESE. The differences between the 2 sperm retrieval techniques are described in the section of surgical retrieval of sperm.

These are similar in what they attempt to achieve but differ by matters of degree and cost.

In cases where obstruction is present, TESE is more than satisfactory with sperm retrieval rates approaching 100%. It is less expensive than microTESE and the recovery is faster.

MicroTESE is considered the gold standard for sperm retrieval in NOA. However, it is much more expensive and the surgery is associated with more risk. The absolute increase in the yield of sperm is between 10-20% higher in absolute terms than for TESE which may or may not be enough to justify the additional expense and morbidity. Another way of stating this benefit is that relatively speaking, microTESE is about 1.3x more likely to retrieve sperm than TESE.

For men in whom it is uncertain if obstruction is present or in those who the increased yield do not justify the costs, TESE is a perfectly reasonable option.

Men with idiopathic NOA have a 30-50% sperm retrieval rate with microTESE and 20-35% with TESE.

Men with a specific cause NOA will have a specific probability assigned to them.

Whether sperm are retrieved by TESE or microTESE, there are 2 options for how to handle them.

1. Fresh: Implant directly into an egg and freeze any remaining sperm.

2. Frozen: Freeze all the sperm and thaw for use at a future date.

Sperm generally freeze very well and can be frozen indefinitely. However, some sperm are always lost during the freeze thaw cycle. In cases where there are few sperm to start, which is very common in NOA, whatever sperm there are may not survive a freeze thaw cycle.

Use of fresh sperm has been advocated as desirable from a purely reproductive perspective since it maximizes the chance of success. However, there are some disadvantages.

In order to use fresh sperm:

1. Hyperstimulation and egg retrieval needs to be times to when the sperm are retrieved. This is logistically challenging because sperm retrieval usually requires microTESE. MicroTESE requires operating resource (the surgeon, anesthesia, an OR room with nurse) and for the Andrology lab to process the specimen over the course of 24-48 hours.

2. This commits a couple to the combined expense of microTESE plus IVF.

3. Donor sperm should be decided upon beforehand.

The use of frozen sperm may be more desirable in some cases.

1. It removes the logistical challenges of coordinated sperm and egg retrieval.

2. It does not commit a couple to IVF. If no sperm are found (which happens in many cases) the couple will have avoided the costs of IVF and can proceed with the less expensive option of insemination with donor sperm.

3. If sperm are found, they may not freeze and thaw successfully. Evidence suggests that this occurs in fewer than 10% of couples who choose to freeze sperm.

Breaking down these numbers, what might the ‘differential advantage’ of using fresh sperm be? Assuming a 50% successful retrieval rate and a 50% probability of successful pregnancy with a combined, if 10% of sperm are non-viable thaw when an egg is ready for fertility, the marginal reduction in pregnancy would be 2.5% (0.5 x 0.5 x 0.1). In plain language, about 1 in 30 patients might end up with a worse outcome if the decided to pursue the frozen vs. fresh approach to sperm utilization. This estimate is highly dependent on the assumptions above - in couples where the chances of successful sperm retrieval or pregnancy (e.g. advanced female age) are lower, the 1 in 30 estimate is going to be overly optimistic and the added benefit of using fresh sperm likely to be much lower (approaching zero).

The best approach, fresh vs. frozen, remains an area of controversy. The best approach is likely to depend on the individual circumstances. The 2023 Canadian Urologic Association guidelines provide a “conditional recommendation” for freezing (i.e. cryopreserving) sperm retrieved surgically in patients with NOA. If one scrutinizes the recommendation, it essentially comes down to one of endorsing either a fresh or frozen approach.

In most cases, frozen sperm may be a reasonable compromise. Only a couple can decide what works best for them.

The question of donor backup only applies if concurrent sperm retrieval and egg retrieval is decided upon (i.e. fresh sperm are used).

This comes down to what will you do with the egg if no sperm are present? While an unfertilized egg can be frozen, eggs do not freeze as well as sperm so one should consider their options well in advance.

While the hope is that sperm will be found, there is never a guarantee and in most cases the chances of NOT finding sperm will be higher than the chances of finding sperm.

The fertility centre looking after you can assist with this. Your urologist only needs to know your decision.