Non-obstructive azoospermia – the hardest problem to treat in the infertile man today
September 12, 2023

One of the most frustrating problems in reproductive medicine today is that of non-obstructive azoospermia. Now this sounds like quite a mouthful, but all it means is that this is a man who has a zero sperm count ( the medical word for which is azoospermia), and the reason for the zero sperm count is that his testis is not producing sperm properly.

Now it's easy to treat men with obstructive azoospermia where the testis are producing sperms, but the passage is blocked. Here we can retrieve the sperm either from the testes or the epididymis, in a procedure called a TESE ( when we use testicular sperm) or PESA ( when we use epididymal sperm), and use these sperm for doing ICSI in order to fertilize the eggs in the laboratory. The good news is that the fertilization rate with these sperms is as good as it is with ejaculated sperms, and success rates are high.

However, the problem arises when it's the testes that are not producing sperm properly. This can be extremely frustrating, especially because it's often not possible to make this diagnosis beforehand, because most of these men look absolutely normal, and many have a normal clinical examination – normal testicular size, and normal male hormonal levels. This is why this diagnosis often comes as a blow - to their ego and self-esteem because they are shooting blanks and can’t get their wife pregnant!

This diagnosis is often a rude shock to the doctor as well because there is no way of predicting whether a man is producing sperm properly in the testis or not because blood tests will not usually answer this question with any degree of certainty. This is because there are two different compartments in the testis: one which produces the male hormone called testosterone, and in a lot of men with testicular failure, this is completely normal, because this compartment is quite hardy, as a result of which not only do these men have normal testosterone levels, normal facial hair growth, and their libido and sexual performance is fine. However, the other compartment which produces sperm - the seminiferous tubules where spermatogenesis occurs - is damaged in these men, because it is more fragile. This means that even though the testosterone levels are normal, the testes are not capable of producing sperm, and this is called testicular failure. We usually cannot determine the reason for the testicular failure, and this causes even more frustration for these men.

We can suspect this diagnosis, especially in men with a small testis, and a high FSH level, but we can't be completely sure, because some men have what is called partial testicular failure. For some men with complete testicular failure, we can make a diagnosis non-invasively, by doing tests such as checking for microdeletion on the Y chromosome, or a karyotype to check for Klinefelter syndrome ( 47, XXY) , but these are rare. For most men with testicular failure, or non-obstructive azoospermia, we can't be sure whether it is partial or complete, and the only definitive way to make the right diagnosis is by doing a testicular biopsy. Now, seems to be a relatively simple minor procedure, but it's actually quite complex. For one, many doctors don't do it properly, and instead of doing a proper testicular biopsy, they do what is called a testicular sperm aspiration, and just send the aspiration for cytological examination in the laboratory. But this is not reliable, because it’s riddled with the problem of false negatives. Men with partial testicular failure will have occasional areas of sperm production, but the sperm aspiration procedure will not pick this up. The proper procedure is an open testicular micro biopsy, and multiple samples need to be taken from both testes to make the right diagnosis. This is because in men with partial testicular failure, some areas produce sperms, and others don't, which is why just one single biopsy is not representative of the whole. But even that doesn't solve the problem, because the way the testicular tissue is handled after the biopsy is extremely important, and unfortunately, it's not treated with the respect it needs to be. For example, this biopsy sample cannot be sent in the regular preservative fluid called formalin to the pathology laboratory, because this distorts the architecture of the testicular tissue, and the pathologist cannot make the right diagnosis. It needs to be sent in a special fluid called Bouin’s fluid, but not many andrologists, urologists, or IVF clinics have this particular preservative. This makes it extremely hard for the pathologist to interpret the biopsy slide, and many aren’t able to do this properly.

Non-obstructive azoospermia is a complex problem, and you need to find a specialist who will treat it with the care it deserves because it's not something that should be handled with a run-of-the-mill, checklist approach, because you may be one of the men with partial testicular failure, where there is occasional sperm production in the testis, and you will be able to have a baby with your own sperm using the technique of TESA-ICSI. Sadly, many IVF clinics aren't expert enough to be able to offer this option to all their patients.

Authored by : Dr Aniruddha Malpani, MD and reviewed by Dr Anjali Malpani.