The Global Andrology Forum First In-Person Conference, May 2025 in Turkey;

An update on Non Obstructive Azoospermia

What is the Global Andrology Forum?

Well, it is certainly global, with 800 members representing nearly every country and many university departments worldwide.  It is all about andrology and encompasses male fertility and all aspects of male sexual function.  About half of its activity is about fertility, and this impacts on male health and sexual wellbeing, but perhaps more importantly it is a forum, not a ‘society’.  This is a subtle but important difference.  Societies inevitably have a hierarchy, a structure and membership fees, and this introduces an element of commercialism and, however inclusive the society tries to be, it will of necessity seek sponsorship and then there is an element of bias, which tends to stifle true freedom of speech and expression.  A society has rules and gradually therefore becomes exclusive.

A forum can more easily explore ideas and innovations without constraint, and this is what happened last week in Turkey.

Our founder, Ashok Agarwal, who has done so much to link male fertility to all the lifestyle factors which we now accept as vital to fertility and male health, created a programme which asked the important questions in male fertility, and clinicians and scientists, all experts in their field, could debate the answers.

So what did I learn?

All the take-home messages were useful.  Some merely emphasised what we thought we already knew!

Azoospermia and sperm retrieval

Not all sperm retrieval operations are the same and they are certainly not equally successful.  A proper micro-TESE operation requires good equipment, plenty of time (maybe more than two hours) and a very skilled on-site team of technicians and embryologists.

It is difficult to prove that sperm retrieval from the testicle, and fresh rather than frozen sperm, has a better outcome, but there is certainly a trend towards this approach, provided we can predict which cases are more likely to succeed.

And what about stem cells?

Using stem cells to treat azoospermia has not yet succeeded.  Early optimistic reports, now 10-years old, have not materialised yet into effective measurable outcomes.

Computer assistance and AI

When we moved from machine learning to complex neural networks, AI is beginning to ‘do better’ in identifying sperm in critical circumstances.

If the humans continue to feed information into the newest AI systems, we are beginning to get much faster and no less reliable results.  It is probably only a matter of time for artificial intelligence to overtake a man or woman with a microscope!  Machines do not get tired and may have fewer ‘bad days’.

Varicocele: the ‘old chestnut’

Varicoceles, which are present in at least 15% of normal fit men, are associated with subfertility because if a man is sub-fertile he will have a 40% chance of having a varicocele, but this simple fact does not mean that all men with varicoceles are sub-fertile or that varicoceles actually cause subfertility in all men.  However, there was absolute consensus that large (greater than 3 mm diameter) varicoceles with reflux of warm blood and abnormal semen analysis parameters, and reduced sperm DNA quality, require treatment – no longer is it, or should it be, the case that ICSI will ‘sort it out’.

What about the microbiome?

If the microbiome, or community of bacteria in the seminal fluid and male genital tract, had been mentioned as a contributor to male subfertility five years ago, I think that nobody would have listened, but now there is significant attention.

The gut microbiome is associated with many human inflammatory and even degenerative conditions.  So ‘biology’ would suggest a similar relationship to some of our most active cells, in this case those which constantly produce sperm.

Surely this is all about genetics?

It probably is, but we still only have relatively simple genetic tests.  There is the karyotype, which looks at all our chromosomes.  We all have 46 of these including an ‘X’ and a ‘Y’.  A man has an X and a Y, which broadly determines ‘maleness’, as a woman has two X’s.  The chromosomes are the hard disks which determine our development and minor rearrangements not resulting in illness or obvious conditions can occur and are associated with severe male infertility.  An extra chromosome, an X, occurs in Klinefelter’s syndrome and this suppresses the function of the Y chromosome, preventing the sperm-producing cells from developing properly.

But other more subtle rearrangements, or translocations, are also associated with male subfertility.

The Y-chromosome itself can be defective, with portions which define proper testicular development absent or deleted.  These abnormalities are well-known and well researched, although we did hear that perhaps we should be looking at that particular region of the Y-chromosome, known as the AZ region, more closely.

The new area of research, however, may be revealed by looking at the whole genome.  Millions of genes are attached to the chromosomes, providing digital instructions controlling the chemical performance of all the specialised cells in our bodies.  To define which of these genes or groups of genes may be faulty or absent in male infertility is theoretically possible using AI, and about a hundred of these genes are beginning to be explored.

The obvious difficulty is defining a suitable target group of infertile or sub-fertile men, and then providing sufficient funds to look at overwhelmingly large numbers who have no other obvious causes for severe male factor infertility.

This is certainly an area for active and important research, and I suspect that in a few years’ time we will be able to do a blood test which will tell us which genes or groups of genes are faulty, and then who knows how we might be able to proceed perhaps five years after that to correct the abnormalities that we have discovered.

So this is a very exciting area and represents, I think, the only real advance in that most elusive part of our practice, which is diagnosing and understanding why a man is sub-fertile.

Overall, this was a really enjoyable, interesting, and useful conference, and I look forward to working with the Global Andrology Forum and its many publications, and the new friends that I have met through this very unusual group of people.

What about the present?

I wish all of you who are reading this, and particularly those troubled by azoospermia, every good fortune in your journey, and I hope that some of you may already have had some success.

In my practice, we do have some new developments.

We are using a new test (cell-free DNA) to try to predict whether a sperm retrieval will succeed, and I am also using a new medical protocol to try to encourage sperm production before a micro-TESE.

Finally, there is a new operating microscope – much better magnification and a joy to use, and I hope that AI will also help us to identify sperm in those difficult cases, and particularly in cases where the first procedure might have failed.

All the best to all of you.