During this event, Professor Sheryl Homa, PhD, ARCS FIBMS, Scientific Director of Andrology Solutions explained the fundamentals of semen analysis and other necessary tests as well as the role of a healthy diet and supplements in male fertility.
Professor Homa explained that male infertility is a condition that affects approximately 1 in 12 men in the general population. Of all couples experiencing infertility, male infertility is the sole cause in approximately 20% of cases, while in another 25% or so of cases, there is both a male and a female factor, hence male infertility contributes to almost 50% of all cases of infertility. It is rarely given 50% of the time to investigate, diagnose and manage the condition compared with its female counterpart.
As with female infertility, male infertility is a condition, and as with all conditions we need to understand the underlying causes before any diagnosis can or any discussion or decisions can be made determining the treatment and management of this condition.
Men infertility is clearly not understood, there is much in the media to suggest that male infertility is all about lifestyle and diet. Some in the medical community suggest that there is no point in investigating male infertility as there’s nothing you can do about it, while others claim that all you can do for men’s infertility is to provide a healthy diet and supplements. Indeed most men with infertility are immediately referred for ICSI treatment without any further investigation, however, most people are unaware that male infertility is usually due to a medical condition, and in many cases, the condition can be diagnosed, and in some cases, it can be successfully treated.
Contrary to the belief that male infertility is only about lifestyle, many clinical factors can cause it. The leading known cause of male infertility is a varicocele, both primary and secondary infertility. This is followed by hormone imbalance or infections of the male accessory glands of the genital urinary tract, and other conditions that might be associated with infertility include obesity, high cholesterol and dysfunctional lipids, high blood pressure, diabetes as well as psychological stress and anxiety.
Usually, the first test to assess men’s infertility is a semen analysis. The semen analysis gives us some very important information about sperm, but it doesn’t explain the cause of the condition. It rather tells us what some effects of the condition are, so to understand what’s causing the problem of male infertility, men just like women must have a comprehensive assessment with a thorough set of investigations. Without this, men may not get a proper diagnosis of their issue, and certainly, they won’t be able to be treated appropriately. According to the European Association of Urology guidelines, a comprehensive andrological workup is always recommended for every infertile couple, irrespective of the semen parameters.
First, it’s very significant to look at the complete clinical history of the man. We need to know his fertility history, whether he has fathered any children in the past, and the period he has been trying to conceive with his current partner. We also need to check if there is any history of testicular cancers or if there are any issues that could relate to infertility in his family. We need to take a general medical history, what is his current health like, does he have high blood pressure, obesity, diabetes, etc., we need to see what other tests he’s had done, if he had any semen analysis, if he had any other investigations, we also need to take a full history of his reproductive health. We need to ask about any urological symptoms, infections, any surgery or injury to the lower abdomen or testes, exposure to toxins, lifestyle, and diet.
Once a clinical history has been checked, it’s also important to consider a physical exam. The physical exam will ensure:
An ultrasound scan, just like for women, is also very significant. There are certain things that you can’t determine just from a physical exam, it can help to measure any abnormalities in the testicular structure to detect possible tumours, confirm varicocele and look for signs of obstruction.
Semen analysis always needs to be included, and from a semen analysis, we can look at the volume of the sample, which is determined by the function of the male accessory gland, any loss in volume will indicate a problem with the main accessory glands, sperm numbers will tell us whether the testes are functioning normally, the motility could tell us whether there’s something toxic in the environment so that the sperm might start to die. Morphology is also something that people worry about, it is a significant parameter, but the reference value for this is 4% of normal forms, which means that a fertile man may have as many as 96% of his sperm that have an abnormal shape and a lot of people get very upset about it, but it’s quite usual to have people with only 4 or 5% of normal forms, it doesn’t seem to affect your fertility.
Is sperm morphology a good predictor of fertility? It’s not always a very good predictor of infertility, while some studies show that poor morphology is related to a lower pregnancy rate with IVF and ICSI, other studies have shown that abnormal morphology is not necessarily associated with a significant decrease in pregnancy rate with IVF and it’s crucial to understand what type of defect it is. There’s bad sperm, and there’s super bad sperm, but we also know that it is possible to conceive naturally with 100% abnormally shaped sperm.
We tend to ignore the rest of the parameters of a comprehensive semen analysis, but don’t forget a semen analysis is about the semen, and the semen contains them, but most of it is fluid, and the fluid comes from the male accessory glands. There are a lot of other details on the report that is going to give you information about how your male accessory glands are functioning. Your prostate, your seminal vesicles, how healthy are they if they’re unhealthy, this is going to affect your fertility. We need to look at things like the appearance of the sample, which can indicate a pathology, but we can also look at things like pH, volume, viscosity and white cells that might indicate male accessory gland infection. Volume, pH, and count might indicate an obstruction. If there are antibodies, it can indicate immunological infertility, and if we have a very low volume and the count is impacted, it might even indicate a retrograde ejaculation where people don’t ejaculate out of the penis, they ejaculate up and back into the bladder, so that means either you end up with no ejaculate or you have a very small ejaculate because most of it has gone back into the bladder.
On the other hand, if we’re diagnosed with a normal semen analysis, does that mean you are fertile? Unfortunately, a normal semen analysis does not necessarily mean that you are fertile because 25 to 30% of cases of men’s infertility remain unexplained, which means you’ve got normal sperm, but nothing’s happening.
How predictive is semen analysis? There have been a lot of studies looking at this, and a lot of the studies show that the prediction of men’s infertility by the World Health Organization (WHO) guidelines is not a very good predictor of infertility. What does the semen analysis tell us, and what are its limitations of it? We know that semen analysis tells us about fertility potential, but it doesn’t tell us 100% what it is. It gives us an indication that if your semen parameters are normal you are more likely to be fertile, but we can’t guarantee it, and likewise, if they’re not normal, you’re more likely to be infertile, but we can’t guarantee it. It can also tell us about testicular function, whether we’re making enough sperm, whether the reproductive tract is open, and there are no obstructions, an indication of accessory gland infection and a possible indication of pathology, but what it doesn’t tell us is whether the sperm when they get to the egg can bind to it, whether they’re able to fertilize the egg when they get into it, whether they’re able to generate the signals that are required to generate a healthy embryo and whether the DNA, the genetic material inside the sperm, is healthy. If you’ve got unhealthy genetic material that you’re putting into the egg, irrespective of how many sperm there are and how well they’re swimming, the embryo is not going to be healthy. You will not get implantation, or if you do, you increase the risk of miscarriage.
DNA damage or DNA fragmentation is crucial for affecting fertility, and DNA fragmentation levels are much more highly correlated with infertility than any of the individual semen parameters that you see on a semen analysis. Furthermore, we now know that the underlying factor that is most likely responsible for DNA damage is an increase in oxidative stress in the reproductive tract. Oxidative stress means an overproduction of oxidants. Oxidative stress and sperm DNA damage have been shown in many papers to be:
Fortunately, there are tests available for oxidative stress and to measure sperm DNA fragmentation. There are lots of different tests out there that you can use to identify oxidative damage and DNA damage, but the problem is that a lot of fertility clinics are reluctant to offer these tests.
In the UK, UKAS (The UK Accreditation Body) has accredited an oxidative stress test and sperm DNA fragmentation testing, furthermore, in the U.S, the Clinical Laboratory Improvement Amendments (CLIA), which is the UKAS equivalent, has also validated these tests. You could perhaps argue that each of these tests gives different results, and they do, DNA damage is not simple. The DNA is a double-stranded molecule, it can be damaged at any point, you can damage the inside bits, the outside bits, the single strands, the double strands and all of these tests that measure different things can give you different results, it doesn’t invalidate the test, it shows you that there is some damage somewhere.
Some also say that there’s insufficient evidence to show they affect fertility, since DNA damage has been discussed for almost 50 years, there are a plethora of papers out there in both the human and animal world studying this, and both The European Association of Urology and The European Society for Human Reproduction and Embryology have now acknowledged that there is sufficient evidence to use these tests, especially for patients with recurrent miscarriages. There is some evidence to show that it’s important for unexplained infertility as well.
What can be done to treat oxidative stress and DNA fragmentation? Mostly it can be treated, but it does depend on the cause of the problem. Firstly, we know that you have a lot of antioxidants if you eat a good healthy diet in your system. We know that antioxidants are very prevalent in fresh fruit and vegetables, and if you eat a lot of those, hopefully, you’ll have a lot of antioxidants in your system to mop up the oxidants. However, if you don’t, you can take supplements which are antioxidants, so the supplements, the scavenging molecules, all the vitamins and the minerals and all these things that you always took and never knew how they were working, work by reducing oxidative stress. The problem is they don’t always work, they only work if you have oxidative stress, but if the oxidative stress is caused by some condition that’s churning out huge amounts of oxidants, maybe the antioxidants that you take with your supplements are not sufficient, so it does behold us all to investigate the causes of the oxidative stress and the DNA damage.
There are many causes of oxidative stress and DNA damage, once we understand that, we can make suggestions on how we can treat it. Firstly, let’s look at the patient there’s a lot of evidence out there to show that as men get older, especially when they get into their 40s, DNA fragmentation levels start to increase. We also know that if men don’t ejaculate regularly, the semen samples that they produce have a higher level of DNA damage, and heat exposure, including high fever like COVID, for example, will cause DNA damage temporarily in the sperm and that is also a problem from a clinical point of view, any testicular trauma, varicoceles, infections are all associated with oxidative stress and DNA damage. From a lifestyle point of view, we’re looking at obesity, poor diet, smoking, recreational drugs or prescribed medication, any environmental toxins such as ionizing radiation any endocrine disruptors or pollution in the environment will cause this. How can we treat it?
We can’t do anything about men’s age, but we can encourage them to ejaculate frequently, you mustn’t store up sperm and only have sex at the time of ovulation because your sperm will be damaged. You need to ejaculate regularly every 3 to 4 days, you need to keep your testes cool. From a clinical point of view, if there are infections, we need to treat those infections, if there’s a varicocele, we need to repair it. In terms of lifestyle, we need to reduce toxin exposure and improve our diets, and if all else fails, there are now advanced techniques which are offered in some IVF units where it is possible to physically select sperm with lower DNA fragmentation, and this would be PICSI or Zymot.
If all else fails, we do know that there is evidence to show that the testicular environment is more protected than the sperm that comes through the epididymis or out into the ejaculate, if you have very high DNA fragmentation levels in the semen, it might be worthwhile having a chat with your urologist to talk about retrieving sperm from the testes. It has been shown to have lower DNA damage.
Are there any other tests for unexplained infertility? We do know that there’s now significant evidence that the microbiome may play a role, and we can do some genitourinary tract infection screens for this. What is the microbiome?
Are there any specific tests for people with very low sperm counts or no sperm? We need to check their health, and hormone profile, and we need to do some genetic screening because it may be a genetic cause.
Once you’ve had all these investigations, how can your fertility be improved? For some of the other causes of infertility, we might want to look at the role of lifestyle because we must address this. Most people are living sort of average lifestyle, so the lifestyle is important, but it’s very rarely going to be the most important contributing factor unless we do things to excess.
Generally, there are treatment options for men, and I think it’s very important that we investigate and deal with these things appropriately so that people can then improve their chances of a natural pregnancy or even improve their chances with IVF. Men infertility is a condition caused by many different clinical factors which may be exacerbated by diet and lifestyle, it must be properly investigated so that men can be treated appropriately, and IVF treatment should only be offered as a last resort if the management of the condition fails to result in a natural pregnancy.
I think that the diet is very important for your infertility, but it’s rarely the major factor unless, as I said, you’re obese or if you are severely underweight or you’re on restricted diets that you’re not getting all the vitamins and minerals and nutrients that you need. Supplements are a difficult one, but I’m a fan of supplements if they’re taken properly. It’s like I’m a fan of antibiotics because I know that they treat bacterial infections, but if you don’t have a bacterial infection, and you’re not well taking antibiotics isn’t going to help you, and it’s the same thing with supplements. You need to do an oxidative stress test because supplements are antioxidants. If you don’t have oxidative stress, and you take supplements, you can put yourself into reductive stress, and that has a similar effect to oxidative stress, so they can be quite dangerous if you take them and you don’t need them. You must do an oxidative stress test before you take the supplements. There are situations where people are struggling with motility, for example, or the sperm quality is really poor, don’t overdose on it either you’ll put yourself into serious damage, just one recommended supplement is enough.
If it’s done properly and it’s a clinical varicocele, there are different grades of varicocele. Subclinical varicocele might not be determined simply by a physical exam, but if you’ve got a doctor who knows what they’re doing, they can pretty much identify a varicocele. Even then, my consultant urologists, who specialize in men’s infertility and do these exams all the time, will still get it confirmed with an ultrasound scan.
MicroTESE is the surgical retrieval of choice for people with azoospermia, with no sperm in the ejaculate. There have been all sorts of reviews coming out on it, and that is the best way to obtain sperm from a patient with azoospermia and obstructive azoospermia. The only other time that you might want to consider microTESE is if you’ve got very high DNA fragmentation levels in an ejaculated sperm where you’ve done all the investigations, and you can’t find any particular cause, you’ve taken all the antioxidants, and it hasn’t reduced the DNA damage. As a last resort, I would recommend MicroTESE sperm retrieved to use instead of ejaculated sperm with ICSI treatment.
It’s not a belief, it’s a fact. Oxidative stress probably does increase during centrifugation, the question is does it increase to a level that it’s going to damage the sperm? When we’re preparing sperm for IVF or IUI there are different ways of preparing them, one is centrifugation, and one is swimming up. With a swim-up, you’ve got the problem that you’ve got potential debris in the semen that the sperm are exposed to for too long while they’re swimming up, so in the centrifuge, you might trigger oxidative stress production and free radical production. What I recommend is that you use as minimal centrifugation as you can. The minimal steps and that you reduce the speed to the absolute minimum and that you use the sperm as soon as you’ve prepped it. Once you leave it in the absence of semen without the antioxidants in the semen, that also causes issues, so you need to prep the sperm and use it for IVF and IUI immediately.
I think a lot of clinics are providing them. The clinic that I’m consultant lead for is not a fertility clinic, it’s a diagnostic clinic, unfortunately, it’s a private clinic, so you have to pay for the test, but at that clinic which is the Doctor’s laboratory, they offer both the MIOXSYS test and also the chemiluminescence test for reactive oxygen species. Both of those tests have been validated, and they’re both UKAS accredited.
It’s very difficult to know about azoospermia and the role of inhibin because there have been studies looking at levels of inhibin, levels of FSH, all these sorts of hormone markers for spermatogenesis, and actually when you come to do surgical sperm retrieval, there aren’t very good indicators at the end of the day whether we would find sperm, so I think it’s very important we need to be measuring these factors again they’re indicators, but at the end of the day, they can never really tell us for sure about whether that there is certainly cell only or whether there is some spermatogenic arrest or what the situation is.