Published 26 February 2019
Jackson Kirkman-Brown, Science Lead at Birmingham Women’s Fertility Centre, UK, and Co-ordinator of ESHRE's SIG Andrology, talks to Focus on Reproduction about the limitations of semen assessment, the broad perspective of 'andrology' and the future directions of research in male fertility.
FoR: The man with fertility problems is not an insignificant factor in reproductive medicine. Yet there's been comment recently that andrology has become the forgotten discipline of reproduction, the Cinderella of infertility. Do you have a view?
JKB: I think it possibly has. We've been through a long period of neglect, a long period in which the demand for sperm is simply to be there in large number. So for a long time people have been obsessed with sperm counts, yet there are many studies showing that we can't even count sperm accurately. So people are preoccupied about these very basic markers because they're being done wrong, which has caused them to take their eye off the ball in terms of having a healthy baby. There's has been a lot of noise about this, which has led many to believe that andrology is only about sperm counts and doing it correctly. But actually sperm count is only a very small part of the discipline. It should have a far wider view of thinking about reproduction from a male perspective.
FoR: So you think there should be a shift in direction away from sperm counting?
JKB: I think we're at a point where the data which gives us a direction is only now beginning to emerge. But what is clear is that sperm count is only a relatively poor index of fertility. You can get equally accurate prediction from testicular volume, so we need a next generation of testing to tell us whether sperm can perform the function it ought to do, whether it can rise to challenge of achieving natural or assisted fertilisation, or whether it has the genetic quality to conceive a healthy child. Even beyond egg activation and fertilisation in ICSI, we now know that sperm-related problems can be a cause of miscarriage. We've just seen the HABSelect study published in The Lancet and one of the findings in that trial was that selecting sperm by a different method for ICSI cut the miscarriage rate by a third in older women. Until now, we would usually assume that a high miscarriage rate was simply because of poor egg quality. But actually, we now see that if you pick the sperm differently there are a third fewer miscarriages - and it's obviously sperm related. So it's changing the paradigm slightly.
FoR: To me, all this raises two very basic questions. First, what difference does sperm count make if you only need one sperm cell for ICSI. And two, whatever test you use you are only testing the sample, and not the single cell.
JKM: Well, yes and no. Some of the sperm technologies coming through do select individual cells based on certain properties. The HABselect process just described in the Lancet trial is one that picks single cells. These would be the cells used for the injection. Secondly, there are technologies which look at how individual cells swim, and these also show some promise in selecting sperm which are genetically able to generate a healthy birth rather than just being there and looking normal. So it's becoming a scenario of using an obstacle course as a diagnostic test for sperm selection.
FoR: But DNA fragmentation tests, for example, are only working on semen samples, not on individual cells?
JKB: Yes, that's true, but unfortunately a lot of them still really lack strong evidence. They all test different things, but everyone tries to relate their data back to one thing. So what we really need is co-ordinated testing, proper trial based evidence on whether they work or not in a clinically relevant way. There are some good studies and some promising data, especially related to miscarriage. But we still need to know what these studies are telling us.
FoR: So let's try and summarise this. Where do you think fruitful beneficial research should go, given that andrology has concentrated too much on sperm count.
JKB: It's got to be research that looks at more predictive early tests that relate to outcome - clinical pregnancy, miscarriage - and that must go hand in hand with evidence for the actions you then take in either sperm selection or lifestyle change.
FoR: So let's pick up that last point. Based on the many small studies that we have, do you really believe that any of our lifestyle interventions - weight loss, diet, antioxidant supplements - actually make any difference to sperm parameters?
JKB: Most of the trials are badly formulated. Many are in men with below-average semen samples, and hope to turn them to normal within the WHO range. As I said, sperm count isn't the be-all and end-all. So studying if a supplement can push a sperm count up from 24 million to 32 million will only generate a low-bar of evidence, and secondly, what's the relevance of that to their true fertility.
FoR: Exactly. These studies assume a direct link between sperm count and fertility.
JKB: Yes, but it's not just sperm count. It's the same with studies looking at more motile sperm. So the endpoint for all these studies must be a healthy birth. A small study whose endpoint is a few more motile sperm is still poor quality evidence, especially when the results might mean delaying childbirth or spending a lot on supplements.
FoR: So what evidence do we have so far for any lifestyle or diet intervention?
JKB: There's probably some evidence about body weight and a generally balanced diet. But beyond that, I think the evidence is limited. We desperately need trials looking at parameters that matter.
FoR: So what you're saying is that studies with sperm concentration as their endpoint don't really matter?
JKB: Yes, even beyond morphology and motility we still need to look at the live birth question. So, if we randomise men into a trial, will we actually change the healthy live birth rate? If we don't ask that question, we'll never know the answer.
FoR: And the evidence is still weak for antioxidants?
JKB: I think so. Initially, I think it's reasonable to look at those markers which they're theoretically affecting. So a good randomised trial on sperm DNA damage . . . but even then you've got to believe that sperm DNA damage matters. All these trials need a good hard endpoint that matters. So it maybe that the relevant endpoint is a reduction in the rate of miscarriage.
FoR: So let's move on the next item of andrology mythology. Do you think that sperm counts generally are falling over time?
JKB: There has been data in the last few years to suggest there is a trend of falling sperm counts. It's not clear that this is a universal problem, rather in different populations at different rates - but it does seem evident in a Western European population.
FoR: Dramatically? The canary in the coalmine?
JKB: It depends what you consider dramatic. Of course, what these studies are showing is an average decrease, so maybe there's a group of men where there's an exaggerated effect. But personally, I don't believe it's a threat to the continued existence of the human race, but I do think it's probable there will be an increase in the number of male factor problems.
FoR: And what about the causes? Environmental pollutants, lifestyle…
JKB: I'm a great believer in Richard Sharpe's data from Edinburgh on fetal programming. It's a susceptibility that the male fetus takes on during the early stages of life, which depends upon the mother. So I don't think it's detrimental to your sperm count to wrap your sandwich in cling-film. Many of the stories we read in the press relate to what many men would presume they'd done wrong in life. But really, if there is something going wrong, it was probably happening while he was a fetus inside his mother. That's when these outcomes were set in motion. I think that's the view which makes most sense. But there are still things which men do which can shift the direction. In gym culture, for example, many men are taking large amounts of protein, which may have marked effects on their fertility. There's no strong data but when our patients stop using protein shakes their sperm counts improve. I think it will be the same in most clinics in Europe. There's a real trend for appearance and beauty in men, and it's difficult for some men to stop these supplements. I've had some patients who preferred donor sperm to stopping their steroid use.
FoR: You have a SIG Campus course coming up on the 'basics' of andrology. Will you be covering these kind of points - looking ahead rather than just reviewing?
JKB: Well, the idea behind it is to bring to the fore the things we're talking about here. So we start from the basics, to ask what happens in terms of male diagnostics, what's the correct pathway to follow from that first diagnosis, right through to treatment. So it's the broad picture of male factor infertility, starting with problems of fetal origin. So we'll be looking at approaches in diagnostics, rather than focussing just on sperm counts. A refocus on the health of the man, not just to find the right sperm but to consider the long-term implications. We'll also be looking at new findings related to human papilloma virus in semen samples used for IUI. It seems that if a man has active HPV infection IUI won't work - but HPV is something we'd rarely test for. So it's a review of most of things we'd usually neglect. It's a look at evidence around the edges - almost everything except sperm count.
FoR: And ESHRE itself? Do you think they do everything they might do for men in reproductive medicine?
JKB: It's always been a challenge, and there's still a long way to go - for ESHRE as much as anyone else - in terms of putting male reproductive health at the core of the agenda. So it is a challenge for ESHRE, but also for andrologists. We need high quality research in order to motivate a group like ESHRE. So it's a two-edged sword.
FoR: But isn't all this really a consequence of ICSI? Of course, the studies need to be done, but we still have a treatment which can routinely deal with most male factor cases. What purpose will more diagnostic precision serve?
JKB: Yes, you can say that about ICSI - you can also say it about IVF itself. IVF got round most other problems. But the challenge now is that many of these technologies have probably run their course. There will be new frontiers, and so far, where we haven't had much progress, is in tuning up the male. If you can pick a better sperm, there's a good chance you'll end up with a better embryo. There's been so much neglect of that, so even if you are doing ICSI there is still an opportunity for real advances to be made.
ANNUAL MEETING 2018 KEYNOTE LECTURE
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