Professor Richard Sharpe, University of Edinburgh
Hormonal activity starts early on in the womb, leading male and female foetuses down very different paths of development. But as with any developmental process, things can go wrong, and male reproductive disorders seem to be on the rise - but what could be causing this? Richard Sharpe runs a research group at the University of Edinburgh in the MRC Centre for Reproductive Health, and has been investigating potential causes for these issues. He started by telling Georgia Mills the roles of hormones in development...
Richard - Ultimately, whether you've got a Y chromosome or not determines whether you become a male. But it won't actually happen unless you make the hormone testosterone or which we call an androgen, so the male sex hormones and that has to be made very early in pregnancy by the male foetus. Itís that hormone that actually transforms you into a male. Otherwise, the setup programme is for the foetus to develop as a female. So, we would all become females if it wasnít for the intervention of the male sex hormone in males.
Georgia - Do we know how these androgens; these male sex hormones, work?
Richard - They work through a sort of a lock and key system. So, they work through what's called the androgen receptor. Thatís a key step in the process. So, you have to produce the hormone, it has to interact with the receptor to cause its biological effects. In this case, masculinisation and development of male reproductive organs. And there are rare cases where you have individuals who are genetic males, who have inactivated mutation in the androgen receptor. So that although they make the hormone, they can't actually respond to it and they develop as phenotypic females.
Georgia - So, the receptors can go wrong and not receive this hormone, but what happens if the hormones arenít released in the correct amounts?
Richard - The current thinking is that this is where most of the common male reproductive disorders originate. So, to give you examples of disorders, one that is one of the most common disorders thatís seen in babies at birth is the failure of the testes to have descended into the scrotum. If we then move through to young adulthood, what's even more common is to have a sperm count so low that it can potentially impair your fertility. Another disorder that originates from foetal life that we see in adulthood is testicular cancer which has been increasing progressively in young men over the past 60 or 70 years. Thatís the commonest cancer of young men.
Georgia - You've said these disorders are quite common. What kind of numbers are we talking about here?
Richard - The figure I often use if I'm talking to an audience is to say something like 1 in 5 or 1 in 6 of the guys in the room will have or will have had one or more of these disorders which I think is quite a discomforting statistic. They shouldnít really occur. They're far more frequent than we think ought to be the case.
Georgia - Why do we think these are so frequent?
Richard - I think the simple answer is that we donít know. But there's certainly growing evidence that itís something in our environment.
Georgia - I know this is something youíve been looking at quite a lot. Do you have any candidates that you think may be quite responsible?
Richard - Yeah, we do have one candidate and it really came very much as a surprise. Itís the painkiller paracetamol that is very widely used. We know from studies in the UK and US that something like 50 to over 60 per cent of pregnant women use paracetamol during pregnancy. There have been 4 studies which have found an association between using paracetamol during pregnancy and an increased risk of testicular nondescent in boys that the women then give birth to. Because the role of androgens in testicular descent is so well established then what this suggested to us was that maybe paracetamol was affecting testosterone production. And itís one thing to have that idea it's another to try and test it or prove it because we have no way of actually measuring testosterone production by the foetal human testes. Remember itís inside the motherís womb and the testes are inside the foetus. So, what you need in this situation is a bit of ingenuity. And so, I had a PhD student, Rod Mitchel whoís a paediatrician who developed an ingenious system to actually try and assess whether paracetamol had effects and involves taking foetal human testes tissue which then gets what we call xenografted into mice. So, that means that you can actually use them as a sort of a test bed for asking if we give the mice a particular drug or chemical. Does this actually affect testosterone production? What heís found is that if you expose them to human therapeutic doses of paracetamol then if you do that for one week then you'd cause quite pronounced suppression of testosterone production. Whereas if you expose them for one day, you donít get any suppression. So, on the basis of that basis of work, then the recommendation is that as current guideline suggests that pregnant women should use paracetamol for the minimum amount of time possible.
Georgia - I find that really surprising because paracetamol is sort of over-the-counter, everyone is using it all the time that it could have such a pronounced effect. Are there any other things that youíve got your eye on that you might test in the future?
Richard - The one thing that we know affects our health perhaps more than any other thing is our diet. There have been huge changes in our diet over the past 50 or so years. So, I would put motherís diet very much on the top of a sort of a suspect list that something about our changing diet could be a factor that could affect testosterone production by the foetal testes, but thatís speculation.