Human infertility – tragedy or godsend?
This essay was written by Paul Burgoyne and was first published in the 2002 Mill Hill Essays.
More years ago than I care to remember, whilst a PhD student in Edinburgh, I attended a Workers Educational Association lecture on ‘Human Population Growth’ given by Aubrey Manning; a compelling speaker, who you may be familiar with as the presenter of the TV science series ‘Earth Story’. I was completely overwhelmed by the stark equation he presented: finite resources plus exponentially increasing numbers of consumers equals ultimate disaster for mankind. My eldest son will attest to the lasting impact of this lecture. On coming bottom of a pocket-money league at primary school, I justified my tight-fisted attitude by explaining that I preferred to funnel as much money as I could to Population Concern; a charity with a holistic approach to the promotion of fertility control worldwide.
In recent years the media have carried reports that we may be moving towards a very different catastrophe – the number of men who are unable to father children is increasing and this has been linked in the press to reports of falling numbers of sperm in their semen. Sperm are the specialised cells that fertilise a woman’s egg and, leaving aside the spectre of human cloning, fertilisation is the first step on the road to parenthood. Although, in theory, a single healthy sperm is all that is needed to fertilise a mother’s egg and produce a child, a fertile man typically inseminates in excess of 250 million sperm during copulation with his partner. Such a large number are required because the journey through the womb to the egg is an extremely hazardous one. In practice, a man’s ability to father children begins to be compromised when the number of sperm he produces in his ejaculate falls below about 50 million. If the trend of decreasing sperm counts continues, the doom merchants ask, might this lead to the demise of the human species?
Given my opening salvo, I am sure you will appreciate that I have viewed the reports of decreasing human fertility as a godsend in global terms; the demise of humankind would undoubtedly be ‘welcomed’ by our fellow travellers on planet earth. The cause of the reported fall in human sperm counts is not clear, but the debate has largely revolved around the likely deleterious effects of various environmental pollutants. Others have pointed to overheating of our sperm “factories” (the testicles or testes) arising from the wearing of trousers and exacerbated by the further insulating effects of car seats; perhaps global warming also has an impact! However, in a recent report from the World Health Organisation, any link between environmental pollutants and declining sperm counts was considered to be tenuous at best; indeed the evidence for a global decline in sperm counts was itself considered to be shaky. So, it appears that our ability to continue to overrun the planet is not yet seriously jeopardised.
More by accident than design, my own research career has led me into a study of some of the genetic causes of male infertility. The remarkable process that leads to the production of sperm is called spermatogenesis. It begins with seemingly unremarkable spherical cells within the testes called spermatogonia that throughout a man’s life divide to generate a continuous stream of cells destined to form sperm. The sperm themselves are highly specialised tadpole-shaped cells that need to be Olympic swimmers in order to reach and penetrate the egg. Each of a man’s spermatogonia has two sets of genes; one set originates from his mother and the second set from his father. These genes are distributed in rows along 23 pairs of structures called chromosomes. Among these 23 pairs is a special pair of chromosomes called the sex chromosomes, which are unusual in that they differ markedly in size, the larger ‘X’ chromosome originating from the mother and the smaller ‘Y’ chromosome originating from the father. The Y chromosome carries one gene that triggers male development and many will remember the media frenzy in 1991 when this gene was isolated by scientists here at Mill Hill and was added to a genetically female (XX) mouse which then developed as a male nicknamed Randy. During sperm production one member of each pair of chromosomes is allocated to each sperm cell. Thus, the sperm that normal men produce have 23 chromosomes each, with one of these being either an X or a Y, and the remaining 22 chromosomes originating either from the man’s mother or father. Since egg cells contain only X chromosomes, if an X sperm fertilises the egg you get a daughter (XX) and if a Y sperm fertilises an X egg you get a son (XY).
As a child on a dairy farm I witnessed the slaughter of a beautiful but economically worthless Jersey bull calf. This may have influenced the choice of my first job which was in a laboratory trying to separate sperm carrying an X chromosome from those carrying a Y chromosome; success in this endeavour would have enabled farmers to choose the sex of calves by using X- or Y-bearing sperm for insemination. I soon became disillusioned with these attempts and decided a more productive approach might be to produce an XX male; such a male would only produce sperm that carried an X chromosome. However, from a reading of the scientific literature available at the time it was evident that this approach would also be doomed to failure, because spermatogonia with two X chromosomes do not survive beyond early spermatogenesis. In normal males which are XY only one X chromosome is present, and for reasons we still don’t understand, having two doses of all the genes on the X chromosome is something that spermatogonia can’t cope with. This is the underlying cause of the infertility of men with Klinefelter’s syndrome, who have three rather than two sex chromosomes, two Xs and one Y. Likewise, the sex-reversed XX mouse Randy was also unable to father any young. Aside from the problem of having two X chromosomes, we now know that spermatogonia also need some genes provided by the Y chromosome. This conclusion was initially drawn from a study of men with Y chromosomes that could be seen to be missing a piece when viewed through a microscope. Subsequent studies of mice and men have in recent years begun to identify some of the Y genes involved. In the mouse one Y gene has been identified that is essential for the production of sperm although the reason for this is quite mysterious. There is however a gene with an apparently identical function on the X chromosome, that is known to provide a key component of the cell’s machinery for manufacturing proteins, the molecules that perform most functions essential for a cell’s survival. While all other cells in the body are happy with just the version of this gene on the X chromosome, perplexingly, spermatogonia require the seemingly identical gene of the Y chromosome as well. Other genes on the Y in mice and men are important in ensuring that sperm are produced in sufficient numbers and are of sufficient quality. It is now possible to screen infertile men to see if they are lacking functional copies of these genes. This can point to which treatment would be appropriate.
A clue to another cause of male infertility has come from studies of mice with an extra Y chromosome. Although these mice produce a few sperm, most of the developing sperm cells die midway through the process, and research has suggested that this a manifestation of a ‘quality control’ process. The process of sperm production, spermatogenesis, is somewhat like an industrial assembly line, with a number of complex processes that have to take place in a timely and orderly fashion. Among these is the re-shuffling of the genes originating from mum and dad and the subsequent sorting of the chromosomes such that each sperm ends up with one of each pair of chromosomes. As with an assembly line, checks are made at crucial points to make sure that everything is proceeding properly, and on the spermatogenesis assembly line, cells that have got it wrong commit suicide! One of the checks is to make sure that all the chromosomes meet up as matched pairs and reshuffle their genes. In XYY mice, it is a case of two’s company while three is a crowd: cells with a sex chromosome without a partner are rejected and ‘opt’ for oblivion. The few sperm that are produced come from rare cells in which the three chromosomes get together as a cosy threesome, but the sperm counts are so low that these XYY mice are almost invariably infertile. However, some years ago we decided to test whether XYY male mice could occasionally father young, and had given a number of such males a series of wives over several months without any ensuing offspring. We then left the lucky males with two young wives for company until the males had reached old age (over one year) when to our great surprise a litter of baby mice appeared in one cage and subsequently in several others. This proved to be because some of the spermatogonia had accidentally lost one of the Y chromosomes, thus reverting to XY, and these cells then gradually expanded in numbers until sufficient sperm were produced to allow fertility. This is in fact what frequently happens in XYY men – many are fertile, but their sperm derive from XY spermatogonia.
Although my research has focussed on some of the genetic causes of infertility, I have never felt that the treating of human infertility was a priority for mankind. If any medical benefits were to arise from my research, I would prefer it to be in improving methods of fertility control. However, when my antipathy to the treatment of infertility surfaced in comments I made at a recent scientific meeting I had a salutary experience. This meeting brought together scientists working on the biology of sperm and egg production, and clinicians who treat patients with fertility problems. After a lecture that reviewed the future prospects for further advances in the treatment of infertile men and women using ‘Assisted Reproductive Technology’ (ART), I questioned whether we should be devoting so many resources to these treatments. My comment engendered a heartfelt response from a lady in the audience, who I subsequently learned had only been able to conceive children by ART. This brought home to me how strongly some people feel the need to conceive children of their own; as someone with children, these are feelings that I am in no position to question or to fully understand.
Although over 50 million sperm in the ejaculate are needed in order to have a reasonable chance of fertilisation, a low sperm count is no longer a barrier to procreation thanks to ART. We can ensure that a reasonable number of sperm meet up with the egg by adding, in a test tube, sperm from the man’s semen directly to an egg recovered from the wife’s ovary (In Vitro Fertilisation, commonly referred to as IVF). The fertilised egg is then allowed to develop for a while before it is transferred back into the mother’s womb. However, men with low sperm counts very frequently also have very poor quality sperm that fail to fertilise the egg even when using IVF techniques. In this case, another technique of assisted reproduction called Intra-Cytoplasmic Sperm Injection (ICSI) can be used. This involves taking a single sperm and injecting it directly into the egg. Where no mature sperm are present in the ejaculate, there are now moves afoot to use immature stages from the testis and to fuse these with the egg.
So, in view of my salutary experience have I modified my views concerning the treatment of infertility? My antipathy towards such treatments undoubtedly stems in large part from my concerns about overpopulation, but the use of ART to enable some otherwise childless couples to have a family really has no relevance to the issue of overpopulation. This notwithstanding, for me some of the ART treatments now being offered are a step too far. A substantial proportion of human infertility will, at least in part, be due to genetic factors that can be transmitted, so by carrying out these treatments we are propagating the causes of infertility. In men with low sperm counts, this can in many cases now be ascribed to the loss of genes carried by the Y chromosome and any sons produced by ICSI will carry the same Y – a theoretical possibility that has already been realised. These sons will inevitably require ICSI if they are in turn going to father children. At the very least I believe there should be informed public debate on the issue of what should be offered by way of treatment by the NHS. As part of the treatment process, counselling should be provided as to alternatives, including the alternative of a fulfilling life without children, rather than promoting procreation at whatever the cost.