Starting from the age of thirty-five, a woman’s eggs start committing suicide at an accelerated speed. So while at the age of thirty-eight a woman may have around twenty-five thousand eggs, by the time she is forty-five she will have closer to five thousand; by her early fifties, she will have only a few hundred left. So regardless of whether a woman becomes pregnant or uses an oral contraceptive, such as the pill, that stops her eggs from being released, a woman’s supply of eggs is doomed to extinction by then. Importantly, those eggs that linger in the ovaries, taking their time to die, will stop doing what they are supposed to.
By and large, as we get older, the machinery in most of our cells simply doesn’t work as well; eggs are not the only cells in a woman’s body that go wrong with age, but they tend to be particularly affected by the process. This is because of the way in which egg cells develop. Unlike other cells, some of the eggs in a female foetus may have to wait for fifty years before they are triggered to mature, in readiness for fertilization. While they wait, the chromosomes they contain are lined up in a relatively orderly fashion on what is called a spindle, a structure that forms when a cell is dividing to create two (or four) new cells. The spindle helps guide chromosomes into newly created cells, so that their distribution is equal. Of course, having too many or too few chromosomes can be disastrous for health, so eggs and sperm must only ever contain twenty-three chromosomes or face serious repercussions. While the egg’s chromosomes sit on this spindle, waiting for half a century for their chance, the DNA they carry may well be degrading. The spindle itself may also become damaged, meaning that the chromosomes are not divvied up as neatly as they should be when the egg finally divides. This is partly because, with age, there is also a decline in the levels of certain proteins, called cohesins, that normally hold chromosomes together by entrapping them in a ring – something that’s essential for chromosomes to split evenly when a cell divides. This is one of the reasons why older women are more likely to produce abnormal eggs, which increase the risk of infertility, miscarriage, and birth defects, including the chances of having a baby with Down syndrome.
Down syndrome babies have three full or partial copies (called a trisomy) of chromosome 21, rather than the usual two. Though approximately twenty-five percent of all spontaneous abortions in the first trimester carry chromosome 21 trisomies, the chromosome error alone obviously does not terminate the pregnancy. Indeed, one in every seven hundred babies is born with chromosome 21 trisomy, and it remains the leading cause of learning difficulties and developmental delays in humans. Women with Down syndrome are sometimes able to reproduce. Most men with chromosome 21 trisomy are sterile from birth. Although the exact causes are not known, this infertility may be caused by hormonal deficits, changes to the shape of the gonads, or problems generating sperm.
Other chromosome trisomies are likely to have devastating effects too. For instance, embryos that have one copy or three copies of chromosomes 1 or 19 end up being miscarried before a woman even thinks to perform a pregnancy test. Similarly, in nearly all recorded cases of girls who carry XXX instead of XX in their sex chromosome, the extra X has come from the mother, not the father, and those mothers were usually older than average. Most XXX girls are of normal weight, height, mental function, and fertility, but they tend to experience a very early menopause, around the age of thirty. Somewhat like taking a too-high dose of a medicine, an extra chromosome translates into a too-high dose of certain genes, and abnormally high dosages are ultimately detrimental to a child’s health. In this case, the more X chromosomes a girl carries, the more severe her symptoms will be. That’s not to say that sperm cannot carry this chromosomal corruption, however. There is a significant increase in rogue X chromosomes found in the sperm of older men. A son who carries an extra X chromosome will suffer from Klinefelter syndrome, and will likely have difficulty producing sperm, to some extent; generally, he will be sterile. The condition affects one in a thousand men.
The eggs may be damaged by the environment of the ovaries themselves, which are no longer a safe haven as a woman ages. For example, oxygen levels, pH balance (whether acidic or basic), and hormone concentrations are in flux, and each of these in turn can make it more difficult for the eggs to separate the chromosomes from each other normally in pairs. If the chromosomes stay together rather than splitting apart, then one of the two new cells will have two of the same chromosomes and the other will have none. As the number of eggs ripening in each cycle drops in the run-up to the menopause, there is an increase in chromosomal abnormalities within the eggs. In fact, in IVF programmes the vast majority of eggs that come from women who are thirty-seven years or older have too many or too few chromosomes, as well as mutations in their DNA and in the machinery that controls the way in which this DNA is expressed. For example, ageing eggs are more prone to producing hydatidiform moles, the grossly distorted embryos that result when genes that are normally silent and locked become active, even without the proper imprinting that tells the DNA what to do. When this happens, the renegade DNA behaves as if it has come from the father rather than the mother, so that the embryo is effectively working with two sets of paternal genes. All that can come out of this combination is a mass of tissue inside the womb that, as of now, can never develop into a baby.
An ageing woman’s eggs no longer mature in readiness for fertilization, as younger, healthy eggs normally would, when they are exposed to follicle-stimulating hormone, or FSH. As the menopause approaches, the ovaries stop responding to FSH (they also stop producing oestrogen and progesterone, as we saw earlier). In response, the body produces more and more FSH – ticking and tocking louder and louder. The interactions between the hypothalamus, the pituitary gland, and the ovary change as well. The seamless orchestration of hormones necessary for successful fertilization and pregnancy transforms into a cacophony. But it is the eggs and their corrupt chromosomes that are most at fault. When an older woman is implanted with young eggs – even just the cytoplasm, that cellular soup inside an egg minus its DNA – they become pregnant, despite all of the other changes going on in the body. In fact, older women actually stand a better chance of becoming pregnant with donated young eggs than younger women do of conceiving naturally.
Something doesn’t seem quite fair about these facts of fertile life, when you start to think about them.
It has long been reasonably obvious that for women, age is the main factor in the loss of fertility. But matters are less clear when it comes to men. In contrast to women’s reproductive ability, male functions do not cease so abruptly – there is no single event that parallels the menopause. This means that throughout their lives, men continue to produce sex hormones and to generate sperm. And yet, the effects of paternal age on a couple’s fertility are significant.
A healthy couple in their mid-twenties has only a twenty to twenty-five percent chance of establishing a ‘natural’ pregnancy in a given month, while a couple aged forty can only match that chance through the use of IVF and other techniques. Because older women tend to have male partners who are around the same age as them, or older, older couples also carry the added risk from the greater number of genetic mutations that occur in the sperm of older men – the curse of corrupt chromosomes.
It is now understood that having a male partner over forty years old is an important factor in failing to conceive, and when a man is over fifty, there is also a significant decrease in how many embryos form properly and how many babies are born alive. If a woman’s male partner is over thirty-five, there is a higher risk of seeing the pregnancy end in miscarriage than for those whose partners are younger, regardless of the woman’s age. If the pregnancy succeeds, sperm-based mutations may lead to a range of lifelong conditions. Autosomal dominant diseases, such as short-limbed dwarfism (achondroplasia) and Marfan syndrome, affect connective tissue and can cause problems in the skeleton, eyes, heart, blood vessels, nervous system, skin, and lungs. Some genetic disorders that arise as fathers get older behave a bit like a jammed CD,
with sequences of the DNA code repeating when they shouldn’t. These conditions include Fragile X syndrome, the most common cause of inherited mental impairment; myotonic dystrophy, a disorder of the muscles and other body systems; and Huntington’s disease, a currently incurable condition that causes deterioration and gradual loss of function in the brain.
When it comes to making babies, time is not on our side, whether you are dealing with egg or sperm. While the link between age and infertility is certainly biological, some people are infertile early or throughout life. Leaving the decision to have a baby until the thirties or forties means that the underlying cause of a person’s infertility won’t be identified until it may be too late to identify or correct. That is to say, most people won’t find out they’re infertile until they start trying, whenever that is. Around one in six couples who cannot establish a pregnancy on their own will seek medical assistance, and the average age for receiving IVF procedures in the UK is thirty-five. Sometimes the problem is a minor one, but that is not always the case. For around one quarter of people who find they cannot get pregnant, the problem cannot be pinpointed at all – the dreaded ‘no diagnosis’. Slowly but surely, scientists are uncovering what may be behind these mysteries.
There is a growing list of genes that have been found to be key players in regulating when a woman is fertile and when she is sterile.
A gene on the X chromosome, FMR1, for example, is coming into use as part of a genetic test that aims to predict the rate at which a woman’s egg supply is running out. FMR1 is known to help regulate the transition of eggs from immaturity to maturity. The sequence of chemicals that spell out the FMR1 gene contains repetitions, and women with a version of the gene that contains more than two hundred repeats of the DNA sequence CGG are likely to have Fragile X syndrome. But there are also women who have fifty-five to two hundred CGG repeats – not quite enough to disturb the gene and cause mental impairment, but enough to put the carrier at increased risk of experiencing an early menopause. If a woman has between twenty-eight and thirty-three repetitions this leads to abnormal levels of anti-Müllerian hormone, or AMH, which fluctuates throughout life. Healthy women with low levels of AMH for their age seem to hit menopause earlier; they also have fewer eggs, lower fertilization rates (whether through ‘natural’ means or IVF assistance), generate fewer embryos, and have a higher incidence of miscarriage during IVF transfers. Women with insufficient AMH have half the number of successful pregnancies compared with women with high AMH levels. In fact, AMH levels are usually a better tip-off than a woman’s age in guessing how successful IVF will be, ranging from how many eggs will be harvested from her ovaries to whether she may miscarry once an embryo is transferred from a Petri dish to the womb.
But FMR1 is not the only genetic clue to a woman’s fertility. It appears the BRCA1 gene mutation – widely known for its role in breast cancer and ovarian cancer – may offer information about the risk of premature ovarian ageing. Normally, BRCA1 rallies other genes in the cell to repair damaged DNA. When the BRCA1 gene itself is damaged, or when damage accumulates on its chromosomes, you start to see the growth of abnormalities and, later, tumours. An inability to repair DNA seems to be an important part of why women’s ovaries age, and that’s where BRCA1 comes in. Manipulating the genes that are involved in DNA repair could be one way to avert failing ovaries in the future. Further, new bits of genes on chromosomes 13, 19, and 20 have been found that influence the age at which a woman experiences menopause, as well as ageing-related diseases such as breast cancer, osteoporosis, and cardiovascular disease.
For a woman facing the dilemma of focusing on career or childbirth in her twenties or thirties, being able to predict the age at which she might begin to have serious difficulty in becoming pregnant would be the holy grail of family planning. The decision isn’t binary, however: it’s not a choice between pregnancy now or never. A woman who wanted to focus on her professional ambitions for the next decade already has the option of freezing her ‘young’ eggs for use in the future. But at a cost of £3000 per attempt, and some women having to undergo three rounds of extraction to get a good harvest of eggs, most women, without sure information, will be likely to defer until later. In the future, gene therapy may also be developed to reinstate the functioning of what is normally lost after menopause, affecting the treatment of fertility and age-related diseases. Such therapies might even extend the life span of a woman’s ovaries and allow a woman to remain ‘naturally’ fertile for far longer than has ever been possible. An ‘old’ mother in the future will probably bear little resemblance to the ‘old’ mothers who hit the front pages today: she would not have needed IVF or a donor egg, because she will be able to use her own, without detrimental effect on her health or life expectancy. Scientists are still uncovering exactly which genes will be useful or amenable to manipulation, but the research is already in full swing.
If the human X chromosome sometimes harbours genes that can cause problems for female fertility, the Y chromosome can be viewed as a disaster zone. The Y chromosome, which once contained as many genes as the X chromosome, has deteriorated so much over time that it now contains fewer than eighty functional genes compared to its partner, which is large and packed with more than one thousand. This deterioration, according to geneticists and evolutionary biologists, is due to accumulated mutations, deletions, and anomalies that get stuck, in a way: they have nowhere to go, because the Y chromosome doesn’t swap genes with the X chromosome like every other chromosomal pair in our cells do.
With such a small number of genes to carry, the Y chromosome is small. It’s also peculiar, filled with many repetitive DNA sequences but not many genes. Unlike the X chromosome, whose genes display a variety of general and specialized functions, the Y carries the codes for only forty-five unique proteins. These proteins are the blueprints essential for the male reproductive system, particularly those important in sperm development. Of course, when an egg is fertilized, the sex chromosomes are matched up. In a woman, the two XXs pair up easily. But because the Y and the X are so different, in size and information, the match isn’t quite right. So in a man, the X and the Y align only in a small region, where you could say the chromosomes are singing from the same hymn sheet. This has helped to perpetuate the diminution of the Y – the parts of the chromosome that don’t match up with the X aren’t necessary; they’re expendable. Thus, the Y has slowly but surely become smaller and less genetically rich compared with its sex partner.
Technically, it’s not simply having a Y chromosome that makes a person male, it’s having the right bits of the Y – the right key genes, known as testes-determining factors. The most important gene of this group is SRY, for sex-determining region of Y, but there are almost certainly other genes that scientists have yet to identify. One case dramatically illustrates the role of SRY: the rare sex chromosome disorder known as de la Chapelle syndrome, also called XX male syndrome. Individuals with the syndrome appear to be male, though they have two X chromosomes and no Y – just like a woman. The critical difference is that the SRY portion of a Y chromosome has usually become attached to one of the X chromosomes. That small error effectively converts an X chromosome into a Y, female into male. The genetic mutation is sometimes evident in a short stature, an abnormally shaped penis, and the appearance of breasts. Curiously, there are a considerable number of cases in which XX males do not carry the SRY gene. Instead, these men have a closely related gene, called SOX9, which also causes skeletal deformations. As a result of these genetic anomalies, somewhere between one in nine thousand and one in twenty thousand men have XX chromosomes, rather than XY. Maleness – to some extent, depending on how you define it – is perfectly possible without a Y chromosome, or even the SRY gene.
Of course, one way in which we define maleness, socially, involves sexual reproduction. People with XX male syndrome have little or no detectable sperm in their semen, making them effectively sterile. Not having a Y chromosome is bad news for fertility. Take XX male
cocker spaniels, for example – without the SRY gene, many turn out to be infertile hermaphrodites. There have also been several reported cases of XX male farm animals, including among pigs and goats. This is unfortunate news for the breeders who own a particular animal, but is not yet a threat to their livelihoods – although that may not be true in the future.
Still, against the odds, the human Y chromosome does not seem to be taking its destruction lying down. Even though it is at a distinct disadvantage by not having a perfect partner match in the cell, it has developed ways to ensure its survival. To get rid of accumulating damage and mutations, the Y chromosome has been swapping its bad bits with intact bits of itself. While this has fixed the problem to a certain degree, it has introduced other places where mistakes can happen. Once the DNA on a Y chromosome is broken up so that it can be swapped, the pieces sometimes end up being put back together incorrectly. This self-protection stratagem triggers a whole range of sexual disorders in otherwise healthy men, including less sperm production, sterility, and sex reversal, as in de la Chapelle syndrome.
Should the Y chromosome crumble into scant genetic bits and bobs, and then disappear altogether, it would not necessarily mean the end of a species. There is hope. Some animals, such as the mole vole (Ellobius lutescens) and the Japanese Ryukyu spiny rat (Tokudaia osimensis), have two sexes but no visible sex chromosomes. The voles, a rodent that burrows underground throughout a wide swathe around the Caucasus mountains, are extremely interesting for one reason: it is impossible to distinguish a female from a male by looking at their chromosomes; both carry only a single X. What is more, scientists have been unable to pick up any bits of SRY gene on any chromosome in the mole vole species. Since SRY normally acts as the primary switch that initiates the development of a testis out of the undecided mass of cells in an embryo, you would expect to see it in an animal that looks male. It’s not there.
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