Like a Virgin (26 page)

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.