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How far tin can female fertility be extended?

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Modernistic medicine is already allowing women to have children far later on in life than their ancestors, but how far can female fertility actually be extended?

"Information technology'due south one of nature's bully inequities," says Dagan Wells, professor of reproductive medicine at the University of Oxford. He is referring to the progressive, and largely irreversible, decline in female fertility from the age of 35 years onwards.

Men also feel a decline in their baby-making ability as they become older, only this autumn in fertility tends to start later and occur much more than slowly than in women. The fertility rate for men tends to begin falling around the age of twoscore-45 years sometime.

But when exactly does a woman'due south fertility first failing? And when does that reject result in the finish of natural fertility?

For millennia, women accept been getting pregnant and begetting children in their teens and early 20s – not much different from the Krapina Neanderthals, living in Northern Republic of croatia xxx,000 years ago, whose fossilised remains propose gave nativity to their first child at fifteen years of age. Prior to the 1960s, women in the United states were having their first child on boilerplate at around the age of 21.

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In 2017, however, the average historic period of mothers giving nativity in all OECD countries was 30. Just under half (44%) of all live births in England and Wales in the aforementioned year were to mothers aged 30 while the average age of women giving birth to their first kid in South Korea was 31.

Fertility treatments and the ability to freeze eggs has allowed more women to have children later than was possible in the by (Credit: Science Photo Library)

But what does this hateful in the context of the ticking clock of female fertility?

Numbers matter

For decades, scientists accept associated the turn down in female fertility with the age-related subtract in the number of eggs independent within a woman's ovaries. Each, if fertilised, has the potential to grow into a baby.

Different men, whose reproductive organs produce millions of fresh sperm on a daily ground, women are born with all the eggs that they volition ever possess. Moreover, this number steadily declines every bit a woman ages: from one million eggs at nativity to 300,000 by puberty, 25,000 by the age of 37 and 1,000 by the age of 51. Of all these, however, just 300 to 400 eggs with babe-making-potential – ordinarily just 1 a calendar month – will mature and eventually be released from a woman'due south ovaries through ovulation across her entire life. For reasons not nevertheless fully understood, the rest undergo a natural procedure of degeneration and will never be ovulated.

Most girls begin menstruating between nine and xiii years of age, but their ovaries don't start releasing eggs until a least a year or two later. Simple mathematics would propose a woman'due south egg supply would then typically exhaust itself effectually 33 years later. And in most women, fertility does indeed tend to terminate up to eight years earlier the onset of menopause, which for American women is around the fourth dimension of their 51st birthday.

While such crude calculations do non take the natural variability that can exist between women into business relationship, or the time windows during which ovaries might release more than than i egg in a month, or months in which no egg is released at all, they tin requite a rough guess of just how long the female fertility timeline can be.

A more precise estimate of a woman's egg count, as well known every bit "ovarian reserve", tin exist obtained by measuring the level of hormone called anti-Mullerian hormone (AMH) in a woman'due south blood. We now know that AMH, produced by the ovaries of fertile, adult women, plays a vital office in the metamorphosis of an immature egg cell into a mature, hopeful egg, complete with all the biological prerequisites to create a good for you baby. Better functioning ovaries, with larger egg stores, produce more AMH.  Levels of the hormone decline as the timeline of female fertility progresses – average levels in 30 to 35 year olds are roughly 2-thirds that of younger women while levels in women aged over 45 years are a quarter of those seen in women in their 20s.

When they are born, women'due south ovaries already comprise all the eggs they will ever produce (Credit: BBC)

Andrea Jurisicova, an embryologist at the Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, has spent years studying the mechanisms that underpin the decline in female fertility with age, and investigating what tin be done to slow this. Her research has plant that ovarian reserve is genetically regulated only that a adult female'south life experiences – such every bit stress, exposure to radiation or toxic chemicals and even those from when she herself was in the womb – determine egg numbers in later life.

Quality matters

But female fertility isn't just about the quantity of eggs. Quality matters too, and is much more technically challenging to assess than egg numbers. While egg counts refuse equally women age, so does the quality of the chromosomes and the DNA independent within each egg.

"Chromosomal abnormalities in human eggs are extremely common," says Wells. "Information technology'due south not something that should exist considered to be a particularly abnormal situation, and in virtually cases its something that all women, even young women, will have in their eggs at a depression level but that level increases with advancing age."

For a adult female in her 20s, a quarter of her eggs may be expected to have chromosomal abnormalities – this increases to up to 40% for a woman betwixt 30 and 35, and "goes upwards merely exponentially from there on". Beyond the historic period of 35, the frequency of these chromosomally abnormal eggs increases by 0.v% per month, and so that for a woman in her early 40s upwards to three-quarters of her eggs volition have chromosomal abnormalities.

Having chromosomal abnormalities in her eggs doesn't necessarily mean a adult female is infertile, merely they practice mean that more of her menstrual cycles will produce eggs that are less likely to produce a viable babe.

Chromosomes are bundles of tightly coiled Dna that hold the genetic information needed for an organism to develop. A man egg contains 23 chromosomes – the one-half of your genetic lawmaking that comes from your mother – which needs to combine with the 23 chromosomes from your father's sperm to develop into a viable embryo. An egg with likewise many or besides few chromosomes, cleaved or damaged chromosomes will often fail to develop properly. In some cases a infant can still be born with chromosomal abnormalities, every bit happens with Down's syndrome.

But well-nigh chromosomal abnormalities tend to be lethal to the extremely young embryo, resulting in the embryo declining to implant in the lining of the womb or a very early miscarriage, often between five and eight weeks of pregnancy.

While the risk of chromosomal abnormalities is known to be higher in the eggs of older women, a contempo European report found that the level of chromosomal abnormalities is likewise loftier in younger women too – from 13 into their early on 20s. The findings suggest that female fertility timeline follows a n-shaped pattern, with peak fertility observed in the mid-20s and lower levels of fertility both in very young and older women.

Older mothers may face greater risks during pregnancy, labour and delivery, only there are bug associated with older fathers likewise (Credit: Getty Images)

Elsewhere in the egg, faulty mitochondria – the tiny power stations that provide energy for our cells and which we all inherit from our mothers – tin can also be a problem in older women. Studies take shown that up to one-half the eggs of women who are older than 35 carry mutations in their mitochondrial DNA, compared to a third of the eggs in younger women.

"An egg needs a threshold of about xl,000 mitochondrial Dna copies to make an embryo," says Jurisicova.

For Wells, the evidence is clear.

"The rate of decline accelerates around the age of 35 and the vast bulk of women are essentially infertile by the time they reach 45," says Wells. "Chiefly, this is years, mayhap fifty-fifty a decade, before menopause. Everyone expects to be a trivial less fertile when you lot are older, but the extent of that reject takes a lot of people by surprise."

It would exist wrong to focus only on female fertility. Some studies have shown that sperm quality too declines with age in men, starting in their 20s. Sperm mobility – the ability of information technology to swim effectually – has been institute to turn down by around 0.7% every year while the sperm of older men carry more mutations in their DNA. Older fathers besides laissez passer on more than mutations to their children than mothers practice from their eggs.

Best egg

"The man egg is a remarkable and unusual cell, information technology'south the biggest prison cell in the torso, and has a unique feature," says Wells. He is referring to the egg's ability to stop halfway through its growth and remain in a state of suspended blitheness for years, even decades, until it is eventually ovulated. His enquiry suggests that it is the egg'due south ability to hold its chromosomes in a stable configuration during this period of hibernation that governs its ability to brand an embryo and a baby.

Jurisicova's work adds another piece to the puzzle. Her work suggests that homo eggs undergo a process of growth and maturation within the ovary for at to the lowest degree nine months earlier they are released during ovulation. "The quality of the egg released is the culmination of all the health and environmental influences on that growing egg over the by ix months," she says. Stress, exposure to radiation or toxic chemicals during this fourth dimension tin can take an adverse furnishings on the developing egg.

It is perhaps interesting that the duration of this incubation period – from when an egg emerges from hibernation and begins developing – uncannily resembles the number of months a infant spends within the womb before it is built-in. During this period of maturation, the egg develops the resources it will need should it be fertilised.

"The egg has to be extremely well resourced," says Wells. "For the first three days post-obit fecundation the embryo doesn't really make anything for itself – it doesn't transcribe its genes, information technology doesn't make proteins – its completely reliant on what the egg has provided for information technology. A more than mature egg is more likely to be better resourced than a less mature one."

While there may be little that science can exercise to modify the number of eggs that nature (or genetics) decides a woman volition take during her life, Wells and Jurisicova concord there are ways to ameliorate, or rescue, egg quality. Adopting a good for you lifestyle, exercising regularly, reducing stress and making sure that health bug such as hypothyroidism and other autoimmune conditions are well controlled can all aid.

The range of factors pitched against an egg being fertilised and developing into a foetus make childbirth seem all the more incredible (Credit: Science Photo Library)

Jurisicova recently institute that giving female mice the antioxidant coenzyme Q10 delivers promising results – the mice that received the supplement produced meliorate quality eggs with more properly aligned chromosomes and better mitochondrial office. They were also more than successful in producing live babies, than the mice that did not receive the supplements. The results are, however, yet to be replicated in humans.

The journeying, not the destination

Mothers don't just need to contend with their fertility as they get older, simply also greater risks during pregnancy, labour and commitment. The Start and Second Trimester Evaluation of Adventure (Faster) trial, a US study funded by the US National Institute of Child Health and Human Development (NICHD), looked at the health records of over 36,000 women. They found mothers over 40 were two to 3 times more likely to experience health bug during pregnancy including diabetes and high blood pressure. They were twice as likely to experience bleeding from their placentas, have a caesarean commitment and to lose their baby afterwards on in pregnancy.

The children of older starting time-time mothers who are 40 years and to a higher place likewise have an increased run a risk of wellness bug at nativity, such equally low nativity weight and congenital abnormalities. They also accept a 50% increased hazard of being born preterm and, possibly consequently, are at increased hazard of requiring neonatal intensive intendance after nascency.

But this is even so merely one half of the equation. Older fathers also bring additional health risks for their children. Babies with older fathers are more likely to exist born prematurely, have a lower birth weight and higher risk of seizures. Some studies have also linked increasing paternal age to a greater risk of conditions such as autism and ADHD where the father is over the age of forty, but the evidence remains inconsistent.

Scientists are developing new techniques to identify the best eggs for use in IVF treatments (Credit: Science Photo Library)

Is it possible to extend female fertility and for how long? As is often the case, where nature creates inequity, science attempts to level the playing field. In September last year, Erramatti Mangamma, a 74-year-erstwhile from southern India become the globe's oldest start-time mother, delivering twin baby girls conceived via In Vitro Fertilisation (IVF) later 57 years of infertility. 3 years ago, 72-year-old Daljinder Kaur, from northward Bharat, gave birth to a son subsequently nearly v decades of spousal relationship and 2 unsuccessful IVF attempts.

The pregnant advances in reproductive medicine over the past decades have profoundly increased the safety, success, accessibility and affordability of artificial reproductive techniques. Approximately 230 babies are born in the UK each year to women aged 50 and over while ix% of all first-time mothers in the United states of america were aged above 35 in 2014.

But as nosotros have seen, these techniques are however express to a degree by the age of the egg. This is, non least, because of the effects of ageing on the DNA, but also because older eggs have been exposed to ecology toxins for a longer amount of fourth dimension. It is possible, of course, for women to undergo IVF using a donated egg from a younger woman. Virtually all fertility clinics across the globe now also offer women an option to store their eggs, frozen in time, until she is ready for them to exist thawed, fertilised and transplanted into her womb.

"The difficulties experienced with older women trying to have children is not related to the uterus merely to the egg, and chromosomal abnormalities are at the heart of that," says Wells. "The egg is the seed rather than the soil. Many of the very early steps in man development are determined past what the egg provides."

With the assist of technologies like pre-implantation genetic testing, Wells and his fellow embryologists are developing means of identifying the best eggs that can be used in IVF treatments. Other techniques such equally mitochondrial replacement therapy are too helping mothers with defects in their eggs requite nascency to healthy children.

Merely while science is making commendable steps to help prolong the ticking clock of female fertility, information technology may not e'er exist possible to proceed it going indefinitely. The decline of natural female fertility is every bit inevitable as it is universal.

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Source: https://www.bbc.com/future/article/20200828-how-fertility-changes-with-age-in-women

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