Early menopause and fertility-related genetic conditions
The devastating diagnosis of premature menopause for women under 40 who have stopped menstruating, some while in their teens, can relegate them to a world of grief and isolation. But Professor William Ledger, head of obstetrics and gynaecology at the University of New South Wales School of Women’s and Children’s Health, suspects some doctors are too quick to diagnose premature menopause without further investigation beyond a blood test and a history of missed or absent periods.
“This has been proven in many case reports of women under 40 who have been told they’ve run out of eggs and will never bear a child, then a few months or years later their periods resume and they fall pregnant,” Ledger says.
He believes that the current guidelines for such diagnoses, which hold that the condition is irreversible, are too simplistic. Further investigation can narrow down cause and allow a patient to explore fertility options that are readily available and cost effective.
“There are fertility-related genetic conditions, for instance, which are not common but sufficiently common to test for. Because if you can identify these conditions early, it gives women the chance to have children before they run out of eggs earlier than expected,” Ledger says.
“Also important is that you can give them warning that there may be something inheritable in their genome that therefore can be passed on to a child.”
Alison, 44, a financial adviser from Sydney who prefers not to give her last name, fits the inheritance scenario raised by Ledger. She unknowingly was a Fragile X carrier when she gave birth to her son at 36.
Fragile X was discovered by United States researchers in 1991 and is responsible for a range of disorders. In female carriers it is known as pre-mutation of the X chromosome, in which one arm of the chromosome is lengthened by repetition of the genetic coding at the point of the FMR1 gene. It is linked to low fertility and premature menopause.
Alison’s son, however, was born with the full-blown mutation known as Fragile X Syndrome (FXS), which is caused by the mutation disrupting the production of a protein necessary for brain development and other functions. Children with FXS suffer a mild to severe intellectual disability and behavioural problems, and the mutation is also linked with autism.
“I took a while to get pregnant, which I just put down to age,” says Alison. Because of her age Alison underwent an amniocentesis – a procedure used in prenatal diagnosis of chromosomal abnormalities such as Down syndrome. She had never heard of Fragile X and it was never suggested she be screened for it.
Alison recalls her son, now seven, as an infant would slump to the side of his highchair, needing towels to prop him up. He would also fall over backwards when sitting.
“I’ve since learnt that is a sign of low muscle tone typical in FXS children,” she says. “But despite the fact my son was referred to a paediatrician at nine months for sleeping problems and delayed development, the mutation wasn’t detected until 10 months later.”
At 37 Alison decide to try for a second child and was able to have artificial insemination of one of her embryos that had been genetically tested for Fragile X before implantation.
“My daughter was lucky to be born because I had so few viable eggs,” says Alison, who realises that she, too, was also lucky to have had the benefit this time
of options after discovering she carried the Fragile X pre-mutation.
She is immensely proud of her son, who is now happily settled in a school for children with special needs, but says he has had to overcome sometimes crippling anxiety to enjoy new experiences such as horseriding or surfing.
“I’m just disappointed it took so long for diagnosis,” she says, “because the earlier you can get intervention and management for any disability, the better the outcome for your child.”
The good news is that scrutiny of knowledge gaps in dealing with infertility issues in younger women is intensifying with an increasing perception of the need for things to change.
Naturally occurring midlife menopause happens on average about the age of 51. Early menopause is under 45 and premature is under 40, with reports of periods stopping and never resuming in females as young as 16.
Premature menopause affects about 1 per cent of women. And for 90 per cent of those it is due to unknown causes. The rest are related to surgery after cancer or linked to genetic mutations.
Royal North Shore Hospital’s Rod Baber, who is professor of obstetrics and gynaecology at the University of Sydney, echoes Ledger’s concerns and says this is encapsulated in the preferred use of the term premature/primary ovarian insufficiency (POI) among health professionals.
“Firstly, ‘menopause’ is harsh and negative in this context and it’s not strictly accurate, so we would call all these younger women POI because about 50 per cent at some stage will start to have periods again and a very small percentage can then spontaneously conceive.”
Baber helps run a public clinic for POI, cancer survivors and menopause at Royal North Shore, and he strongly advocates that after family planning options have been addressed it is essential to move on to management of hormone replacement (HRT) for loss of oestrogen and progesterone.
“Without hormones, [the women] are at increased risk of cardiovascular disease, osteoporosis and to some degree increased risk of cognitive impairment,” says Baber.
“If they don’t get oestrogen from the time they are in their 20s or early 30s, it’s going to have a serious impact on most aspects of their lives by the time they are in the 50s and 60s.
“There have been studies going back 40 years that say no matter what age you go through menopause, your risk of heart disease is a lot higher than a peer of the same age who is still having periods. With women with POI, regardless of cause, it’s three times higher.”
One of the most recent progressive moves to improve knowledge about this condition is a collaborative project among Melbourne researchers, medical societies and health and non-profit organisations aimed at cutting through the misinformation and getting everybody on the same page.
The team, based at Monash and RMIT universities, has been gathering narratives from health professionals and the women themselves on their experiences and their opinions on what is needed to improve patient outcome. The results will be used to produce an online research-based resource for women, their families and health professionals by the end of 2018 that can be constantly updated.
“It’s really difficult for these young women diagnosed with POI,” says Amanda Vincent, president of the Australasian Menopause Society and one of the key researchers from Monash University.
“We know they often have increased psychological distress, anxiety, depression and a feeling of being out of step with their peers,” she says. “I had one patient say to me, ‘I’m going through menopause before my mother and I can relate more to my grandmother than I can to my friends.’ ”
Vincent says one of the gaps that will be addressed is confusion over HRT, although worldwide guidelines say women with POI should use this therapy until the age of natural menopause unless there is a medical reason not to.
Much of this confusion arose from the Women’s Health Initiative study in the US that suggested in 2002 there was a small risk of breast cancer with HRT. Vincent points out, however, that the average age of the 27,000 breast cancer sufferers in the study was 63, and results were incorrectly extrapolated to women with POI, which led to a great deal of fear among this group as well as doctors who prescribed them HRT.
Professor Ledger fully supports the idea of a well-researched website to provide accurate information.
“Most of us now go to the internet for information when we need more than we have in our own brain,” he says. “I find it helpful for patients and family members to access authoritative and well-written resources above and beyond what they can get from a 20-minute consultation from a doctor.
“To be able to link people into those resources is critical because there is an awful lot of nonsense flying around on the internet.”
This article was first published in the print edition of The Saturday Paper on Nov 18, 2017 as "Pause for thought". Subscribe here.