Judy Blume’s novel about early female puberty, Are You There, God? It’s Me, Margaret, depicts a group of 12-year-old girls eagerly willing their first periods to arrive, impatient to be in on the unfathomable mystery of monthly bleeds. Little do they know that the mysteries surrounding their ovaries and wombs will only ever deepen, in ways unique to each of them. The mood swings, the cramps, the headaches, the pimples, the energy dips, the secretions, the libidinous peaks and troughs – right up to the perimenopause. Doctors won’t be much help, because there is scant precise science on much of this.
And then, at about 50, when the ovaries have run out of eggs, it all goes quiet. I have heard middle-aged women express profound relief at reaching this moment. But what if the ovaries didn’t go quiet for another decade, or ever? Making this happen is being hailed as the next frontier in women’s health: to delay or avoid menopause and, in doing so, curtail the increased health risks associated with it.
The idea is that by extending the working life of the ovaries, which impact systemic health from metabolism to bone and connective tissue quality, to cognitive function and mood, women may have a better chance of staving off heart disease, dementia, osteoporosis, obesity, diabetes and other conditions that can affect their health.
In July, a team at Columbia University announced some preliminary results in their quest to prolong ovarian life, using a well-established, cheap off-patent drug called rapamycin. Traditionally used as an immunosuppressant for organ transplant patients, the drug slows the natural loss of eggs from the ovaries and has been shown to increase ovarian life in mice. After the first three months of clinical trials using a low weekly dose on 34 women of up to 35 (1,000 will take part eventually), the team has reported that there appear to be positive changes in some of the participants. It is a blind study so the researchers can’t say at this stage whether or not these women are in the placebo group, but they have felt positive enough to say publicly that the results are “very, very exciting”.
The scientists estimate that the drug could slow ovarian ageing by about 20%, which might neatly delay menopause sufficiently to reflect our increased lifespan these days. “The onset of menopause has profound socioeconomic, quality of life and health implications,” reads the description for the clinical trial. “The narrow reproductive window adds socioeconomic pressure on women to complete childbearing within a limited timeframe, or preserve their fertility with egg or embryo freezing.”
Another approach under investigation, also aiming to slow down egg release, is being developed by Oviva Therapeutics, a US biotech company. It is using “an engineered protein based on a hormone called anti-Müllerian hormone (AMH),” CEO and founder Daisy Robinton says. Anyone who has undergone fertility tests will be familiar with AMH because the amount of it present in a woman’s bloodstream provides clinicians with the best, albeit fairly unreliable, estimate of a woman’s egg reserves. In fact, it is one of the ways the rapamycin study is measuring ovarian ageing.
“AMH is produced naturally in women’s bodies and men’s,” says Robinton. “In women, it helps to regulate how many eggs are maturing with every cycle. If you have very high levels of AMH, more eggs stay protected. If you have lower levels, then more of them will be released.” Typically, she says, menstruating women lose around 1,000 eggs each cycle, even though usually just one is ovulated – or discharged from the ovary. Robinton says Oviva Therapeutics’ “grand vision” is: “To elevate levels of this protein in the blood, so we can reduce how many eggs are lost over time, and in doing so extend the runway to menopause.”
In older women, you might expect the extra remaining eggs that would delay menopause to be of poor quality, but Robinton does not think this will affect the broader health impacts of keeping the ovaries working. “There’s no evidence that the ovary has to have a quality egg to produce the hormones that maintain our health and wellbeing.” She says AMH exposure could potentially support egg quality, although this isn’t definite: “It has some sort of role in DNA damage repair that’s not particularly well understood yet.”
There could be other benefits to increasing AMH levels, such as maintaining fertility a little longer for women in their 30s or 40s. But the aim of the drug is not to help older women bear children. “To have a 55-year-old woman be able to get pregnant, your whole body is older, and that’s riskier, for a lot of reasons,” says Robinton. Also, in studies of animals given the AMH drug (it hasn’t been tried on humans yet), it has been shown to have a contraceptive effect. This means that, in theory, young women could take the drug instead of the pill, simultaneously preserving their eggs and ovarian lifespan. If a woman on it wanted to get pregnant, she could stop the therapy temporarily.
The company is mooting developing a gene therapy version (although Robinton says this technology is a good 10 years off), which would mean one dose could permanently create higher levels of AMH in the body. “I think that’s very attractive for a woman who either doesn’t want to go into menopause or doesn’t want children and feels comfortable making that permanent change, because it is permanent … There wouldn’t be a downside to that, aside from potentially the fact that you would continue menstruating. But we don’t have human data on this so this is speculative.”
Paula Briggs, consultant in sexual and reproductive health at Liverpool Women’s NHS foundation trust, does not see this as a positive. “There are things about menopause which are really helpful,” she says. “Not every woman wants to have a bleed every month. Not bleeding is a health benefit. You don’t drop your haemoglobin, you won’t get depression linked with anaemia. Any symptoms associated with hormonal changes will improve, whether that’s migraine or premenstrual mood disorders. There are lots of things that get better with menopause without treatment, and that’s been completely swept under the carpet. You’ve got hormonal stability.”
She points out, too, that at a time of life, “when you’ve got ageing parents, adolescent children, having proper periods again, and worrying about getting pregnant is the last thing people need”.
Briggs is concerned about the message that this increasingly high-profile area of research is putting out. “It’s a red herring for women to start feeling that when their ovaries go, they’re dead,” she says. “Hundreds of women historically have been much, much older, and they’ve done incredible things.” And fixing ovaries can’t make up for the biggest lifestyle killers, such as smoking. “People don’t necessarily want to engage in exercise or a healthy diet … super simple stuff that would extend their life,” says Briggs. “Yet we’re investing money in extending the life of an ovary with a drug when we don’t know exactly what kind of impact it would have on general health.”
As an example, Briggs says that even if somebody has their ovaries removed, they won’t necessarily develop dementia or any other of the listed conditions. “Risk is multifactorial, so if the person runs for half an hour a day, eats a good diet, they keep the brain active, they’re not necessarily going to have a poor outcome.” In any case, we have HRT, tried and tested for many years. “Why would you take a drug to extend the life of your ovary, which potentially could have side-effects when you could just use HRT?”
Robinton has an easy comeback to this, simply because of the medical mysteries of how, precisely, the ovaries govern general health. Much of what we do know is based on associations, so there could be more to the ovaries and their power over women’s bodies than the oestrogen we give women for HRT (with progesterone to decrease the risk of uterine cancer). “We just don’t really understand so much,” she says. “There’s certainly a lot of things that the ovaries produce that we haven’t really characterised and understood … Data just is extremely limited with regard to the complexity of the biology and a lot of assumptions are made.”
It should be said that there is already a company in the UK offering a medical intervention to delay menopause. ProFam offers clients the chance to remove some healthy, young ovarian tissue and freeze it. When you defrost it and graft it back into the body, it can restore hormonal function, and possibly egg production, says Melanie Davies, consultant obstetrician and gynaecologist at University College London Hospitals NHS foundation trust, with special interests in gynae-endocrinology and fertility preservation. “We’ve been doing it for quite a while for young women with cancer.”
Chemotherapy can cause damage to ovaries and infertility, but if you remove some healthy tissue first and then put it back after treatment, she says: “In most cases, that tissue will start working again as it develops a blood supply. And after a few weeks or months, it starts making its hormones again. And they produce eggs. So there are babies born – a few hundred babies around the world. The first one, in 2004, was born to a young woman who had tissue frozen at the time of a cancer diagnosis, then went through treatment, developed a very early menopause, and then had their tissue grafted.” A systematic review found about a 25% birthrate resulting from this procedure.
To do it to delay natural menopause seems rather drastic to Davies and she doesn’t think the risks justify it. “You go through two operations, take out some ovary that was working perfectly well, with a rather uncertain benefit, when actually HRT works. It’s safe. It’s simple. It’s easily available.” But it is different when she sees a “young woman or even a child who’s going to have a bone marrow transplant with radiation, and you know that they have more than a 95% chance of permanent infertility”.
Women who have had cancer, or have a family history of the disease, are often advised not to take HRT because there is an increased risk of developing oestrogen-dependent cancers such as breast, ovarian and endometrial (uterine) cancer. But delaying menopause may not be the best alternative for these women because this would keep oestrogen circulating, too. In fact, naturally starting menopause later than 55 is one of the risk factors for developing these cancers. “Women who have late menopause have more natural oestrogen for longer and are at a somewhat higher risk of breast cancer. Some people would give that as a concern about any technology that extends reproductive lifespan,” says Davies. But you can minimise the risk in other ways. “The breast cancer risk from being very overweight is higher than the risk from taking oestrogen,” she says. “Being a heavy drinker increases your risk of breast cancer.”
There is no denying that scientific scrutiny of women’s health is long overdue. So regardless of whether these new ideas prove to work sufficiently, without unintended negative consequences, they could at the very least further our understanding of female fertility in relation to general health. To single out the ovaries, says Briggs, “is oversimplifying things, and we’re probably looking at how, in 30 to 50 years, they might manage this life stage differently, but I cannot see how that particular research will make a difference right now”.
There are very polarised views, she says, about women feeling that they must do something about their menopause, and this could distract women from getting on with the more fundamental elements of a healthy lifestyle. “I think a bit of research on longer-term ovarian function is interesting,” she says, “but it’s something to be factored into the whole way in which we manage women in what will hopefully be the final third of their lives. There are so many different options, some of which might involve lifestyle changes, hormone replacement therapy and, perhaps, one day, ovarian preservation.”
