It always happens at the worst possible moment. In a work meeting or at dinner with your partner’s parents. Panicked, you excuse yourself, lock the bathroom door and furiously try to wash the blood off the crotch of your trousers. Inevitably you think: how did we build a space station before fixing this?
Even for those not diagnosed with disorders like endometriosis or adenomyosis, menstruation can make everyday life stressful, if not unbearable. Up to 70% of menstruating under-25s experience pain, fatigue and mood swings, while nearly 30% across age groups report bleeding heavily. This puts them at risk of iron deficiency anaemia, a “global” and “totally under-recognised” problem, says Hilary Critchley, a gynaecologist and academic at the University of Edinburgh.
Cultural taboos, and the well documented dismissal of women’s pain, have hidden the scale of the problem, but it is also bigger than it used to be. Previous generations spent more time pregnant and undernourished, so they had fewer cycles.
Besides womb surgery – which 30,000 undergo as treatment for heavy bleeding every year in England and Wales – and painkillers, treatment consists of blood clotting agents and hormonal contraceptives. While some use them successfully to lighten or even stop their periods, they don’t work well for everyone and may have unacceptable side-effects. “Almost everyone is bothered by this at some point,” says gynaecological surgeon Dharani Hapangama from the University of Liverpool, “so there should be easy, manageable treatments.” But according to Critchley, there has been “no new class of medical treatments for heavy menstrual bleeding for over 30 years”.
Chronic underfunding hasn’t helped. “You could theorise that there is a bias against women-related research,” says Günter Wagner from Yale University, who studies the evolution of menstruation. Within the American National Institutes of Health (NIH), he says, “there’s a national institute for every organ system except for the female reproductive tract. It’s actually pretty scandalous.” That menstruation-related symptoms and disorders are life-altering and not life-threatening bumps them further down the priority list. But there are signs the tide is turning.
Just last month, the US Senate passed a bill increasing funds for research on endometriosis, and sometime this spring, the UK government will publish its eagerly anticipated Women’s Health Strategy. At the same time, technical breakthroughs and surprise discoveries have opened the door to a new era of menstrual health research. These offer cutting-edge tools to address debilitating periods, and fresh insight into our own evolution.
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Biologically, menstruation is odd. The vast majority of animals don’t do it, and consequently there is a lot we don’t know about it. But what we do know is that the menstrual cycle is a monthly process of pregnancy preparation, driven by hormones. In anticipation of a fertilised egg, ie an embryo, the womb thickens the layer of cells that lines it, called the endometrium. When the embryo arrives, it buries into the endometrium and kicks off pregnancy. If the egg is not fertilised, the endometrium breaks down, bleeds and flushes out. That’s what we call a period.
In most mammals, this preparation doesn’t start until the embryo arrives. Which creatures get periods, then, “seems to be a question of whether the species ‘feels the need’ to prepare for the arrival of an embryo before the embryo is there,” says Wagner. A few other species feel the need, too: some primates, a few bats and the elephant shrew (which, strangely, is neither shrew nor elephant). Contrary to popular belief, dogs don’t have periods – their bleeding is from their vaginas, not their wombs.
Beyond periods, it is not obvious what links this diverse group of animals. Apart from the primates, they are not closely related, which suggests that menstruation evolved independently several times. Evolutionary biologists like Wagner are trying to explain why this would have happened. Currently, he says, “it’s entirely unclear”.
Unsurprisingly, then, it caused a huge stir when scientists discovered in 2016 that there is another species in the menstruation club: the common spiny mouse, Acomys cahirinus, a fragile animal with amazing wound-healing abilities and which, a bit like a lizard, can lose its skin to escape predators. This little rodent has periods, too.
“No one would have expected that a rodent would menstruate,” says Peter Temple-Smith, a reproductive biologist at Monash University. It was Temple-Smith’s former student, Nadia Bellofiore, who, during a study on spiny mouse reproduction, noticed that their vaginal smears sometimes came out bloody. “We were incredibly surprised,” says Temple-Smith.
It turns out that spiny mouse menstruation is remarkably similar to ours. Spiny mice spend the same percentage of their cycle menstruating, they go through a kind of menopause, and they even seem to get premenstrual syndrome (PMS). In humans, PMS is very common and features mood swings, food cravings and general discomfort. At the same point in their cycle, spiny mice seek isolation, resist touching and eat more. These similarities mean that treatments for humans could potentially be tested in spiny mice first.
Temple-Smith believes that the spiny mouse is overall the best model of human menstruation. “It’s getting harder and harder to justify work on primates, and the cost is phenomenal,” he says. Instead researchers use the induced mouse model, where a regular mouse has its ovaries removed, and is subjected to hormones that make it bleed from the womb. “I think if you’re honest about it, you need to have a natural model that works without the need to pump [it] up with progesterone and oestrogen.”
Some, like Hapangama, are sceptical that the similarity to humans is strong enough, and some things do differ: spiny mice don’t seem to naturally get endometriosis, for example. But for Wagner’s studies of evolution, there is little competition. He has just started his own colony. “To have a rodent is a huge opportunity,” he says. “It’s just such a chance.”
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In one respect, spiny mice are so like humans that it complicates matters. Alongside German pharmaceutical company Bayer, Temple-Smith’s group recently tried to breed heavy-bleeding spiny mice, which could be helpful for understanding and developing treatment for that symptom. But just like humans, some spiny mice have heavy periods while others don’t. Breeding them to bleed heavily exclusively is very difficult, says Temple-Smith, and neither he nor Bayer have managed to do it.
The persistent individuality of period symptoms – in spiny mice and in humans – makes a clear case for personalised treatment. This now looks achievable with another new development, first reported almost simultaneously by teams at the University of Cambridge and KU Leuven in 2017: endometrial organoids. These are three-dimensional miniature versions of the real endometrium, grown from individual human biopsies. Exposed to hormones, they can even have a kind of menstrual cycle, where cells first grow and then die, ready to be “flushed out”.
Margherita Yayoi Turco, formerly of the Cambridge group and now based at the Friedrich Miescher Institute, says different people’s organoids show great variability in the way they grow and respond to hormones, even in the absence of disease. “There is a real need to understand, what is this diversity? What is normal?” Her new technique to grow them from menstrual fluid rather than “scratch biopsies”, where endometrial tissue is scraped out through the vagina, means they are easier than ever to obtain.
Once we have a solid idea of “normality”, we can compare the organoids of people with bad periods to understand where the problem lies. We already know that organoids generated from diseased tissue, such as from endometriosis or cancer, reflect the stage of disease. Then “you can look at the effect of a battery of drugs,” says Hugo Vankelecom, who leads the KU Leuven team. While his research is focused on endometrial diseases, he sees no reason why those same techniques could not be used in the context of debilitating periods, too.
But so far organoids only include one endometrial cell type. “Organoids are a good start,” says Hapangama, “but the endometrium is a multicellular organ.” Turco and Vankelecom are now trying to incorporate more cell types, while Hapangama is working on a complete system that even includes blood vessels.
The cutting edge of this is the “assembloid”, an organoid combined with layers of another endometrial cell type, first reported last year by a team including Jan Brosens, a clinician and scientist based at the University of Warwick. Brosens has an additional interest driving his work: he, like Wagner, wants to understand why we menstruate. And he has a compelling theory.
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Strange links between fertility and miscarriage in his patients led Brosens to think that menstruation could be implicated in sorting out bad embryos before a potential pregnancy. He recalls a recurrent-miscarriage patient who reported becoming pregnant on practically the first try before each of her eight miscarriages. “It was weird,” he says, because her chance of conceiving within one month was one in five.
Then, his colleague Nick Macklon contacted him about an illuminating experiment. Macklon had put embryos on top of endometrial cells in a dish, and when the embryo was weak, the cells aggressively pulled their vital support. When the embryo was strong, it was left to develop.
Brosens realised that this could explain his fertile miscarriage patient. If the womb quality-checks embryos, then dodgy embryos flush out with menstruation and never become pregnancies. But if the selection process is faulty, bad embryos stick; you become pregnant more easily and end up miscarrying later. This fits with clinical evidence showing that recurrent miscarriage patients usually get pregnant more easily than others, ie within three months of trying, compared to the normal six months.
The selection process, Brosens says, is built into the menstrual cycle. When thickening up, the endometrium becomes “super sensitive to embryonic signals”, just as in Macklon’s experiment. But unless it gets the right signal, it will eventually break down and wash everything away as a period. Brosens’ assembloids now allow him to study in detail what happens when embryos interact with the sensitive endometrium.
It’s easy to see how embryo selection before a taxing and dangerous pregnancy could amount to an evolutionary advantage. Wagner thinks Brosens’s hypothesis is probably correct, although “we don’t have particularly strong evidence” to prove it is the reason we menstruate, and there are many questions left to answer.
For example, why would humans and other menstruating animals be in special need of embryo selection? And does embryo selection really make up for literally leaving behind a trail of blood for predators to sniff out? However, armed with a new colony of African spiny mice and ever more elaborate assembloids, those answers may be just around the corner.
