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The mysterious uterus

The uterus is a key player in all aspects of mammalian reproduction, from ovulation to birth. None of us would be here without it and half the population have one, so why are the mechanisms behind some of its main functions still shroudedin mystery?

Nestled away in the pelvic cavity, between the bladder and the rectum, the uterus is actually only the size of a fist during most of a woman’s life, but remarkably, it can grow and stretch to accommodate the growth of a baby during pregnancy. The top of the uterus is connected to the fallopian tubes, which deliver eggs from the ovaries to the uterine cavity. The lining of the cavity, the endometrium, responds to hormones produced by the ovaries and the brain. Every month these hormones tell the endometrium to develop into a thick layer of tissue, rich in blood vessels and glands. In this state, the endometrium can provide support and protection for a fertilised egg while it develops into a fetus. If an egg isn’t fertilised, the endometrium is redundant and breaks down, causing menstruation. The muscle layer of the wall of the uterus, the myometrium, is particularly important in labour; its main role being to rhythmically contract and help push the baby out of the birth canal. These contractions are controlled by signals from the brain and other organs, but currently the exact mechanism remains a mystery.

During development, the fallopian tubes, uterus and vagina start off as two tubes (the Müllerian ducts); the lower portions of these tubes then fuse to varying degrees depending on the species. Complete fusion gives rise to a single uterine cavity and cervix, as seen in humans and other higher primates. Other placental mammals show different structures; for example rodents and rabbits have two completely separate uteruses and two cervixes. Problems in human development may lead to an abnormally shaped single uterus or even two uteruses. In severe cases, these malformations can cause infertility, irregular periods, miscarriage and kidney problems.

Aside from incorrect development, there are many other medical disorders that affect the uterus including abnormal, heavy, or prolonged bleeding during a period, endometrial cancer and uterine fibroids (non-cancerous tumours of the myometrium that may cause pain during sex and painful periods). The uterus can also cause problems during pregnancy. If contractions begin too early (before 37 weeks of gestation), the baby is born prematurely. This spontaneous preterm labour occurs in around 7% of all pregnancies and is a major problem as prematurity is the leading cause of illness and death in newborn babies.

Partly because of all these problems, it’s fair to say that the uterus has received some bad press. Historically it has been considered something of a taboo. The Ancient Greeks regarded it as a troublesome beast that roams the female body causing symptoms including anxiety, irritability and fainting. In fact, up until 1952, doctors often diagnosed women with such symptoms as having ‘hysteria’ (from the Greek word for uterus). The condition was believed to be most severe in older (post-menopausal) and celibate women, who were not appeasing their uterus by bearing children. Early treatments for hysteria included beating the woman, bloodletting and hysterectomy (the complete removal of the uterus). These later evolved to include psychosexual counselling and genital massage to the point of orgasm. This was performed by a doctor, or later by an electrical vibrator marketed solely for this purpose. Other early descriptions of the uterus labelled it as a cold, dry organ and as a ‘sewer’ of poisons that are toxic to the mother. It’s likely that some of these attitudes would have stood in the way of scientific research and many patients with uterine disorders may have been dismissed as having ‘women’s problems’ that would be best kept ‘hush-hush’.

However, it’s not all doom and gloom for the womb, because like the woman it resides inside, the healthy uterus is actually a very sophisticated multitasking system. In pregnancy, the endometrium provides the fertilised egg with a cushiony surface to implant into and also supplies it with all the nutrients it needs to grow into an embryo. The myometrium spends nine months growing to give the baby room to develop and then contracts to help transport it to the outside world when it’s ready. Importantly and cleverly, these contractions are forceful but intermittent, so they don’t cut off the baby’s blood supply from the placenta. Even when a woman isn’t pregnant, the unique role of the uterus is still apparent. Whereas a breakdown in many other tissues would take a long time to heal and leave a scar that might affect its function, the endometrium manages to bounce back very quickly following menstruation. Understanding this process in the uterus may help us understand why other tissues fail to heal quickly or are heavily scarred. So surely we should be in awe of the uterus, not preferring to pretend it doesn’t exist!

The uterus is such a complex organ that we are still a long way off knowing everything about it. However, it is really important that we improve our understanding so that we can treat and prevent some of the disorders that affect it and millions of women worldwide. The University of Edinburgh has several research groups that study the uterus and its many and varied functions and problems.

It is hoped that by understanding menstrual bleeding, more effective treatments for irregular, heavy and painful periods will be found. Dr Jackie Maybin, a clinical lecturer from the Centre for Reproductive Biology explains, “These disorders are incredibly common, with one in three women thinking that their periods are too heavy, increasing to one in two as the menopause approaches. Some women are rendered housebound for one week out of four as their bleeding is so heavy.” While this is undoubtedly very disruptive to a woman’s life, the only truly effective treatment for severe cases is a hysterectomy. Unfortunately, this is a drastic measure and is associated with other complications, such as post-surgical infection, an increased risk of cardiovascular disease and hormonal imbalance, not to mention that without a uterus women are unable to bear children. Dr Maybin is currently investigating how the endometrium manages to break down and repair itself every month. She says, “My work focuses on the mechanisms of endometrial repair, trying to work out the factors involved and their regulation. In particular, I'm trying to identify if there is defective repair in women with heavy menstrual bleeding, compared to women with short, light periods. I'm making small steps of progress and hope my work will provide new treatments for these women.”

Another problem slowing research of the uterus, and prolonging the mystery, is the lack of good animal models. Dr Maybin carries out her research on human tissue, and for a very good reason, “There are no good models of menstruation: only humans, old world primates and fruit bats menstruate! Therefore, we rely on women to provide us with tissue.” Fortunately, a source for such tissue is not too far away thanks to collaboration with the Royal Infirmary who encourage the participation of patients. Dr Maybin feels that, “We are very lucky in Edinburgh that we have a fantastic set up, with doctors and scientists working closely to allow bedside-bench-bedside research, a truly translational approach. Women attending the gynaecology department are fantastic at giving permission for us to perform research on their biopsy and hysterectomy specimens.”

Tissue samples from patients at the Royal Infirmary are also being used in studies attempting to understand what triggers the myometrium to begin contracting and initiate labour. This is proving particularly useful because findings in other species (even other primates) don’t seem to apply to humans. For example, in sheep, blood levels of the hormones progesterone and oestrogen change at the end of pregnancy and this appears to trigger labour. If pregnant sheep are injected with oestrogen or a drug that stop the effects of progesterone, then the ewes will reliably go into labour. However, in humans there is no fall in progesterone levels at the end of pregnancy and labour is more difficult to predict and induce. The biggest problem is that we don’t know what triggers the myometrium to begin contracting in a normal birth; therefore we can’t tell why these contractions sometimes begin early, resulting in premature babies. Unfortunately, this means even in our developed world, the rate of preterm labour isn’t decreasing and millions of families are still suffering as a result.

Another group in the University, headed by Professor Jane Norman, are trying to unravel the conundrum of the contraction, i.e. exactly what initiates them. They have recently demonstrated that many molecules known to be involved in immunity and inflammation are also involved in triggering labour. Professor Norman explained to me, "Not only is child birth an inflammatory event, but also many of the adverse consequences of preterm labour (for the baby) relate to inflammation.” The group have shown that white blood cells, key molecules in immune and inflammatory responses, become more active during labour. Further to this, they found that cells in the myometrium of the uterus become more responsive to chemicals released from these active white blood cells at the end of pregnancy. The group is currently using this finding to help develop better drugs to stop preterm labour. Professor Norman said, “The best treatments for preterm labour are likely to be those which inhibit inflammation as well as uterine contractions."

As our understanding of its functions improves, the air of mystery is beginning to clear and the uterus is now thankfully recognised not as a troublesome beast, but rather as a fascinating and complex organ.

Gemma Sharp is a PhD Student at the Centre for Reproductive Biology


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