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The great escape: Ending period pain
26 September 2007
NewScientist.com news service
Hannah Hoag
THEY are a rite of passage for young women and a sign of likely fertility and health. For some women they are welcome proof that they are not pregnant. But generally speaking periods aren't much fun. What with radical mood swings, migraines, cramps, bloating and nausea, at best they are an irritation, at worst they require medication.
Now, though, women can choose to opt out entirely. In July, pharmacies in the US began stocking a new oral contraceptive designed for women "interested in putting their menstrual cycle on hold". The pills can be taken 365 days a year with no need to break for a monthly bleed. Other forms of hormonal contraception are on the cards too. Researchers are experimenting with ways to keep periods at bay by blocking the body's own progesterone.
All of this has reignited the debate over whether it is healthy for women to disrupt their monthly cycle and even stop having periods altogether. Some say that the rate at which the average western woman menstruates could actually be bad for her health - causing an increased risk of ovarian cancer and many other disorders. Others argue that long-term exposure to the hormones in birth control pills could be harmful, that it's wrong to medicalise menstruation and that not having periods could mask signs of infertility until it's too late.
The regular contraceptive pill has changed very little since it was first licensed in the 1960s. Today's pills contain a much lower dose of hormones than they did back then, but the concept remains the same. Most are made of synthetic versions of the key reproductive hormones oestrogen and progesterone, which prevent pregnancy by stopping the ovaries from releasing an egg. They also thicken the cervical mucus, making it nearly impossible for sperm to pass into the uterus.
The pill was designed to be taken for 21 days in a row, followed by a week of either placebo pills or no pills at all. Over the first 21 days, the endometrium - the lining of the uterus - reinforces itself, building up tissue into a lush nourishing environment in anticipation of a fertilised egg, which of course will never arrive. When the pills run out, the drop in progesterone triggers the expulsion of this blood vessel-rich tissue, mimicking a period.
However, not all women follow this schedule. Some choose to take the pill every day, skipping the seven-day break or placebo pills and avoiding any bleeding. Women have been doing this ever since the pill was formulated. Some did it for convenience, others to rid themselves of unwanted symptoms. Patricia Sulak, an obstetrician at Texas A&M University Health Science Center College of Medicine in Temple, is among the many physicians - and women - who challenged the idea of the seven-day break early on. "I did my medical residency in the early 80s. Many of us were on continuous pills then, and we have been recommending it to many of our patients since," she says.
Now, after more than 20 years of clandestine menstrual suppression continuous contraception is becoming mainstream and the standard pill regime is beginning to look a bit passé. In recent years, some pharmaceutical companies have repackaged their pills into products that allow women who take them to have just four periods a year. One, Seasonale, was approved by the FDA in September 2003, while Seasonique was approved in May 2006.
Yearly cycle
Lybrel, manufactured by the pharmaceutical giant Wyeth, is the first oral contraceptive to be approved for continuous use. The drug, to be marketed as Anya in Canada and the European Union, is taken daily, turning that time of the month into that time of the year - and only then if a woman chooses to stop taking the pills. David Archer, director of the Clinical Research Center at the Eastern Virginia Medical School in Norfolk, oversaw some of the clinical trials for Lybrel. He says there's no real reason to stop after a year. "If you have done well the first year, why not go on for a second?" he says.
Sulak is among a growing group of medics who feel that having fewer periods is a good thing and that a monthly period may even be bad for a woman's health. Richard Anderson of the Centre for Reproductive Biology at the University of Edinburgh, UK, agrees. He says he can think of no medical reason why women need to experience a monthly bleed. "It really just reflects that you haven't got pregnant and that there is no embryo trying to implant into the uterus," he says.
In fact, bleeding every month is not necessarily the norm. Anthropological studies of women in contemporary hunter-gatherer societies show that they have far fewer periods than western women and suggest that women in pre-industrial times had far fewer periods than women today. In the 1980s, Beverly Strassmann, now at the University of Michigan in Ann Arbor, spent more than two years living among the Dogon people of Mali in west Africa. She found that menstruation was a relatively rare event: between the ages of 20 and 24, women had on average just two periods a year. Strassmann calculated that a Dogon woman has only around 110 periods in her lifetime. The rest of the time she is pre-pubescent, pregnant, lactating or post-menopausal. In contrast, the average woman in New York, London or Toronto has 350 to 400 periods between menarche and menopause. Her first period arrives earlier, she bears children later, has fewer of them, and doesn't breastfeed for as long.
“Having a monthly period is not necessarily the norm. It may even be bad for a woman's health”
All these factors lead to almost incessant ovulation and menstruation. Sulak reels off a list of problems that may be associated with or worsened by uninterrupted menstrual cycles: ovarian cancer, increased risk of endometriosis, anaemia, uterine fibroids, premenstrual syndrome (PMS) and premenstrual dysphoric disorder - a severe, disabling form of PMS. "We weren't designed to have decades of periods," she says.
But while taking the pill continuously might reduce your risk of developing some of these conditions, the pill brings health concerns of its own. Few long-term studies have addressed potential risks to breast, bone and cardiovascular health, but there have been high profile scares. For example, since 2004, the FDA has required that Depo-Provera, a long-term injectable contraceptive, include a warning about how it may lead to reduced bone density.
More generally, women with a history of cardiovascular disease, or who are obese, those with high cholesterol levels, and smokers over the age of 35 face a greater risk of blood clots that could lead to pulmonary embolisms, strokes or heart attacks when taking any contraceptive pill. Some studies have shown that the pill may bring an increased risk of cervical cancer.
As well as health concerns, long-term use of oral contraceptives can have unwanted side effects. Unpredictable bleeding is a common reason for women to stop taking the pill and Lybrel is no exception. During a phase III clinical trial more than half of the 2134 women who took part dropped out, many of whom cited bleeding as the cause. Of those that remained in the study, 40 per cent still experienced irregular bleeding after 12 months.
Faced with these problems, researchers are now looking at different forms of contraception altogether. Rather than using synthetic oestrogen and progestin to control the menstrual cycle, they are using antiprogestins to block the body's own progesterone. This is the hormone responsible for the build-up of blood vessels in the uterus, so if this can be prevented, there is no lining to shed and no period. Antiprogestins would also suppress ovulation, making them potential contraceptives.
The first antiprogestin was synthesised in 1980. Since then more than 400 others have been identified, but only a handful have been tested in humans. Some say antiprogestins herald a revolution in reproductive science, offering control of menstruation without the need for long-term exposure to oestrogen and progestin. "You won't get a contraceptive that is more effective than current methods and intrauterine devices, but you can get one that has added health benefits," says David Baird, a reproductive biologist at the University of Edinburgh.
Baird and his colleagues have been studying the contraceptive properties of the antiprogestin mifepristone for many years. In early clinical trials the hormone has lived up to its potential as an extended-use contraceptive. Most recently the team compared it with the progestin-only pill - also called the mini-pill - in a trial with 97 volunteers. More than 80 per cent of the women who took mifepristone daily for six months did not experience any bleeding or spotting, or had less than two days of bleeding or spotting per month (Human Reproduction, vol 22, p 2428).
Another study published in June demonstrated an alternative approach. Researchers at the Oregon National Primate Research Center in Beaverton tested an intrauterine device (IUD, also known as a coil) that released an antiprogestin called ZK 230211 directly into the uterus of macaques. Robert Brenner, who led the study, found that although there was extended bleeding immediately after the IUD was fitted, the longer it was in place, the less likely the macaques were to experience bleeding or spotting. And although the study did not directly test the device as a contraceptive, Brenner believes such a device could potentially offer a long-term, reversible option with minimal breakthrough bleeding and few side effects (Contraception, vol 75, p S104).
"There is no doubt that antiprogestins can suppress bleeding," Brenner says. "The question is what is the best drug and the best way to deliver that drug?" To him, an IUD makes sense, because the actions of the antiprogestins remain largely localised, minimising any unwanted effects elsewhere in the body.
Body blocking
As well as acting on the endometrium, progesterone affects the ovaries, breast tissue and brain. If the antiprogestin is swallowed, as it is in Baird's trials, it will distribute itself throughout the body and may be more likely to cause side effects. Although Baird reported no major adverse effects in his study (minor side effects included abdominal pain, headaches and mood swings), a phase III trial of a larger number of women would give a better idea.
One particular concern is the fact that the body would be constantly exposed to oestrogen without the inhibitory effects of progesterone. Since endometrial cancer is often linked to exposure to excessive oestrogen, some researchers are concerned that blocking progesterone might make endometrial cancer more likely. In Baird's trial, almost half of the women had some changes to their uterus, although none had over-proliferation of the endometrial lining that could be the early signs of endometrial cancer.
In the west, IUD uptake has lagged behind that of the pill, but Sulak and Anderson say they have recently become more popular, particularly the new hormone-containing coils such as Mirena, which slowly releases a progestin called levonorgestrel over five years. According to its manufacturer Bayer, 90 per cent of women who use Mirena can expect less menstrual bleeding and 20 per cent have no periods after a year. However, many women find the amount of breakthrough bleeding that occurs in the first three months unacceptable, Brenner says, which is why he began testing the antiprogestin IUD.
Antiprogestins seem to have great potential for contraception and the suppression of periods, but their use is controversial. In 1980, soon after researchers at the French pharmaceutical company Roussel Uclaf discovered mifepristone, also called RU-486, the drug was found to be able to abort pregnancies. Since then mifepristone has been widely used in Europe and the US in combination with another drug, misoprostol, for medical abortions.
This fact has dogged the development of antiprogestins as contraceptives, say Brenner, Baird and others. "It has made it anathema among those opposed to abortion, especially in the US. Many drug companies have shied away from developing this class of drug because of the controversy associated with its use in medical abortions," Brenner says.
Baird has no further plans to study the hormone as a contraceptive. "It has reached a stage where we can't take it any further until a commercial company takes it on for phase III development," he says. "You're talking about an investment of between $5 million and $8 million. The companies are convinced there is a market for it, but it is a question about whether they want to get into this area."
It's hard to say whether or not antiprogestins will make it to the clinic. The pill is approaching its 50th birthday, and while there are many more choices available for women today, there is still no sign of the perfect contraceptive. Let's hope it arrives well before it reaches 100.
Hannah Hoag is a freelance science writer based in Montreal, Canada
From issue 2623 of New Scientist magazine, 26 September 2007, page 40-43
