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Where the Scientific Community Stands on the Safety of Hormone Therapy

By Nora Underwood

The pendulum swings back toward the wider-ranging health benefits of hormone therapy.

Once considered a debacle, it seems a more nuanced reading of the science and approach to treatment is providing new hope for the men and women who need it.

Many women who are lucky enough to live good, long lives will spend more than a third of those lives (roughly) dealing with all that happens to them physically and emotionally during the child-bearing years and another third (roughly) coping with what happens when those years are over. Certainly, there are women who barely notice perimenopause and menopause — maybe they toss the blankets off in the middle of the night once in a while or find their skin’s a little drier than it once was. But nothing serious.

For the rest — and that’s a good quarter of women — in the years leading up to and through menopause and beyond, some of these symptoms may ring a bell: hot flashes, night sweats, mood swings, sleep problems, depression, anxiety, low libido, vaginal dryness, pain during sex, memory and concentration problems, palpitations, weight gain around the abdomen, sore joints, dry skin, thinning hair, fatigue. And these are just the ones that are the most documented. Some women get pimples when they’ve never had them before or a new intolerance for sun or wine or caffeine or any number of things; in my late 40s, I’d get spontaneous streaks and splotches of bruising on my face that would appear suddenly and be gone three days later.

Women are one of only three species that outlive their ovaries (killer whales and short-finned pilot whales do, too). Most other species die giving birth or when they are no longer able to have offspring. Why this happens is not known for certain. One popular theory is the “grandmother hypothesis” — as women get older, they lack the necessary energy to raise children of their own; their use becomes, instead, in contributing to the survival of their grandchildren. Whatever the reason, the precipitous decline of estrogen, the primary female sex hormone, in the years leading up to and through menopause means the time is often a fraught one.

In the early 1940s, almost two decades before the invention of the Pill, researchers discovered a way to manufacture estrogen out of the urine of pregnant mares. Doctors prescribed Premarin to women who were suffering from hot flashes and/or night sweats, and it worked. But it was only the initial swing of the hormone therapy (HT) pendulum — first, from the 1970s, when it was found that using estrogen alone increased the risk of endometrial cancer in women with a uterus to the addition of uterus-protective progesterone only a few years later. By the early 1990s, Premarin was again widely prescribed. A 1991 article in the New England Journal of Medicine entitled “Uncertainty about Postmenopausal Estrogen: Time for Action, Not Debate” noted a reduction in ischemic heart disease of as much as 50 per cent, which killed many more women than breast cancer. But less than a decade later, enthusiasm over hormone therapy came to a screeching halt.

In 1991, the U.S. National Institutes of Health launched the Women’s Health Initiative (WHI), a multimillion-dollar 15-year study of more than 160,000 post-menopausal women between the ages of 50 and 79 to determine how certain diseases affected older women. In one arm of the study, researchers followed post-menopausal women who were taking estrogen and progestin (a synthetic progesterone) to determine whether the hormones offered protection against cardiovascular disease and fractures related to bone loss. But by 2002, scientists detected an increased risk of breast cancer, heart disease, blood clots and stroke among the women in the study. As a result, the HT arm of the study was abruptly suspended.

There was helpful information in the study results — that women more than a decade past menopause or who are at risk for heart disease would be unwise to take HT or at least the combination of drugs that was used in the study. And that was partly the aim of the WHI, to confirm previous studies that showed, among other things, a 40 per cent reduction of heart disease in women who were on HT during menopause; researchers were trying to determine whether all women should be offered HT because of those protective benefits. “When it showed there was, in fact, this risk of harm, that completely addressed their question – no, everybody shouldn’t,” says Dr. Jennifer Blake, CEO of the Society of Obstetricians and Gynecologists of Canada. “But what it buried was that when they looked back at only the women who were within 10 years of menopause, there was about 40 per cent less heart attack and heart disease and a 40 per cent overall decrease in mortality. In fact, it was actually quite beneficial and, at the very least, safe for women within 10 years of menopause.”

Within months of the initial release of the results — and thanks, in part, to some pretty scary headlines — HT use had dropped dramatically all over the world; guidelines were revised, doctors appeared less inclined to prescribe them and many women suffered needlessly as a result. “After the WHI, there wasn’t a lot of research and a lot of attention paid to menopause,” says Dr. JoAnn Pinkerton, executive director emeritus of the North American Menopause Society (NAMS) and professor of obstetrics and gynecology and director of Midlife Health at the University of Virginia Health System in Charlottesville. “We took a step backwards in women’s health.”

Lost in the sensationalistic headlines and backlash against HT were some important facts: for one thing, the average age of women in the study was 63. More than a third of them were clinically obese. Just over a third were being treated for high blood pressure; nearly half were past or current smokers. “Women over the age of 60 or 10 years after the onset of menopause are not women we initiate menopausal hormone therapy in,” says Dr. Marla Shapiro, a family physician in Toronto and past president of NAMS. “The women we’re initiating hormone therapy in are typically late in transition of their perimenopause and their early years of menopause, where symptoms can be quite intractable and really impact their quality of life.”

As a result, many women went off HT out of fear, and those for whom HT was not a problem suddenly lost the protection it afforded against heart disease and bone loss. “There were definitely negative consequences to this message being transmitted to patients for whom it wasn’t helpful advice,” says Blake. “But once you plant a fear, it’s very hard to uproot.”

The WHI study also addressed the question of whether HT use led to an increase in risk of breast cancer. Blake says doctors always knew that they were seeing a slight increase in breast cancer in long-term users of hormone therapy — “and, of course, no increased risk is what we’re shooting for,” she adds — but the magnitude of that risk was lost in the uproar. In reality, the risk of HT was the same as it would be for a woman who doesn’t have her first pregnancy before the age of 30. “Typically, when we talk about risks that are very meaningful, we mean a risk that is three to five times greater,” Blake explains. “This is a 1.2.” That’s the kind of increased risk you assume if you drink alcohol with your meals, if you are 20 per cent overweight or if you had an early onset of period or a late menopause. “If you’re the person who has breast cancer, you’re unlikely to say it’s because I had wine with dinner or because I was over 30 when I had my child; it’s more likely you’ll think it’s because of what you did during menopause,” she adds. “But that’s just human nature. We aren’t always rational in the way we understand risk.”

When Jane* was 53, she started to experience terrible hot flashes. Her doctor encouraged her to consider going on hormone therapy, but Jane was afraid of raising her risk of breast cancer and was just plain scared of it. As time went on, she became severely sleep-deprived, up many times every night changing soaking-wet sheets and subjecting her husband to sleeping in a room with a huge fan going all night in the winter.

One night, when she was 55, she was at the same dinner party as her doctor. “It was winter, and the whole night I was taking off my clothes,” says Jane. “I was down to a tank top, I was sweating and, at the end of the meal, my doctor said, ‘As your doctor, I can’t watch this. I don’t even believe you’re tolerating this.’”

Jane decided to try hormone therapy and remained on it, happily, for five years. On her 60th birthday, she figured she’d been on long enough and stopped taking the medication. Within three months, she was back on. “It was intolerable,” says Jane, 62. “I just know I don’t have a choice. I feel like I’m back to being a human being. I’m working, I’m functioning, I’m sleeping. It’s really made a massive difference in quality of life.”

Another unfortunate result of the WHI, according to Toronto-based Dr. Jennifer Pearlman, was that doctors no longer learn about hormone therapy in medical school — despite the fact that menopausal women make up a third of visits to a GP. “Even a gynecologist committed to caring for women’s health does not have a mandatory curriculum on menopause,” says Pearlman, who specializes in women’s health and aging. “It’s an elective or a fellowship.” Which is pretty shocking, to say the least.

But if WHI back-burnered hormone therapy for all those years, the pendulum does finally seem to be swinging back, as doctors understand more about hormone therapy, and newer options abound. One of the many misconceptions was that women should only use hormone therapy at the lowest dose for the shortest period of time — five years, max. “The position statement of NAMS stresses the importance of individualizing therapy,” says Shapiro. “We now encourage the phrase ‘the appropriate dose, route and formulation for the appropriate patient and for the appropriate period of time’.” The other misconception is that there is a mandatory stop date because for at least 15 per cent of women, for example, hot flashes don’t disappear. “For many of those women to arbitrarily be stopped because of some arbitrary stop rule may be potentially detrimental for a subgroup of women who continue to have either severe or frequent vasomotor instability,” she adds.

Women each come to the table with a different history, and that’s what a well-versed doctor explores — personal risk factors, family history of disease and so on — to determine whether they’re candidates for hormone therapy and, if so, what type, at what dose and through what delivery route. In women under 60 or within 10 years of menopause with a personal history that doesn’t raise any red flags, the benefits of hormone therapy are considered to outweigh the risks. “We have data now that tells us that women who initiate hormone therapy before age 60 or within 10 years of menopause may have a reduction in coronary heart disease,” says Shapiro. “I do not think you are going to hear physicians saying hormones should be used to prevent heart disease, but we do know that women who use menopausal hormone therapy will have cardiovascular protection.”

There are different delivery methods — pills, patches, gels, rings — and plenty of options, including a newer class of medication called SERMs (selective estrogen receptor modulators). When one particular SERM, bazedoxefine, is combined with a low-dose of conjugated estrogen, the combination is more favourable in terms of breast health while still protecting the lining of the uterus. Many more treatments are in the research or approval stages. Researchers are also looking at different nonhormonal types of treatment of hot flashes, such as injectibles (see pg 67), that work through receptors in the nervous system and the brain.

Practitioners may use biosimilar (what many people call bioidentical) hormones when treating a patient as opposed to synthetic hormones, which are those produced by pharmaceutical companies. And here’s where it gets a bit confusing. As Pinkerton explains, ”The term bioidentical hormone refers to hormones that are biochemically similar to the hormones made within the human body.” They may be formulated out of soy or yam but they need to be modified so that they can be absorbed by the body and transform into active hormones.

Where some experts express concern is around non-FDA-approved compounded bioidentical therapies that start with the same ingredients but which are neither monitored nor regulated. Those may be prescribed by natural health practitioners, who are not medical doctors, as well as by qualified doctors like Pearlman. Compounded hormones are specially made by a trained compounding pharmacist from a health-care practitioner’s prescription. While compounding is common in other areas of medicine such as dermatology, many experts express concern about using compounded therapies to bring hormones into balance. “One of the big concerns is that the estrogen levels vary quite a bit, and some of them can be quite high,” Pinkerton says, “so there may be an imbalance of too much estrogen and not enough progesterone, which puts you at risk for endometrial cancer.” She and others believe that compounded hormone therapy should only be used in certain cases; for example, where a patient can’t tolerate the government-approved drugs or who need a special formulation or dose.

Other doctors, such as Pearlman, feel strongly that compounded
bioidenticals prescribed by a doctor with expertise in the area are important tools to help women. “If you’re premenopausal or perimenopausal, there are no approved options,” says Pearlman, “and these are often the most symptomatic women who are getting their periods on an irregular basis. Often these women may not be sleeping, they have brain fog, they have body shape or weight changes, they’re irritable and impatient, and it’s affecting their professional and personal world.” At that stage, the only thing that GPs can prescribe is the Pill and/or antidepressants, as menopausal hormone therapy is currently only indicated after 12 months have elapsed from the woman’s last period.

Compounding allows Pearlman, who for 10 years helped run the largest menopause clinic in Canada, at Mount Sinai Hospital, to do things that can’t be done conventionally. For example, she says, there is a huge body of evidence for the use of testosterone, the primary male sex hormone, to treat low libido in women. “In parts of the world, this would be a government-approved product but, in Canada, there’s no approval for testosterone in women, despite the benefits being supported by clinical evidence,” Pearlman explains. “As opposed to trying to work with male products that would overdose a woman, I often choose to provide a more customized solution in the right dose, format and vehicle for application.”

Where there is no difference of opinion between these experts is on the subject of so-called bioidentical compounds that are ordered by alternative-care practitioners. Pearlman believes that the post-WHI panic left room for other unregulated, unmonitored providers to fill the void. “It’s a total falsehood that creams from naturopaths are in any way safer,” says Pearlman. “People have mixed up the idea of compounding and the false use of the word ‘natural’ with the pseudoscience that’s being peddled out there. It’s the Wild West. I condone none of that.”

Shapiro agrees. “I caution women that if they go to someone who says ‘I’m going to make something based on your saliva,’ which is certainly not based on medical evidence, that it is not safer and may be more harmful,” she says. “I don’t want women to believe there are no side-effects because they’re so-called bioidentical and compounded. That’s just not true.”

Hormone therapy has come a long way since the Women’s Health Initiative and, for the right woman, it can be a godsend. Shapiro encourages women to get their information from a knowledgeable health-care practitioner. NAMS certifies doctors who have completed menopause competency exams, and a list of some of those experts is on the organization’s website.

Are there concerns about HT? There are side-effects to every medication, and taking anything is always a question of weighing benefits to risks. Women should never suffer needlessly. “We’ve learned a lot since 2001,” says Blake. “There’s not too much in medicine that is governed by a single study that’s 18 years old. So it’s time to give it another look.”

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