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Is estrogen safe this week? Does it matter when you start hormone therapy? What does "bioidentical" mean, anyway? Mary Duenwald scours the latest science for the answers even your doctor may not have.
In a windowless high school auditorium a few blocks from where Highways 6 and 50 intersect in Delta, Utah, you could hear the rain and thunder picking up steam. But for 100 or so women attending a menopause workshop one Sunday, the storm was inside, where the topic of a lecture was about how changing hormones affect sex drive—not the sort of thing people usually talk about in this rural community of alfalfa hay farmers. The speaker was just opening the discussion for questions when the power went out. "It was just so perfect. Suddenly, hands went up everywhere and the women were asking all kinds of questions they wouldn't have been willing to ask when the lights were on. One wanted to know about orgasm—really personal questions," recalls Linda Ekins, 60, the registered nurse who organized the event.

That was five years ago; today the workshop has expanded into an annual conference called Women in Motion that draws 250 to 300 attendees. The idea came to Ekins when she realized she wasn't alone in having to bushwhack her way through menopause. All across the country, millions of women are dealing with the end of fertility, many of them muddling along in discomfort and frustration. It isn't just a jarring reminder that one is aging; it can also wreak havoc on the body—and the mind. Sudden outbursts of temper, creeping anxiety, depression, loss of passion, or foggy thinking sends many sufferers in search of psychological help; others rush to trainers when their waistlines start expanding; still others go crazy buying supplements to combat thinning hair and painful joints. And often these women don't realize that the real cause of these symptoms—not to mention hot flashes, night sweats, vaginal dryness, and insomnia—is the onset of menopause, which officially starts after 12 consecutive months of having no menstrual periods.

Scientists have yet to figure out why declining levels of estrogen (which occurs when the ovaries stop producing eggs) should have such wide-ranging effects. But they do know that cells throughout the body have receptors for the hormone and that its withdrawal impacts everything from the blood vessels to the brain. "The layperson has very little information about this," Ekins says. "My women are confused. They're having hot flashes. They're bitchy with their husbands, grouchy with their kids, angry at the world, absolutely miserable." And ebbing libido—particularly how it's affecting their marriages—is a huge concern (a course called "Hormones in the Bedroom" drew a standing-room-only crowd a couple of years ago). "My aim is to give women information, so they can visit with their physicians and intelligently come up with a plan," she says. "We do not need to be afraid. We need to be educated."

And yet even smart, well-informed women often hit a wall when it comes to deciding which symptoms are menopausal and how to deal with them. Hormone therapy (HT)—specifically supplemental estrogen, alone or combined with progesterone (usually progestin)—is the most studied and effective form of treatment to date for symptoms such as hot flashes and night sweats. But the treatment developed a bad reputation in 2002 after the Women's Health Initiative (WHI)—which conducted the largest, most rigorous study ever on HT—issued alarming findings that taking estrogen and progestin could increase the risk of both breast cancer and heart disease. In addition, it later came out that the hormones didn't seem to help much with sleep, depression, energy, or sexual satisfaction compared with a placebo. "There is still a lot of confusion even among physicians about hormone therapy, and many avoid prescribing it," says JoAnn Manson, MD, chief of preventive medicine at Harvard's Brigham and Women's Hospital and a principal investigator of the WHI study. "It can be a real problem for women to find a doctor who is willing to discuss all the benefits and risks of hormone therapy."

To more safely and comfortably navigate this major phase of life, it helps to understand a bit about past hormone research and what science is discovering even as we speak.

Go inside the February 2009 issue of O, The Oprah Magazine:

It was back in 1966 that Robert Wilson, MD, a Brooklyn gynecologist, published his best-selling book, Feminine Forever, and declared that taking estrogen was a postmenopausal woman's best chance to lead a healthy, happy, and sexually active life. In the ensuing decade, prescriptions for the hormone almost doubled. But then came evidence that taking estrogen could lead to uterine cancer, and prescriptions dropped off dramatically.

Hormone therapy regained its popularity, however, after the discovery that adding progestin headed off the risk of uterine cancer. In the early 1980s, scientists began to focus on how estrogen could protect women's bones against osteoporosis. By the '90s, research seemed to confirm its long-suspected link to preventing heart disease, at which point the American Heart Association and the American College of Physicians came onboard. Once again, hormone therapy looked like a smart idea.

But in 2002, the Women's Health Initiative caused scientific whiplash. According to its findings, the hormone pills in question—Prempro, the most popular brand of estrogen and progestin—not only failed to protect against heart disease but actually raised the risk. Crunching the data, the researchers projected that among 10,000 women taking these hormones for a year, compared with a placebo, there would be seven more cases of coronary heart disease, eight more cases of stroke, and 18 more cases of blood clots. "There was much rending of clothes and gnashing of teeth when this study came out, because the results were very unexpected," says Nanette Santoro, MD, director of reproductive endocrinology and infertility at Albert Einstein College of Medicine, in the Bronx.

Less shocking but more unnerving for many: Among 10,000 women on Prempro, there would also be eight additional cases of invasive breast cancer. (The fact that there was a lower risk of colorectal cancer and hip fractures got lost in the shuffle.)

The WHI findings made major headlines and were particularly scary to the public, given that researchers stopped the study three years early to protect participants' health. Women by the millions threw out their hormone pills. And seven years later, many are still wary. "I can understand the mistrust," says Carla Lupi, MD, an assistant professor of clinical obstetrics and gynecology at the University of Miami Miller School of Medicine. "These women grew up being told that hormone therapy was the greatest thing since sliced bread, only to wake up and be told that there actually are some risks."

Unfortunately, scientists have yet to unearth a more effective remedy than estrogen, and that may reflect what's been a relatively narrow approach to the profound mind-body shifts that occur during menopause. "All of this focus on estrogen may be a bit misplaced," says Lisa Sanders, MD, clinical instructor at Yale University School of Medicine. "Women exist in an incredibly complicated hormonal milieu during menopause. Estrogen declines, but so does testosterone, which is why libido goes down. We're also losing hormones that we really don't know much about, and we haven't asked the questions."

The fact is, however, researchers do know a lot more about hormone therapy today. Since the WHI shake-up, they have begun to explore—and shed light on—how the formulation and timing of HT may lower its risks and improve its benefits. And the result is a more nuanced knowledge of how the treatment might be most safely applied. 

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Vivian Torres-Suarez, 54, a healthcare executive from Queens, New York, was one of millions of women suspicious of hormone therapy in the wake of the WHI findings. But her symptoms were getting to her—not only hot flashes but also a hot temper that had prompted her to lash out at a colleague during a staff meeting. "I don't remember exactly what he said, but I must have turned into a wicked witch," Torres-Suarez recalls. "Then he said, 'Are we having a bad menopausal day?' And I just blasted him."

Torres-Suarez's gynecologist recommended the estrogen pill Premarin, which contains the same type of estrogen used in the WHI study. "I don't feel comfortable with that, I really don't," Torres-Suarez told her doctor. And there are experts who would agree with that choice, arguing that Premarin and Prempro are not ideal products because they're derived from the urine of pregnant horses. Instead, these doctors prefer a synthetic estrogen, estradiol (found in Estrace, Climara, Estring); it's chemically identical to the kind made by women's ovaries, which is why it is described as "bioidentical." Between 2003 and 2008, prescriptions for bioidentical estradiol-based products rose from 22 to 35 percent of the supplemental estrogen market while those for Premarin tablets fell from 53 to 35 percent, according to IMS Health, a healthcare information and consulting company.

Manhattan internist Erika Schwartz, MD, prescribes estradiol made by pharmaceutical companies or orders a transdermal cream from a compounding lab, which customizes it for individual patients. When Torres-Suarez visited Schwartz for a second opinion, the bioidentical hormones made sense to her, and she liked the idea of a cream (hers includes bioidentical progesterone), which she applies to her chest twice a day. "My hot flashes haven't disappeared, but they're much better," she says. "And I'm no longer like the girl in The Exorcist. I felt like I was losing my mind, and I'm not like that—I'm really a nice person. This has absolutely made me better."

Yet, whether bioidentical estrogen and progesterone are safer or superior is unproved. It's entirely possible that they have the same risks that Prempro does. "There was a flight from reason when the WHI results were published," says Santoro, referring to the illogical assumption that if a hormone product wasn't used in the study it must therefore be safe. She adds: "To prescribe something more physiologic may make sense, but what's really physiologic for a 55-year-old woman is to have less hormone, period."

Kirtly Parker Jones, MD, a professor of reproductive endocrinology at the University of Utah, in Salt Lake City, points out another important fact of biology. The body often takes the estrogen it's given and changes its form so that a woman may use estradiol only to have her body turn it into estrone sulfate, the main ingredient in Premarin and Prempro. "Some well-meaning practitioners probably don't know the endocrinology," Jones says. One trial in the works called the Kronos Early Estrogen Prevention Study (KEEPS) is giving some subjects estradiol patches and others Premarin pills, with the goal of determining whether the patch is as effective as, and potentially safer than, the pill. But the results aren't expected until 2012.

In the meantime, a number of practitioners who are deeper into the bioidentical movement are stirring up controversy by measuring the hormone levels in women's saliva, a method unproven by mainstream science, in order to concoct products that may contain mixtures of various kinds of bioidentical hormones, as well as ingredients that have not been approved by the Food and Drug Administration. Last January the FDA took action, sending warning letters to seven compounding pharmacies stating that their claims of producing drugs that are safer, more natural, and superior to FDA-approved HT drugs are "false and misleading" and unsupported by medical evidence. In particular, estriol, one form of estrogen used by these pharmacies, has never been approved by the FDA, and its safety and effectiveness are unknown.

Official statement from the FDA on bioidentical hormones

For many women, the specter of breast cancer is what drives them away from HT—and for those who have a higher-than-average risk of the disease, such fears make sense. The link between HT and breast cancer has been supported by studies in the United States, Sweden, and the United Kingdom.

While finessing the chemistry of estrogen won't likely mitigate the breast cancer risk, tinkering with the progestin component of HT might. "Study after study seems to indicate that the increased risk of breast cancer is not related to estrogen but to progestin," says Steven R. Goldstein, MD, a professor of obstetrics and gynecology at New York University School of Medicine. A separate component of the WHI study in which subjects were not given progestin (because they'd had hysterectomies and stood no risk of uterine cancer) did not show an increase in breast cancer risk.

Goldstein has begun to experiment with prescribing his patients much less progestin, while regularly monitoring their uterine lining with ultrasound—the idea being that a smaller amount of the hormone may be enough to prevent cancer there. Still, he makes clear, "there has been no long-term study of this methodology."

When it comes to heart disease risk, the research is most promising. Because the WHI was designed in part to investigate HT's effect on heart disease, the researchers chose mostly women who were older (and more likely to have cardiac events); the average age of the 27,347 subjects was 63, and a majority of them were at least ten years past having their last menstrual period. But now a new theory has taken shape and steadily gained credibility: that hormones might be less dangerous, and perhaps even beneficial, if started closer to the time women reach menopause (the average age is 51). According to this new theory, estrogen introduced before too much plaque begins to build in a woman's arteries might actually help keep blood vessels healthy. Only after the plaques have gained a foothold might HT make things worse. Further analyses of the WHI data support this idea. As it turns out, a subgroup of younger women in the estrogen-alone study had a significantly reduced risk of heart attacks and cardiac death; those with the increased risk were the ones who'd started hormones more than 10 years beyond menopause.

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Starting HT earlier might also positively affect memory, concentration, and cognition. Alas, here again there is no good clinical trial data. But a half-dozen small studies have had promising results, says Sarah Berga, MD, chairwoman of the department of gynecology and obstetrics at Emory University School of Medicine in Atlanta. "Estrogen seems to lubricate the brain, in some ways, for thinking," she explains.

Better evidence for—or against—early timing may arrive when the KEEPS study, whose subjects range in age from 42 to 58, is completed. "What I hope the study will show," says Santoro, one of its principal investigators, "is that for women close to menopause, the risks of hormone therapy are low and they may get some cardio protection."

There is already a growing consensus around this idea. Many leading experts now recommend HT at the lowest dose and for the shortest time possible—the first few years of menopause—along with regular checkups and mammograms for women with debilitating symptoms (assuming they don't have high risk of heart disease or breast cancer). Manson recommends staying on hormones two to three years, five at the most, after which hot flashes usually subside. "Five to 10 percent of women have persistent significant symptoms more than ten years after menopause," she says; in those cases, doctors and patients must weigh the individual health risks against quality of life benefits. "But the vast majority of women can come off HT after a few years and do fine." This, by the way, is now the position of the North American Menopause Society and the American Association of Clinical Endocrinologists.

But we still have a long way to go in terms of getting the answers we need—which means that women really must take the steering wheel in directing their care. For Linda Ekins, the nurse in Utah, menopause has been a challenging journey. "It's not just about medication," she says, explaining that her menopausal troubles started 20 years ago with depression. "I couldn't figure out what was going on. I went into therapy and realized that part of it was menopausal." When hot flashes came soon after, she was able to keep them at bay by taking the herbal supplement dong quai (although research has failed to prove it a reliable treatment). "But at 55," she says, "the hot flashes were breaking through, and I wanted information." She'd read about bioidentical hormones and found her way to the University of Utah's Kirtly Parker Jones, who prescribed them to her in a progesterone pill and estrogen patch. "I asked for the lowest dose possible, and Dr. Jones said I could try cutting the patch in half. I did, but then I started having hot flashes again, so I've gone back to the full dose. The hormones have done really well for me, including helping vaginal dryness, which I don't choose to experience because I'm still sexually active; as long as my husband is happy and I'm happy, things are good." But, she adds, there's so much more to managing menopause on an emotional and spiritual level. To that end, Ekins has expanded her conference by bringing in experts in yoga and energy work. "Find friends and support systems," she urges. "A pill or patch can certainly help, but it won't be the answer to everything."
As a reminder, always consult your doctor for medical advice and treatment before starting any program.


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