By Sarah Henry
It was big news in 2002 when researchers called a halt to a major government-run study of a hormone therapy used by millions of older women. Researchers stopped the study, one of a series of clinical trials under the Women's Health Initiative (WHI), after they found that long-term use of estrogen and progestin raised the risk of heart disease, stroke, blood clots, and invasive breast cancer.
The cardiovascular and cancer risks of estrogen plus progestin outweigh any benefits -- and a 26 percent increase in breast cancer risk was too high a price to pay, even if there were a heart benefit, said Claude Lenfant, MD, director of the National Heart, Lung, and Blood Institute, the agency that halted the study.
The next year, the Journal of the American Medical Association (JAMA) reported more bad news for women getting HRT. The journal published a study of women who took a combination of estrogen and progestin, a synthetic form of progesterone, and showed they were at risk of getting a more aggressive form of breast cancer than women who didn't get HRT.
Not only were women more likely to develop breast cancer if they took the hormones, researchers wrote, but their tumors tended to be larger and more advanced than breast cancers that developed in women who took a placebo. Women on combination hormone therapy were also more likely to have abnormal mammograms -- even in the first year of treatment -- than women taking a placebo, according to the same study.
It was a series of big setbacks in less than a year for combination HRT. Other studies soon found HRT also increased the risk of Alzheimer's, dementia, and asthma. And in 2010, research found that combined estrogen-progestin HRT increased the risk for more severe forms of breast cancer and increased a woman's chances of dying from the disease or other causes.
Although there had been some reports that women on HRT developed less aggressive cancers, the researchers found that was far from the case. On the contrary, women taking the combined HRT were 25 percent more likely to have an invasive breast cancer than women in the placebo group, 78 percent more likely to have cancer that had spread to the lymph nodes, and were almost twice as likely as the placebo group to die of breast cancer (and 57 percent more likely to die of other causes).
However, some research since that time suggests that the timing of HRT is important and that the use of HRT should be decided on a case by case basis. (See "Is HRT Safe?" below)
What exactly is hormone replacement therapy?
As you approach menopause, your levels of estrogen and progesterone (the hormones that cause you to ovulate and menstruate each month) start to decline, often triggering a whole host of symptoms that can range from annoying to incapacitating. Replacing the lost estrogen with hormone supplements can alleviate these problems, which may include hot flashes, depression, mood swings, vaginal dryness, sleep disturbances, and clouded thinking.
Is hormone replacement therapy safe?
Some women may be able to take hormone replacement therapy to treat hot flashes and other menopausal symptoms in the short term without any ill effects. However, some doctors believe that the risks are serious enough to outweigh the benefits of the therapy for many women. After five years of taking a combination of estrogen and synthetic progesterone, women in the national WHI clinical were found to be at such high risk for life-threatening diseases that their portion of the trial was halted three years early in 2002. "We conclude that estrogen plus progestin does not prevent heart disease and is not beneficial overall," the researchers wrote.
In 2015, a study from Oxford University and published in the journal Cochrane Library found that if women start HRT more than 10 years after menopause, their risk of stroke increased slightly and their risk of blood clots rose as well. If women began the therapy within 10 years of menopause, however, the stroke risk disappeared and there was some small protection against heart disease. However, they still had an increased risk of blood clots.
Subsequent studies have been less alarming. A study published in the Journal of the American Medical Association in 2017 that tracked women for 18 years found no difference in the mortality rates from all causes between those who took HRT and the placebo group. The researchers said it reinforced the belief that short-term HRT for younger women was relatively safe but there was no evidence that the therapy was effective against heart disease or other conditions.
The use of HRT is a decision between a woman and her doctor and should be made on a case-by-case basis, according to the Cochrane study authors. Many experts advise that HRT, if it's prescribed, should be used for the shortest therapeutic time possible due to the risks of cancer, stroke and other significant risks.
What about taking a hormone replacement pill that contains only estrogen?
Estrogen taken without progestin can cause uterine cancer. Therefore, for some years doctors have recommended that the only women who should take estrogen without progestin on a continuous basis are women who have had a hysterectomy. For women without a hysterectomy, the only recommended hormone replacement therapy is the combination of estrogen and progestin, which does not cause an increased risk of uterine cancer.
But a study reported in the Journal of the American Medical Association links the use of estrogen alone as a hormone replacement therapy to a possible increase in the risk of ovarian cancer. Researchers studied medical records dating as far back as 1973 of 44,421 women on ERT and found they had at least a 60 percent higher risk of ovarian cancer than women who had never used hormone replacement therapy. In view of this latest news, some doctors are reevaluating the safety of estrogen replacement therapy for everyone except women who have had a hysterectomy and who have had both ovaries removed.
Why is the Women's Health Initiative study so important?
It's the largest and most definitive study to date on hormone replacement therapy. In a study of more than 16,000 women, sponsored by the National Heart, Lung and Blood Institute (NHLBI), the test group was given a pill containing a combination of estrogen and progestin. A control group was given a placebo, or dummy pill.
Back in 2002, compared with the women who took placebos, the rate of coronary heart disease among women in the test group taking an HRT drug was 29 percent higher. The same group had a 41 percent increase in the rate of strokes, twice the number of blood clots, and a 26 percent increase in invasive breast cancer rates. The rate of cardiovascular disease increased by 22 percent.
That's not all. In a sub-study of 4,500 women aged 65 and older in the WHI, those on the HRT regimen were found to be twice as likely to develop Alzheimer's disease or another form of dementia within five years compared with women who took a placebo. This part of the study, reported in JAMA, also found that the estrogen/progestin therapy was ineffective in preventing mild cognitive impairment, a dimming of cognitive function that is less severe than dementia and which sometimes occurs as we age.
HRT had often been prescribed for the treatment of urinary incontinence. An analysis by WHI investigators found that HRT caused or worsened urinary incontinence in participants in the trial. Researchers found that women taking estrogen combined with progesterone had a 39 percent greater risk of urinary incontinence than participants taking a placebo. Women taking only estrogen had a 52 percent greater risk than women not taking the hormone, according to the JAMA study.
The WHI study did find a few benefits from the HRT regimen, including a 37 percent reduction in the rate of colorectal cancer, one-third fewer hip fractures, and a 24 percent reduction in total fractures. The authors of an article on the trial's results, published in JAMA, stress that even though the percentage of risk was high compared to women who didn't take hormones, the actual number of women getting these illnesses was small.
This means that out of 10,000 women taking HRT, seven more would be expected to have coronary heart disease events, eight more would have breast cancer, eight more would have strokes, and eight more would have blood clots. And 22 more women over 65 would develop Alzheimer's disease or another form of dementia.
On the plus side, six fewer women would have colorectal cancer and five fewer women would have hip fractures. But the difference between the women taking HRT and those on placebo was alarming enough to halt at five years a portion of the study that was supposed last more than eight years.
"The good news is that after women stop taking combination hormone therapy, their risk of heart disease appears to decrease," said Elizabeth G. Nabel, MD, NHLBI director. "Today's report confirms the study's primary conclusion that combination hormone therapy should not be used to prevent disease in healthy, postmenopausal women."
If I am on HRT therapy now, what should I do?
Since the women in the WHI clinical trial taking a combined estrogen-progestin pill have been asked to stop taking it, it's important to discuss this with your physician. If you are taking the combined hormone pill for the long-term treatment of chronic disease such as osteoporosis, federal researchers have urged that you and your doctor discuss the possibility of stopping the therapy or tapering it off. For postmenopausal women with osteoporosis, for example, there are a number of treatments that have been shown to be more effective than hormone replacement therapy. Ask your doctor about taking these medicines instead of hormone replacement pills.
For women with moderate to severe or disabling symptoms of menopause, taking hormones for short-term use may make sense. Still, even in these cases, women should be on the minimum dose to relieve their symptoms and consider tapering off of their medications over time.
If I do decide to take HRT for short-term use to control my hot flashes, what should I do?
See your doctor for a thorough exam and discuss whether the treatment is right for you. If you decide to go ahead, you'll need a prescription -- either for estrogen alone, in the form of a pill, patch, or cream, or for the regimen of pills that contain both hormones. The patch goes on your abdomen or thigh and needs to be changed every week or two. Estrogen cream can be rubbed into your vagina to lessen vaginal dryness.
As mentioned, doctors choose to prescribe progestin along with estrogen because estrogen taken alone can increase the risk of uterine cancer, unless you've had a hysterectomy. Progestin keeps uterine cells from dividing and causes the uterus to shed its lining each month. However, the new government findings on combination therapy may influence you and your doctor's decision. If you do use HRT, you'll need to have an annual checkup, including a blood-pressure check, breast and pelvic exams, and a Pap test.
You may notice breast tenderness, headaches, bloating, and mood changes while you're on hormone replacement therapy, especially if you're taking progestin. You might also find that you start having periods again or bleeding irregularly. Your doctor can help you experiment with the dosages to pinpoint those that relieve your symptoms without adding too many new ones, although the amounts may need to be adjusted over time as your own hormone levels taper off.
Getting HRT may be inadvisable if you have a personal or family history of breast cancer or if you've ever had uterine cancer, liver disease, a blood clot, heart disease, high blood pressure, a heart attack, or a stroke. It may also not be a good choice if you have uterine fibroids, since estrogen can make them grow bigger, and thus cause pain and bleeding.
How long should I stay on the therapy?
Discuss this concern with your doctor, who can help you weigh the risks. The Women's Health Initiative trial didn't evaluate short-term use of HRT, but as noted, researchers reported an increase in heart disease, invasive breast cancer, and blood clots associated with long-term use. In her JAMA editorial, in fact, Harvard physician Suzanne Fletcher urged clinicians to stop prescribing the combined estrogen/progestin pill for long-term use. The WHI study, she wrote, "demonstrates that risks from the drug add up over time."
What are my alternatives to HRT?
Many bothersome symptoms associated with menopause, including hot flashes and mood swings, frequently get better on their own. One of the best things women can do, according to the National Cancer Institute (NCI), is to adopt a healthy lifestyle -- including not smoking, getting regular exercise, and having a good, nutritious diet. This will help lower your risk of bone loss, which increases as you age. You may also want to take calcium and vitamin D supplements.
If you are at risk of heart disease or osteoporosis, and lifestyle changes don't seem to be working, there are many prescription drugs available to help ward off those conditions. And there are a variety of nonhormonal therapies to treat bladder problems and vaginal dryness associated with menopause.
Unfortunately, few effective alternative treatments exist for menopausal symptoms that are severe. But many women seek relief from hot flashes, mood swings, and other annoying symptoms of menopause through yoga, wearing layers of loose-fitting cotton clothing, and relaxation exercises. They may also try alternative remedies such as foods that contain plant estrogens (including soy products and whole-grain cereal), herbs such as black cohosh, and vitamin E and B complexes, according to the NCI. The safety and effectiveness of these remedies is still being studied, so be sure to discuss your decision with your physician.
References
JoAnn E. Manson, Aaron K. Aragaki, Jacques E. Rossouw, JAMA https://jamanetwork.com/journals/jama/fullarticle/...
Boardman, Henry et al. Cochrane Library Review
Synthetic HRT Therapy Raises Breast Cancer Risk. Journal of the American Medical Associatio
Susan L. Hendrix, DO; Barbara B. Cochrane, RN, PhD et al, "Effects of Estrogen With and Without Progestin on Urinary Incontinence,"JAMA. 2005;293:935-948.
Women's Health Initiative Participants Web Site. WHI Findings Summary. Effects of Estrogen With and Without Progestin on Urinary Incontinence
Vastag B. Hormone replacement therapy falls out of favor with expert committee. JAMAr 17;287(15):1923-4.
Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med.;1 33:933-941.
Grady D, Hulley SB. Hormones to prevent coronary disease in women: when are observational studies adequate evidence? Ann Intern ;133:999-1001.
Mosca L, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001 Jul 24;104(4):499-503.
Alexander KP et al. Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up. J Am Coll Cardiol ;38(1):1-7.
Hormone Replacement Therapy: Weighing the Hazards and Rewards. Clinician Reviews 7(9):53-56, 59-60, 62, 65-66, 69-72. 1997.
Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women - Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA.;288:321-333
Shumaker SA, et al. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA.;289:2651-2662.
Chlebowski RT, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy menopausal women. JAMA ;289:3243-3253.
Li CI, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA ;289:3254-3263.
Women's Health Initiative Participants Web Site. WHI Findings Summary. Estrogen plus progestin effects on breast cancer and mammograms.
National Institutes of Health. Effect of Hormone Therapy on Risk of Heart Disease May Vary by Age and Years Since Menopause.
National Institutes of Health. WHI Follow-up Study Confirms Risks of Long-Term Combination Hormone therapy Outweigh Benefits for Postmenopausal Women.
Heiss G, et al. Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin. Journal of the American Medical Association. Volume 299, Number 9.
National Institutes of Health. NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit.
