Hormone Replacement Therapy
Since the Women's Health Initiative (WHI) was stopped early due to risk of heart attack and stroke, the use of hormone replacement therapy (HRT) has been debated in research, in the media and among women across the country. Second Opinion explores the risks and benefits of hormone replacement therapy.
Women's Health Initiative
Millions of post-menopausal women felt they had hit the bottom of the ride on July 9, 2002. That was the day the National Heart, Lung, and Blood Institute (NHLBI) announced they were suspending one arm of their large clinical trial, the Women's Health Initiative (WHI), because the risks of combined estrogen and progestin hormone replacement therapy (HRT) outweighed its benefits.1 WHI results showed that, instead of protecting women against heart disease as had been initially thought, the therapy could actually increase their risk for that disease as well as for breast cancer, stroke and blood clots. Women who had been taking the drugs – some for many years – were frightened and confused, and they abandoned their use of hormone replacement therapy in droves.
In May 2003 the Women's Health Initiative Memory Study (a sub-study of the WHI) reported that hormone replacement therapy may double the risk of Alzheimer's disease and other dementias in women over 65.2 In March 2004 WHI suspended the estrogen-only arm of the study because they found it can put women at increased risk of stroke.3 Then, in October 2004 WHI investigators reported that hormone replacement therapy increases breast density, making breast cancer more difficult to detect.4
How could this happen in an era where drugs go through such a long period of development, testing, and review? The short answer is that no drug will ever be 100 percent safe for every individual. Raymond Woosley, MD, Ph.D., the founding President and Chairman of the Board of The Critical Path Institute (a non-profit corporation formed by the Food and Drug Administration) said in an interview for the PBS program Frontline: Dangerous Prescription "I think Americans need to recognize that every time they put a pill in their mouth, especially a new pill that they've never taken before, it's an experiment. How big an experiment depends on the pill and how well it's been studied...Even the old [drugs] that we think we know a lot about, we're learning every day that we missed something along the way. At the same time, I have to say we know more about a new medicine today when it goes on the market than we've ever known before."
How do clinical trials work?
What, you ask, about the clinical trials required by the Food and Drug Administration before a new drug can be brought to market? Trials have limitations. Phase III clinical trials, the final stage before a drug is approved for sale, are generally conducted on patient populations of 300 to 3,000; they can not show that a drug is risk-free for all individuals. They also must, of necessity, be of limited duration and can not show whether a drug might have unexpected long-term side effects. The FDA has a tough job. Do you get promising new drugs to people who need them as soon as possible or do you slow the process down to study risks more fully? There are compelling arguments on both sides.
New Information About Hormone Replacement Therapy
Today, the hormone replacement therapy debate continues. Based on further analysis of WHI data as well as new information from follow-up studies, scientists now believe:
- Age is a crucial factor. After looking at data for different age ranges in the WHI age 50 to 79 population (average age 63), investigators think healthy women between 50 and 59 and those who begin HRT less than 10 years after starting menopause may not be at increased risk for heart disease or impaired cognition.
- Pre-existing conditions and lifestyle must be considered. Many of the WHI study group were former smokers, obese and had a history of hypertensive disorders.5 However, this doesn't mean they are not representative of the population of women who will need to make a decision about HRT. Second Opinion panelist and Immediate Past President of the Board of Directors of WomenHeart, Kathy Kastan reveals, "Eighty percent of women age 40 to 60 have one or more risk factors for heart disease."
- Treatment for menopausal symptoms should start with the lowest effective dose. The dose of 0.625 mg/day used in the WHI study was higher than many lower-dose versions available today.
- Women who use HRT for two to five years are less likely to be at an increased risk for breast cancer in the short term (long-term risk is still unknown). An increased risk of breast cancer was seen only in women who had taken HRT prior to study entry.
1 NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit; Press Release; July 9, 2002.
2 Rates of Dementia Increase Among Older Women on Combination Hormone Therapy; Press Release; May 27, 2003.
3 NIH Asks Participants in Women's Health Initiative Estrogen-Alone Study to Stop Study Pills, Begin Follow-up Phase; Press Release; March 2, 2004.
4 HRT Doubles Breast Density, Abnormal Mammogram Possible; Healthcare in the News, October 20, 2004. Article on presentation at meeting of the American Association for Cancer Research; Lead researcher Dr. Anne McTiernan.
5 Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials-time out for hormone replacement therapy studies?; Human Reproduction, Vol. 18, No. 11, 2241-2244, November 2003.
- A woman has reached menopause when she has not had a period for 12 months in a row. It is a normal change in a woman's life.
- During menopause a woman's body slowly produces less of the hormones estrogen and progesterone. This often happens between the ages of 45 and 55 years old.
- Lower hormone levels in menopause may lead to hot flashes, vaginal dryness, mood swings, sleep disorders, urinary problems and decreased sexual desire.
- No two women will experience menopause in the exact same way.
- Hormone replacement therapy (HRT), hormone therapy (HT) or menopausal hormone therapy (MHT) can refer to the use of estrogen alone or to a combination of estrogen and a progestin. Occasionally, testosterone may be added to treat decreased libido. Other terminology includes ERT (estrogen replacement therapy) and ET (estrogen therapy) for estrogen only; EPT (estrogen progestin therapy) for combination estrogen and progestin.
- Like all medicines, hormone therapy has risks and benefits.
- The Women's Health Initiative found:
- The risks of combined estrogen and progestin hormone replacement therapy (HRT) outweigh its benefits by increasing risk for heart disease, breast cancer, stroke and blood clots.
- Estrogen-only therapy can put women at increased risk of stroke.
- HRT increases breast density, making breast cancer more difficult to detect.
- The Women's Health Initiative Memory Study (a sub-study of the WHI) reported HRT may double the risk of Alzheimer's disease and other dementias in women over 65.
- Pre-market clinical trials do not uncover all possible risks nor do they guarantee the absolute safety of a drug. Side effects may appear only when a drug is used in combination with another medicine, in patients who were not represented in previous test groups or only after years of use.
- There is no single right answer on whether or not to use hormone therapy. Each individual needs to talk to their doctor about their own personal risk-to-benefit ratio – to decide if a drug's advantages outweigh the possibility of adverse side effects.
- Hormone therapy is the most effective FDA approved medicine for relief of hot flashes, night sweats or vaginal dryness.
- Healthy women between 50 and 59 and those who begin HRT less than 10 years after starting menopause may not be at increased risk for heart disease or impaired cognition.
- Treatment for menopausal symptoms should start with the lowest effective dose.
- Women who use HRT for two to five years are less likely to be at an increased risk for breast cancer in the short term (long-term risk is still unknown).
Ask Your Doctor
- What are my risk factors for using HRT?
- Why should I consider HRT?
- Which symptoms can HRT help with?
- Is there anything else I can do to relieve my symptoms?
- Does it make a difference what form of hormones I use? Which hormone therapy delivery method is right for me?
- What is the lowest dose of hormone therapy that I can take to relieve my symptoms?
- How long should I take hormone therapy?
- What side effects should I expect?
- Will the side effects go away?
- What can I do to prevent osteoporosis, high cholesterol levels, heart disease, stroke, breast cancer, etc.
- What check-ups and screenings will I need? How often?
Key Point 1
Research brings out new and sometimes confusing information all the time. It can be frustrating for patients and doctors alike. You need to stay in touch with your doctor to make sure that your care is as up to date as possible.
Exactly what is a "safe" drug? Consider the ubiquitous aspirin. An aspirin-like substance made from willow bark was used by the ancient Greeks and aspirin powder became the number one drug in the world in 1899.1 Yet, it was not until the 1960s and beyond that we came to understand how it works2 and began to investigate its characteristics for disease prevention, its effect on the stomach lining and the danger it can pose when used by children.
Today, the U.S. Food and Drug Administration require that every drug undergo rigorous laboratory, animal and human clinical testing before it can be put on the market. But, FDA approval is not an unconditional endorsement. The FDA reviews research to validate ingredients and provisionally determine that a drug is effective and safe to treat a specific condition or disease. Safety is viewed in terms of its risk-to-benefit ratio – in other words, to decide if a drug's advantages outweigh the probability it will cause substantial adverse side effects. An acceptable risk/benefit ratio for a relatively benign condition will be very different than that for a life-threatening one. Pre-market clinical trials do not uncover all possible risks nor do they guarantee absolute safety. That means follow-up tests for a drug need to be done after it is in widespread use. (See the introductory page for this topic for more information.) According to a 1998 article in the Journal of the American Medical Association, 51 percent of approved drugs may have serious adverse effects not detected prior to approval".3
Furthermore, the FDA does not approve every use to which a medical productmight be put.4 Once a drug is sanctioned by the FDA for one disease or condition, physicians can prescribe it for other conditions, for patient populations who were not part of the clinical trial, and in different dosages. It is called off-label prescribing and it is very common. One in five prescriptions for the 500 most commonly prescribed drugs in 2001 was for off-label use.5 As with all things, there are pros and cons. In the pro column: physicians can make use of evidence as it becomes available and patients can benefit from more options and earlier access to the newest treatments. In the con column: the absence of data can make it difficult to determine a risk/benefit ratio.
Contradictions in investigations are not unusual. In fact, surprises can happen with even the most carefully tested drugs. Side effects may appear only when a drug is used in combination with another medicine, in patients who were not represented in previous test groups or only after years of use.
There are fundamental differences in types of studies. The two major categories are observational studies and randomized trials. In an observational study, investigators observe what happens to people in their everyday lives, grouping them according to whether or not they take a drug, make certain lifestyle choices or have been exposed to something. In a randomized trial, investigators assign people to two or more study groups and then control what treatment or exposure each group receives. Usually, they compare the treated subjects to subjects who receive no treatment or standard treatment. While a controlled study is generally considered more reliable than an observational study, the two types are complementary with a legitimate role for each in optimizing scientific advancement. For example, there are instances where a randomized trial in humans can not be ethically performed, such as the identification of cigarette smoking as a cause of lung cancer. Due to stringent ethical requirements, financial limitations, and other feasibility issues, it will never be possible to address all therapeutic questions with randomized trials.6
Study validity also depends on the size of the group being studied. The smaller the study, the higher the margin of error; the bigger the group, the more reliable the conclusions. While an unnecessarily large study can be wasteful of resources and results may take longer than ideal, relativelyfew studies are too big.6
Second Opinion panelist, Lou Papa, MD, describes the history of hormone therapy research as an "undulating wave" leaving women with a "to use or not to use" dilemma. A few historical milestones illustrate his point:
1 Bayer HealthCare, Leverkusen, Germany.
2 Jeffreys, Diarmuid (August 11, 2005). Aspirin: The Remarkable Story of a Wonder Drug. Bloomsbury USA, 73. ISBN 1582346003. Jeffreys, Aspirin, pp. 226-231)
3 Moore, TJ, Psaty, BM, Furberg, CD. Time to act on drug safety. JAMA, 1998 May 20, 279(19):1571-3.
4 Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice; Richard A. Deyo, The Journal of the American Board of Family Practice 17:142-149 (2004).
5 Archives of Internal Medicine; 2006.
6 Are Observational Studies ‘Just as Effective' as Randomized Clinical Trials?; Tom Greene; Blood Purif 2000;18:317–322.
7 Synthetic generic conjugated estrogens: Timeline
8 B.M. Caldwell & R.I. Watson, An Evaluation of Psychologic Effects of Sex Hormone Administration in Aged Women: Results of Therapy After Six Months, 7 J. GERONTOLOGY 228 (1952).
9 Stanley Wallach & Philip H. Henneman, Prolonged Estrogen Therapy in Postmenopausal Women, 171 JAMA 1637 (1959).
10 Robert A. Wilson, The Roles of Estrogen and Progesterone in Breast and Genital Cancer, 182 JAMA 327 (1962).
11Harry K. Ziel & William D. Finkle, Increased risk of endometrial carcinomas among users of conjugated estrogens, 293(23) New England Journal of Medicine 1167-1170 (1975).
12D.C. Smith et al., Association of exogenous estrogen and endometrial carcinoma, 293(23) New England Journal of Medicine 1164-1167 (1975).
13 M. H. Thom et al., Prevention and Treatment of Endomtrial Disease in Climacteric Women Receiving Estrogen Therapy, 2 (8140) The Lancet 455-457 (1979).
14 R. Don Gambrell Jr. et al., Use of the Progestrogen Challenge Test to Reduce the Risk of Endometrial Cancer, 55 OBSTETRICS & GYNECOLOGY 732.1980.
15 Boston Collaborative Drug Surveillance Program, Surgically Confirmed Gallbaladder Disease, Venous Thromboembolism and Breast Tumors in Relation to Postmenopausal Estrogen Therapy, 290(1) New England Journal of Medicine 15-19 (1974).
16 Robert Hoover et al., Menopausal Estrogens and Breast Cancer, 295 NEW ENG. J. MED. 401 (1976).
17 M.J. Stampfer et al., A Prospective Study of Postmenopausal Estrogen Therapy and Coronary Heart Disease, 313(17) New England Journal of Medicine 1044-1049; 1985)
18 P.W. Wilson et al., Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50, 313(17) New England Journal of Medicine 1038-1043;1985.
19 R.L. Prince et al., Prevention of Postmenopausal Osteoporosis: A Comparative Study of Exercise, Calcium Supplementation, and Hormone-Replacement Therapy, 325 NEW ENG. J. MED. 1189 (1991).
20 The Writing Group for the PEPI Trial, Effects of Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women, 273 JAMA 199 (1995).
21 Stephen Hulley et al., Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women, 280 JAMA 605. 1998.
22Graham A. Colditz et al., Type of postmenopausal hormone use and risk of breast cancer: 12-year follow-up from the Nurses' Health Study, 3 Cancer Causes and Control 433-439 (1992).
23Graham A. Colditz et al., Hormone Replacement Therapy and Risk of Breast Cancer: Results from Epidemiologic Studies,168(5) American Journal of Obstetrics & Gynecology 1473-80 (1993).
24 Edel Daly et al., Risk of Venothromboembolism in Users of Hormone Replacement Therapy, 348(9033) The Lancet 977-980 (1996).
25 Deborah Grady et al., Postmenopausal Hormone Therapy Increases Risk for Venous Thromboembolic Disease: The Heart and Estrogen/Progestin Replacement Study, 132(9) Annals of Internal Medicine 689-696 (2000).
26 Hulley, S; Grady, D; Bush, T; Furberg, C; Herrington, D; Riggs, B; Vittinghoff, E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613. doi: 10.1001/jama.280.7.605
27 NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit; Press Release; July 9, 2002
28 NIH Asks Participants in Women's Health Initiative Estrogen-Alone Study to Stop Study Pills, Begin Follow-up Phase; Press Release; March 2, 2004.
29 HRT Doubles Breast Density, Abnormal Mammogram Possible; Healthcare in the News, October 20, 2004. Article on presentation at meeting of the American Association for Cancer Research; Lead researcher Dr. Anne McTiernan.
30 Rates of Dementia Increase Among Older Women on Combination Hormone Therapy; Press Release; May 27, 2003.
31 Emily Banks, et al., Breast Cancer and Hormone-Replacement Therapy in the Million Women Study, 362(9382) The Lancet 419-427 (2003).
Key Point 2
Hormone replacement therapy is a viable option for some women. As with any other therapy, there are pluses and minuses. There is controversy around HRT. All those TV reports are not about you. You really need to talk with your doctor about your specific risks and benefits.
Does the mere thought of menopause strike fear in your heart? Or do you look forward to the freedom from periods and pregnancy it offers? Whatever your mindset, there are two things to consider:
- No two women will experience menopause in the exact same way. Some will have no or very few symptoms; some will have symptoms that are bothersome but not disruptive; and some will have the severe symptoms that are the stuff of menopause horror stories. (See the Second Opinion episode on Menopause (Episode 112) for more information.)
- There is no single right answer on whether or not to use hormone therapy.
Today, the only FDA approved indication for hormone replacement therapy (HRT) is for the treatment of menopausal symptoms, such as hot flashes, vaginal dryness, mood swings, sleep disorders, urinary problems and decreased sexual desire. Since the Women's Health Initiative (WHI) results were published in 2002, physicians no longer recommend it for secondary prevention of other conditions, even though research has confirmed it can help increase bone mineral density, reducing risk for bone fracture, and it may lower risk for colorectal cancer. (See the introductory page for this topic for more information.)
Hormone replacement therapy can refer to the use of estrogen alone or to a combination of estrogen and a progestin. Occasionally, testosterone may be added to treat decreased libido. There is a whole alphabet soup of abbreviations: ERT (estrogen replacement therapy) and ET (estrogen therapy) for estrogen only; EPT (estrogen progestin therapy) for combination estrogen and progestin; HRT (hormone replacement therapy), HT (hormone therapy) and menopausal hormone therapy (MHT) for any of the above.
Choosing whether or not to use hormone therapy will depend on:
- The severity of your symptoms
- Your medical history
- Your current health status
Like almost all medications, hormone replacement therapy has side effects. Some are merely bothersome; some are potentially serious. In the bothersome category are monthly bleeding, spotting, bloating, breast tenderness, abdominal cramps, headaches, skin discoloration, and emotional side effects like anxiety, irritability, and depression. In the serious category are increased risks for heart disease, breast cancer, stroke and blood clots, gallbladder disease, Alzheimer's disease and other dementias.
The WHI studyconcluded that for every 10,000 women taking estrogen and progestin,there would be (annually):1
- Eighteen more cases of blood clots (including pulmonary embolism)
- Eight more cases of invasive breast cancer
- Seven more cases of heart disease (mostly nonfatal)
- Eight more strokes
For every 10,000 women taking estrogen alone, there would be (annually):1
- Twelve more strokes
- Six more cases of blood clots
You may be a good candidate for HRT if you are recently menopausal and do not have a history of heart disease, breast cancer or blood clots. You will want to avoid HRT if you have active or past breast or uterine cancer, liver disease, gallbladder disease, a history of blood clots or stroke, heart disease or multiple risk factors for heart disease (such as diabetes, high blood pressure, etc).
Before deciding about HRT, you may want to work with your doctor to explore alternatives. They include:
- Lifestyle changes. These include eating a healthy diet, regular physical exercise, maintaining a healthy weight, not smoking and limiting how many alcoholic beverages you drink.
- Certain antidepressants. These have not been approved for this use, but clinical trials have shown them to be a moderately effective treatment for relief of hot flashes.
- Botanicals and the dietary supplement DHEA (dehydroepiandrosterone). The National Center for Complementary and Alternative Medicine says that while there is very little scientific evidence to support the effectiveness of these remedies, it is possible that some may provide relief to some women. However, they can have side effects and can also interact with other botanicals or supplements or with drugs.2
- Acupuncture. The National Center for Complementary and Alternative Medicine is supporting several studies looking at the effect of acupuncture on the occurrence and severity of hot flashes in postmenopausal women.2
Another debate that exists on the horizon for HRT is in the form of bio-identical hormones. After the WHI results were published in 2002, women began looking for alternatives to conventional HRT. Suzanne Somers published a book in 2004 that raised the profile of bio-identical hormones with the public. The problem is that the term "bio-identical" is used to describe two very different categories of products:
- FDA-approved, plant-based hormones. Quality and safetyis regulated.
- Made-to-order hormones created by compounding pharmacies. Although the ingredients are approvedby the FDA,the compounds are not. The dosage can change with each batch and they have not been tested for purity, potency, efficacy or safety.
To date there is no scientific proof to show that bio-identicalhormones are safer to use than the synthetic hormones of conventional HRT.3
Despite all the controversy and confusion, the medical community agrees, in general, that HRT is still the most effective medical tool they have for helping women cope with the symptoms of menopause. Notwithstanding, there are steps you should take before and while using hormone replacement therapy. Talk to your doctor about:
- Your personal risk-to-benefit ratio
- Lifestyle changes or medications to prevent osteoporosis, high cholesterol levels, heart disease, stroke, breast cancer, etc.
- Lifestyle changes to augment HRT in symptom control
- Whether a pill, patch, cream or ring is best for you
- What check-ups and screenings you will need and how often (blood pressure, pelvic and breast exams, mammograms)
- If dosage can be lowered as you age (in general, symptoms become less severe the longer you are past menopause)
Since research on HRT is ongoing and symptoms change, women should revaluate their treatment plans every year.
1 The National Institutes of Health, Postmenopausal Hormone Therapy
2 National Center for Complementary and Alternative Medicine, Menopausal Symptoms and CAM
3 Robert B. Jaffe, MD, Leslie Salomone, MD and Richard J. Santen, MD; Bioidentical (Natural) Hormones and Menopause, The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11