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When Public Citizen’s Health Research Group published the book “Women’s Health Alert” in 1991, the evidence clearly showed that hormone replacement therapy (HRT) drugs — those containing estrogen, with or without progestin, designed to replace women’s hormones following menopause — caused breast cancer. The book stated, “Female replacement hormones may someday be remembered as the most recklessly prescribed and dangerous drugs of this century.”[1]
Two major clinical trials published...
When Public Citizen’s Health Research Group published the book “Women’s Health Alert” in 1991, the evidence clearly showed that hormone replacement therapy (HRT) drugs — those containing estrogen, with or without progestin, designed to replace women’s hormones following menopause — caused breast cancer. The book stated, “Female replacement hormones may someday be remembered as the most recklessly prescribed and dangerous drugs of this century.”[1]
Two major clinical trials published in 2002 and 2004 — more than a decade after that statement was published — revealed a high incidence of breast cancer and stroke with long-term use of HRT. The medical community finally recognized the severe risks of HRT, and sales plummeted. From before the publication of the first study in 2002, when annual prescriptions of all HRT products (PREMARIN, PREMPRO and other formulations) were about 90 million, there was a decrease to less than 60 million a year by 2003.[2],[3]
Although HRT use is now much lower than either before or after the 2002 study, the number of prescriptions for HRT remains troublingly high and may be increasing. Prescriptions for oral and vaginal PREMARIN and PREMPRO topped 7.6 million in fiscal year 2013, with dozens of other brand-name and generic versions of HRT available.[4] In addition, an unknown number of women obtain unapproved HRT products, often marketed as “bioidentical” or “natural,” from compounding pharmacies and other questionable sources. Overall, HRT prescriptions may be fueled by misinformation about the products, including questionable conclusions from data suggesting that HRT may be safer in young women than in older women, as well as celebrity endorsements of bioidentical hormones as safer than other forms of HRT.
In fact, while HRT is effective in treating moderate to severe menopause symptoms in women during early menopause (ages 50 to 59), it also carries a number of serious and even life-threatening risks. It should therefore be used at the lowest dose and for the shortest time necessary to meet treatment goals. Protect yourself and loved ones by learning about this effective but potentially very harmful therapy.
Risks and benefits
HRT is a generic term used to refer to many different products approved by the Food and Drug Administration (FDA) to manage moderate to severe symptoms of menopause by replacing hormones that normally decline during menopause. These symptoms usually include hot flashes, night sweats and changes around the vagina (dryness or pain). Several HRT drugs also are approved to prevent (but not treat) osteoporosis.[5],[6]
Most of the best evidence on the safety of HRT comes from two very large randomized, controlled trials of long-term HRT use conducted by Women’s Health Initiative (WHI). In the first trial, more than 16,000 postmenopausal women with intact uteruses were randomized to receive either conjugated estrogens plus the progestin medroxyprogesterone or placebo.[7] In the second trial, more than 10,000 women ages 50-79 who had undergone hysterectomy (removal of the uterus) were randomized to receive either conjugated estrogens or placebo.[8] Only women with hysterectomies could enroll in the second trial because estrogen alone is associated with a two-to-tenfold increased risk of uterine cancer. Combined estrogen plus progestin, as used in the first trial, largely negates this increased risk.[9]
Both the WHI trials were eventually stopped due to adverse events in the HRT group. The combined estrogen/progestin arm was stopped in 2002 due to increased risk of invasive breast cancer.[10] The estrogen-only study was halted in 2004, after researchers discovered an excess risk of stroke.[11] Both HRT treatments reduced the risk of fractures and menopausal symptoms, but researchers concluded that these benefits were far outweighed by life-threatening risks of treatment.
Since 2004, researchers have explored additional risks and benefits using data from the two WHI studies. Other significant risks seen in one or both studies include dementia, blood clots, gallbladder disease and urinary incontinence, while additional detected benefits of therapy included reduced diabetes and joint-pain risks.[12]
The significant risks and benefits of estrogen plus progestin compared to placebo, and estrogen alone compared to placebo, are outlined in the table on below. Estrogen plus progestin appeared to have more risks overall compared to estrogen only (for example, estrogen only does not increase the risk of breast cancer). However, it is important to remember that the table does not compare the risk of uterine cancer, which is much higher in women receiving estrogen without progestin. Women with an intact uterus should take estrogen only in combination with progestin (unless they are using a vaginal product).
|
Risks Detected in the WHI Trials[13] |
|---|
| Health Event[14] | Significant Risks: Increased Harm Per 10,000 Women Using HRT for One Year | |
|---|---|---|
| Estrogen plus Progestin Compared to Placebo | Estrogen Only Compared to Placebo | |
| Any Cardiovascular Event (Including Stroke, Heart Attack and Heart Surgery | 19 | 27 |
| Strokes | 9 | 11 |
| Invasive Breast Cancer | 9 | |
| Blood Clots in Large Veins | 12 | 7 |
| Blood Clots Traveling to Lungs | 9 | |
| Probable Dementia | 23 | |
| Gallbladder Disease | 47 | 58 |
| Urinary Incontinence | 549 | 852 |
| Health Event | Significant Benefits: Reduced Harm Per 10,000 Women Using HRT for One Year | |
|---|---|---|
| Estrogen plus Progestin Compared to Placebo | Estrogen Only Compared to Placebo | |
| Menopause Symptoms | -2,816 | -1,205 |
| Colorectal Cancer | -6 | |
| Spine Fractures | -6 | -6 |
| Type II Diabetes | -16 | -21 |
| Joint Pain | -386 | |
| Uterine Cancer | studied, but no increased risk detected | not studied, but increased risk detected in other studies |
After the women who had been treated in the WHI study of combined estrogen/progestin HRT therapy stopped treatment, researchers continued to observe them. After an average of about two and a half years, women who stopped treatment were no longer at higher cardiovascular risk or lower fracture risk.[15] However, they remained at significantly higher risk of cancer.[16]
Is earlier use safer?
Researchers have continued to analyze the initial WHI and other study results, and some have suggested that risks may be less severe for women who start HRT early (between the ages of 50 and 59).[17] Some experts suggest that HRT therapy even reduces mortality for women in this age group.[18]
In general, this evidence does not support broad conclusions that HRT is safe or beneficial for widespread use among younger women. There is limited evidence that women with hysterectomies who took estrogen-only therapy may have been less likely to experience some side effects if they were younger when they underwent treatment (ages 50 to 59).[19] For women taking estrogen plus progestin, however, age at time of treatment did not make a significant difference on most outcomes.[20]
Regardless of a woman’s age, HRT should only be used to treat moderate to severe menopause symptoms, at the lowest dose and for the shortest amount of time necessary to treat symptoms.
Are bioidentical hormones safe?
You may have heard about bioidentical hormones. This term can be used to describe either FDA-approved products that use a type of hormone chemically identical to naturally produced female hormones (e.g., estradiol)[21] or unapproved products advertised as “safe” or “natural” alternatives to HRT therapy.
There is no plausible biological explanation or credible data from randomized trials demonstrating that bioidentical hormones (FDA approved or unapproved) would be safer than the hormones used in the WHI trials.[22] Until better evidence is available, it is unsafe to assume these newer products are better than older, better-tested hormones simply because they are marketed as more “natural.”
Moreover, bioidentical products made by compounding pharmacies have not been FDA-approved and vary widely in quality. Studies have routinely shown that about one-fifth to one-third of all compounded products do not contain the correct potency of active ingredient reflected on the labeling.[23],[24],[25] Compounding pharmacies use less standardized processes than drug manufacturers and are not well-monitored by regulatory authorities, increasing the risk of human error. In rare cases, this can result in products that are 10, 100 or even 1,000 times more potent than the declared labeling.[26],[27],[28]
What You Should Do
Do not use HRT for prevention of any chronic diseases, including osteoporosis. Experts generally recommend against using HRT to prevent heart disease or other chronic diseases because its harms far outweigh its benefits.
For prevention of osteoporosis, the FDA considers HRT to be the last choice for postmenopausal osteoporosis, to be used only after trying other approaches, such as calcium, vitamin D, exercise and drugs such as alendronate (FOSAMAX).[29]
We categorize HRT as Do Not Use for osteoporosis prevention, as long-term use carries many harms that outweigh the benefit of reduced fracture risk. HRT also is not established as an effective treatment for osteoporosis and should not be used by women who have already developed the condition. For more information about ways to prevent osteoporosis, see the entries on osteoporosis, calcium and vitamin D at WorstPills.org.
Be cautious about using HRT to manage menopause symptoms.
Experts generally agree that HRT is appropriate as a short-term treatment for moderate or severe menopause symptoms for relatively young women (up to age 59 or within 10 years of menopause) who are otherwise healthy.[30] But HRT is not indicated for mild symptoms of menopause. For mild hot flashes, use lifestyle-related strategies, such as keeping the core body temperature cool and participating in regular exercise.[31] To treat vaginal dryness and pain during intercourse, try a lubricant cream without hormones.[32]
If these approaches fail, and you are still experiencing debilitating symptoms (symptoms so severe they prevent you from working or carrying out other important activities), use HRT at the lowest dose needed to address symptoms. To control hot flashes or night sweats, take a pill or patch. Use a combination estrogen plus progestin product if you have an intact uterus, and an estrogen-only product if you have had a hysterectomy.
If HRT is prescribed to treat vaginal changes due to menopause, use a local low-dose vaginal estrogen product, such as the estradiol vaginal insert (ESTRING) and vaginal tablet (VAGIFEM).[34],[35] This will help limit your body’s overall exposure to the hormone.[36] A progestin is generally not indicated when estrogen is administered locally in a low dose for vaginal symptoms.[37]
Use HRT for the shortest duration possible. Try taking it for three months and then ask your doctor to help you slowly taper down the drug and watch for returning symptoms. Start taking HRT again only if the symptoms return, are severe enough to require treatment, and do not respond to other, safer approaches mentioned above. In the WHI studies, most women with moderate to severe menopause symptoms at the start of the study also experienced returning menopause symptoms upon stopping treatment, but almost 90 percent were able to successfully manage these symptoms without re-initiating HRT therapy.[38] If your first attempt to quit fails, try again as soon as possible. It is important to stop treatment as soon as possible, because the cardiovascular and cancer risks increase the longer you stay on the drug.
|
How Did the Estrogen Vogue Begin, and Why Did it Continue? I think [bioidentical hormones are] a good idea if you want to stay alive for twice as long as your body intended. Without estrogen, your brain doesn’t work as well. That’s what all that foggy thinking is about which eventually leads to Alzheimer’s. . . . Keeping your hormone levels optimal will protect your brain and your bones, and you won’t get depression, so you won’t need to take Prozac. And you won’t need to take painkillers because you won’t have the joint pain that’s associated with aging. The doctors I interviewed say eliminate all these drugs and put back those natural biologically identical hormones. I use an estrogen cream every day and progesterone cream two weeks a month. That’s why, at 62, I don’t require any pharmaceutical drugs.[44]
Statements like these are extremely misleading. No well-designed study of bioidentical hormones has demonstrated that they are safer than the versions of HRT used in the WHI studies and other trials, and strong evidence indicates that HRT causes dementia and cognitive impairment, rather than preventing these problems. |
References
[1] Wolfe SM, Donkin Jones R, Women’s Health Alert. New York: Addison Wesley; 1991.
[2] Sumit R. Majumdar, MD, MPH; Elizabeth A. Almasi; Randall S. Stafford, MD, Ph.D. Promotion and prescribing of hormone therapy after report of harm by the Women’s Health Initiative. JAMA. 2004;292(16):1983-1988.
[3] Hass JS, Kaplan CP, Gerstenberger EP, Kerlikowske K, Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med. 2004;140(3):184-188.
[4] MedScape. TOP 100 drugs through September reported. http://www.medscape.com/viewarticle/813571#3. Accessed December 18, 2013.
[5] Food and Drug Administration. Highlights of prescribing information: Menostar. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020375s028lbl2.pdf. Accessed December 18, 2013.
[6] Food and Drug Administration. Premarin. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/004782s162s164s167lbl.pdf. Accessed December 18, 2013.
[7] Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288:321-333.
[8] Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation. 2006;113:2425-2434.
[9] The 2012 Hormone Therapy position statement of the North American Menopause Society. Menopause. 2012;19(3):257-271.
[10] Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288:321-333.
[11] Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation. 2006;113:2425-2434.
[12] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA. 2013;310(13):1353-1368.
[13] Ibid.
[14] Ibid.
[15] Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299(9):1036-1045.
[16] Ibid.
[17] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA. 2013;310(13):1353-1368.
[18] The 2012 Hormone Therapy position statement of the North American Menopause Society. Menopause. 2012;19(3):257-271.
[19] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA. 2013;310(13):1353-1368.
[20] Ibid.
[21] 2010 position statement of the North American Menopause Society. Menopause. 2010;17(2):242-255.
[22] Panay N. Does hormone replacement therapy cause breast cancer? Commentary on Shapiro et al., Parts 1-5. J Fam Plann Reprod Health Care. 2013(39):72-74.
[23] Food and Drug Administration. 2006 limited FDA survey of compounded drug products. Last updated March 22, 2010. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm204237.htm. Accessed March 22, 2013.
[24] Food and Drug Administration. 2006 limited FDA survey of compounded drug products. Last updated March 22, 2010. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm204237.htm. Accessed March 22, 2013.
[25] Missouri Division of Professional Registration: Board of Pharmacy. Compounding report. http://pr.mo.gov/pharmacists-compounding.asp. Accessed March 26, 2013.
[26] Romano, MJ. A 1,000-fold overdose of clonidine caused by a compounding error in a 5-year-old child with attention deficit/hyperactivity disorder. Pediatrics. 2001;108(2):471-472.
[27] Suchard JR, Graeme KA. Pediatric clonidine poisoning as a result of pharmacy compounding. Pediatric Emerg Care. 2002;18(4):295-296.
[28] North Carolina Board of Pharmacy. Consent order of discipline: Jewel Freeman. July 19, 2012. http://www.ncbop.org/Disciplinary%20Actions%20-%20PHARMACISTS/FreemanJewel10249.pdf#search. Accessed April 16, 2013.
[29] Food and Drug Administration. Premarin. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/004782s162s164s167lbl.pdf. Accessed December 18, 2013.
[30] Stuenkel CA, Manson JE, Pal L. A decade after the Women’s Health Initiative – the experts do agree. Menopause. 2012; 19(8):846-847..
[31] Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11(1):11-33.
[32] Wolfe, S et al. Worst Pills, Best Pills. New York: Simon & Schuster; 2004.
[33] Manson J, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative Randomized Trials. JAMA. 2013;310(13):1353-1368.
[34] Food and Drug Administration. Vagifem label. http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20908lbl.pdf. Accessed December 18, 2013.
[35] Food and Drug Administration. Estring label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020472s007lbl.pdf . Accessed December 18, 2013.
[36] The 2012 Hormone Therapy position statement of the North American Menopause Society. Menopause. 2012;19(3):257-271.
[37] The 2012 Hormone Therapy position statement of the North American Menopause Society. Menopause. 2012;19(3):257-271.
[38] Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA. 2005;294:183-193.
[39] Hass JS, Kaplan CP, Gerstenberger EP, Kerlikowske K, Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results Ann Intern Med. 2004;140(3):184-188.
[40] WorstPills.org. Hormone replacement therapy. www.worstpills.org/member/page.cfm?op_id=15. Accessed December 18, 2013.
[41] Ibid.
[42] Ibid.
[43] Ibid.
[44] U.S. News & World Report. Why Suzanne Somers Loves Bioidentical Hormones. http://health.usnews.com/health-news/blogs/on-women/2009/03/25/why-suzanne-somers-loves-bioidentical-hormones. Accessed December 18, 2013.
