Natural’ alternatives may be just as risky
Recent news that the risks of long-term hormone replacement therapy (HRT) may exceed its benefits has alarmed many women who use HRT to treat symptoms associated with menopause.
Pharmacists should advise these patients to always consult with their prescribers before stopping drug therapy that was intended to be chronic, says Gayle Hudgins Cochran, PharmD, director of experiential education, School of Pharmacy & Allied Health Sciences, University of Montana, Missoula.
Beware symptom flare-ups
"While there aren’t dangers such as withdrawal symptoms or other problems with suddenly stopping HRT, there could be a flare-up of perimenopausal symptoms that could be quite uncomfortable for the person," Cochran says.
The concerns about HRT relate to a July 9 announcement by the National Heart, Lung, and Blood Institute of the National Institutes of Health that it was stopping a combination conjugated equine estrogen/medroxyprogesterone acetate (Prempro) trial. The study, part of the Women’s Health Initiative (WHI), was stopped more than three years early (after an average follow-up of 5.2 years) because of an increased risk of invasive breast cancer.
The trial also found that increases in coronary heart disease, stroke, and pulmonary embolism in study participants, compared to women taking placebo, exceeded the benefits of the drug. The benefits included fewer cases of hip fractures and colon cancer.
A separate WHI study is assessing the long-term use of an estrogen replacement (Premarin) in postmenopausal women who do not have a uterus. This study is ongoing because the balance of risks and benefits is not known.
Specific study findings for the estrogen plus progestin group compared to placebo include:
- 41% increase in strokes;
- 29% increase in coronary heart disease (CHD);
- a doubling of rates of venous thromboembolism;
- 22% increase in total cardiovascular disease;
- 26% increase in breast cancer;
- 37% reduction in cases of colorectal cancer;
- a one-third reduction in hip fracture rates;
- 24% reduction in total fractures;
- no difference in total mortality (of all causes).
The increased risks for cardiovascular disease and invasive breast cancer were present across racial/ethnic and age groups and were not influenced by antecedent risk status or prior disease.
The study was conducted to assess whether long-term use of the combination hormone therapy would reduce the risk of CHD in postmenopausal women. The randomized, controlled primary prevention trial involved 16,608 women ages 50 to 79 with an intact uterus. Patients either received the combination hormone replacement therapy, 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate, or placebo. The results of the study were published in the July 17 issue of the Journal of the American Medical Association.
A look at alternative therapies
The study did have its limitations. The trial tested only one drug regimen, and it was not designed to distinguish the effects of estrogen from those of progestin. The study did not address the short-term risks and benefits of hormones for the relief of menopausal symptoms.
More information on any benefits of HRT is also needed. "The possible benefits of the reduced incidence of colon cancer, reduction in tooth loss, reduction in macular degeneration, improvement in cognition, and reduction of Alzheimer’s disease all need further scientific study," says Ronald Ruggiero, PharmD, Women’s Health Pharmacy Residency Project Director for the University of California - San Francisco National Center of Excellence.
In light of the study, all of a person’s symptoms and risk factors need to be evaluated before a decision is made to start or continue with HRT, Hudgins says. "There are some women for whom the risks are acceptable, if they have severe perimenopausal symptoms that are relieved by HRT and have low risk for the potential cardiovascular or cancer side effects."
Some women may feel uncomfortable with the risk and want an alternative therapy. Their options for other therapies depend on the reason for which their HRT treatment was prescribed. Estrogen by itself is not a viable alternative for most women for a couple of reasons, Cochran says. One is the lack of good evidence regarding which component of HRT, estrogen or progestin, is responsible for the cardiovascular side effects. In addition, unless the woman has had a hysterectomy, unopposed estrogen by itself increases the risk for uterine cancer.
Consider non-hormonal drugs
If HRT is primarily being used for perimenopausal symptoms (such as hot flashes and vaginal dryness), patients can opt instead for non-hormonal drugs that help with hot flashes and topical (vaginal) estrogen that can help with the vaginal symptoms.
If the HRT is primarily being used for the prevention of osteoporosis, more specific drugs such as the biphosphonates (Fosamax) can be used. Also, if the HRT is primarily being used for the prevention of cardiovascular disease, the patient can use cardiac-specific drugs instead.
Turning to "natural" estrogens, soy, and herbals that contain estrogenic compounds is another alternative that may be helpful, particularly with perimenopausal symptoms, Cochran says. However, she says she doesn’t think there is convincing evidence that any of these natural estrogens has fewer risks associated with it. "They generally are weaker estrogen compounds, providing weaker estrogen effects, and thus fewer estrogen side effects. If taken or used in equipotent dose to the prescription HRT, the side effects may be much the same. Plus, because the compounding or manufacturing of these products is largely unregulated, there are additional risks associated with their use."
"For patients who decide to continue HRT therapy, the current recommendation is the use of ERT or HRT at a lower dose of conjugated estrogens tablets (Premarin) 0.3 mg or its equivalent for symptoms for three to five years," Ruggiero says. Long-term use is not encouraged.
"If [women with an intact uterus] are taking the [estrogen plus progestin] combination for short-term relief of symptoms, it may be reasonable to continue, since the benefits are likely to outweigh the risks," says Jacques Rossouw, MD, acting director of the WHI, in a statement. "Longer-term use or use for disease prevention must be re-evaluated given the multiple adverse effects noted in WHI."
Limit use to shortest possible duration
The manufacturer of the hormone agrees in an Aug. 28 "Dear Health Care Professional Letter."
"Prempro, Premphase and Premarin are not indicated and should not be used to prevent coronary heart disease," Wyeth Pharmaceuticals notes in the letter. "The product indications remain the same. However, because of the potential increased risks of cardiovascular events, breast cancer and venous thromboembolic events, use of Prempro, Premphase and Premarin should be limited to the shortest duration consistent with treatment goals and risks for the individual woman, and should be periodically reevaluated. When used solely for the prevention of osteoporosis, alternative treatments should be carefully considered."
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