Vol. 16 •Issue 9
• Page 35
Hormone Therapy In Menopause
Exploring Current Recommendations
By Emily L. Rouhas, NP
Over the past 40 years, hormone therapy for menopausal women has been both celebrated and shunned. Today, it is generally viewed with caution as research and clinical practice determine its appropriate medical role.
History of Hormone Use
Historically, menopause has been medicalized as a disease of deficiency. This led to a belief that it could be "cured" by replacing hormones that were lost. The idea that hormones could be used to treat menopause symptoms came in part from the best-selling 1966 book Feminine Forever, by gynecologist Robert Wilson. He promoted the idea that hormones could keep women young and attractive.1Even the name of the treatment, "hormone replacement therapy," suggested that the drugs could somehow replace what was lost to aging.
In the 1960s and 1970s, sales of conjugated equine estrogen (Premarin) rose dramatically due to these beliefs. In 1975, researchers began to link estrogen use with an increased incidence of endometrial cancer. By 1979, the general recommendation for hormone replacement was for women to use it for the shortest possible time in the lowest possible dose to manage hot flashes and vaginal dryness.1In the 1980s, data began to show that the addition of progesterone to estrogen therapy lowered endometrial cancer risk. The popularity of hormone replacement (this time combined estrogen and progesterone) surged. When research — mostly observational studies — demonstrated that combination therapy could decrease osteoporosis risk and was protective against heart disease, the rationale for treatment changed from symptom relief to disease prevention.1
In the 1990s, the U.S. Preventive Services Task Force (USPSTF) recommended that all women consider hormone therapy.1 nd until 2002, up to one-third of women older than 50 were taking hormones.2
The Women's Health Initiative
In 1993, the federally funded Women's Health Initiative (WHI) began a study to determine whether hormone therapy, a low-fat diet and calcium supplementation reduced the risk for certain diseases affecting older women.3 he study lasted 12 years and enrolled more than 161,000 women. The hormone portion of the trials tested Prempro (estrogen plus progestin) against a placebo, and Premarin (estrogen) against a placebo in women who had had hysterectomies.3
Researchers cut the Prempro portion of the trial short after they documented more heart attacks, strokes, blood clots and breast cancer in the study group compared with the placebo group.3Prempro slightly decreased the women's risk for hip fractures and colon cancer, but the researchers concluded benefits didn't outweigh risks.
In light of these findings, many women stopped hormone therapy. This research also led to a change in clinical terminology: The term "hormone therapy" (HT) now refers to combined estrogen-progestin therapy, and the term "estrogen therapy" (ET) refers to treatment with estrogen only.
Fifteen years after the start of the WHI, confusion still exists among patients and providers, and there seems to be no consensus about whether, when or for how long to prescribe hormone therapy.
Hormones and Breast Cancer
Because breast tissue is sensitive to reproductive hormones, there is reason for concern about a link between hormone therapy and breast cancer. The WHI's Prempro arm recorded eight more cases of breast cancer per 10,000 women who took the drug compared with the placebo group.3One criticism of this finding is that the average age of women at the start of the study was 63, and breast cancer risk is known to increase with age. Other known risk factors for developing breast cancer include female sex, nulliparity, first pregnancy after age 30, menarche before age 12, menopause after age 55, family history of breast cancer, and presence of BRCA1 and BRCA2 genetic mutations.1The WHI documented no effect of Prempro on breast cancer mortality.4
After the WHI, a multidisciplinary panel of women's health experts convened by the North American Menopause Society (NAMS) developed consensus-based recommendations for several clinical scenarios. This panel concluded that HT is not appropriate for women with an elevated risk of breast cancer.5The American College of Obstetricians and Gynecologists (ACOG) officially stated that HT is associated with an increased risk for breast cancer.5Importantly, ET is not associated with an increased risk for breast cancer. But women who have a uterus are not candidates for ET because exposure to unopposed estrogen increases uterine cancer risk.4
The USPSTF also weighed in on the issue and concluded that "fair to good" evidence shows that HT slightly increases the incidence of breast cancer, but HT's effects on breast cancer mortality are uncertain.4Other, more recent research suggests that the timing is important. One study found that postmenopausal women younger than 65 who took HT had a slightly elevated risk for breast cancer that became more pronounced with increasing months of use.6The risk increased more than three times among premenopausal women who took HT. The highest risk was documented in premenopausal women who initiated HT in middle age (43 to 53) and took it for more than 5 years. Notably, the harmful effects dissipated with time after menopause.6
Another recent analysis estimated that ET or short-term HT (about 5 years) was also associated with a slightly increased risk in younger women. The increase in cumulative risk was greatest (2% to 3%) in women who had used HT for 10 years or more.7This analysis, as well as the International Menopause Society (IMS), noted that the risk of breast cancer decreases rapidly after cessation of HT.8By 5 years post-therapy, the risk may be no higher than in women who never took hormones.8
Hormones and Heart Disease
The incidence of cardiovascular disease (CVD) increases with age, and women experience an additional boost in occurrence as a result of menopause. This is due in part to lower levels of estrogen contributing to increased low-density lipoprotein levels.4Other general risk factors for cardiovascular disease are cigarette smoking, diabetes, high blood pressure, high cholesterol, obesity, physical inactivity and stress.1In the WHI's Prempro trial, researchers documented more cases of heart attack, stroke and blood clots among women who took HT.
As in the breast cancer analysis of WHI, one criticism is that the average age of women in the trial was 63. In addition, some of the women studied were overweight or obese, and some may have had undetected atherosclerosis when they began the trial.3,8As many as 38% had high blood pressure at baseline.9
Regardless of possible confounding factors, the NAMS panel concluded that it is never appropriate to recommend HT for the prevention of CVD.5The panelists also stated that HT should never be prescribed for women with an elevated risk for stroke or blood clots. But the panel concluded it is appropriate to prescribe HT for menopause symptom relief in women who have typical CVD risks.
ACOG also recommends against HT for the prevention of CVD and advises that if patients take HT to treat menopausal symptoms, they should be counseled about the risks of stroke and blood clots.5
On the issue of HT and CVD, the USPSTF concluded that HT may increase the incidence of CVD, and that "fair" evidence shows it increases stroke risk and "good" evidence shows it increases blood clot risk.4Duration and timing may also influence CVD risk.8When HT is started around the time of menopause and continued until around age 60, it may reduce a woman's risk for diabetes, hyperlipidemia and metabolic syndrome.8 ne study suggests that HT started within a few years of menopause onset and before age 60 reduces cardiovascular disease and mortality.9Recent analyses suggest that younger women and women who begin HT soon after menopause experience no increased risk and may actually receive some CVD protection.7
econdary analyses of WHI results by the National Heart, Lung and Blood Institute suggest that women who begin HT within 10 years of menopause may have less risk for coronary heart disease due to HT than women farther from menopause.10
Protective Benefits of Hormones
The decline of estrogen production during menopause is associated with a reduction in bone mineral density.4The WHI documented fewer cases of osteoporosis and colon cancer in women who took Prempro compared with placebo.3The USPSTF concluded that "good" evidence shows that HT increases bone mineral density and reduces fractures, and "fair" evidence shows that it reduces colorectal cancer incidence.4
Although HT is effective in preventing postmenopausal bone loss, its benefits must be weighed against its associated risks. The WHI found that the benefits of reduced hip fractures did not outweigh the risks for stroke and blood clots, even in women at increased risk for osteoporosis.5Stopping HT is correlated with rapid bone loss and increased fracture risk, suggesting that HT treatment must be continuous to maintain its benefits on bone.7The NAMS panel concluded that for women with an elevated risk of fracture, very low-dose transdermal estrogen therapy is appropriate. But for women with typical fracture risk, HT is an inappropriate intervention for bone preservation. The panel considered other medications, such as raloxifene (Evista) and bisphosphonates (Fosamax, Boniva, etc.), more appropriate than HT.5
The USPSTF concluded that for most women, the harmful effects of HT exceed its chronic disease prevention benefits.4In contrast, ACOG recommends HT as appropriate for women with osteopenia or osteoporosis in early menopause.5,11
The current recommendation from IMS is that HT is appropriate for postmenopausal women who present with increased risk for fracture. Finally, in terms of general protective effects, women who experience menopause before age 45 (and especially before 40) are at a higher risk for cardiovascular disease and osteoporosis. The society believes that these women would benefit from HT.8
Hormones and Symptomatic Relief
HT remains the gold standard for treating menopause-related hot flashes and urogenital symptoms in women without contraindications.12Other menopause-related complaints may also improve with HT.8
The Food and Drug Administration categorizes moderate to severe hot flashes as seven to eight per day or at least 60 per week. A more important consideration is how much they negatively affect daily life. Quality of life and sexuality are key factors to consider.8Hormone therapy is appropriate when prescribed for generally healthy women for short-term relief of menopause symptoms.5ACOG recommends counseling patients about specific risks, using the lowest effective dose for the shortest time and re-evaluating the patient annually.5
Current Recommendations
The table accompanying this article provides a comparative overview of the recommendations by major organizations. The current main recommendation is essentially a repeat of what existed in 1979: Hormones may be prescribed in a low dose and for the shortest possible time for symptomatic relief of hot flashes and vaginal dryness.
Most of the evidence about HT comes from observational studies that did not differentiate between specific hormone preparations and doses, and thus little specific information about doses and treatment duration exists.4Some experts state that a short duration of treatment is less than 5 years.5 ne article compared the different preparations of hormones and defined low-dose forms as preparations that contain 0.3 mg/day or less of conjugated estrogen, 0.5 mg/day or less of oral estradiol, 2.5 mcg/day or less of ethinyl estradiol, or 0.025 mg/day or less of transdermal estradiol.13
Another important point is that although reputable sources have concluded that the harmful effects of HT outweigh the benefits of disease prevention, the absolute increase in risk from HT is modest: 10,000 women who take HT for 1 year might experience seven additional coronary heart disease events, eight more strokes, eight more pulmonary emboli and eight more invasive breast cancers, but they would also have six fewer cases of colorectal cancer and five fewer hip fractures.4Some women might find this risk acceptable, depending on the severity of their vasomotor symptoms.
The NAMS position statement provides specific steps for the treatment of women who seek relief from vasomotor symptoms.Tailor treatment to each woman's needs, using various options. First, consider lifestyle changes (dressing in layers, exercise, reducing body mass index, smoking cessation and relaxation). Next, although studies have not necessarily proven them effective, consider nonprescription methods such as dietary isoflavones (soy), black cohosh or vitamin E — none of which has been linked with significant side effects. If these therapies are ineffective, consider prescription hormonal formulations.
Finally, consider prescription nonhormonal options in women who cannot or do not want to take hormones. Details about these are beyond the scope of this article, but they include certain antidepressants, gabapentin (Neurontin) and certain antihypertensives.
Putting It Into Practice
Because so many factors must be considered when it comes to HT, recommendations should be made on a case-by-case basis. Literature published in 2007 suggests that experts are moving toward individualization of treatment. This concept takes into account that women have differing family and medical histories, symptom severity and expectations of hormone treatment.14Unfortunately, the literature provides little specific guidance about how to make HT decisions.
Without a solid published framework for clinical practice, nurse practitioners need to consider each patient's risk factors, preferences and attitudes. Discuss short-term versus long-term risks and benefits of HT. This is difficult since each health issue involves many different risk factors. Epidemiologically, the probability that a menopausal woman will develop chronic diseases in her lifetime is estimated at 46% for cardiovascular disease, 20% for stroke, 15% for hip fracture, 10% for breast cancer, 6% for colorectal cancer, and 2.6% for endometrial cancer.4These risks exist whether or not a woman takes hormones.
References
1. Shuiling K, Likis F. Women's Gynecologic Health. Boston: Jones and Bartlett Publishers, Inc; 2006: 249-284.
2. Kolata, G. Reversing trend, big drop is seen in breast cancer. New York Times. Dec. 15, 2006.
3. Women's health initiative: not over yet. Harvard Women's Health Watch. 2006;13(9):1-3.
4. U.S. Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med. 2005;142(10):855-860.
5. Ettinger B, et al. When is it appropriate to prescribe postmenopausal hormone therapy? Menopause. 2006;13(3):404-410.
6. Shantakumar S, et al. Age and menopausal effects of hormonal birth control and hormone replacement therapy in relation to breast cancer risk. Am J Epidemiol. 2007;165(10):1187-1198.
7. Alexander I. Overview of current HT recommendations using evidence-based decision making. Amer J Nurse Practit. 2007;11(10):29-41.
8. International Menopause Society. IMS updated recommendations on postmenopausal hormone therapy. Climacteric. 2007;10(3):181-194.
9. Rosano G, et al. Menopause and cardiovascular disease: the evidence. Climacteric. 2007;10(Suppl 1):19-24.
10. National Institutes of Health. Effect of hormone therapy on risk of heart disease may vary by age and years since menopause. Available at: http://www.nih.gov/news/pr/apr2007/nhlbi-03.htm. Accessed May 22, 2008.
11. American College of Obstetricians and Gynecologists. Response to Women's Health Initiative study results by the American College of Obstetricians and Gynecologists. Available at: http://www.acog.org/member_access/misc/whiResponse.cfm. Accessed May 22, 2008.
12. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11(1):11-33.
13. Warren M. Historical perspectives in postmenopausal hormone therapy: defining the right dose and duration. Mayo Clinic Proc. 2007;82(2):219-226.
14. Pines A. Postmenopausal hormone therapy: the way ahead. Maturitas. 2007;57(1):3-5.
Emily Rouhas is a women's health and adult nurse practitioner in New York City. She recently graduated from Columbia University's NP program.
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