It was a jolt for health care providers and patients alike: Hormone replacement therapy, for years a mainstay for postmenopausal women, had been found to have more risks — and fewer protective benefits — than previously thought. The release, in 2002, of the findings of the Women’s Health Initiative (WHI) study and the Heart and Estrogen/Progestin Replacement Study Follow-Up (HERS II) changed health care for postmenopausal women.

A measure of the studies’ impact is the change in nomenclature — from hormone replacement therapy (HRT) to hormone therapy (HT). The focus has changed from attempting to replace estrogen in menopausal women to using estrogen for a limited time to manage menopausal symptoms. Nurses advising menopausal women need to be familiar with dramatic changes in thinking about HT and the current options for women experiencing menopausal symptoms.

Estrogen replacement therapy (ERT) and HRT had been popular for decades. The use of Premarin (a synthetic form of estrogen) to relieve menopausal symptoms became common in the 1960s. It became the No. 1 prescribed drug in the United States in 1966.¹ In 2000, there were 46 million prescriptions for Premarin, accounting for more than $1 billion in sales.³ While estrogen was the dominant hormone used initially, an increase in endometrial cancer among users resulted in the addition of progestin for women with an intact uterus. Use of estrogen/progestin combinations such as Prempro (0.625 mg conjugated equine estrogen [CEE] and 2.5 mg medroxyprogesterone acetate) had steadily increased since the1980s² and accounted for 22 million prescriptions in 2001.³ Much of the popularity of ERT and HRT was due to early research that indicated protection for postmenopausal women likely to develop osteoporosis and heart disease as well as the relief of menopausal symptoms.

But everything changed with the release in 2002 of findings from WHI and HERS II. WHI found that estrogen/progestin (HT) did not protect against the development of coronary artery disease, and HERS II found that HT did not prevent progression of CAD.^3,4 In addition, the WHI found that women taking Prempro faced a slight increased risk of breast cancer, coronary heart disease, stroke, and pulmonary emoblus, and women taking estrogen alone experience an increased risk of CVA and venus thromobils events.²

With the release of this new data, providing heath care for menopausal women has become more challenging. To help patients make intelligent choices, clinicians should become familiar with the findings of HERS and WHI.

HERS

Conducted between 1993 and 1998, the first HERS was a randomized, blinded trial of 2,763 women with a history of CAD. The goal was to determine the effect of estrogen/progestin (in the form of Prempro) compared with placebo in women with established coronary disease. While estrogen/progestin seemed to show a beneficial effect on cardiovascular disease with increased duration of use, the findings did not conclusively support the initiation of HT for the prevention and treatment of coronary heart disease in women with existing cardiovascular disease.⁵

The HERS II was a follow-up study to examine the long-term effects of an estrogen/progestin (Prempro) on the reduction of secondary risks of CAD in menopausal women with pre-existing CAD. Ninety-three percent of the 2,763 women who participated in HERS continued to participate in HERS II, which was extended an additional 2.7 years.⁶ Women in HERS II were randomly assigned Prempro or placebo, with their health assessed at regular intervals.

The most disappointing findings of HERS I and HERS II were that there was no overall beneficial effect of hormone therapy for women with existing cardiovascular disease.^7,8,9 There was, in fact, an unexpected initial increase in coronary risk that was observed to decrease in the later years of the study.^1,2 The study also concluded that estrogen/progestin therapy increased the rates of venous thromboembolism in older women with coronary disease.^6,7,8 Researchers believe that this is likely due to the estrogen component of the hormonal therapy. An increased rate of biliary surgery of 19.1 per 1,000 person-years in the Prempro group—an increase of 6.2 per 1,000 person-years over the placebo group—was also noted. This confirmed previous study findings that postmenopausal women receiving estrogen had a higher incidence of gallbladder disease.⁶

HERS and HERS II had strengths and limitations. HERS and HERS II have increased our understanding of the effects of hormones in women who already have heart disease. However, several elements of HERS limit our ability to generalize its findings to young, healthier postmenopausal women or to hormonal formulations other than Prempro:⁶

• The participants were an older population of postmenopausal women (average age 67 at the beginning of the study and 74 at the end) and had established heart disease.
• Only one type of estrogen/progestin (Prempro) was studied. No lower-dose estrogen/progestin combinations were studied, nor were transdermal or transvaginal combination formulations evaluated.

The WHI

Between 1993 and 1998, 16,608 women aged 50-79 with an intact uterus were recruited by 40 clinical centers in the United States to participate in the estrogen/progestin component of the WHI study. Half of the women were randomly assigned Prempro while the other half received placebo. The goal was to assess the risks and benefits of most commonly prescribed form of the combination of estrogen and progestin. It was the first large, randomized, blinded clinical trial to determine whether estrogen plus progestin had an overall favorable or unfavorable effect on prevention of coronary heart disease. In this case the participants were healthy postmenopausal women as opposed to the women in the HERS study, who had pre-existing heart disease.^1,6

Formal monitoring began in 1997, and the study was expected to continue through 2005, with an average of 8.5 years of follow-up. As early as 1999, a small increase in adverse cardiovascular events was observed; however, the increase was not judged large enough to endanger participants. In May 2002, experts monitoring the safety of the trial found that the adverse cardiovascular events persisted. But a more disturbing finding was that the risk for breast cancer exceeded the preset safety limit. The trial was halted early, after 5.2 years, because the evidence for increased risk of breast cancer, coronary heart disease, stroke, and pulmonary embolus outweighed the benefits for prevention of fractures and possibly colon cancer.⁷

The estrogen-only arm of the WHI was also stopped earlier than expected, in February 2004. About 10,000 women, aged 50-79, who had had hysterectomies were started on estrogen alone (as conjugated equine estrogen [CEE 0.625]) in this arm of the study. The study was terminated early when the incidence of stroke increased without observing a decrease in CAD.^1,6 WHI trials suggest that estrogen alone may have advantages over estrogen plus progestin. The estrogen-plus-progestin study showed an increase in CVA, cardiovascular disease, pulmonary emoboli, and breast cancer. But the estrogen-only arm showed an increase in CVA and pulmonary emboli, not breast cancer or cardiovascular disease. Both regimens showed benefits in decreasing fractures.^1,6

Earlier nonrandomized, observational studies had suggested that there was a small protective effect against cardiovascular disease associated with use of hormones. But the WHI found that the relative risk of developing cardiovascular disease increased 29% for women taking estrogen and progestin when compared to those taking placebo.⁷ While the percentage of increase seems significant and alarming, the overall risk for an individual is relatively small. For example, if 10,000 women took HRT for a year, there would be seven more cardiovascular events compared to the placebo group.^1,9 Additionally, there was a 41% increase in strokes (29 cases vs. 21 cases per 10,000 person-years). These were mostly nonfatal events.^1,9 Later updates of the evaluation of this data showed that the greatest risk occurred in the first year of use and later declined.^10,11

The most disturbing finding of the WHI was the increased risk of invasive breast cancer. The rate of increased risk was 26%: 38 women out of 10,000 would get breast cancer if they took HT compared to 30 women out of 10,000 if they did not take HT.⁸ These results confirm findings from the Breast Cancer Detection Demonstration Project: a 1.2-fold increase in breast cancer in women taking estrogen alone and a 1.4-fold increase in those taking estrogen/progestin.⁷

Ongoing WHI data have produced other concerns. The outcomes of the WHI Memory Study, another arm of the original WHI study, have indicated that for older menopausal women HT may pose some increased risk of dementia. It was noted that there would likely be 23 more cases of dementia per 10,000 women older than 65. Since women under 65 were not included in this arm of the study, it is difficult to determine the meaning of this increase in younger menopausal women.¹²

The WHI study produced positive findings: The rate of colon cancer decreased by 37% (10 vs. 16 per 10,000 person-years). There was a decrease in hip fractures (10 vs. 15 per 10,000 person-years).⁹ The data on the reduction of osteoporotic fractures are consistent with other observational studies and support the benefit of estrogen with or without progestin to maintain bone mineral density.⁹

Although the studies did not evaluate hormones’ beneficial effects on menopausal symptoms, numerous previous studies have established this benefit. But it is unclear how to weigh this benefit against the risks the WHI and HERS II identified.

The WHI is a powerful, blinded, randomized, controlled trial. It is the only trial thus far to directly assess the risks and benefits of HT on coronary heart disease and the overall effects on healthy postmenopausal women. Significant limitations to the study have been noted. It addressed the effects of only one drug (Prempro) and its effect on healthy postmenopausal women. The results do not address the effects of other formulations, lower dosages, or formulations using a different route, such as transdermal preparations. While the study did involve women without established heart disease, the average age of the participants was 63, 12 years after the age of onset of menopause, and early, subclinical changes of cardiovascular disease might not be detectable.^1,2 Due to this age disparity, it is difficult to extrapolate the impact of HT in women in very early menopause. Probably the most important limitation is that it could not separate the effects of estrogen and progestin since Prempro contains both. It is theorized that the effects of progestin on breast tissue and on atherosclerotic disease may be a significant factor in the findings of the study.

What now?

In light of the recent studies, women have more questions and doubts than ever before about HT. The American College of Obstetricians and Gynecologists advises that the decision to take HT should be a joint one between a patient and her health care provider and should be made on a case-by-case basis.^1,2,10 Before deciding to start HT, a woman should consider her overall health status and risk factors. A history of blood clots, liver disease, breast cancer, and unexplained vaginal bleeding is generally considered a contraindication to HT. Women also need to be aware that HT is no longer recommended for primary or secondary protection against heart disease.^1,2,13

Breast cancer: In most cases, women who have had breast cancer are not candidates for HT. Women with a family history of breast cancer may also wish to avoid HT.

Cardiovascular disease: The WHI and HERS showed an increase in risk for heart disease of 29% in the group taking combined HT (Prempro). There was a 41% increased risk of stroke and a twofold increased rate of blood clots in the HT group compared with those taking a placebo.^1,2,13

Osteoporosis: The WHI showed an overall decrease in fractures in the HT group. There was a decrease of 24% in total fractures and a 34% decrease in hip fractures. Family history, as well as alternative treatments for prevention of osteoporosis, should be considered.^1,2,10 Alternative treatments exist, but the medications are relatively new and their long-term use may also lead to future disappointments. In addition, these medications present other risks for women with GI diseases.^1,2

Menopausal symptoms: Although the management of menopausal symptoms was not well addressed in WHI and HERS, menopausal symptoms are often the primary reason women seeks help from health care providers. HT continues to be one of the most effective therapies in managing menopausal symptoms, such as the vasomotor changes of hot flashes and night sweats, vaginal and urogenital dryness, and palpitations. Insomnia, mood swings, nervousness, irritability, and fatigue may also accompany menopause and have significant negative impact on quality of life. Each woman will experience varying symptoms for differing amounts of time, but on average symptoms persist for about five years. The current recommendations for HT is that it be used primarily for symptom relief and for a limited time. A woman’s continued use of HT should be re-evaluated yearly.^1,2,14

Looking for alternatives

The findings of the WHI have left women wondering what therapies are safe to use to relieve menopausal symptoms.¹¹ Women who used HT believing that there were few risks are now wondering whether other modalities they choose today may later turn out to be questionable.

The results of the WHI and HERS have made women more skeptical of hormonal options. Often, women turn to herbal treatments that they view as more “natural” and less worrisome. Unfortunately, results of placebo-controlled trials of vitamin E, soy protein, isoflavones, red clover, and black cohosh have shown, at best, a very slight improvement in vasomotor symptoms. Some women may get symptom relief with any one or combination of these alternatives. But the long-term effects are not known, and the data do not suggest any particular alternative herbal remedy. There are concerns about the quality and ingredients of herbal remedies because the FDA does not regulate them. Other alternatives include acupuncture, relaxation techniques, and relaxation breathing. Several well-designed studies are under way that should provide better answers.

Antidepressants such as the selective serotonin reuptake inhibitors (e.g., fluoxetine [Prozac, Serafem]; paroxetine [Paxil]; and venlafaxine [Effexor]) were shown to reduce the effects of hot flashes in some women with breast cancer who were not candidates for HT.¹⁵ However, a reduction of sexual drive and satisfaction is often an unpleasant adverse effect, especially in menopausal women, who may already be experiencing diminished libido.¹⁵

A healthy diet and exercise can improve symptoms of menopause.^1,2,15 Women with acute vasomotor symptoms should avoid foods that trigger hot flashes, such as spicy foods, alcohol, and caffeinated beverages. A diet high in lean meats, fruits, and vegetables is preferable to fast food and important for overall health. Exercise may also be of benefit in improving mood, moderating weight gain, and maintaining bone health.^1,13 Weight-bearing exercises and resistance training appear to be of great importance in preventing osteoporotic fractures. Staying active and fit also acts to prevent loss of equilibrium and subsequent falls.^1,2

WHI and HERS II indicate that HT should not be prescribed to prevent cardiovascular disease. If women are taking HT in an attempt to prevent cardiovascular disease, HT should be discontinued.¹³ Other methods of reducing the risk of cardiovascular disease — such as a healthy diet, exercise, and smoking cessation — are extremely important. Statins or other medications to lower cholesterol may be used if indicated by the health care provider.¹⁶

Selective estrogen receptor modulators (SERMS), such as raloxifene (Evista), and bisphosphonates, such as Fosamax or Actonel, may be used for the prevention of osteoporosis. Women with vasomotor symptoms may benefit from short-term HT and switch to SERMS or bisphosphonates when the symptoms resolve.^1,13

Women who experience vaginal dryness or genitourinary symptoms may benefit from vaginal estrogen creams, rings, or tablets. These methods do not seem to increase systemic levels of estrogen although their long-term use is continuing to be evaluated.^17,18

Where do we go from here?

WHI and the HERS studies added to our knowledge about HT. Further research is necessary to determine the effects of other formulations, lower dosages, and different routes of administrations, such as transdermal. There is still much work to do to ensure that women have access to the safest therapies to manage the symptoms of menopause.

Nurses have many opportunities to be involved in conducting and participating in research as well as ensuring that women have up-to-date information and can participate in decisions about their health care. The nursing roles of educator and patient advocate are very much suited to help menopausal women improve their future health.