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Postmenopausal hormone replacement therapy after the Women’s Health Initiative

Based on WHI findings, women taking HRT might expect to experience 19 more events per year per 10,000 women than will women who don’t take hormones. How do these results apply to your patients?

Timothy J. Doty, PA-C, MPAS

Mr. Doty works for a subsidiary company of Northrop Grumman and provides primary and emergency care to a small group of Americans working and living on an Egyptian Air Force base near the Suez Canal. The author has indicated no relationships to disclose relating to the content of this article.

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CME

Earn Category I CME credit by reading this article and the asssociated article and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct.

This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of January 2005.

Until relatively recently, hormone replacement therapy (HRT) was used to relieve a variety of menopausal symptoms and for the prevention of osteoporosis. In addition, HRT was prescribed for prevention of a number of chronic conditions, and many observational studies had reported benefits with this therapy.1,2 In 1997, HRT use among menopausal and postmenopausal women was increasing at a rate of about 1% per quarter.3

Then the results of the Heart and Estrogen/progestin Replacement Study (HERS) were reported. HERS was the first randomized, blinded, placebo-controlled study to determine whether estrogen plus progestin therapy (EPT) alters the risk of coronary events in postmenopausal women with coronary heart disease (CHD).2,4 No overall reduction in events was found in the EPT group, and HRT use began to decline at about 1% per quarter after this study came out.24

In July 2002, the National Heart, Lung, and Blood Institute brought the EPT arm of the Women’s Health Initiative (WHI) to a halt; the reason was that the subjects who took EPT were found to have an increased risk of breast cancer, and EPT was shown to have a lack of overall benefit.5 The rate of decline in HRT use then jumped to 18% per quarter.3

In early 2003, the FDA required changes to the labeling of various HRT products, saying they were indicated only for treatment of moderate to severe vasomotor symptoms and symptoms of vulvar and vaginal atrophy associated with menopause.6

Despite this sequence of events, however, clinicians should bear in mind that the WHI trial had many shortcomings. Women with moderate to severe postmenopausal symptoms are still good candidates for HRT and should be integrally involved in treatment decisions.7,8 In discussing HRT and the WHI results with menopausal women, clinicians should consider the following:

  • The WHI selection criteria were biased away from women with symptoms related to menopause and focused instead on chronic diseases; thus the criteria for this study did not include relief of menopausal symptoms.9,10
  • The average age of the women in the WHI was 63 years—which is considerably older than are most women who seek treatment for menopausal symptoms.4
  • Many of the subjects in the WHI may have had undiagnosed atherosclerosis.10 According to one author, “If trials were done early . . . when the endothelium is likely still to be intact . . . treatment might be shown to prevent CHD.”7
  • The WHI evaluated only one dosage of hormones and one route of administration.11,12

The WHI and HERS results

The EPT arm of the WHI enrolled 16,608 healthy postmenopausal women aged 50 to 79 years (mean age, 63 years) with intact uteri and randomly assigned them to take 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate, or placebo, daily. This study was scheduled to continue until 2005 but was stopped in July 2002 because of the finding that women on active treatment had an increased risk of breast cancer.

Interestingly, the study designers preset the breast cancer stopping point purposefully low, and after an average follow-up of 5.2 years the threshold was passed. This, along with an increased rate of coronary events, stroke, and pulmonary embolism found in the study—and despite a decreased rate of colorectal cancer and fractures in women receiving active treatment—prompted the data and safety monitoring board to recommend stopping the trial.5,13

Another arm of the WHI enrolled 10,739 healthy women aged 50 to 79 years (mean age, 64 years) who had had hysterectomies and randomly assigned them to take 0.625 mg of conjugated equine estrogens or placebo daily. This estrogen-only arm was supposed to continue until March 2005 but was stopped in February 2004, after an average follow-up of 6.8 years, because the women on active treatment had an increased risk of stroke.14

HERS included 2,763 postmenopausal women younger than 80 years (mean age, 66.7 years) with intact uteri who were known to have CHD. The study investigators randomly assigned them to take 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate, or placebo, daily. After an average follow-up of 4.1 years, no reduction in coronary events was found to have occurred. The principal investigators concluded that they do not recommend starting this treatment “. . . for the purpose of secondary prevention of CHD.”15

Other studies

The currently accepted clinical practice is not to use HRT for the prevention of disease in postmenopausal women. The WHI and HERS have been pivotal in this change of practice. Women with postmenopausal symptoms are still seeking treatment for these symptoms, however, and those who have taken HRT still want medical advice. They want to know the risks and benefits of using HRT for menopausal symptoms and the long-term risks associated with their use of HRT in the past.

This article discusses specific risks and benefits using data from HERS and the WHI, as well as data collected in two large reviews conducted by the US Preventive Services Task Force (USPSTF) and the North American Menopause Society (NAMS) and a few more recent articles.8,16

The USPSTF conducted systematic searches of the literature on HRT use among postmenopausal women, its effectiveness for the primary prevention of chronic conditions, and its association with harmful outcomes.16 The task force specifically addressed primary prevention, not secondary prevention, and did not include data concerning the treatment of postmenopausal symptoms. They focused on studies that reported specific health outcomes, conducted several meta-analyses, and calculated the numbers of events caused or prevented per year of HRT use per 10,000 women.

NAMS used the MEDLINE database to find medical literature specifically addressing treatments for hot flashes and night sweats, looking primarily for data from randomized, controlled clinical trials but also using data from systematic reviews.8 NAMS recommends lifestyle changes and nonprescription remedies as the first steps in treating women with menopausal vasomotor symptoms, but the organization’s position statement also notes that “. . . hormonal approaches, primarily systemic ET/EPT, are most often prescribed and are the only governmentapproved therapies in the United States and Canada for treating moderate to severe hot flashes.”8 NAMS also recommends using the lowest dosage of hormones that gives adequate symptom relief to the patient and discontinuing therapy as soon as possible.

The risks of HRT

Breast cancer EPT arm of the WHI was ended ahead of schedule because the risk of breast cancer was increased in the active treatment group.5,13 The breast cancer rate crossed the preset threshold after 5 years of EPT use. There were 245 cases of breast cancer in the hormone group compared with 185 in the placebo group (HR [hazard ratio], There 1.24; weighted P>.001); the numbers of cases of invasive breast cancer were 199 and 150, respectively (HR, 1.24; weighted P=.003).17

The invasive breast cancers in the treatment group were larger and at a more advanced stage than were those in the placebo group. Also of significance was that after 1 year, the number of women with abnormal mammograms was significantly greater in the treatment group (716, or 9.4% of 7,656 women) compared with the placebo group (398, or 5.4% of 7,310 women; P>.001). These results suggest that EPT may stimulate the growth of breast cancer and hinder the diagnosis of the disease.

The estrogen alone arm of the WHI, however, failed to demonstrate a statistically significant change in risk of breast cancer.18 There were 30 fewer cases of breast cancer—94 cases in those women taking estrogen alone versus 124 cases in those women taking placebo—but the confidence interval (CI) crossed 1.00 (HR, 0.77; 95% CI 0.59-1.01).

The USPSTF review stated that most recent goodquality studies, including three meta-analyses, showed that current estrogen users have an increased risk of breast cancer ranging between a relative risk (RR) of 1.21 and 1.40.16 Some recent studies suggest an increased risk when estrogen is combined with progestin, while others do not. Trend data indicate that risk for breast cancer increases as duration of use increases. However, the majority of studies of women who have ever used HRT (as opposed to current users) report no increase in risk of breast cancer (RRs range from 0.85-1.14). Six recent cohort studies that looked at breast cancer mortality in those who had ever used HRT found either no effect or decreased mortality, and in those who had used HRT for less than 5 years, the RR ranged from 0.5 to 1.0.

Cardiovascular disease HERS was a secondary prevention trial that examined the rate of coronary events in postmenopausal women with established CHD.15 Overall, there was no significant difference between the EPT group and placebo group, with 172 and 176 women respectively suffering an MI or death from CHD (HR, Women who use 0.99; 95% CI, 0.80-1.22). There was a significant time trend noted, however, with more CHD events in the hormone group in year 1 and fewer in years 4 and 5.

The EPT arm of the WHI demonstrated no cardiac protection and possibly even an increased risk of CHD, especially during the first year of hormone therapy.19 There was a 24% overall increased risk of CHD (HR, 1.24; 95% CI 1.00-1.54). The risk was 81% at 1 year (HR, 1.81; 95% CI, 1.09-3.01).

The overall incidence of peripheral arterial events did not differ between the hormone and the placebo groups (HR, 0.89, 95% CI, 0.63-1.25).20 There was, however, a difference with duration of hormone treatment. The risk was greater with hormone treatment in years 1 (HR, 1.33) and 2 (HR, 1.27) and was lower in years 5 (HR, 0.85) and 6 (HR, 0.87).

The estrogen arm of the WHI failed to demonstrate a statistically significant change in risk of CHD (HR, 0.91; 95% CI, 0.75-1.12). In this arm of the trial, the risk for death from CHD (HR, 0.94; 95% CI, 0.65-1.36) and nonfatal MI (HR, 0.89; 95% CI, 0.70-1.12) were similarly not significant.18

The USPSTF review showed an interesting mix of results. Five studies evaluating overall CHD mortality revealed a significant reduction of risk in “. . . those using HRT at the time of assessment (RR, 0.62; 95% CI, 0.40-0.90), but not in ever, past, or any users.”16 For risk of CHD incidence, the task force evaluated three cohort studies, nine case-control studies, and one small randomized, controlled trial with similar results. CHD incidence was reduced in those who were using HRT at the time of assessment (RR, 0.80; 95% CI, 0.68-0.95) but was not reduced in ever, past, or any users. Their summary for CHD incidence for all HRT use was not statistically significant (RR, 0.91, 95% CI, 0.67-1.33).

Stroke In the EPT arm of the WHI, there was a significant increase in the risk for stroke in the hormone group (HR, 1.31; 95% CI, 1.02-1.68), with the risk for ischemic stroke found to be higher (HR, 1.44; 95% CI, 1.09-1.90) than the risk for hemorrhagic stroke (HR, 0.82; 95% CI, 0.43-1.56). This increased risk for all strokes appeared to be similar in all subgroups of baseline stroke risk.21

The estrogen arm of the WHI was stopped ahead of schedule because of an increased risk of stroke, with 158 strokes occurring in the hormone group and 118 in the placebo group (HR, 1.39; 95% CI, 1.10-1.77).14 The risk of nonfatal stroke was statistically significant (HR, 1.39; 95% CI, 1.05-1.84), but the risk of fatal stroke was not (HR, 1.13; 95% CI, 0.54-2.34).

The USPSTF review revealed a small increase in stroke incidence (RR, 1.12; 95% CI, 1.01-1.23) with HRT use in a combined review of nine studies.16 Results of a subanalysis found a significant increase in risk for thromboembolic stroke (RR, 1.20; 95% CI, 1.01-1.40), but not for hemorrhagic stroke, among women who had ever taken HRT. One cohort and one case-control study failed to demonstrate an association between long-term estrogen use (greater than 5 years) and risk of stroke. The USPSTF review of the Nurses Health Study showed a 45% increased risk of stroke among women using EPT compared with women who had never used HRT (RR, 1.45; 95% CI, 1.10-1.92) but no statistically significant difference with estrogen use alone (RR, 1.18; 95% CI, 0.95-1.46). The USPSTF did note a significant dose-response relationship between stroke and estrogen dosages of 0.3 mg/d (RR, 0.54; 95% CI, 0.28-1.06), 0.625 mg/d (RR, 1.35, 95% CI, 1.08-1.68) and 1.25 mg/d (RR, 1.63, 95% CI, 1.18-2.26).

Thromboembolism In the EPT arm of the WHI, there was a significant twofold increase (HR, 2.11; 95% CI, 1.58-2.82) for all venous thromboembolic disease.13 Deep vein thrombosis was more than twice as likely to occur (HR, 2.07; 95% CI, 1.49-2.87). So was pulmonary embolism, with 70 occurring in the hormone group and 31 in the placebo group (HR, 2.13; 95% CI, 1.39-3.25), and the trend was toward higher rates early in the course of use.

The WHI estrogen arm did demonstrate a statistically significant risk of deep vein thrombosis (HR, 1.47; 95% CI, 1.04-2.06), with 77 incidents in the hormone group and only 54 in the placebo group, but the estrogen arm did not demonstrate a statistically significant risk of pulmonary embolism (HR, 1.34; 95% CI, 0.87-2.06), with 48 in the hormone group and 37 in the placebo group.18 Composite risk for all venous thromboembolic disease did not reach statistical significance (HR, 1.33; 95% CI, 0.99-1.79).

The USPSTF investigators reported composite venous thromboembolism, not the events of deep vein thrombosis or pulmonary embolism.16 Combining 12 studies with meta-analysis demonstrated a moderate increase in risk from HRT use (RR, 2.14; 95% CI, 1.64-2.81). The risk was much greater in the first year of use (RR, 3.49; 95% CI, 2.33-5.59) based on six studies that reported risk by duration of use. The USPSTF also noted that several small studies indicated there was greater risk with dosages of conjugated estrogens higher than 0.625 mg/d than with lower dosages, and that there was a higher risk noted with EPT than with estrogen alone.

Cholecystitis Neither arm of the WHI reported on cholecystitis or biliary tract surgery rates.13,18 However, the USPSTF review included this as one of the major risks, citing HERS II and the Nurses Health Study.16 The HERS II trial reported an increase in biliary tract surgery among those using HRT compared with placebo users (RR, 1.44; 95% CI, 1.10-1.90) over the 6.8 years of followup. The Nurses Health Study, a cohort analysis comparing users of HRT use with those who had never used HRT, revealed an increased risk for cholecystitis (RR, 1.8; 95% CI, 1.6-2.0).

Cognitive function The WHI Memory Study (WHIMS) is a subgroup of the WHI. From the EPT arm, 4,532 postmenopausal women (aged 65-79 years) free of probable dementia enrolled into WHIMS.22 Evaluation was performed with the Modified Mini-Mental Status Examination. Probable dementia was diagnosed in 61 women, 40 women in the hormone group and 21 in the placebo group (HR, 2.05; 95% CI, 1.21-3.48). The most common classification of dementia in both groups of women was Alzheimer’s disease. No significant increase in risk of mild cognitive impairment (MCI) was found in either group (HR, 1.07; 95% CI, 0.74-1.55).

The WHIMS participants from the estrogen arm of the WHI consisted of 2,947 women (aged 65-79 years) free of probable dementia at the time of enrollment into the study.23 Probable dementia was diagnosed in 47 women, 28 from the hormone group and 19 from the placebo group (HR,1.49; 95% CI, 0.832.66). When the data were pooled according to the original WHIMS protocol, the overall HR was 1.76 (95% CI, 1.19-2.60).

The rate of mild cognitive impairment in this arm was greater than in the EPT arm, with 76 women from the hormone group and 58 women from the placebo group having MCI, but this rate was still below statistical significance (HR, 1.34; 95% CI, 0.95-1.89). The authors concluded, “Pooling data for estrogen alone and estrogen plus progestin resulted in increased risks for both end points. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.”23

The USPSTF review studied 19 randomized controlled trials and 10 cohort studies on HRT use and risk of cognitive decline or dementia.16 Because of methodologic limitations and inconsistencies among the studies, they came to no conclusions.

The benefits of HRT

Osteoporosis According to Bachmann, “Estrogen therapy is considered the optimal therapy for osteoporosis. Oral and transdermal routes have been approved for osteoporosis prevention in postmenopausal women who are at risk.”1 She referenced a meta-analysis of 22 trials with data on 8,800 women using HRT that showed a 27% reduction in risk of nonvertebral fractures. This paper also showed a reduction in risk of hip and wrist fractures of 40% in older women and 55% in women younger than 60 years.

The EPT arm of WHI demonstrated an increased bone mineral density (BMD) of 3.7% after 3 years of treatment compared with 0.14% in the placebo group, and a reduced risk in the treatment group of all fractures (HR, 0.76; 95% CI, 0.69-0.83), hip fractures (HR, 0.66; 95% CI, 0.45-0.98), and vertebral fractures (HR, 0.66; 95% CI, 0.44-0.98).24

The WHI estrogen-only arm revealed a decreased risk of all fractures (HR, 0.70; 95% CI, 0.63-0.79).18 There were 38 hip fractures in the women in the hormone group compared to 64 hip fractures in the placebo group (HR, 0.61; 95% CI, 0.41-0.91) and 39 vertebral fractures in the hormone group compared to 64 in the placebo group (HR, 0.62; 95% CI, 0.42-0.93).

The USPSTF review demonstrated a decreased RR for hip fractures among those who had ever used HRT (RR, 0.76, 95% CI, 0.56-1.01).16 They also reported reduced risks for wrist fracture (RR, 0.44; 95% CI, 0.23-0.84) and vertebral fractures (RR, 0.60; 95% CI, 0.74-0.86).

Colorectal cancer The EPT arm of the WHI demonstrated a significant decrease in the risk of colorectal cancer, with 43 cancers in the hormone group and 72 in the placebo group (HR, 0.56; 95% CI, 0.38-0.81; P=.003).25 However, women in the hormone group had more advanced cancers with greater lymph node involvement than did women in the placebo group. This difference began to emerge early in the initial follow-up year, signifying an effect on established cancers. This suggests the need for routine bowel screening in women who use EPT, despite the lower overall incidence of colorectal cancer in this group. The WHI estrogen-only arm demonstrated no statistically significant difference in risk of colorectal cancer, with 61 cancers in the hormone group and 58 in the placebo group (HR, 1.08; 95% CI, 0.75-1.55).18

The USPSTF review revealed a 20% reduction in colon cancer among women who had ever used HRT as compared with those who had never used HRT (RR, 0.80; 95% CI, 0.74-0.86).16 There was a 34% reduction in women who were using HRT at the time of the assessment (RR, 0.66; 95% CI, 0.59-0.74). The results for rectal cancer were quite similar. In these observational studies, the hormone users were at somewhat decreased risk of colorectal cancer because they were healthier, less obese, more active, and eating healthier diets.

Quality of life The EPT arm of the WHI resulted in no significant perception of effect on general health, vitality, mental health, depressive symptoms, or sexual satisfaction.26 There was a small benefit on sleep disturbance with hormone use in the younger group of women (aged 50-54 years) with moderate to severe vasomotor symptoms at baseline. No comments from the WHI estrogen-only arm on quality of life have so far been published.18

To participate in the WHI trial, women already taking hormones had to go through a 3-month washout period before enrollment.13 Thus, there was a strong selection bias against women who might have experienced a benefit in terms of quality of life.9 The WHI investigators did not recruit women with menopausal symptoms, and relief of symptoms was not truly evaluated or measured.10,27

According to Bachmann’s review, “With estrogen use, women report less vaginal irritation, pain, dryness, or burning during intercourse. Relief . . . often leads to an increased sexual desire and arousal. . . . This contributes to an improved quality of life for many women.”27

The NAMS authors write, “Prescription systemic ET/EPT remains the gold standard for treating moderate to severe menopause-related hot flashes in women without contraindications.”8 They reference a Cochrane Group meta-analysis of 21 randomized controlled trials representing 2,511 women that reported a significant improvement in vasomotor symptoms, including a 77% reduction in hot flash frequency and an 87% reduction n symptom severity in women taking estrogen rather ing a menopausal woman with vasomotor or vulvarthan placebo.

A probabilistic clinical decision analysis published in the British Medical Journal hypothesized a population of 50-year-old white women in the United Kingdom with different baseline risks for breast cancer. The women were then evaluated for gain or loss in quality-adjusted life-years (QALYs).28 According to the authors, “Our model showed a net harm associated with HRT use for 5 years in asymptomatic women, which increased with baseline risk of breast cancer.” But when considering the population with moderate to severe vasomotor symptoms, they wrote, “. . . our main analysis showed HRT to be on average beneficial in women with menopausal symptoms.” The QALYs decreased as the baseline risk of breast cancer increased.

Current recommendations

The overall health risks exceed the benefits when healthy postmenopausal women use 0.625 mg/d of conjugated equine estrogens plus 2.5 mg/d of medroxyprogesterone acetate for the primary prevention of various chronic diseases. Thus, the use of combined hormones should not be recommended for chronic disease prevention in postmenopausal women.13 The burden of incident disease events was equivalent in groups taking 0.625 mg of conjugated equine estrogens and placebo, indicating no overall benefit. Thus, conjugated equine estrogens should not be recommended for chronic disease prevention in postmenopausal women.18 In summary, current data make it clear that the use of hormone therapy for the prevention of chronic disease in women who do not have menopausal symptoms is unjustified.6,8,13,18,28

The use of estrogen or EPT in women with intact uteri is approved by the FDA for the treatment of moderate to severe vasomotor symptoms associated with menopause, and for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. For osteoporosis prevention, estrogens and combined estrogen-progestin products should be considered only for women who have a significant risk of osteoporosis that outweighs the risks of taking hormones. When used, hormones should be prescribed at the lowest effective dosage and for the shortest duration possible.6

NAMS recommends a stepped approach when treating a menopausal woman with vasomotor or vulvar-vaginal symptoms.8 As in most cases in clinical practice, the first step is getting a detailed history from the patient that includes frequency and severity of symptoms as well as how much the symptoms are affecting daily life. What the patient desires from treatment is also important, as some women may only need reassurance or minimal alleviation of symptoms while others may desire complete amelioration.

For women with mild vasomotor symptoms, NAMS recommends first lifestyle changes such as environmental manipulation to keep the core body temperature cool, behavioral changes, regular exercise, and avoiding hot flash triggers. Many OTC remedies are reported to help with menopausal symptoms. NAMS recommends trying dietary isoflavones, black cohosh, or vitamin E as these might be helpful and have not been found to have much adverse effect, with the possible exception of isoflavones in women with a history of breast cancer.8

NAMS considers the treatment of moderate to severe vasomotor symptoms associated with menopause to be a primary indication for systemic estrogen therapy and EPT.8 Numerous combinations, strengths, and routes of delivery are available. The response of individual women to various dosages of hormone levels varies widely, with some women responding to very low dosages of estrogen and others requiring higher dosages, and NAMS recommends starting with lower dosages and increasing them as necessary.

NAMS also recommends several nonhormonal prescription treatments for women in whom hormonal therapy is contraindicated or for those who are concerned about hormone treatment and would prefer to try other options. The antidepressants venlafaxine (Effexor), paroxetine (Paxil), and fluoxetine (Prozac) provide moderate relief for many women. Improvement has also been reported with relatively low dosages of the anticonvulsant gabapentin (Neurontin) and, to a lesser degree, with the antihypertensive clonidine (Catapres).

The decision to treat menopausal symptoms must be a mutual one arrived at by the patient and her health care provider based on the severity of symptoms, the goals of treatment, and both parties’ understanding of the likely risks and benefits of that treatment.1,8-10,27,28 The risks and benefits discussed in this article are important, but the HRs, RRs, and CIs may confuse the patient who seeks symptom relief but is also worried about the effects of HRT. The absolute risk projections presented by the Writing Group for the WHI Investigators and the WHI Steering Committee may provide more understandable risk/benefit information for the typical patient. They wrote, “The absolute excess risk (or risk reduction) attributable to estrogen plus progestin was low.”13,18

It may help to explain risks to patients this way: Based on the WHI estrogen plus progestin arm over 1 year, 10,000 healthy women (average age, 63 years) taking 0.625 mg/d of conjugated equine estrogens plus 2.5 mg/d of medroxyprogesterone acetate might experience seven more coronary events, eight more strokes, eight more pulmonary emboli, eight more invasive breast cancers, six fewer colorectal cancers, and five fewer hip fractures than women taking a placebo.13 Combining all the monitored events, women taking HRT might expect 19 more events per year per 10,000 women than would women taking placebo.

Based on the WHI trial estrogen-only arm over 1 year, 10,000 healthy women (average age, 63 years) taking 0.625 mg/d of conjugated equine estrogens might experience 12 more strokes, six fewer hip fractures and seven fewer breast cancers than women taking placebo.18 Combining all the monitored events suggests that the risks and benefits are in overall balance and, importantly, that there is no effect on total mortality.

Recommendations for the future

Further studies of different combinations of hormones, different strengths, and different routes of delivery, especially in younger populations, will help clinicians to make appropriate treatment recommendations in the future.11 Many studies have demonstrated that lower hormone dosages relieve vasomotor symptoms as effectively as do higher dosages.8 Unlike oral preparations, transdermal estrogens (TDE) are not affected by firstpass metabolism; and low-dose TDE is well tolerated and effective.29,30

Estrogen treatment in monkeys with healthy arteries prevented the development of atherosclerosis, even in the presence of an atherogenic diet.10 According to Mikkola and Clarkson, “Estrogen treatment of younger postmenopausal women or monkeys in the early stages of atherosclerosis progression has marked beneficial effects.”31 The FDA states that the recent findings still leave some very important questions unanswered and encourages further research.6

Conclusion

WHI and HERS have caused many patients and their providers significant consternation about whether to prescribe HRT and whether to continue to use it. HRT is now primarily recommended for the treatment of moderate to severe vasomotor and vulvar-vaginal symptoms associated with menopause. Patients who are considering treatment with hormones for these symptoms should make their decisions in concert with their medical providers after reviewing the potential risks and benefits as they are currently understood. Further controlled studies are recommended by many in the medical community and may provide more information in the future.

REFERENCES

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