Should Symptomatic Menopausal Women Be Offered Hormone Therapy?

Abstract and Background

Abstract

Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms.

Major Findings

Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause.

Conclusions

Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.

Background

The use of hormone therapy in menopausal patients underwent a dramatic shift following the published results of the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI). Hersh and colleagues[1] evaluated national trends in hormone therapy use between January 1995 and July 2003 using the National Prescription Audit and the National Disease and Therapeutic Index databases. Prior to the release of the HERS and WHI results, approximately 42% of women aged 50–74 years were taking hormone therapy. Following the publication of HERS and WHI results in 2002, hormone therapy exposure declined to 28% of women in this age group. Further, annual prescriptions fell 38%, from 91.0 million in 2001 to 56.9 million in 2003. The greatest decline in hormone use was among the oral estrogen and oral estrogen/progestin preparations, contrasting that of transdermal and vaginal formulations which remained stable.

HERS showed that in women with preexisting coronary heart disease (CHD), hormone therapy (conjugated equine estrogens [CEE] 0.625 mg and medroxyprogesterone acetate [MPA] 2.5 mg) was not effective as a means of preventing cardiovascular events and was associated with an increased risk for myocardial infarction in the first year in some women.[2] Similarly, the attributable risk (per 10,000 person-years) as reported by the WHI was 7 more CHD events, 8 more strokes, and 8 more invasive breast cancers, as well as 5 fewer hip fractures and 6 fewer colorectal cancers.[3] However, selective reporting from the popular media and some scientific sources have clouded the overall results from WHI by emphasizing results in terms of relative risks. For example, the 29% increase in CHD, 41% increase in stroke, 26% increase in breast cancer, 37% reduction in colorectal cancer, and 34% reduction in hip fractures were presented as a meaningful increase in risk rather than risks which were all less than 1.5 times the placebo rate. In the case of CHD, the final data analysis found that the relative risk decreased from 29% to 24%, and the overall risk of CHD did not achieve statistical significance.[4]

A number of position papers by major organizations have attempted to clarify the risks and benefits with hormone therapy in the aftermath of the recent clinical trials. However, despite such efforts, the popular media failed to correctly communicate the clinical implications of the results for everyday practice of providing healthcare to the individual patient. The influence of the media on this matter was underscored by a postal survey of 1700 current users of hormone therapy in Sweden. Hoffmann and colleagues[5] found that women (53–54 years of age) perceived hormone therapy as more risky and less beneficial in 2003 (post HERS II and WHI) compared with 1999. The major sources of information that women relied on were from print media (43.8%) and television/radio (31.7%). Only 18.3% of women received information about hormone therapy from their healthcare providers. Use of hormone therapy decreased from 40.5% to 25.3%, and this decline was significantly correlated with the changes in attitudes towards hormone therapy (P < .001).

Many physicians also remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. For example, Williams and colleagues[6] conducted a postal survey in March 2004 of all primary care physicians in Florida about their understanding of the risks and benefits of hormone therapy. The respondents comprised 600 primary care specialists, including 203 ob/gyns, 145 internists, 219 family practitioners, and 33 “other.” They found that respondents overestimated the magnitude of risks and benefits with hormone therapy 67% of the time. The study authors postulated that the lack of understanding regarding attributable risk and relative risk may have contributed to the overestimation of risk (and benefit). These concepts will be discussed later in this article.

The data from Williams and colleagues, as well as others, underscore the need to educate physicians to address perceptions of hormone therapy based on WHI findings and clarify the appropriate use of hormone therapy in symptomatic menopausal women. In October 2004, the American Society for Reproductive Medicine (ASRM) reported the results of an online survey of 556 reproductive health professionals at its annual meeting. Nearly 100% of the reproductive health professionals surveyed agreed that their patients are confused about menopausal treatments, and 73% said that they spend a considerable amount of time counseling their menopausal patients about the best treatment. On the basis of the survey results and many informal conversations, ASRM concluded that additional guidance and educational tools were needed to assist general gynecologists and primary care practitioners in appropriate decision-making for the treatment of symptomatic menopausal women.

In November 2005, ASRM supported a workshop that convened a multidisciplinary group of healthcare providers to discuss whether it would be appropriate to treat healthy women at the onset of menopause who were complaining of menopausal symptoms. This was not a consensus meeting and there was no intent to duplicate or modify position papers of major organizations such as the American College of Obstetrics and Gynecologists, American Society for Reproductive Medicine, the North American Menopause Society, etc. Eighteen national societies whose members provide primary care for women were invited to send representatives to the workshop. It was predetermined, however, that these member representatives were representing themselves and not the official positions of the societies. Presentations focused on hormone therapy as a therapeutic option for the major symptoms (ie, vasomotor symptoms, vulvovaginal problems, mood/depression, and changes in sleep and sexual function) associated with the onset of menopause. This publication is not a position statement, nor does it represent the official positions of the societies who sent representatives. Rather, this document is a condensed summary of the presentations, discussions, and clinical experience of the group in addressing this important clinical scenario of the symptomatic menopausal woman seeking treatment.

Efficacy of Hormone Therapy

Vasomotor Symptoms

Vasomotor symptoms are prevalent and a source of significant quality-of-life issues for many women entering the menopause. The Study of Women's Health across the Nation (SWAN), which was a community-based survey of 16,065 women aged 40–55 years, found that approximately 32% of women (mean range by ethnicity 17.7% to 45.6%) complained of hot flushes or night sweats.[7] In a cross-sectional general-population survey of 5213 women aged 39–60 years, Oldenhalve and colleagues[8] found that the incidence and severity of hot flushes and sweating increased up to and immediately following menopause and negatively affected quality of life. These authors also noted that women who experienced severe flushes and sweating were more likely to also experience a larger number of other symptoms, called “irregular complaints,” in particular tenseness and tiredness.

In a number of surveys, conducted prior to and after HERS and WHI, menopausal symptoms were the most frequently cited reason by current users of hormone therapy for initiating hormone therapy.[9,10] For example, Strothmann and colleagues[10] conducted a cross-sectional survey of US women aged 45–75 years of age. Of the 5002 women surveyed, 17% were currently using hormone therapy, 24% were former users, and 60% had never used hormone therapy. Hormone therapy use was most common among those aged 50–54 (22%) and 55–59 (26%) years of age. The most common reasons for initiating hormone therapy were menopausal symptoms (58%), post surgery (39%), and general well-being (36%). These results are consistent with a previous report from these investigators who conducted a similar survey among European women.[11]

The primary indication for hormone therapy is the treatment of moderate-to-severe vasomotor symptoms. The average patient is a woman 45–60 years of age and uses hormone therapy for an average of 3 years or less. It should be noted that HERS and WHI were not designed to evaluate the effect of hormone therapy on vasomotor symptoms and included patients who were generally 60 years or older.

There are numerous randomized controlled trials appropriately designed for evaluating the impact of hormone therapy on vasomotor symptoms. The results from these trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms.[12–20] In a meta-analysis of 14 clinical trials, conjugated equine estrogens (CEE) and 17beta-estradiol demonstrated comparable effects in significantly reducing the weekly number of hot flushes compared with placebo.[12] The Women's Health, Osteoporosis, Progestin, Estrogen (HOPE) study evaluated the effect of CEE alone (0.3, 0.45, and 0.625 mg/day), CEE plus medroxyprogesterone acetate (MPA) (0.3/1.5, 0.45/1.5, 0.45/2.5, and 0.625/2.5 mg/day), and placebo on relief of vasomotor symptoms in 241 women.[14] After 1 year (13 cycles), all hormone treatments, at each dose level, were significantly more effective than placebo in reducing the number and severity of hot flushes within the first few weeks of the study (P < .01). Lower doses of CEE plus MPA were equally effective as standard doses of this combination for the relief of vasomotor symptoms. Standard doses usually were the equivalent of CEE 0.625 mg or micronized estradiol 1 mg. Lower doses are doses smaller than this. The use of MPA with lower doses of CEE (0.45 and 0.3 mg/day) appears to enhance the efficacy of CEE in relieving vasomotor symptoms. Similar results have been shown with both low (ie, ≤ 0.45 mg/day) and standard (≥ 0.625 mg/day) doses of synthetic conjugated estrogens preparations, as well as with oral, transdermal, and vaginal estradiol preparations (with or without the addition of norethindrone acetate).[13,16–20] In a recent report, Ettinger[13] suggested that lower doses may be underused and that by using lower doses for vasomotor symptoms, women may experience fewer side effects.

Lifestyle changes alone or combined with alternative therapies (ie, progestins, selective serotonin receptor inhibitors [eg, venlafaxine, paroxetine, fluoxetine], anticonvulsants [eg, gabapentin], and antihypertensives [eg, clonidine]) may be an option for some women, especially those with mild vasomotor symptoms. Studies have shown that some alternate therapies are more effective than placebo for the treatment of vasomotor symptoms. Many of the trials suffer from too small sample size and for being too short in duration; the strong placebo effect begins to dissipate with time. Results vary from trial to trial and these alternatives are not free of adverse events.[21–29] To this end, it was the opinion of the group that these alternatives were not as effective as hormone therapy for the treatment of vasomotor symptoms associated with menopause, but may be an option for some women.

Vulvovaginal Problems

Vulvovaginal changes associated with estrogen depletion include loss of collagen and adiposity in the vulva, loss of protective covering over the glans clitoris, and thinning of the vaginal surface, making it less elastic and more friable. Atrophy and thinning of the vaginal epithelium can lead to vaginitis, dyspareunia, and vaginismus. If untreated, vaginal atrophy progressively worsens over time.

In a longitudinal, population-based study of 438 women aged 45–55 years, Dennerstein and colleagues[30] found that the percentage of women reporting vaginal dryness increased progressively as women approached and passed through menopause. Among premenopausal women, 3% reported vaginal dryness compared with 25% of women postmenopausal by 1 year and 47% of women postmenopausal by 3 years. In a study of 285 perimenopausal and postmenopausal women, Versi and colleagues[31] found that the percentage of women showing both superficial dyspareunia and signs of vulvovaginal atrophy increased with menopausal age. Among perimenopausal women, 15% reported superficial dyspareunia, but this number increased to 28% for postmenopausal women. Additionally, 40% of sexually active women reported dyspareunia; however, the increase in vulvovaginal atrophy was more pronounced than that of dyspareunia.

The use of estrogen hormone therapy is indicated for the treatment of vulvar and vaginal atrophy associated with menopause. Topical vaginal formulations, which have been shown to achieve greater symptom relief than oral, transdermal, or parenteral routes of administration, should be considered when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy.[32] Estrogen therapy reverses vaginal atrophy, promotes cell growth and maturation in estrogen-sensitive cells, enhances blood flow in vaginal tissue and reduces pH, and reduces urinary tract infections. Outcomes depend on the timing of therapy relative to the severity of vaginal atrophy at the time of initiating therapy.[33] Improvements in vaginal dryness, genital atrophy, decreased vascularization, and decreased vaginal elasticity with estrogen therapy can have a beneficial effect on sexual functioning in women whose symptoms are suggestive of dyspareunia.[34] (Note: Hormone therapy is not indicated by the US Food and Drug Administration for the treatment of female sexual dysfunction.)

In the short-term, randomized, controlled trials have shown no evidence of endometrial proliferation associated with vaginal administration of unopposed estrogen at lower doses in menopausal women with a uterus.[35] Overall doses below 25 mcg twice weekly of estradiol, or 0.5 mg of estriol weekly, have not been associated with endometrial proliferation in either short (ie, 1–3 weeks) or long (3–12 months) courses of therapy. This finding is irrespective of the pharmaceutical formulation,[32] tablet, cream, or ring.[36–43] These data suggest that the risk for endometrial stimulation with vaginal administration of unopposed estrogen in women with an intact uterus is minimal.[35]

Urinary incontinence affects approximately 5% to 14% of women 60 years of age or older. Recent data on hormone therapy suggest that it increases urinary incontinence in menopausal women.[44,45] However, trials demonstrating these negative effects were not designed to include urinary incontinence as a primary endpoint. The results were reported for women who did not have incontinence as a primary complaint. Some, but not all, earlier studies have demonstrated a benefit with estrogen formulations administered via the vaginal route for women who were complaining of incontinence.[44] Local vaginal estrogen therapy may be able to relieve certain urinary complaints because of the presence of estrogen receptors in urethral mucosa and smooth muscle. In addition, data do show that estrogen therapy reduces the frequency of urinary tract infections in menopausal women.[46]

Mood and Sleep Disorders

The prevalence of mood symptoms varies from 8% to 37% in premenopause, from 11% to 21% in perimenopause, and from 8% to 38% in postmenopause.[47,48] Over the past 3 decades, the relationship between mood and menopause has been extensively studied.[49,50] Results from these studies indicate that there is not a specific relationship between natural menopause and mood syndromes.[50] Nevertheless, although the majority of women do not experience a mood or anxiety disorder, there is a subgroup of women who do, and there are some women who experience symptoms (ie, depression, mood swings, irritability, and anxiety) but no identifiable psychiatric disorder.[51]

Data from earlier clinical studies have shown that conventional doses of estrogen enhance mood in nondepressed postmenopausal women but not in severely depressed women.[52–63] Randomized placebo-controlled trials of estrogen for depression occurring during perimenopause indicate that it also is an effective treatment for affected women.[51,64] These authors found that 60% to 75% of patients receiving 4–12 weeks of transdermal estradiol (50–100 mcg/day) had partial or total remission of depressive episodes compared with a response rate of 20% to 30% achieved with placebo. Improvements in mood were independent of severity of depressive symptoms and of estrogen's effect on vasomotor symptoms. Data from an open-label study suggest that citalopram and mirtazapine are effective adjuncts to estrogen therapy when depression symptoms do not respond to estrogen alone.[65] No data are available on the impact of hormone therapy in patients with a diagnosis of depression. It should be noted that hormone therapy is not indicated for the treatment of mood or sleep disorders, although there are some data to support a beneficial effect in some women, as described below.

Sleep disorders are a hallmark of the menopausal transition. The prevalence of sleep disturbance varies from 16% to 42% in premenopause, from 39% to 47% in perimenopause, and from 35% to 60% in postmenopause.[47] Sleep disorders have a complex etiology, and hormone therapy may be useful if sleep disruption is due to flushing or other vasomotor symptoms that affect sleep patterns. Estrogen has been shown to decrease sleep latency, decrease the number of episodes of awakening, increase total sleep time, decrease the number of cyclic spontaneous arousals, and increase the amount of slow-wave sleep and REM. In a post-hoc subgroup analysis of WHI, Hays and colleagues[66] found that estrogen plus progestin therapy improved sleep disturbances among menopausal women 50–54 years of age with moderate-to-severe vasomotor symptoms at baseline.

Clinically, the improvement in overall sense of well-being in postmenopausal women receiving hormone therapy probably results from the beneficial effect of estrogen on a number of variables (ie, vasomotor symptoms, vaginal dryness, and sleep). Data from epidemiologic studies, such as the Rancho Bernardo study[67] and the ARIC study,[68] found no association between estrogen use (whether current or past) and protection against age-related cognitive decline. In contrast, results from a growing number of randomized clinical trials indicate that estrogen maintains some aspects of cognitive functioning in the postmenopausal years.[69–71] Data from Kampen and colleagues[71] found that estrogen users performed significantly better on tests of immediate and delayed paragraph recall compared with a group of never-users who had been matched for age, number of years of education, and socioeconomic status. This study, however, found no between-group differences in other domains of language and spatial skills. These results suggest that estrogen affects various brain functions differentially, exerting a specific (ie, verbal memory) rather than global effect on cognition.

Dose Considerations

There is considerable evidence supporting the use of lower doses of hormone therapy in symptomatic women.[13,14,16–18,72–77] Low doses of hormone therapy are effective in patients with vasomotor symptoms and vulvovaginal problems.[14] In addition, low doses of hormone therapy have beneficial effects on bone mineral density, plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism in menopausal women as compared with placebo.[74,75] The use of lower doses of estrogen is associated with 50% lower rates of irregular bleeding or breast tenderness (which is not a surrogate for breast cancer risk) compared with women taking standard doses of hormone therapy.[78] There are also observational data suggesting a reduced risk for serious thrombosis and no increased risk for stroke.[79] Low-dose estrogen preparations include oral preparations of CEE (0.3 and 0.45 mg/day), esterified estrogens (0.3 mg/day), and micronized estrogen (0.5 mg/day). Low-dose transdermal preparations include 17beta-estradiol (0.025 and 0.037 mg/day).

Safety

It was not the purpose of this workshop to dwell on adverse symptomatology, such as bleeding, but to focus on major risks such as cancer and cardiovascular disease, which will be covered here. Issues of adverse symptoms may be dealt with somewhat by the use of lower doses of hormones as suggested above.

Risks are a major concern for women who do not accept hormone therapy, and they also influence the prescribing habits of providers.[6,10,11] In a cross-sectional survey of 5002 US women (age 45–75 years), cancer, in particular breast cancer, was the major risk of hormone therapy identified by 53% of US women, followed by cardiovascular disease (16%) and stroke (6%).[10,11] Williams and colleagues[6] found that the overall perception of hormone therapy differed among primary care specialties (n = 600). Using a scale of 1–5 (1 = negative, 3 = neutral, 5 = positive), perception scores for hormone therapy among ob/gyns was 3.89 compared with 2.71 for internists and 3.08 for family practitioners.

As previously mentioned, Williams and colleagues[6] postulated that the reason for physicians' overestimation of the magnitude of risks and benefits with hormone therapy was misunderstanding regarding attributable risk and relative risk. Relative risk is different from attributable risk, and relative risk should not be interpreted as attributable risk. Relative risk refers to the likelihood of disease in patients exposed to a potential risk factor compared with those not exposed. Relative risk is independent of the overall incidence of disease in the population. In contrast, attributable risk refers to the disease incidence in patients exposed to a potential risk compared with those unexposed. For clinical decision-making, it is important to know the attributable risk associated with any potential risk factor and the number of individuals who may be affected.

Cancer Risks

Breast Cancer

Data from the WHI showed that the overall relative risk of invasive breast cancer was 1.24 (95% CI 1.01–1.54) in women with standard dosages of estrogen plus progestin (CEE + MPA) who were followed for a mean of 5.6 years (maximum 8.6 years).[80] The attributable risk was 8 more cases of invasive breast cancer per 10,000 person-years among those receiving estrogen plus progestin. The increase in risk, however, occurred only in those women who were prior users of hormone therapy. This risk was not statistically significant over the period of the trial in those women who had never received hormone therapy. It is important to note that there is uncertainty about whether risk estimates from the WHI can be applied to other types of estrogens and progestins.

The estrogen-only portion of the WHI found no increase in breast cancer risk, even in those with prior exposure to estrogen. The overall relative risk of total breast cancer and invasive breast cancer with estrogen only was 0.82 (95% CI 0.65–1.04) and 0.80 (95% CI 0.62–1.04), respectively.[81] An earlier report found a relative risk of invasive breast cancer of 0.72 (95% CI 0.43–1.21) among those aged 50–59 years at the time of initiating estrogen-only therapy.[82] Although mammographic density increased with estrogen-only and hormone therapy, the increase in density does not appear to correlate with cancer incidence.

The pattern of risk of invasive breast cancer seen in the WHI for both estrogen with or without progestin was similar to that reported in prior studies.[32] A recent report from the Nurses Health Study of hysterectomized women receiving standard doses of estrogen alone was consistent with the results from the WHI and did not show an increased risk for breast cancer for up to 20 years of use.[83] It is logical to assume that the use of lower doses of hormone therapy and minimizing progestin exposure would be associated with an even lower risk for breast cancer. However, there are no data at present to validate this assertion.

Endometrial Cancer

With regard to endometrial cancer, data from the WHI were consistent with those of many studies showing that estrogen-plus-progestin therapy does not increase the risk of developing endometrial cancer. Note also that other studies have shown a decreased risk of developing endometrial cancer with estrogen-plus-progestin therapy.[81] The relative risk in WHI was 0.83 (95% CI 0.29–2.32). The risk for endometrial cancer with unopposed estrogen in women with intact uteri is well documented.[32] The risk is 2.0-fold higher (95% CI 1.8–2.2) with less than 5 years' exposure and 6.7-fold higher (95% CI 5.9–7.6) with longer durations of exposure. There is no difference among the different estrogen preparations with regard to risk for endometrial cancer.

Colorectal Cancer

Nanda and colleagues[84] conducted a meta-analysis of 25 epidemiologic studies and found that recent use of hormone therapy was associated with a 33% reduction in the risk for colon cancer (relative risk 0.67; 95% CI 0.59, 0.77). The benefits were limited to recent users of hormone therapy, and duration of hormone therapy use did not appear to modify reduction in colon cancer risk. The risk for death from colon cancer was also reduced among hormone therapy ever-users (relative risk 0.72; 95% CI 0.64–0.81). The risk for rectal cancer was not associated with hormone therapy. Data from the WHI[82] were consistent with the findings of Nanda and colleagues. There were 10 new colorectal cases per 10,000 women-years with estrogen-only therapy compared with 16 new cases with placebo (relative risk 0.63; 95% CI 0.32–1.24). The greatest benefit of hormone therapy was seen among those who were 50–59 years of age at the start of the WHI (relative risk 0.59; 95% CI 0.25–1.41) followed by those 60–69 years of age (relative risk 0.88; 95% CI 0.52–1.48).

Ovarian Cancer

Research findings on the impact of hormone therapy on ovarian cancer are inconsistent.[85–89] If an increase in risk exists, then it is small and difficult to demonstrate from study to study. There is a possible weak association with long-term (greater than 10 years) use of unopposed estrogen, but these data are inconclusive. Overall, the data are not sufficient to offer a clinical recommendation.

Cardiovascular Risks

The results from HERS (women with established CHD) and WHI (women without established CHD) demonstrated an overall increased risk for CHD events within the first year among women taking hormone therapy.[4,82,90] This phenomenon, often referred to as “early harm,” appears to be a characteristic of older women with existing atherosclerosis. Plaque instability caused by hormone therapy is a plausible hypothesis for this circumstance in that in women receiving statin therapy, “early harm” was not witnessed in HERS.[91] The average age of women participating in both HERS and WHI was greater than 60 years (66.7 and 63 years of age for HERS and WHI, respectively).[82,90] In addition, women with severe vasomotor symptoms were excluded from WHI because these women would most likely drop out of the trial if randomized to the placebo arm. These distinctions are important because the majority of women who choose to receive hormone therapy do so for symptom relief during the early menopausal years (ie, younger than 60 years of age). Thus, understanding early CHD risk in this younger menopausal population is important.

In the WHI, approximately 32% of women were 50–59 years of age.[3,82] Subgroup analyses of women receiving CEE plus MPA found no significant increase in CHD events among those who had begun menopause within the past 10 years (hazard ratio 0.89) or who were 50–59 years of age and had hot flushes (hazard ratio 0.95) at baseline.[4] A recent analysis of these data showed a suggestion of lower CHD risk among women beginning hormone therapy near menopause.[92] In this study, reanalysis of data from the Nurses' Health Study strongly supports the concept that women who are close to the age of menopause benefit the most, while those 10 or more years after menopause do not have a coronary benefit from hormone therapy. Similarly, in the CEE-only arm of the WHI, the hazard ratio for CHD events among women 50–59 years of age at baseline was 0.56 (95% CI 0.3–1.03) vs 0.92 (95% CI 0.69–1.23) and 1.04 (0.75–1.44) for those 60–69 and 70–79 years of age, respectively. Recent data showed a borderline trend for a reduction in CHD in women ages 50–59, which was statistically significant for coronary revascularization and confirmed angina.[93] Similar age-related differences in stroke risk was also found with hazard ratios of 1.08 (0.57–2.04), 1.65 (1.16–2.36), and 1.25 (0.85–1.82) for those 50–59, 60–69, and 70–79 years of age, respectively.

The risk for venous thrombolic events (VTE) in the WHI was increased among all age groups of women receiving oral estrogen with or without progestin. However, nonoral formulations of hormone therapy may be safer. Scarabin and colleagues[94] conducted a hospital-based case-control study of 155 postmenopausal women (1999–2002) with a first documented episode of idiopathic VTE (92 with pulmonary embolisms and 63 with deep venous thrombosis) and 381 matched controls. The adjusted odds ratio for VTE in current users of oral vs that of transdermal estrogen was 4.0 (95% CI 1.9–8.3).

To further evaluate the impact of hormone therapy on CHD risk, Lobo and colleagues[95] combined evidence from 2 large similar cohorts (Women's HOPE study and Menopause Study Group) that included younger, healthy postmenopausal women (average 53 years, 4.9 years from last menstrual period). A total of 322 women received placebo and 4065 women received CEE with or without MPA. There were no CHD events among women receiving hormone therapy in either trial compared with 1 event in the placebo arms (0 vs 3.01 per 1000 women). The expected CHD rate in the United States for the group 35–64 years of age is 2–3 per 1000 women.

Thus, it appears that the risk for CHD with hormone therapy is principally in those older women distant from menopause who have atherosclerosis. While it should be emphasized clearly that hormone therapy is not effective for the treatment of CHD, younger women may have some benefits, at least with estrogen alone.[93] This latter point remains to be clarified in future randomized trials.

Conclusions

The November 2005 ASRM workshop focused on symptomatology in the young, healthy, perimenopausal/menopausal woman. We conclude that young, healthy symptomatic women should be offered the option of hormone therapy. There is clear evidence that hormone therapy improves vasomotor and urogenital symptoms and provides benefits to many women with sexual dysfunction and psychological disturbances related to estrogen deficiency. Taken together, the beneficial effects of hormone therapy for many younger women outweigh the risks and provide an overall improvement in quality of life. Thus, the fears of hormonal therapy in this setting do not seem to be justified. All hormonal therapy should be individualized in symptomatic women. This involves prescribing the regimen and dosage according to individual needs.

Funding Information

Financial support was provided by an unrestricted educational grant to the ASRM from Solvay Pharmaceuticals Inc. and Wyeth Pharmaceuticals.