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Estrogens in postmenopausal women: recent insights
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Estrogens in postmenopausal women: recent insights Ginger D Constantine and James H Pickar Recent literature has consistently supported the use of postmenopausal estrogens for treatment of moderate-to-severe vasomotor symptoms and for prevention of osteoporosis. Although assessment of quality of life is complex, symptom relief has often been shown to translate into improvements in quality of life measures for women. Recent studies have reported a small increase in breast cancer with long-term hormone therapy, as well as a small increase in cardiovascular events and dementia when therapy is started in a population that is, on average, 13 years post-menopause. Ongoing investigations into different formulations and dosing options, as well as genetic factors that might influence the response to therapy, should provide valuable information.
recent years, however, significant attention has been paid to the potential preventive benefits of ET/HT on other chronic diseases, such as cardiovascular disease (CVD) and Alzheimer’s disease. Since 2002, a large number of studies has been published (over 190 Medline citations), often with conflicting findings. We attempt to summarize these data, delineating the differences in study design that might account for conflicting results and also taking account of the Women’s Health Initiative (WHI) findings. In addition, we highlight new research findings and approaches, and suggest future directions HT may take, including the use of lower doses of estrogens and progestins.
Addresses Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA Correspondence: Ginger Constantine; e-mail: [email protected]
Menopausal symptom relief
Current Opinion in Pharmacology 2003, 3:626–634 This review comes from a themed issue on Endocrine and metabolic diseases Edited by John Kirkland 1471-4892/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2003.07.003
Abbreviations BMD bone mineral density CE conjugated estrogens CHD coronary heart disease CI confidence interval CVD cardiovascular disease ET estrogen-only therapy HERS Heart and Estrogen/progestin Replacement Study HR hazard ratio HT hormone therapy MPA medroxyprogesterone acetate ORAG Osteoporosis Research Advisory Group PHASE Papworth HRT Atherosclerosis RR relative risk UQOL Utian Quality of Life Scale WHI Women’s Health Initiative
Introduction This paper reviews the clinical literature on postmenopausal hormone therapy that has been primarily published since 2002. Postmenopausal estrogens (estrogenonly therapy [ET] or hormone therapy [HT; estrogen in combination with progestin]) have been used for decades and are indicated for the treatment of moderate-tosevere vasomotor symptoms, vulvovaginal atrophy and the prevention of postmenopausal osteoporosis. In Current Opinion in Pharmacology 2003, 3:626–634
The primary reason women seek treatment with ET/HT is menopausal symptom relief. Hot flushes are the most common symptom, affecting up to 93% of women [1,2]. Given that women report up to a third of hot flushes as ‘severe’ [3], treatment of these disruptive symptoms can afford significant improvement in overall well-being. Investigation of the treatment of vasomotor symptoms should use reproducible and valid outcome measures that include the evaluation of the number and severity of flushes [4]. A potentially high placebo response rate and a lack of efficacy in women without significant baseline flushing can yield misleading results. 12 recently published clinical trials designed to examine the efficacy of estrogens, including conjugated estrogens (CE) [5–10], oral [5,11] or transdermal 17b-estradiol [12–14] and intranasal estradiol [15,16], on menopausal symptom relief have all reported an improvement in vasomotor symptoms with various formulations (Table 1), but only two of these trials [13,16] employed the US Food and Drug Administration’s recommended inclusion criteria of 7–8 moderate-to-severe hot flushes per day, or 50–60 per week at baseline [4]. In two studies that focused on older women, CE (0.625 mg) plus medroxyprogesterone acetate (MPA; 2.5 mg) provided symptom relief [6,17]. In an older population (average 13 years post-menopause) without significant vasomotor symptoms, HT was not found to be beneficial [17]. Although the majority of women experience hot flushes for fewer than five years, it has been estimated that 10% of postmenopausal women suffer vasomotor symptoms for more than 11 years [18]. Recently, the use of lower doses of ET/HT has been investigated for the relief of menopausal symptoms [13,16,19]. Lower-dose formulations with transdermal www.current-opinion.com
Estrogens in postmenopausal women Constantine and Pickar 627
Table 1 Recent randomized clinical trials on estrogen and menopausal symptom relief. Treatment groups (all doses in mg/d)
n
Mean age (years)
Study length
Effect of ET/HT on menopausal symptom relief
References
CE (0.625) þ MPA (5.0)
45
53
1 year
Significant improvement in vasomotor symptom control, urogenital and sexual health symptoms
[8]
Tibolone (2.5) CE (0.625) þ MPA (2.5)
40 1 380
51 67
4 years
Improvement in menopausal symptoms reported in HT group by year one, persisted through year four
[6]
Placebo CE (0.625) þ MPA (2.5)
1 383 14
67 52 5
16 weeks
Significant reduction in vasomotor symptoms as demonstrated by decreases in GCS vasomotor subscale; significant reduction in sexual dysfunction symptoms
[7]
JWSYS herbal preparation CE (0.625) þ MPA (2.5)
24 251
50 3 55
1 year
Improvement in vasomotor symptoms as demonstrated by decreases in GCS
[10]
Tibolone (2.5) CE (0.6)
250 22
55 40-60
3 months
Significant reduction of symptoms demonstrated by change in MRS for CE and phytoestrogen preparation
[9]
Cimicifuga racemosa (phytoestrogen preparation) Placebo Oral estradiol (1.0) Placebo Continuous estradiol (1.0) þ NETA (0.5)
20
90 days
Significant (>50%) reduction in hot flash number
[11]
9 months
Reduction of symptoms for both groups demonstrated by change in MRS; after three months, a change from baseline of approximately 90% was observed for both therapies
[5]
Significant reduction in hot flashes for women on estradiol 25 mg/d and 50 mg/d. At eight weeks, women on 25 mg/d reported approximately three-fold less daily symptoms than women on 50 mg/d >93% women in estradiol groups experienced reduction in hot flashes as determined by a modified KI
[14]
3 months
Significant reduction in number and severity of hot flashes with both doses seen at end of week two, persisted through three cycles. Both doses significantly reduced proportion of women experiencing vaginal dryness
[13]
1 year
Significant improvement in scores on the Women’s Health Questionnaire for vasomotor symptoms for all three doses of HT at cycle 13
Sequential CE (0.625) þ MG (5.0) Transdermal 17b-estradiol (0.025) plus sequential progesterone in women with a uterus — dose increased to 0.050 if required Cyclic combined transdermal 17bestradiol (0.050) þ NETA (0.25) Transdermal 17b-estradiol (0.050) þ oral MP (200 mg twice a week) Tibolone (2.5) Study 1
Transdermal 17b-estradiol (0.045) þ levonorgestrol (0.03) Transdermal 17b-estradiol (0.045) þ levonorgestrol (0.04) Placebo Study 2
20 12 12 223
53 2 52 1 50–56
223 62
49–56 51 5
16 weeks
55
50 4
1 year
55
51 4
55
51 4
96
52
104
52
93
52
[12]
Transdermal 17b-estradiol þ levonorgestrel at: 0.045 þ 0.00 0.045 þ 0.015 0.045 þ 0.030 0.045 þ 0.040 Intransal estradiol (0.30)
204 212 211 213 101
56 56 56 55 50 3
24 weeks
Significant decreases in KI score and incidence of hot flushes at 24 weeks for both therapies
[15]
Oral micronized estradiol (2.0) Intranasal estradiol (0.15)
100 54
51 3 53 5
12 weeks
Mean daily number of moderate-to-severe vasomotor symptoms and KI score decreased significantly in both estradiol groups. The decrease reached significance for the 300 mg group at week two, and for the 150 mg group at week eight
[16]
Intranasal estradiol (0.30) Placebo
54 57
52 6 52 5
Based on inclusion criteria, no average age of participants provided. GCS, Greene Climacteric Scale; JWSYS, Jia-Wey Shiau-Yau San; KI, Kupperman Index; MG, medrogestone; MP, micronised progesterone; MRS, Menopause Rating Scale; NETA, norethisterone acetate.
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Current Opinion in Pharmacology 2003, 3:626–634
628 Endocrine and metabolic diseases
and intranasal estradiol have been shown to be efficacious [13,16]. Similarly, the combination of CE (0.45 mg) and MPA (1.5 mg), and that of CE (0.3 mg) and MPA (1.5 mg), provided clinically significant symptom relief similar to that seen with CE (0.625 mg) and MPA (2.5 mg) [19]. The dose-response seen with CE alone (0:625 mg > 0:45 mg > 0:3 mg) was eliminated with the addition of MPA [19].
Quality of life The assessment of change in a woman’s quality of life is complex and has led to the development of a variety of measurement tools. Recent advances in scale development include the Utian Quality of Life Scale (UQOL) [20], which uses psychometric measures to assess a woman’s overall sense of well-being. To provide a comprehensive overview of menopausal symptoms and their impact, Utian, Janata, Kingsberg, Schluchter and Hamilton [20] recommend that the UQOL is combined with a validated menopausal symptom inventory, such as the Greene Climacteric Scale. Further evaluation of the UQOL, alone and in combination with other measures in clinical practice, is required. Data from randomized trials assessing the effect of ET/ HT on health-related quality of life have yielded different results depending on the study design, population and test instruments. Recent studies that have evaluated changes in quality of life measures with ET/HT have employed the Women’s Health Questionnaire [5,13], the Greene Climacteric Scale [7], the Menopause Rating Scale [9], the Quality of Life, Enjoyment and Satisfaction Questionnaire [10] and the Kupperman Index [15,16] (or a modified version [12]); they all reported improvements with CE and oral, transdermal or intranasal estradiol. Often, the beneficial effects on quality of life can depend on the presence of menopausal symptoms. For example, in the Heart and Estrogen/progestin Replacement Study (HERS), older women with flushing experienced significant improvements in mental health and depressive symptoms, whereas women without flushing did not [21].
Bone health Studies have consistently demonstrated that ET/HT is effective in, and hence is indicated for, the prevention of postmenopausal osteoporosis. A recent meta-analysis that included data from 21 randomized trials reported by the Osteoporosis Research Advisory Group (ORAG) found an approximate 7% difference in the percentage change in lumbar spine bone mineral density (BMD) after two years on HT [22]. Other randomized trials have focused on the effectiveness of lower-dose CE/MPA formulations [23,24], transdermal delivery systems [25,26] or hormones combined with interventions such as alendronate [27] and exercise [28] in maintaining BMD (Table 2). In the large prospective randomized Women’s Health, Osteoporosis, Progestin, Estrogen (Women’s HOPE) Current Opinion in Pharmacology 2003, 3:626–634
substudy, 822 women were treated with CE (0.625 mg) or CE (0.625 mg) in combination with MPA (2.5 mg), as well as lower doses. Two years of treatment with CE (0.45 mg) plus MPA (1.5 mg) or CE (0.3 mg) plus MPA (1.5 mg), as well as the other doses studied, resulted in significant gains in hip BMD for all CE/MPA and CE dosage groups when compared with placebo (P < 0:001), with no significant differences between CE/MPA formulations and the comparable dose of CE alone [23]. Similarly, examinations of lower-dose transdermal formulations have found that lower-dose estrogen can be effective as higher doses in maintaining BMD [25,26]. The importance of estrogens on fracture prevention was also investigated in the ORAG report [22]. A pooled estimate of data from over 20 494 women (including results from ORAG and WHI) showed a significantly decreased risk of nonvertebral fractures with HT use (relative risk ½RR ¼ 0:78; 95% confidence interval [CI], 0.64–0.96) [29]. This reduction in nonvertebral fractures is similar to the 27% reduction reported in an earlier meta-analysis by Torgerson and Bell-Syer [30]. Two separate meta-analyses report a trend toward an approximate 33% reduced incidence of vertebral fractures with HT use [22,31].
Cardiovascular disease The prevalence of coronary heart disease (CHD) rises dramatically among women with increasing age; approximately one in 20 women aged 45–54 years experience CHD, compared with one in 10 women aged 65–74 years [32,33]. For women who have undergone surgical menopause, the risk of CHD with age rises more sharply than for those who experience a natural transition [34]. The loss of endogenous estradiol at menopause, coupled with a concomitant increase in CHD risk, suggests that exogenous estrogen might reduce the risk of CHD in women. Indeed, the majority of published observational, preclinical and surrogate marker data has suggested a lower incidence of CHD among users of postmenopausal ET/HT compared with non-users. A recent meta-analysis of observational studies that adjusted for socioeconomic status found no association between any postmenopausal ET/HT use and CHD events (RR ¼ 0:88; 95% CI, 0.64–1.21) [35]. Two recent randomized secondary prevention trials in women with pre-existing CVD, the HERS [36] and the Papworth HRT Atherosclerosis (PHASE) study [37], have suggested an early increased risk of CVD with HT. The HERS study showed no overall increased risk, whereas the PHASE study showed an increase within the first 30 months, at which time the trial was discontinued. The WHI [38] also showed an early increase in risk that appeared to decrease subsequently, except during the fifth year, which seems to be an outlier (caused by an unusual decline in events in the placebo group in that year). www.current-opinion.com
Estrogens in postmenopausal women Constantine and Pickar 629
Table 2 Recent randomized clinical trials on estrogen and bone density. Treatment groups (all doses in mg/d)
n
Mean age (years)
Study length (years)
Effect of ET/HT on bone density
References
Sequential CE (0.625) þ MPA (10)
20
52 3
1
BMD at the spine, trochanter and the femoral neck increased compared with baseline for both doses; there were no significant differences between doses
[24]
Sequential CE (0.30) þ MPA (10) CE alone at: 0.625 0.45 0.3 CE þ MPA at:
14
52 5 2 52 52 52
All active treatments resulted in significant increases in spine and hip BMD
[23]
84 91 87 81 87 89 91 85 15 12 10
52 52 51 51 51 50–57 50–57 50–57
15 30
0.625 þ 2.5 0.45 þ 2.5 0.45 þ 1.5 0.3 þ 1.5 Placebo Estradiol (2.0) þ NETA (1.0) Exercise alone Estradiol (2.0) þ NETA (1.0) þ exercise Control Oral estradiol (1.0) þ NETA (0.50) Genistein (54.0) Placebo Transdermal 17b estradiol (0.10) (E-100) Transdermal 17b estradiol (0.05) (E-50) Placebo patch EMTDS at: 0.025 0.050 0.075 Placebo Micronized estradiol (2.0) þ alendronate (10) Micronized estradiol (2.0) þ alendronate (5.0) Micronized estradiol (2.0) þ placebo
For spine, the addition of 2.5 mg MPA to CE significantly increased BMD relative to CE alone at two years for the 0.625 mg and 0.45 mg doses For hip, there were no significant differences between CE þ MPA and the comparable dose of CE at two years 1
HT and exercise both improved BMD at proximal femur and tibial shaft. HT combined with exercise exceeded the effects of the two agents alone at all measured sites
[28]
50–57 52 5
1
HT and genistein significantly increased BMD in femoral neck and lumbar spine
[80]
30 30 100
52 3 51 4 54 4
2
[25]
54
54 4
E-100 and E-50 patches (100 mg/d and 50 mg/d, respectively) resulted in significant increases in lumbar, wrist and hip BMD from baseline. E-50 was as effective as E-100
53
53 4 2 52 54 54 54 62 4
All doses of EMTDS significantly increased lumbar BMD from baseline (1.6%, 4.0% and 4.8% increases for 0.025 mg/d, 0.050 mg/d and 0.075 mg/d EMTDS respectively)
[26]
89 90 89 87 42y
2
[27]
44y
60 4
43y
61 4
At two years, BMD at lumbar spine, trochanter and femoral neck was significantly increased in all groups compared with baseline; the addition of alendronate to ET was beneficial, with both doses showing a similar effect
Based on inclusion criteria, no average age of participants provided. ySurgically postmenopausal women with osteoporosis. EMTDS, estradiol matrix transdermal delivery system; NETA, norethisterone acetate.
There has been one other meta-analysis and over 60 clinical reports published since 2002 that examined the role of ET/HT as risk factors for CVD. Of the eight trials that examined more than 250 women, two have demonstrated positive effects [39,40], two (including the PHASE study) demonstrated negative effects [37,41], and four reported a neutral effect of various HT regimens [42–45]. The largest of these trials was the Estrogen in the Prevention of Re-Infarction Trial (ESPRIT), a two-year secondary prevention trial of 1 017 women (average age 63 years) who had survived a myocardial infarction and had been given either placebo or unopposed oestradiol valerate (2 mg/d) [45]. There were no significant differences between groups in the overall frequency of reinfarction or cardiac deaths (RR ¼ 0:79; 95% CI, 0.50– 1.27) [45]. Examination of cardiovascular events in pooled www.current-opinion.com
data from 7 333 younger healthy postmenopausal women (average age 53 years) enrolled in four large randomized trials with different ET/HT regimens found that ET/HT use was not associated with an early increase in CHD events when compared with placebo [46]. The reason for the inconsistent effects of HT seen in observational and controlled clinical trials remains unclear. One explanation might be the healthy user bias among women in the observational trials who chose to use hormones [47]. Another is that the timing of initiation of HT is critical; that is, initiation more than a decade after menopause (e.g. in the HERS and WHI trials) when underlying atherosclerosis is likely to be substantial is too late to yield any benefit. In contrast, initiation at the time of menopause (typically the case in the observational Current Opinion in Pharmacology 2003, 3:626–634
630 Endocrine and metabolic diseases
trials) before atherosclerosis has developed in any substantial way might provide cardiovascular benefits. This latter explanation is consistent with preclinical data involving cynomolgus monkeys [48,49] and with data from the Estrogen in the Prevention of Atherosclerosis Trial [50]. A series of reports has suggested that a woman may be more or less favorably affected by HT with regard to cardiovascular risks on the basis of their genotype [51,52,53]. For example, a factor V Leiden genotype has been shown to increase a woman’s risk of venous thromboembolic events with HT [52]. The potential association between either genotype or ET/HT and the risk of clinical cardiovascular events is not fully established, but this area of research could become important in identifying appropriate candidates for ET/HT.
Cognition and dementia McLay, Maki and Lyketsos [54] reported recently that greater exposure to endogenous estrogens (e.g. in nulliparity and late menopause) is associated with decreased cognitive decline. Evidence of specific estrogen receptor polymorphisms being linked to cognitive impairment further supports an association between estrogen and cognitive function [55]. Recent reviews that have examined the role of postmenopausal hormones in cognitive performance have concluded that ET/HT can improve or act to maintain certain aspects of cognition, such as verbal memory, vigilance, learning and reasoning [56]; however, other findings have produced mixed results [57,58]. In the review by Nelson, Humphrey, Nygren, Teutsch and Allan [58], estrogen-related improvements in cognition only occurred in women with menopausal symptoms. Lack of cognitive improvement in asymptomatic women was also reported in HERS, which found that after four years there were no differences in age-adjusted cognitive function test scores between the HT and placebo groups [59]. Studies of long-term HT use and Alzheimer’s disease are not consistent. A meta-analysis of 12 cohort or casecontrolled studies published before 2000 found that HT use was associated with a 34% reduction in the risk of dementia [58]. Recent observational data from the Cache County Study [60] indicated that women who initiate estrogens closer to the onset of menopause and use ET/HT for longer than 10 years benefited by a significant decrease in the incidence of Alzheimer’s. In contrast, women who initiated HT within 10 years of the onset of Alzheimer’s disease received little benefit. The finding that HT benefits are limited to an early initiation of use is consistent with recent randomized trials which suggested that HT is not effective in mitigating the progression of cognitive decline when initiated in older women [61] or women with established Alzheimer’s disease [62], although one small trial of women with Alzheimer’s disease did report benefits [63]. At present, there is no consistent evidence to suggest that ET/HT is Current Opinion in Pharmacology 2003, 3:626–634
an effective treatment for elderly women already diagnosed with Alzheimer’s [56].
Breast cancer The 1997 Collaborative Group re-analysis of data from 51 epidemiological studies reported a relative risk for breast cancer of 1.31 for long-term HT users [64]. Conversely, a review published in September 2001 reported that there was not sufficient evidence to conclude that HT increases the risk of breast cancer [65]. Since 2002, case-control [66–68] and cohort [69] studies, as well as one randomized trial [38], have all reported an increase in the relative risk of breast cancer with longer duration ET/HT similar to that reported by the Collaborative Group. Studies that examined the outcomes of women who used ET/HT have generally documented improved survival [70,71], possibly caused by favorable tumor biology resulting in less aggressive tumors [71,72]. A recent case-control study in Australia found that ET/HT use after diagnosis reduced tumor recurrence by up to 40% [73].
The Women’s Health Initiative One of the studies published in 2002 that garnered attention from clinicians, patients and the media was issued from the HT arm of the WHI [74]. In part, the WHI was designed to evaluate specific potential longterm benefits and risks of ET (CE 0.625 mg/d) and HT (CE 0.625 mg/d plus MPA 2.5 mg/d). The primary endpoint was the prevention of CHD; other endpoints included breast cancer, colon cancer, stroke, venous thromboembolic events and fractures. In the HT arm of the WHI [38], 16 608 women (mean age at entry 63.3 years) were randomized to receive either CE/MPA or placebo. The investigators reported that this study was stopped early (after a mean follow-up of 5.2 years) because, according to a pre-defined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the pre-specified long-term benefits [38]. The WHI reported an estimated hazard ratio (HR) for CHD of 1.29 (95% nominal CI, 1.02–1.63) and of 1.03 (95% nominal CI, 0.90–1.17) for total CVD (arterial and venous disease). The ET (CE) arm of the WHI is currently ongoing. The WHI has provided important information on selected potential risks and benefits of HT; however, it does not address some of the therapeutic issues relevant to the majority of HT users. The WHI was not designed to assess menopausal symptoms and actually discouraged recruitment of women with moderate-tosevere vasomotor symptoms [74]. In addition, the older population of women examined in WHI may be different from the population of early postmenopausal women who initiate HT for symptom relief. Approximately twothirds of the subjects in the WHI were >60 years of www.current-opinion.com
Estrogens in postmenopausal women Constantine and Pickar 631
age and less than a fifth were within five years of menopause, the period during which menopausal symptoms are greatest [75]. Stevenson and Whitehead [76] have recommended that estrogen doses lower than 0.625 mg CE (the dose administered in the WHI) are used as a starting dose for women in this older age range. Moreover, many of the participants in the WHI had risk factors for CVD; two-thirds of participants were overweight, a third was hypertensive, and nearly 8% had a history of CVD [77]. Following this initial publication, several reports from the WHI have been published in 2002 and 2003. With respect to vasomotor symptoms, Hays et al. [17] reported that 12% of participants had vasomotor symptoms at baseline and that one year of treatment with CE/MPA significantly improved the severity of both hot flashes and night sweats in this group. Although HT resulted in a statistically significant difference favoring the HT group in three out of 12 measures of quality of life, these measures were not considered clinically meaningful [17]. In the WHI Memory Study (an ancillary study of the WHI), 4 532 postmenopausal women 65 years of age ( 53% were 70 years old) were monitored for the incidence of probable dementia. After four years, 40 women in the HT group and 21 in the placebo group were diagnosed with probable dementia, resulting in a HR of 2.05 (95% nominal CI, 1.21–3.48) [61]. In a related report from the WHI Memory Study, the rate of decline in global cognition (measured by the Modified Mini-Mental State Examination) diverged after two years and was statistically greater with HT use (P ¼ 0:03); this decline was consistent for all subgroups but was not considered by the investigators to be clinically significant [78]. For a small number of women who initiated HT during the late postmenopausal period, a detrimental effect on cognition was observed. These findings contrast with those reported in the HT arm of the WHI [17], in which no effect of HT on cognition was noted over one or three years in participants 65 years of age. In their analysis of the stroke data from the HT arm of the WHI, Wassertheil-Smoller et al. [79] reported that 1.8% of women in the HT group and 1.3% of women in the placebo group had ischemic (79.8%) or hemorrhagic strokes. The HR for ischemic stroke with HT use was 1.44 (95% nominal CI, 1.09–1.90) and 0.82 (95% nominal CI, 0.43–1.56) for hemorrhagic stroke. In the initial report from the WHI trial [38], the HR for breast cancer was 1.26 (95% nominal CI, 1.00–1.59) after 5.2 years, and was similar in magnitude to that of two previous observational trials [64]. In subgroup analysis of the WHI, the increased incidence of breast cancer was confined to women who had used HT before entering the www.current-opinion.com
study, with the HR varying according to extent of prior use (e.g. HR ¼ 2:13; 95% nominal CI, 1.15–3.94 for women with < five years prior use versus HR ¼ 4:61; 95% nominal CI, 1.01–21.02 for women with 5–10 years prior use). No increased risk of breast cancer was evident among the 74% of participants who had never used HT (HR ¼ 1:06; 95% nominal CI, 0.81–1.38) [38]. In contrast, HT use resulted in a decreased risk of colon cancer (HR ¼ 0:63; 95% nominal CI, 0.43–0.92). Finally, the initial WHI report [38] has reiterated findings of observational studies that the use of HT significantly reduces hip, vertebral and total fractures. It is important to note that this is the first study to observe a fracture benefit in women who were not at known risk for osteoporosis.
Conclusions ET/HT remains a clinically proven treatment for the relief of vasomotor symptoms and vulvovaginal atrophy, and is effective in the prevention of osteoporosis. In other areas of research, notably in cardiovascular and central nervous system effects, the recent literature has produced conflicting results. This lack of agreement between studies might, in part, be a result of the type of assessment tool, the population studied and/or the timing and duration of use. Clinical research continues into genetic factors influencing the response to ET/HT, different estrogen formulations, different modes of delivery and lower-dose options. This research will assist patients and clinicians in making treatment decisions on the basis of an individual’s needs and risks, and should enhance a woman’s ability to undergo the menopausal transition with minimal disruption to her quality of life.
Acknowledgements The editorial assistance of Karen Mittleman is greatly acknowledged.
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9.
Wuttke W, Seidlova-Wuttke D, Gorkow C: The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a doubleblind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 2003, 44(Suppl 1):S67-S77.
10. Huber J, Palacios S, Berglund L, Hanggi W, Sathanandan SM, Christau S, Helmond F: Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates, quality of life and tolerability in postmenopausal women. BJOG 2002, 109:886-893. 11. Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 2002, 77:487-490. 12. Mendoza N, Pison JA, Fernandez M, Sanchez MC, Malde J, Miranda JA: Prospective, randomised study with three HRT regimens in postmenopausal women with an intact uterus. Maturitas 2002, 41:289-298. 13. Shulman LP, Yankov V, Uhl K: Safety and efficacy of a continuous once-a-week 17b-estradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials. Menopause 2002, 9:195-207. 14. Gadomska H, Barcz E, Cyganek A, Leocmach Y, Chadha-Boreham H, Marianowski L: Efficacy and tolerability of low-dose transdermal estrogen (OesclimW) in the treatment of menopausal symptoms. Curr Med Res Opin 2002, 18:97-102. 15. Ozsoy M, Oral B, Ozsoy D: Clinical equivalence of intranasal estradiol and oral estrogens for postmenopausal symptoms. Int J Gynaecol Obstet 2002, 79:143-146. 16. Rozenbaum H, Chevallier O, Moyal M, Durand G, Perineau M, This P: Efficacy and tolerability of pulsed estrogen therapy: a 12-week double-blind placebo-controlled study in highly symptomatic postmenopausal women. Climacteric 2002, 5:249-258. 17. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ et al.: Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003, 348:1839-1854. 18. Feldman BM, Voda A, Gronseth E: The prevalence of hot flash and associated variables among perimenopausal women. Res Nurs Health 1985, 8:261-268. 19. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH: Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001, 75:1065-1079. This important dosage study examined a series of CE alone or CE/MPA doses and compared them with placebo for the relief of vasomotor symptoms. Lower-dose CE/MPA formulations (i.e. 0.45 mg CE with 2.5 mg or 1.5 mg MPA, and 0.3 mg CE with 1.5 mg MPA) relieved vasoCurrent Opinion in Pharmacology 2003, 3:626–634
motor symptoms and vaginal atrophy with similar efficacy to 0.625 mg CE plus 2.5 mg MPA. 20. Utian WH, Janata JW, Kingsberg SA, Schluchter M, Hamilton JC: The Utian Quality of Life (UQOL) Scale: development and validation of an instrument to quantify quality of life through and beyond menopause. Menopause 2002, 9:402-410. 21. Hlatky MA, Boothroyd D, Vittinghoff E, Sharp P, Whooley MA: Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the heart and estrogen/progestin replacement study (HERS) trial. J Am Med Assoc 2002, 287:591-597. This important study demonstrates that the effects of HT on quality of life might depend on the presence of menopausal symptoms. In the HERS population of older postmenopausal women, symptomatic women had improvements in emotional measures of quality of life after three years of HT, whereas women without symptoms did not. 22. Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N, Robinson V, Henry D, O’Connell D, Cranney A: V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002, 23:529-539. A clear review and meta-analysis from the Osteoporosis Research Group of 57 randomized studies on the effect of HT on bone density and fractures. They conclude that HT has been shown to have a consistent effect on bone density, but a potential benefit on fractures requires substantiation. 23. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH: Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. J Am Med Assoc 2002, 287:2668-2676. This large randomized two-year controlled trial involving 822 early postmenopausal women (average age 52 years) demonstrated that doses of CE or CE plus MPA lower than the 0.625 mg CE and 2.5 mg MPA combination per day effectively increased BMD and bone mineral content. 24. Gass M, Liu J, Rebar RW: The effect of low-dose conjugated equine estrogens and cyclic MPA on bone density. Maturitas 2002, 41:143-147. 25. Arrenbrecht S, Boermans AJ: Effects of transdermal estradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebocontrolled trial. Osteoporos Int 2002, 13:176-183. 26. Notelovitz M, John VA, Good WR: Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women. Menopause 2002, 9:343-353. 27. Palomba S, Orio F Jr, Colao A, Di Carlo C, Sena T, Lombardi G, Zullo F, Mastrantonio P: Effect of estrogen replacement plus low-dose alendronate treatment on bone density in surgically postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002, 87:1502-1508. 28. Cheng S, Sipila S, Taaffe DR, Puolakka J, Suominen H: Change in bone mass distribution induced by hormone replacement therapy and high-impact physical exercise in post-menopausal women. Bone 2002, 31:126-135. 29. Rosen C: Presentation at the Scientific Workshop: Menopausal Hormone Therapy, October 23-24 2002. National Institutes of Health, Office of Research on Women’s Health. [URL: http:// www4.od.nih.gov/orwh/htslides/rosen2.ppt] 30. Torgerson DJ, Bell-Syer SEM: Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. J Am Med Assoc 2001, 285:2891-2897. 31. Torgerson DJ, Bell-Syer SEM: Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials. BMC Musculoskeletal Disorders 2001, 2:7-10. 32. American Heart Association: 2002 Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association; 2001. 33. Kannel WB, Hjortland MC, McNamara PM, Gordon T: Menopause and risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1976, 85:447-452. www.current-opinion.com
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34. American Heart Association: Heart and Stroke Facts. Dallas, Texas: American Heart Association; 2001.
should be applied to younger healthy postmenopausal women who initiate HT for menopausal symptom relief.
35. Humphrey LL, Chan BKS, Sox HC: Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002, 137:273-284.
47. Barrett-Connor E: Postmenopausal estrogen and prevention bias. Ann Intern Med 1991, 115:455-456.
36. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. J Am Med Assoc 1998, 280:605-613.
48. Clarkson TB, Anthony MS, Jerome CP: Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 1998, 83:721-726. 49. Clarkson TB, Anthony MS, Morgan TM: Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab 2001, 86:41-47.
37. Clarke SC, Kelleher J, Lloyd-Jones H, Slack M, Schofield PM: A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study. BJOG 2002, 109:1056-1062.
50. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu C-R, Liu C-H, Azen SP: Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebocontrolled trial. Ann Intern Med 2001, 135:939-953.
38. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. J Am Med Assoc 2002, 288:321-333. The National Institutes of Health sponsored the WHI, designed as a randomized placebo-controlled clinical trial, to quantify selected longterm risks and benefits of ET and HT. The investigators reported that the CE/MPA subset of the WHI trial was stopped early (after a mean follow-up of 5.2 years) because, according to the predefined stopping rule, the increased incidence of breast cancer and cardiovascular events exceeded the pre-specified long-term benefits that included a reduction in fractures and colorectal cancer.
51. Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Meyers DA et al.: Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not Creactive protein. Circulation 2002, 105:1879-1882. This paper demonstrates that a common estrogen receptor polymorphism can augment HT-associated reductions in E-selectin levels but does not affect HT-associated elevations in C-reactive protein levels. The authors raise the possibility that, on the basis of genotype, a subset of women might be more or less favorably affected by HT with respect to cardiovascular risk.
39. Pornel B, Chevallier O, Netelenbos JC: Oral 17b-estradiol (1 mg) continuously combined with dydrogesterone improves the serum lipid profile of postmenopausal women. Menopause 2002, 9:171-178. 40. Meuwissen JHJM, Beijers-De Bie L, Vihtamaki T, Tuimala R, Siseles N, Magaril C, The HS, Houben PWH, Murga M, Spielmann D et al.: Assessment of the metabolic tolerance in postmenopausal women over a 1-year period of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone. Gynecol Endocrinol 2002, 16:155-162. 41. Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson P, Tardif JC, Higginson L et al.: Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. J Am Med Assoc 2002, 288:2432-2440. 42. Byington RP, Furberg CD, Herrington DM, Herd JA, Hunninghake D, Lowery M, Riley W, Craven T, Chaput L, Ireland CC et al.: Effect of estrogen plus progestin on progression of carotid atherosclerosis in postmenopausal women with heart disease: HERS B-mode substudy. Arterioscler Thromb Vasc Biol 2002, 22:1692-1697. 43. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S et al.: Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). J Am Med Assoc 2002, 288:49-57. 44. Shulman LP: Effects of progestins in different hormone replacement therapy formulations on estrogen-induced lipid changes in postmenopausal women. Am J Cardiol 2002, 89:47E-54E. 45. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, Elstein M, Kay C, Seif M et al.: Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002, 360:2001-2008. 46. Lobo RA, Pickar JH: Evaluation of cardiovascular-event rates with hormone replacement therapy in healthy postmenopausal women. Obstet Gynecol 2003, 101:95s. This pooled analysis of over 7 000 young postmenopausal women (average age 53 years) enrolled in four large ET/HT trials found that ET/HT use was not associated with an early increase in CHD events, in contrast to recent results from the WHI. These data question whether the WHI results www.current-opinion.com
52. Herrington DM, Vittinghoff E, Howard TD, Major DA, Owen J, Reboussin DM, Bowden D, Bittner V, Simon JA, Grady D et al.: Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol 2002, 22:1012-1017. 53. Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Brosnihan KB, Meyers DA, Bleecker ER: Estrogenreceptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002, 346:967-974. 54. McLay RN, Maki PM, Lyketsos CG: Nulliparity and late menopause are associated with decreased cognitive decline. J Neuropsychiatry Clin Neurosci 2003, 15:161-167. 55. Yaffe K, Lui L-Y, Grady D, Stone K, Morin P: Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women. Biol Psychiatry 2002, 51:677-682. 56. Sherwin BB: Estrogen and cognitive functioning in women. Endocr Rev 2003, 24:133-151. A comprehensive analysis of the effects of both endogenous and exogenous estrogen, as well as selective estrogen receptor modulators, on cognitive functioning in women that includes an explanation of the components of cognition and sex-based differences in cognitive functioning. The author raises the possibility that the immediate postmenopausal period may constitute a critical window for treatment with ET that maximizes its potential to protect against cognitive decline with ageing and/or to reduce the risk of Alzheimer’s disease. 57. Maki P, Hogervorst E: HRT and cognitive decline. Best Pract Res Clin Endocrinol Metab 2003, 17:105-122. 58. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD: Postmenopausal hormone replacement therapy: scientific review. J Am Med Assoc 2002, 288:872-881. 59. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E: Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med 2002, 113:543-548. 60. Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JCS: Hormone replacement therapy and incidence of Alzheimer disease in older women. The Cache County study. J Am Med Assoc 2002, 288:2123-2129. 61. Shumaker SA, Legault C, Rapp SR, Thal LWRB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM et al.: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women’s Health Initiative Memory Study: a randomized controlled trial. J Am Med Assoc 2003, 289:2651-2662. Current Opinion in Pharmacology 2003, 3:626–634
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This report from the Women’s Health Initiative Memory Study, an ancillary study to the WHI, reported that in women aged 65 years the RR of probable dementia in the HT group was twice that of the placebo group. However, the absolute risk remained relatively small. When assessed independently from probable dementia, there was no statistical difference between groups in the risk of developing mild cognitive impairment. 62. Thal LJ, Thomas RG, Mulnard R, Sano M, Grundman M, Schneider L: Estrogen levels do not correlate with improvement in cognition. Arch Neurol 2003, 60:209-212. 63. Yoon B-K, Kim DK, Kang Y, Kim J-W, Shin M-H, Na DL: Hormone replacement therapy in postmenopausal women with Alzheimer’s disease: a randomized, prospective study. Fertil Steril 2003, 79:274-280. 64. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997, 350:1047-1059. 65. Bush TL, Whiteman M, Flaws J: Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 2001, 98:498-508. 66. Newcomb PA, Titus-Ernstoff L, Egan KM, Trentham-Dietz A, Baron JA, Storer BE, Willett WC, Stampfer MJ: Postmenopausal estrogen and progestin use in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 2002, 11:593-600. 67. Weiss LK, Burkman RT, Cushing-Haugen KL, Voigt LF, Simon MS, Daling JR, Norman SA, Bernstein L, Ursin G, Marchbanks PA et al.: Hormone replacement therapy regimens and breast cancer risk. Obstet Gynecol 2002, 100:1148-1158. 68. Chen C-L, Weiss NS, Newcomb P, Barlow W, White E: Hormone replacement therapy in relation to breast cancer. J Am Med Assoc 2002, 287:734-741. 69. Olsson HL, Ingvar C, Bladstrom A: Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer 2003, 97:1387-1392. 70. Eden J: Progestins and breast cancer. Am J Obstet Gynecol 2003, 188:1123-1131. A thorough overview of the controversial relationship between the use of postmenopausal estrogen — with or without a progestin — and the development of breast cancer. Mechanistic studies examining progestins in human breast cancer cell lines, results from the WHI trial and epidemiologic studies are all assessed. The author concludes that, in the absence of large-scale randomized studies on different progestin regimens, a clear consensus regarding the relationship between HT and breast cancer risk cannot yet be drawn. 71. Cheek J, Lacy J, Toth-Fejel S, Morris K, Calhoun K, Pommier R: The impact of hormone replacement therapy on the detection and stage of breast cancer. Arch Surg 2002, 137:1015-1021.
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72. Ursin G, Tseng C-C, Paganini-Hill A, Enger S, Wan PC, Formenti S, Pike MC, Ross RK: Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer? J Clin Oncol 2002, 20:699-706. 73. Durna EM, Wren BG, Heller GZ, Leader LR, Sjoblom P, Eden JA: Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. Med J Aust 2002, 177:347-351. 74. Women’s Health Initiative Study Group: Design of the women’s health initiative clinical trial and observational study. Control Clin Trials 1998, 19:61-109. 75. Rodstrom K, Bengtsson C, Lissner L, Milsom I, Sundh V, Bjorkelund C: A longitudinal study of the treatment of hot flushes: the population study of women in Gothenburg during a quarter of a century. Menopause 2002, 9:156-161. 76. Stevenson JC, Whitehead MI: Hormone replacement therapy. BMJ 2002, 325:113-114. 77. McDonough PG: The randomized world is not without its imperfections: reflections on the Women’s Health Initiative Study. Fertil Steril 2002, 78:951-956. 78. Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J et al.: Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women’s Health Initiative Memory Study: a randomized controlled trial. J Am Med Assoc 2003, 289:2663-2672. 79. Wassertheil-Smoller S, Hendrix S, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE et al.: Effect of estrogen plus progestin on stroke in postmenopausal women: The Women’s Health Initiative: a randomized trial. J Am Med Assoc 2003, 289:2673-2684. An extension of the first WHI report examining the effects of estrogen plus progestin on ischemic and hemorrhagic stroke over an additional four months, featuring central adjudication of stroke events by neurologists, the addition of new cases, data on the effects of estrogen plus progestin in various subgroups of women, and assessment of the impact of lipid levels and biomarkers of inflammation and thrombosis on stroke risk. The investigators reported that women taking estrogen plus progestin had a significant increase in the RR of ischemic stroke compared with those taking placebo. Too few hemorrhagic strokes occurred to draw conclusions about that type of stroke, although no significant difference was observed. The authors reported that the observed increase in ischemic stroke was unrelated to several other risk factors, including age and a prior history of CVD, hormone use or hypertension. 80. Morabito N, Crisafulli A, Vergara C, Gaudio A, Lasco A, Frisina N, D’Anna R, Corrado F, Pizzoleo MA, Cincotta M et al.: Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res 2002, 17:1904-1912.
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Estrogens in postmenopausal women: recent insights Ginger D Constantine and James H Pickar Recent literature has consistently supported the use of postmenopausal estrogens for treatment of moderate-to-severe vasomotor symptoms and for prevention of osteoporosis. Although assessment of quality of life is complex, symptom relief has often been shown to translate into improvements in quality of life measures for women. Recent studies have reported a small increase in breast cancer with long-term hormone therapy, as well as a small increase in cardiovascular events and dementia when therapy is started in a population that is, on average, 13 years post-menopause. Ongoing investigations into different formulations and dosing options, as well as genetic factors that might influence the response to therapy, should provide valuable information.
recent years, however, significant attention has been paid to the potential preventive benefits of ET/HT on other chronic diseases, such as cardiovascular disease (CVD) and Alzheimer’s disease. Since 2002, a large number of studies has been published (over 190 Medline citations), often with conflicting findings. We attempt to summarize these data, delineating the differences in study design that might account for conflicting results and also taking account of the Women’s Health Initiative (WHI) findings. In addition, we highlight new research findings and approaches, and suggest future directions HT may take, including the use of lower doses of estrogens and progestins.
Addresses Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA Correspondence: Ginger Constantine; e-mail: [email protected]
Menopausal symptom relief
Current Opinion in Pharmacology 2003, 3:626–634 This review comes from a themed issue on Endocrine and metabolic diseases Edited by John Kirkland 1471-4892/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2003.07.003
Abbreviations BMD bone mineral density CE conjugated estrogens CHD coronary heart disease CI confidence interval CVD cardiovascular disease ET estrogen-only therapy HERS Heart and Estrogen/progestin Replacement Study HR hazard ratio HT hormone therapy MPA medroxyprogesterone acetate ORAG Osteoporosis Research Advisory Group PHASE Papworth HRT Atherosclerosis RR relative risk UQOL Utian Quality of Life Scale WHI Women’s Health Initiative
Introduction This paper reviews the clinical literature on postmenopausal hormone therapy that has been primarily published since 2002. Postmenopausal estrogens (estrogenonly therapy [ET] or hormone therapy [HT; estrogen in combination with progestin]) have been used for decades and are indicated for the treatment of moderate-tosevere vasomotor symptoms, vulvovaginal atrophy and the prevention of postmenopausal osteoporosis. In Current Opinion in Pharmacology 2003, 3:626–634
The primary reason women seek treatment with ET/HT is menopausal symptom relief. Hot flushes are the most common symptom, affecting up to 93% of women [1,2]. Given that women report up to a third of hot flushes as ‘severe’ [3], treatment of these disruptive symptoms can afford significant improvement in overall well-being. Investigation of the treatment of vasomotor symptoms should use reproducible and valid outcome measures that include the evaluation of the number and severity of flushes [4]. A potentially high placebo response rate and a lack of efficacy in women without significant baseline flushing can yield misleading results. 12 recently published clinical trials designed to examine the efficacy of estrogens, including conjugated estrogens (CE) [5–10], oral [5,11] or transdermal 17b-estradiol [12–14] and intranasal estradiol [15,16], on menopausal symptom relief have all reported an improvement in vasomotor symptoms with various formulations (Table 1), but only two of these trials [13,16] employed the US Food and Drug Administration’s recommended inclusion criteria of 7–8 moderate-to-severe hot flushes per day, or 50–60 per week at baseline [4]. In two studies that focused on older women, CE (0.625 mg) plus medroxyprogesterone acetate (MPA; 2.5 mg) provided symptom relief [6,17]. In an older population (average 13 years post-menopause) without significant vasomotor symptoms, HT was not found to be beneficial [17]. Although the majority of women experience hot flushes for fewer than five years, it has been estimated that 10% of postmenopausal women suffer vasomotor symptoms for more than 11 years [18]. Recently, the use of lower doses of ET/HT has been investigated for the relief of menopausal symptoms [13,16,19]. Lower-dose formulations with transdermal www.current-opinion.com
Estrogens in postmenopausal women Constantine and Pickar 627
Table 1 Recent randomized clinical trials on estrogen and menopausal symptom relief. Treatment groups (all doses in mg/d)
n
Mean age (years)
Study length
Effect of ET/HT on menopausal symptom relief
References
CE (0.625) þ MPA (5.0)
45
53
1 year
Significant improvement in vasomotor symptom control, urogenital and sexual health symptoms
[8]
Tibolone (2.5) CE (0.625) þ MPA (2.5)
40 1 380
51 67
4 years
Improvement in menopausal symptoms reported in HT group by year one, persisted through year four
[6]
Placebo CE (0.625) þ MPA (2.5)
1 383 14
67 52 5
16 weeks
Significant reduction in vasomotor symptoms as demonstrated by decreases in GCS vasomotor subscale; significant reduction in sexual dysfunction symptoms
[7]
JWSYS herbal preparation CE (0.625) þ MPA (2.5)
24 251
50 3 55
1 year
Improvement in vasomotor symptoms as demonstrated by decreases in GCS
[10]
Tibolone (2.5) CE (0.6)
250 22
55 40-60
3 months
Significant reduction of symptoms demonstrated by change in MRS for CE and phytoestrogen preparation
[9]
Cimicifuga racemosa (phytoestrogen preparation) Placebo Oral estradiol (1.0) Placebo Continuous estradiol (1.0) þ NETA (0.5)
20
90 days
Significant (>50%) reduction in hot flash number
[11]
9 months
Reduction of symptoms for both groups demonstrated by change in MRS; after three months, a change from baseline of approximately 90% was observed for both therapies
[5]
Significant reduction in hot flashes for women on estradiol 25 mg/d and 50 mg/d. At eight weeks, women on 25 mg/d reported approximately three-fold less daily symptoms than women on 50 mg/d >93% women in estradiol groups experienced reduction in hot flashes as determined by a modified KI
[14]
3 months
Significant reduction in number and severity of hot flashes with both doses seen at end of week two, persisted through three cycles. Both doses significantly reduced proportion of women experiencing vaginal dryness
[13]
1 year
Significant improvement in scores on the Women’s Health Questionnaire for vasomotor symptoms for all three doses of HT at cycle 13
Sequential CE (0.625) þ MG (5.0) Transdermal 17b-estradiol (0.025) plus sequential progesterone in women with a uterus — dose increased to 0.050 if required Cyclic combined transdermal 17bestradiol (0.050) þ NETA (0.25) Transdermal 17b-estradiol (0.050) þ oral MP (200 mg twice a week) Tibolone (2.5) Study 1
Transdermal 17b-estradiol (0.045) þ levonorgestrol (0.03) Transdermal 17b-estradiol (0.045) þ levonorgestrol (0.04) Placebo Study 2
20 12 12 223
53 2 52 1 50–56
223 62
49–56 51 5
16 weeks
55
50 4
1 year
55
51 4
55
51 4
96
52
104
52
93
52
[12]
Transdermal 17b-estradiol þ levonorgestrel at: 0.045 þ 0.00 0.045 þ 0.015 0.045 þ 0.030 0.045 þ 0.040 Intransal estradiol (0.30)
204 212 211 213 101
56 56 56 55 50 3
24 weeks
Significant decreases in KI score and incidence of hot flushes at 24 weeks for both therapies
[15]
Oral micronized estradiol (2.0) Intranasal estradiol (0.15)
100 54
51 3 53 5
12 weeks
Mean daily number of moderate-to-severe vasomotor symptoms and KI score decreased significantly in both estradiol groups. The decrease reached significance for the 300 mg group at week two, and for the 150 mg group at week eight
[16]
Intranasal estradiol (0.30) Placebo
54 57
52 6 52 5
Based on inclusion criteria, no average age of participants provided. GCS, Greene Climacteric Scale; JWSYS, Jia-Wey Shiau-Yau San; KI, Kupperman Index; MG, medrogestone; MP, micronised progesterone; MRS, Menopause Rating Scale; NETA, norethisterone acetate.
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628 Endocrine and metabolic diseases
and intranasal estradiol have been shown to be efficacious [13,16]. Similarly, the combination of CE (0.45 mg) and MPA (1.5 mg), and that of CE (0.3 mg) and MPA (1.5 mg), provided clinically significant symptom relief similar to that seen with CE (0.625 mg) and MPA (2.5 mg) [19]. The dose-response seen with CE alone (0:625 mg > 0:45 mg > 0:3 mg) was eliminated with the addition of MPA [19].
Quality of life The assessment of change in a woman’s quality of life is complex and has led to the development of a variety of measurement tools. Recent advances in scale development include the Utian Quality of Life Scale (UQOL) [20], which uses psychometric measures to assess a woman’s overall sense of well-being. To provide a comprehensive overview of menopausal symptoms and their impact, Utian, Janata, Kingsberg, Schluchter and Hamilton [20] recommend that the UQOL is combined with a validated menopausal symptom inventory, such as the Greene Climacteric Scale. Further evaluation of the UQOL, alone and in combination with other measures in clinical practice, is required. Data from randomized trials assessing the effect of ET/ HT on health-related quality of life have yielded different results depending on the study design, population and test instruments. Recent studies that have evaluated changes in quality of life measures with ET/HT have employed the Women’s Health Questionnaire [5,13], the Greene Climacteric Scale [7], the Menopause Rating Scale [9], the Quality of Life, Enjoyment and Satisfaction Questionnaire [10] and the Kupperman Index [15,16] (or a modified version [12]); they all reported improvements with CE and oral, transdermal or intranasal estradiol. Often, the beneficial effects on quality of life can depend on the presence of menopausal symptoms. For example, in the Heart and Estrogen/progestin Replacement Study (HERS), older women with flushing experienced significant improvements in mental health and depressive symptoms, whereas women without flushing did not [21].
Bone health Studies have consistently demonstrated that ET/HT is effective in, and hence is indicated for, the prevention of postmenopausal osteoporosis. A recent meta-analysis that included data from 21 randomized trials reported by the Osteoporosis Research Advisory Group (ORAG) found an approximate 7% difference in the percentage change in lumbar spine bone mineral density (BMD) after two years on HT [22]. Other randomized trials have focused on the effectiveness of lower-dose CE/MPA formulations [23,24], transdermal delivery systems [25,26] or hormones combined with interventions such as alendronate [27] and exercise [28] in maintaining BMD (Table 2). In the large prospective randomized Women’s Health, Osteoporosis, Progestin, Estrogen (Women’s HOPE) Current Opinion in Pharmacology 2003, 3:626–634
substudy, 822 women were treated with CE (0.625 mg) or CE (0.625 mg) in combination with MPA (2.5 mg), as well as lower doses. Two years of treatment with CE (0.45 mg) plus MPA (1.5 mg) or CE (0.3 mg) plus MPA (1.5 mg), as well as the other doses studied, resulted in significant gains in hip BMD for all CE/MPA and CE dosage groups when compared with placebo (P < 0:001), with no significant differences between CE/MPA formulations and the comparable dose of CE alone [23]. Similarly, examinations of lower-dose transdermal formulations have found that lower-dose estrogen can be effective as higher doses in maintaining BMD [25,26]. The importance of estrogens on fracture prevention was also investigated in the ORAG report [22]. A pooled estimate of data from over 20 494 women (including results from ORAG and WHI) showed a significantly decreased risk of nonvertebral fractures with HT use (relative risk ½RR ¼ 0:78; 95% confidence interval [CI], 0.64–0.96) [29]. This reduction in nonvertebral fractures is similar to the 27% reduction reported in an earlier meta-analysis by Torgerson and Bell-Syer [30]. Two separate meta-analyses report a trend toward an approximate 33% reduced incidence of vertebral fractures with HT use [22,31].
Cardiovascular disease The prevalence of coronary heart disease (CHD) rises dramatically among women with increasing age; approximately one in 20 women aged 45–54 years experience CHD, compared with one in 10 women aged 65–74 years [32,33]. For women who have undergone surgical menopause, the risk of CHD with age rises more sharply than for those who experience a natural transition [34]. The loss of endogenous estradiol at menopause, coupled with a concomitant increase in CHD risk, suggests that exogenous estrogen might reduce the risk of CHD in women. Indeed, the majority of published observational, preclinical and surrogate marker data has suggested a lower incidence of CHD among users of postmenopausal ET/HT compared with non-users. A recent meta-analysis of observational studies that adjusted for socioeconomic status found no association between any postmenopausal ET/HT use and CHD events (RR ¼ 0:88; 95% CI, 0.64–1.21) [35]. Two recent randomized secondary prevention trials in women with pre-existing CVD, the HERS [36] and the Papworth HRT Atherosclerosis (PHASE) study [37], have suggested an early increased risk of CVD with HT. The HERS study showed no overall increased risk, whereas the PHASE study showed an increase within the first 30 months, at which time the trial was discontinued. The WHI [38] also showed an early increase in risk that appeared to decrease subsequently, except during the fifth year, which seems to be an outlier (caused by an unusual decline in events in the placebo group in that year). www.current-opinion.com
Estrogens in postmenopausal women Constantine and Pickar 629
Table 2 Recent randomized clinical trials on estrogen and bone density. Treatment groups (all doses in mg/d)
n
Mean age (years)
Study length (years)
Effect of ET/HT on bone density
References
Sequential CE (0.625) þ MPA (10)
20
52 3
1
BMD at the spine, trochanter and the femoral neck increased compared with baseline for both doses; there were no significant differences between doses
[24]
Sequential CE (0.30) þ MPA (10) CE alone at: 0.625 0.45 0.3 CE þ MPA at:
14
52 5 2 52 52 52
All active treatments resulted in significant increases in spine and hip BMD
[23]
84 91 87 81 87 89 91 85 15 12 10
52 52 51 51 51 50–57 50–57 50–57
15 30
0.625 þ 2.5 0.45 þ 2.5 0.45 þ 1.5 0.3 þ 1.5 Placebo Estradiol (2.0) þ NETA (1.0) Exercise alone Estradiol (2.0) þ NETA (1.0) þ exercise Control Oral estradiol (1.0) þ NETA (0.50) Genistein (54.0) Placebo Transdermal 17b estradiol (0.10) (E-100) Transdermal 17b estradiol (0.05) (E-50) Placebo patch EMTDS at: 0.025 0.050 0.075 Placebo Micronized estradiol (2.0) þ alendronate (10) Micronized estradiol (2.0) þ alendronate (5.0) Micronized estradiol (2.0) þ placebo
For spine, the addition of 2.5 mg MPA to CE significantly increased BMD relative to CE alone at two years for the 0.625 mg and 0.45 mg doses For hip, there were no significant differences between CE þ MPA and the comparable dose of CE at two years 1
HT and exercise both improved BMD at proximal femur and tibial shaft. HT combined with exercise exceeded the effects of the two agents alone at all measured sites
[28]
50–57 52 5
1
HT and genistein significantly increased BMD in femoral neck and lumbar spine
[80]
30 30 100
52 3 51 4 54 4
2
[25]
54
54 4
E-100 and E-50 patches (100 mg/d and 50 mg/d, respectively) resulted in significant increases in lumbar, wrist and hip BMD from baseline. E-50 was as effective as E-100
53
53 4 2 52 54 54 54 62 4
All doses of EMTDS significantly increased lumbar BMD from baseline (1.6%, 4.0% and 4.8% increases for 0.025 mg/d, 0.050 mg/d and 0.075 mg/d EMTDS respectively)
[26]
89 90 89 87 42y
2
[27]
44y
60 4
43y
61 4
At two years, BMD at lumbar spine, trochanter and femoral neck was significantly increased in all groups compared with baseline; the addition of alendronate to ET was beneficial, with both doses showing a similar effect
Based on inclusion criteria, no average age of participants provided. ySurgically postmenopausal women with osteoporosis. EMTDS, estradiol matrix transdermal delivery system; NETA, norethisterone acetate.
There has been one other meta-analysis and over 60 clinical reports published since 2002 that examined the role of ET/HT as risk factors for CVD. Of the eight trials that examined more than 250 women, two have demonstrated positive effects [39,40], two (including the PHASE study) demonstrated negative effects [37,41], and four reported a neutral effect of various HT regimens [42–45]. The largest of these trials was the Estrogen in the Prevention of Re-Infarction Trial (ESPRIT), a two-year secondary prevention trial of 1 017 women (average age 63 years) who had survived a myocardial infarction and had been given either placebo or unopposed oestradiol valerate (2 mg/d) [45]. There were no significant differences between groups in the overall frequency of reinfarction or cardiac deaths (RR ¼ 0:79; 95% CI, 0.50– 1.27) [45]. Examination of cardiovascular events in pooled www.current-opinion.com
data from 7 333 younger healthy postmenopausal women (average age 53 years) enrolled in four large randomized trials with different ET/HT regimens found that ET/HT use was not associated with an early increase in CHD events when compared with placebo [46]. The reason for the inconsistent effects of HT seen in observational and controlled clinical trials remains unclear. One explanation might be the healthy user bias among women in the observational trials who chose to use hormones [47]. Another is that the timing of initiation of HT is critical; that is, initiation more than a decade after menopause (e.g. in the HERS and WHI trials) when underlying atherosclerosis is likely to be substantial is too late to yield any benefit. In contrast, initiation at the time of menopause (typically the case in the observational Current Opinion in Pharmacology 2003, 3:626–634
630 Endocrine and metabolic diseases
trials) before atherosclerosis has developed in any substantial way might provide cardiovascular benefits. This latter explanation is consistent with preclinical data involving cynomolgus monkeys [48,49] and with data from the Estrogen in the Prevention of Atherosclerosis Trial [50]. A series of reports has suggested that a woman may be more or less favorably affected by HT with regard to cardiovascular risks on the basis of their genotype [51,52,53]. For example, a factor V Leiden genotype has been shown to increase a woman’s risk of venous thromboembolic events with HT [52]. The potential association between either genotype or ET/HT and the risk of clinical cardiovascular events is not fully established, but this area of research could become important in identifying appropriate candidates for ET/HT.
Cognition and dementia McLay, Maki and Lyketsos [54] reported recently that greater exposure to endogenous estrogens (e.g. in nulliparity and late menopause) is associated with decreased cognitive decline. Evidence of specific estrogen receptor polymorphisms being linked to cognitive impairment further supports an association between estrogen and cognitive function [55]. Recent reviews that have examined the role of postmenopausal hormones in cognitive performance have concluded that ET/HT can improve or act to maintain certain aspects of cognition, such as verbal memory, vigilance, learning and reasoning [56]; however, other findings have produced mixed results [57,58]. In the review by Nelson, Humphrey, Nygren, Teutsch and Allan [58], estrogen-related improvements in cognition only occurred in women with menopausal symptoms. Lack of cognitive improvement in asymptomatic women was also reported in HERS, which found that after four years there were no differences in age-adjusted cognitive function test scores between the HT and placebo groups [59]. Studies of long-term HT use and Alzheimer’s disease are not consistent. A meta-analysis of 12 cohort or casecontrolled studies published before 2000 found that HT use was associated with a 34% reduction in the risk of dementia [58]. Recent observational data from the Cache County Study [60] indicated that women who initiate estrogens closer to the onset of menopause and use ET/HT for longer than 10 years benefited by a significant decrease in the incidence of Alzheimer’s. In contrast, women who initiated HT within 10 years of the onset of Alzheimer’s disease received little benefit. The finding that HT benefits are limited to an early initiation of use is consistent with recent randomized trials which suggested that HT is not effective in mitigating the progression of cognitive decline when initiated in older women [61] or women with established Alzheimer’s disease [62], although one small trial of women with Alzheimer’s disease did report benefits [63]. At present, there is no consistent evidence to suggest that ET/HT is Current Opinion in Pharmacology 2003, 3:626–634
an effective treatment for elderly women already diagnosed with Alzheimer’s [56].
Breast cancer The 1997 Collaborative Group re-analysis of data from 51 epidemiological studies reported a relative risk for breast cancer of 1.31 for long-term HT users [64]. Conversely, a review published in September 2001 reported that there was not sufficient evidence to conclude that HT increases the risk of breast cancer [65]. Since 2002, case-control [66–68] and cohort [69] studies, as well as one randomized trial [38], have all reported an increase in the relative risk of breast cancer with longer duration ET/HT similar to that reported by the Collaborative Group. Studies that examined the outcomes of women who used ET/HT have generally documented improved survival [70,71], possibly caused by favorable tumor biology resulting in less aggressive tumors [71,72]. A recent case-control study in Australia found that ET/HT use after diagnosis reduced tumor recurrence by up to 40% [73].
The Women’s Health Initiative One of the studies published in 2002 that garnered attention from clinicians, patients and the media was issued from the HT arm of the WHI [74]. In part, the WHI was designed to evaluate specific potential longterm benefits and risks of ET (CE 0.625 mg/d) and HT (CE 0.625 mg/d plus MPA 2.5 mg/d). The primary endpoint was the prevention of CHD; other endpoints included breast cancer, colon cancer, stroke, venous thromboembolic events and fractures. In the HT arm of the WHI [38], 16 608 women (mean age at entry 63.3 years) were randomized to receive either CE/MPA or placebo. The investigators reported that this study was stopped early (after a mean follow-up of 5.2 years) because, according to a pre-defined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the pre-specified long-term benefits [38]. The WHI reported an estimated hazard ratio (HR) for CHD of 1.29 (95% nominal CI, 1.02–1.63) and of 1.03 (95% nominal CI, 0.90–1.17) for total CVD (arterial and venous disease). The ET (CE) arm of the WHI is currently ongoing. The WHI has provided important information on selected potential risks and benefits of HT; however, it does not address some of the therapeutic issues relevant to the majority of HT users. The WHI was not designed to assess menopausal symptoms and actually discouraged recruitment of women with moderate-tosevere vasomotor symptoms [74]. In addition, the older population of women examined in WHI may be different from the population of early postmenopausal women who initiate HT for symptom relief. Approximately twothirds of the subjects in the WHI were >60 years of www.current-opinion.com
Estrogens in postmenopausal women Constantine and Pickar 631
age and less than a fifth were within five years of menopause, the period during which menopausal symptoms are greatest [75]. Stevenson and Whitehead [76] have recommended that estrogen doses lower than 0.625 mg CE (the dose administered in the WHI) are used as a starting dose for women in this older age range. Moreover, many of the participants in the WHI had risk factors for CVD; two-thirds of participants were overweight, a third was hypertensive, and nearly 8% had a history of CVD [77]. Following this initial publication, several reports from the WHI have been published in 2002 and 2003. With respect to vasomotor symptoms, Hays et al. [17] reported that 12% of participants had vasomotor symptoms at baseline and that one year of treatment with CE/MPA significantly improved the severity of both hot flashes and night sweats in this group. Although HT resulted in a statistically significant difference favoring the HT group in three out of 12 measures of quality of life, these measures were not considered clinically meaningful [17]. In the WHI Memory Study (an ancillary study of the WHI), 4 532 postmenopausal women 65 years of age ( 53% were 70 years old) were monitored for the incidence of probable dementia. After four years, 40 women in the HT group and 21 in the placebo group were diagnosed with probable dementia, resulting in a HR of 2.05 (95% nominal CI, 1.21–3.48) [61]. In a related report from the WHI Memory Study, the rate of decline in global cognition (measured by the Modified Mini-Mental State Examination) diverged after two years and was statistically greater with HT use (P ¼ 0:03); this decline was consistent for all subgroups but was not considered by the investigators to be clinically significant [78]. For a small number of women who initiated HT during the late postmenopausal period, a detrimental effect on cognition was observed. These findings contrast with those reported in the HT arm of the WHI [17], in which no effect of HT on cognition was noted over one or three years in participants 65 years of age. In their analysis of the stroke data from the HT arm of the WHI, Wassertheil-Smoller et al. [79] reported that 1.8% of women in the HT group and 1.3% of women in the placebo group had ischemic (79.8%) or hemorrhagic strokes. The HR for ischemic stroke with HT use was 1.44 (95% nominal CI, 1.09–1.90) and 0.82 (95% nominal CI, 0.43–1.56) for hemorrhagic stroke. In the initial report from the WHI trial [38], the HR for breast cancer was 1.26 (95% nominal CI, 1.00–1.59) after 5.2 years, and was similar in magnitude to that of two previous observational trials [64]. In subgroup analysis of the WHI, the increased incidence of breast cancer was confined to women who had used HT before entering the www.current-opinion.com
study, with the HR varying according to extent of prior use (e.g. HR ¼ 2:13; 95% nominal CI, 1.15–3.94 for women with < five years prior use versus HR ¼ 4:61; 95% nominal CI, 1.01–21.02 for women with 5–10 years prior use). No increased risk of breast cancer was evident among the 74% of participants who had never used HT (HR ¼ 1:06; 95% nominal CI, 0.81–1.38) [38]. In contrast, HT use resulted in a decreased risk of colon cancer (HR ¼ 0:63; 95% nominal CI, 0.43–0.92). Finally, the initial WHI report [38] has reiterated findings of observational studies that the use of HT significantly reduces hip, vertebral and total fractures. It is important to note that this is the first study to observe a fracture benefit in women who were not at known risk for osteoporosis.
Conclusions ET/HT remains a clinically proven treatment for the relief of vasomotor symptoms and vulvovaginal atrophy, and is effective in the prevention of osteoporosis. In other areas of research, notably in cardiovascular and central nervous system effects, the recent literature has produced conflicting results. This lack of agreement between studies might, in part, be a result of the type of assessment tool, the population studied and/or the timing and duration of use. Clinical research continues into genetic factors influencing the response to ET/HT, different estrogen formulations, different modes of delivery and lower-dose options. This research will assist patients and clinicians in making treatment decisions on the basis of an individual’s needs and risks, and should enhance a woman’s ability to undergo the menopausal transition with minimal disruption to her quality of life.
Acknowledgements The editorial assistance of Karen Mittleman is greatly acknowledged.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1.
Freedman RR: Menopausal hot flashes. In Menopause: Biology and Pathobiology. Edited by Lobo R, Kelsey J, Marcus R. San Diego, CA: Academic Press; 2000:215-227.
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Thompson B, Hart SA, Durno D: Menopausal age and symptomatology in a general practice. J Biosoc Sci 1973, 5:71-82.
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4.
Food and Drug Administration: FDA approves new labeling and provides new advice to postmenopausal women who use or who are considering using estrogen and estrogen with progestin. FDA Fact Sheet [URL: http://www.fda.gov/bbs/topics/ factsheets/2003/fs1.html]. Current Opinion in Pharmacology 2003, 3:626–634
632 Endocrine and metabolic diseases
5.
von Holst T, Lang E, Winkler U, Keil D: Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone. Maturitas 2002, 43:265-275.
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Barnabei VM, Grady D, Stovall DW, Cauley JA, Lin F, Stuenkel CA, Stefanick ML, Pickar JH: Menopausal symptoms in older women and the effects of treatment with hormone therapy. Obstet Gynecol 2002, 100:1209-1218.
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Chen LC, Tsao YT, Yen KY, Chen YF, Chou MH, Lin MF: A pilot study comparing the clinical effects of Jia-Wey Shiau-Yau San, a traditional Chinese herbal prescription, and a continuous combined hormone replacement therapy in postmenopausal women with climacteric symptoms. Maturitas 2003, 44:55-62.
8.
Baracat EC, Barbosa IC, Giordano MG, Haidar MA, Marinho RM, Menegocci JC, Morais KM, Tomaz G, Wehba S: A randomized, open-label study of conjugated equine estrogens plus medroxyprogesterone acetate versus tibolone: effects on symptom control, bleeding pattern, lipid profile and tolerability. Climacteric 2002, 5:60-69.
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Wuttke W, Seidlova-Wuttke D, Gorkow C: The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a doubleblind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 2003, 44(Suppl 1):S67-S77.
10. Huber J, Palacios S, Berglund L, Hanggi W, Sathanandan SM, Christau S, Helmond F: Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates, quality of life and tolerability in postmenopausal women. BJOG 2002, 109:886-893. 11. Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 2002, 77:487-490. 12. Mendoza N, Pison JA, Fernandez M, Sanchez MC, Malde J, Miranda JA: Prospective, randomised study with three HRT regimens in postmenopausal women with an intact uterus. Maturitas 2002, 41:289-298. 13. Shulman LP, Yankov V, Uhl K: Safety and efficacy of a continuous once-a-week 17b-estradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials. Menopause 2002, 9:195-207. 14. Gadomska H, Barcz E, Cyganek A, Leocmach Y, Chadha-Boreham H, Marianowski L: Efficacy and tolerability of low-dose transdermal estrogen (OesclimW) in the treatment of menopausal symptoms. Curr Med Res Opin 2002, 18:97-102. 15. Ozsoy M, Oral B, Ozsoy D: Clinical equivalence of intranasal estradiol and oral estrogens for postmenopausal symptoms. Int J Gynaecol Obstet 2002, 79:143-146. 16. Rozenbaum H, Chevallier O, Moyal M, Durand G, Perineau M, This P: Efficacy and tolerability of pulsed estrogen therapy: a 12-week double-blind placebo-controlled study in highly symptomatic postmenopausal women. Climacteric 2002, 5:249-258. 17. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ et al.: Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003, 348:1839-1854. 18. Feldman BM, Voda A, Gronseth E: The prevalence of hot flash and associated variables among perimenopausal women. Res Nurs Health 1985, 8:261-268. 19. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH: Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001, 75:1065-1079. This important dosage study examined a series of CE alone or CE/MPA doses and compared them with placebo for the relief of vasomotor symptoms. Lower-dose CE/MPA formulations (i.e. 0.45 mg CE with 2.5 mg or 1.5 mg MPA, and 0.3 mg CE with 1.5 mg MPA) relieved vasoCurrent Opinion in Pharmacology 2003, 3:626–634
motor symptoms and vaginal atrophy with similar efficacy to 0.625 mg CE plus 2.5 mg MPA. 20. Utian WH, Janata JW, Kingsberg SA, Schluchter M, Hamilton JC: The Utian Quality of Life (UQOL) Scale: development and validation of an instrument to quantify quality of life through and beyond menopause. Menopause 2002, 9:402-410. 21. Hlatky MA, Boothroyd D, Vittinghoff E, Sharp P, Whooley MA: Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the heart and estrogen/progestin replacement study (HERS) trial. J Am Med Assoc 2002, 287:591-597. This important study demonstrates that the effects of HT on quality of life might depend on the presence of menopausal symptoms. In the HERS population of older postmenopausal women, symptomatic women had improvements in emotional measures of quality of life after three years of HT, whereas women without symptoms did not. 22. Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N, Robinson V, Henry D, O’Connell D, Cranney A: V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002, 23:529-539. A clear review and meta-analysis from the Osteoporosis Research Group of 57 randomized studies on the effect of HT on bone density and fractures. They conclude that HT has been shown to have a consistent effect on bone density, but a potential benefit on fractures requires substantiation. 23. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH: Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. J Am Med Assoc 2002, 287:2668-2676. This large randomized two-year controlled trial involving 822 early postmenopausal women (average age 52 years) demonstrated that doses of CE or CE plus MPA lower than the 0.625 mg CE and 2.5 mg MPA combination per day effectively increased BMD and bone mineral content. 24. Gass M, Liu J, Rebar RW: The effect of low-dose conjugated equine estrogens and cyclic MPA on bone density. Maturitas 2002, 41:143-147. 25. Arrenbrecht S, Boermans AJ: Effects of transdermal estradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebocontrolled trial. Osteoporos Int 2002, 13:176-183. 26. Notelovitz M, John VA, Good WR: Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women. Menopause 2002, 9:343-353. 27. Palomba S, Orio F Jr, Colao A, Di Carlo C, Sena T, Lombardi G, Zullo F, Mastrantonio P: Effect of estrogen replacement plus low-dose alendronate treatment on bone density in surgically postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002, 87:1502-1508. 28. Cheng S, Sipila S, Taaffe DR, Puolakka J, Suominen H: Change in bone mass distribution induced by hormone replacement therapy and high-impact physical exercise in post-menopausal women. Bone 2002, 31:126-135. 29. Rosen C: Presentation at the Scientific Workshop: Menopausal Hormone Therapy, October 23-24 2002. National Institutes of Health, Office of Research on Women’s Health. [URL: http:// www4.od.nih.gov/orwh/htslides/rosen2.ppt] 30. Torgerson DJ, Bell-Syer SEM: Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. J Am Med Assoc 2001, 285:2891-2897. 31. Torgerson DJ, Bell-Syer SEM: Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials. BMC Musculoskeletal Disorders 2001, 2:7-10. 32. American Heart Association: 2002 Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association; 2001. 33. Kannel WB, Hjortland MC, McNamara PM, Gordon T: Menopause and risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1976, 85:447-452. www.current-opinion.com
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34. American Heart Association: Heart and Stroke Facts. Dallas, Texas: American Heart Association; 2001.
should be applied to younger healthy postmenopausal women who initiate HT for menopausal symptom relief.
35. Humphrey LL, Chan BKS, Sox HC: Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002, 137:273-284.
47. Barrett-Connor E: Postmenopausal estrogen and prevention bias. Ann Intern Med 1991, 115:455-456.
36. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. J Am Med Assoc 1998, 280:605-613.
48. Clarkson TB, Anthony MS, Jerome CP: Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 1998, 83:721-726. 49. Clarkson TB, Anthony MS, Morgan TM: Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab 2001, 86:41-47.
37. Clarke SC, Kelleher J, Lloyd-Jones H, Slack M, Schofield PM: A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study. BJOG 2002, 109:1056-1062.
50. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu C-R, Liu C-H, Azen SP: Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebocontrolled trial. Ann Intern Med 2001, 135:939-953.
38. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. J Am Med Assoc 2002, 288:321-333. The National Institutes of Health sponsored the WHI, designed as a randomized placebo-controlled clinical trial, to quantify selected longterm risks and benefits of ET and HT. The investigators reported that the CE/MPA subset of the WHI trial was stopped early (after a mean follow-up of 5.2 years) because, according to the predefined stopping rule, the increased incidence of breast cancer and cardiovascular events exceeded the pre-specified long-term benefits that included a reduction in fractures and colorectal cancer.
51. Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Meyers DA et al.: Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not Creactive protein. Circulation 2002, 105:1879-1882. This paper demonstrates that a common estrogen receptor polymorphism can augment HT-associated reductions in E-selectin levels but does not affect HT-associated elevations in C-reactive protein levels. The authors raise the possibility that, on the basis of genotype, a subset of women might be more or less favorably affected by HT with respect to cardiovascular risk.
39. Pornel B, Chevallier O, Netelenbos JC: Oral 17b-estradiol (1 mg) continuously combined with dydrogesterone improves the serum lipid profile of postmenopausal women. Menopause 2002, 9:171-178. 40. Meuwissen JHJM, Beijers-De Bie L, Vihtamaki T, Tuimala R, Siseles N, Magaril C, The HS, Houben PWH, Murga M, Spielmann D et al.: Assessment of the metabolic tolerance in postmenopausal women over a 1-year period of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone. Gynecol Endocrinol 2002, 16:155-162. 41. Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson P, Tardif JC, Higginson L et al.: Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. J Am Med Assoc 2002, 288:2432-2440. 42. Byington RP, Furberg CD, Herrington DM, Herd JA, Hunninghake D, Lowery M, Riley W, Craven T, Chaput L, Ireland CC et al.: Effect of estrogen plus progestin on progression of carotid atherosclerosis in postmenopausal women with heart disease: HERS B-mode substudy. Arterioscler Thromb Vasc Biol 2002, 22:1692-1697. 43. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S et al.: Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). J Am Med Assoc 2002, 288:49-57. 44. Shulman LP: Effects of progestins in different hormone replacement therapy formulations on estrogen-induced lipid changes in postmenopausal women. Am J Cardiol 2002, 89:47E-54E. 45. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, Elstein M, Kay C, Seif M et al.: Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002, 360:2001-2008. 46. Lobo RA, Pickar JH: Evaluation of cardiovascular-event rates with hormone replacement therapy in healthy postmenopausal women. Obstet Gynecol 2003, 101:95s. This pooled analysis of over 7 000 young postmenopausal women (average age 53 years) enrolled in four large ET/HT trials found that ET/HT use was not associated with an early increase in CHD events, in contrast to recent results from the WHI. These data question whether the WHI results www.current-opinion.com
52. Herrington DM, Vittinghoff E, Howard TD, Major DA, Owen J, Reboussin DM, Bowden D, Bittner V, Simon JA, Grady D et al.: Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol 2002, 22:1012-1017. 53. Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Brosnihan KB, Meyers DA, Bleecker ER: Estrogenreceptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002, 346:967-974. 54. McLay RN, Maki PM, Lyketsos CG: Nulliparity and late menopause are associated with decreased cognitive decline. J Neuropsychiatry Clin Neurosci 2003, 15:161-167. 55. Yaffe K, Lui L-Y, Grady D, Stone K, Morin P: Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women. Biol Psychiatry 2002, 51:677-682. 56. Sherwin BB: Estrogen and cognitive functioning in women. Endocr Rev 2003, 24:133-151. A comprehensive analysis of the effects of both endogenous and exogenous estrogen, as well as selective estrogen receptor modulators, on cognitive functioning in women that includes an explanation of the components of cognition and sex-based differences in cognitive functioning. The author raises the possibility that the immediate postmenopausal period may constitute a critical window for treatment with ET that maximizes its potential to protect against cognitive decline with ageing and/or to reduce the risk of Alzheimer’s disease. 57. Maki P, Hogervorst E: HRT and cognitive decline. Best Pract Res Clin Endocrinol Metab 2003, 17:105-122. 58. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD: Postmenopausal hormone replacement therapy: scientific review. J Am Med Assoc 2002, 288:872-881. 59. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E: Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med 2002, 113:543-548. 60. Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JCS: Hormone replacement therapy and incidence of Alzheimer disease in older women. The Cache County study. J Am Med Assoc 2002, 288:2123-2129. 61. Shumaker SA, Legault C, Rapp SR, Thal LWRB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM et al.: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women’s Health Initiative Memory Study: a randomized controlled trial. J Am Med Assoc 2003, 289:2651-2662. Current Opinion in Pharmacology 2003, 3:626–634
634 Endocrine and metabolic diseases
This report from the Women’s Health Initiative Memory Study, an ancillary study to the WHI, reported that in women aged 65 years the RR of probable dementia in the HT group was twice that of the placebo group. However, the absolute risk remained relatively small. When assessed independently from probable dementia, there was no statistical difference between groups in the risk of developing mild cognitive impairment. 62. Thal LJ, Thomas RG, Mulnard R, Sano M, Grundman M, Schneider L: Estrogen levels do not correlate with improvement in cognition. Arch Neurol 2003, 60:209-212. 63. Yoon B-K, Kim DK, Kang Y, Kim J-W, Shin M-H, Na DL: Hormone replacement therapy in postmenopausal women with Alzheimer’s disease: a randomized, prospective study. Fertil Steril 2003, 79:274-280. 64. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997, 350:1047-1059. 65. Bush TL, Whiteman M, Flaws J: Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 2001, 98:498-508. 66. Newcomb PA, Titus-Ernstoff L, Egan KM, Trentham-Dietz A, Baron JA, Storer BE, Willett WC, Stampfer MJ: Postmenopausal estrogen and progestin use in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 2002, 11:593-600. 67. Weiss LK, Burkman RT, Cushing-Haugen KL, Voigt LF, Simon MS, Daling JR, Norman SA, Bernstein L, Ursin G, Marchbanks PA et al.: Hormone replacement therapy regimens and breast cancer risk. Obstet Gynecol 2002, 100:1148-1158. 68. Chen C-L, Weiss NS, Newcomb P, Barlow W, White E: Hormone replacement therapy in relation to breast cancer. J Am Med Assoc 2002, 287:734-741. 69. Olsson HL, Ingvar C, Bladstrom A: Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer 2003, 97:1387-1392. 70. Eden J: Progestins and breast cancer. Am J Obstet Gynecol 2003, 188:1123-1131. A thorough overview of the controversial relationship between the use of postmenopausal estrogen — with or without a progestin — and the development of breast cancer. Mechanistic studies examining progestins in human breast cancer cell lines, results from the WHI trial and epidemiologic studies are all assessed. The author concludes that, in the absence of large-scale randomized studies on different progestin regimens, a clear consensus regarding the relationship between HT and breast cancer risk cannot yet be drawn. 71. Cheek J, Lacy J, Toth-Fejel S, Morris K, Calhoun K, Pommier R: The impact of hormone replacement therapy on the detection and stage of breast cancer. Arch Surg 2002, 137:1015-1021.
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72. Ursin G, Tseng C-C, Paganini-Hill A, Enger S, Wan PC, Formenti S, Pike MC, Ross RK: Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer? J Clin Oncol 2002, 20:699-706. 73. Durna EM, Wren BG, Heller GZ, Leader LR, Sjoblom P, Eden JA: Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. Med J Aust 2002, 177:347-351. 74. Women’s Health Initiative Study Group: Design of the women’s health initiative clinical trial and observational study. Control Clin Trials 1998, 19:61-109. 75. Rodstrom K, Bengtsson C, Lissner L, Milsom I, Sundh V, Bjorkelund C: A longitudinal study of the treatment of hot flushes: the population study of women in Gothenburg during a quarter of a century. Menopause 2002, 9:156-161. 76. Stevenson JC, Whitehead MI: Hormone replacement therapy. BMJ 2002, 325:113-114. 77. McDonough PG: The randomized world is not without its imperfections: reflections on the Women’s Health Initiative Study. Fertil Steril 2002, 78:951-956. 78. Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J et al.: Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women’s Health Initiative Memory Study: a randomized controlled trial. J Am Med Assoc 2003, 289:2663-2672. 79. Wassertheil-Smoller S, Hendrix S, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE et al.: Effect of estrogen plus progestin on stroke in postmenopausal women: The Women’s Health Initiative: a randomized trial. J Am Med Assoc 2003, 289:2673-2684. An extension of the first WHI report examining the effects of estrogen plus progestin on ischemic and hemorrhagic stroke over an additional four months, featuring central adjudication of stroke events by neurologists, the addition of new cases, data on the effects of estrogen plus progestin in various subgroups of women, and assessment of the impact of lipid levels and biomarkers of inflammation and thrombosis on stroke risk. The investigators reported that women taking estrogen plus progestin had a significant increase in the RR of ischemic stroke compared with those taking placebo. Too few hemorrhagic strokes occurred to draw conclusions about that type of stroke, although no significant difference was observed. The authors reported that the observed increase in ischemic stroke was unrelated to several other risk factors, including age and a prior history of CVD, hormone use or hypertension. 80. Morabito N, Crisafulli A, Vergara C, Gaudio A, Lasco A, Frisina N, D’Anna R, Corrado F, Pizzoleo MA, Cincotta M et al.: Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res 2002, 17:1904-1912.
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