Sage Journals: Discover world-class research

Abstract

Contrary to the exaggerated risks associated with HRT that developed after the initial press reports held by the Women's Health Initiative (WHI) writing group, the recent approach to hormone therapy is more balanced and evidence based. A review of over 40 years of scientific studies demonstrates that estrogen is a medication that can decrease mortality, cardiovascular disease, osteoporosis fracture, urogenital atrophy and dementia. When timing of administration, dose of therapy and route of administration are considered, estrogen is associated with low risks and substantial benefits. The decision of whether or not to take HRT for either short symptom relief or for long-term therapy, should be based on an accurate risk–benefit analysis. Adjusting the dose of therapy and considering a transdermal approach, particularly in high-risk patients, are important considerations.

Keywords

cardiovascular disease in postmenopausal women estrogen replacement HRT hypoestrogenism low-dose estrogen therapy menopausal hormone therapy menopause osteoporosis reducing mortality in women risks and benefits of hormone replacement strategies to minimize risk timing hypothesis transdermal estrogen therapy Women's Health Initiative

After the release of the Women's Health Initiative (WHI) press reports in the USA in 2002, the use of HRT among women around the world declined abruptly. Since then, a better understanding of risks and benefits of hormone therapy has clarified the WHI findings and led to a more balanced approach to counseling. One of the most important findings of the WHI is that the age of initiation of therapy has profound effects on the risk and benefit profile. Currently there are very important ongoing studies designed to further characterize the timing hypothesis that simply says that timing of initiation is critical to understanding the therapeutic actions of estrogen [1,101]. These data are not expected to be known for several years. However, even without these results, careful review of over 40 years of studies demonstrates several important points. Estrogen is a medication that can decrease mortality, decrease cardiovascular disease, decrease osteoporosis fracture, urogenital atrophy and dementia. Strategies to minimize risk include initiation of therapy within 10 years of menopause or under 60 years of age, using low-dose estrogen, adding a low-dose progestin in women with a uterus, and use of transdermal therapy in women with risk factors for cardiovascular disease.

Strategies to minimize risk

Many women may want the benefits associated with hormone therapy including protection from cardiovascular disease, osteoporosis and fracture, urogenital atrophy, skin atrophy and dementia. Minimizing the risks of taking hormone therapy for these women is an important consideration.

Timing hormone therapy: when started in women under 60 years or within 10 years of their menopause, is not associated with an increased risk of heart disease and many studies show that estrogen therapy actually protects the coronary vessels. Continuing therapy, at least through 65 years of age, appears to continue this protection [2].

Minimizing the dose: using the lowest effective dose for menopausal symptoms lowers the risk of side effects and bleeding problems. Low-dose therapy is also associated with beneficial effects on bone metabolism and vaginal tissue.

Delivery method may be important: estrogen can be administered by patch, gel, mist, vaginal cream, vaginal suppository or vaginal rings. Use of these non-oral delivery methods minimizes the effect of estrogen on hepatic proteins. The non-oral delivery methods are recommended for women with suspected or known cardiovascular disease, clotting abnormalities, thromboembolic history, pronounced obesity, prolonged hypertension or diabetes, advanced age or prolonged immobilization. Minor differences among these transdermal estrogen preparations or among the many oral estrogen preparations is not the focus of this article.

Adding a progestin: for women who have not had a hysterectomy, addition of a progestin to estrogen therapy is necessary to protect the endometrium from overstimulation. One of the advantages of using a low-dose estrogen product is that it allows for minimizing the dose of the progestin. The combination products on the market contain balanced levels of estrogen and progestin and generally minimize uterine bleeding. Some clinicians and patients prefer to select separate estrogen and progestin products. There are a large variety of progestins that can be used in this manner and differences in the progestins may offer clinical advantages. In general, these differences are minimal when a low-dose option is used and are not the focus of this article.

Consider high risk factors: women with a personal history of breast cancer or active liver disease are generally advised to avoid hormone therapy. Those with heart disease, a history of blood clots, advanced age, longstanding diabetes, longstanding hypertension or those with prolonged immobilization should fully evaluate a risk–benefit profile before initiating hormone therapy and consider low-dose transdermal therapy.

Accurate evaluation of the WHI: risks & benefits

Clinical practice was abruptly changed after data from the WHI were released to the media in June 2002. Rather than a first presentation to the medical profession to allow wide peer review, the results were first presented to a media conference in a manner that allowed a media-driven frenzy and an exaggerated public view of the risks associated with hormone therapy.

The WHI results were published in July 2002 showing small increases (often borderline or not statistically significant) in the risk of cardiovascular disease, breast cancer and stroke in postmenopausal women taking combination estrogen and progestin therapy compared with untreated controls [3]. These results were in stark contrast to the vast majority of earlier studies that reported large decreases in overall death rate, cardiovascular disease, osteoporosis, bone fractures, dementia, colon cancer and a host of other diseases in postmenopausal women taking hormone therapy compared with nontreated age-matched women [4 –14]. The public has yet to understand the limitations of the study or to appreciate the study reported benefits associated with hormone therapy including a decreased hip fracture rate, decreased overall fracture rate and decreased colorectal cancer risk associated with combination estrogen plus progestin therapy (Table 1).

Table 1.

Women's Health Initiative reported risks and benefits of estrogen, estrogen plus progestin and combined studies.

Event	Estrogen only per 10,0000 women		Estrogen plus progestin per 10,000 women		Combined studies per 10,000 women
	Risk	Benefit	Risk	Benefit	Risk	Benefit
CHD
Overall stratified data	7 more			5 less
Age of initiation
– 50–59 years						2 less
– 60–69 years						1 less
– 70–79 years					19 more
Time since menopause
– <10 years				4 less		6 less
– 10–19 years		14 less	7 more		4 more
– >21 years	7 more	1 less	30 more		16 more
p-value for trend		0.15		0.05		0.02
Stroke	8 more Starting-age dependent		7 more Starting-age dependent
VTE	18 more		7 more
p-value for trend	p < 0.05		p < 0.05
Breast cancer	8 more			7 less
Colon cancer		8 less
Hip fracture and other		5 less		6 less
fractures		47 less		50 less
p-value for trend		<0.05		<0.05
Mortality Stratified data
Age of initiation
– 50–59 years		10 less		9 less		10 less
– 60–69 years	2 more		4 more		3 more
– 70–79 years	24 more		5 more		14 more
p-value for trend		0.05				0.02

Women's Health Initiative results: annual risks and benefits of estrogen or estrogen plus progestin therapy. CHD: Coronary heart disease; VTE: Venous thromboembolism. Data taken from [3,25,50].

Despite the wealth of evidence contrary to this single study and the fact that the paper was criticized heavily for a number of important reasons as shown in Box 1, the report quickly became the defining evidence against using hormone therapy. In August 2002, the US FDA released a statement acknowledging the WHI findings and a new consensus opinion emerged. In direct contrast to earlier guidelines, the new consensus opinion was that the risks associated with hormone therapy were unacceptably high and women were discouraged from using anything but short-term estrogen therapy for symptomatic relief.

Box 1.

Criticisms of the Women's Health Initiative.

The study was conducted mostly in elderly, largely asymptomatic, obese women, many with cardiovascular disease, and not an appropriate population to extrapolate its results to normal users of HRT who initiate therapy around menopause

The preparation/dose of HRT used was not appropriate for at least 70% of the population included in the trial

The study had an unacceptably high dropout in rates, high unblinding rate, less than adequate compliance (only approximately half or study subjects were on therapy at the end of trial)

Risks of treatment exaggerated by a media frenzy

The dismissal of estrogen as a long-term beneficial treatment for postmenopausal women was not universally accepted. The beneficial effects of estrogen on bone and urogenital health remained important reasons to continue estrogen therapy beyond the early years of menopause. And even more importantly, it was not easy to dismiss the numerous studies demonstrating significant protection from cardiovascular disease and dementia and lowered risks of mortality associated with long-term estrogen therapy in women. Detailed analysis of older studies and the WHI data revealed important findings that helped to explain why the studies had such disparate results [15 –17]. A major factor affecting the risk–benefit profile, that was appreciated before is the age of initiation of estrogen therapy. Estrogen therapy if started within 10 years of the menopause or generally between 50 and 60 years minimizes the risk of therapy

(Table 1). The risk–benefit profile of estrogen therapy is also strongly affected by the dose of estrogen and route of administration. Initiation of high-dose hormone therapy in elderly women as was done in the WHI would be expected to result in a high complication route.

Understanding menopause & the consequences of hypoestrogenism

The transition from reproductive status to menopausal status is a result of a substantial reduction in hormone production by the ovaries. Generally this is not a sudden or abrupt transition but occurs over a period of years. The word menopause literally means cessation of monthly menses and it is a natural consequence of aging. There is a wide age range in which menopause can occur but for most it occurs in the late 40s or early 50s. For many women, the symptoms accompanying the menopausal transition and early menopausal years can significantly disrupt their daily activities and their sense of well-being. The loss of estrogen has profound effects on a variety of tissues including urogenital, skeletal, vascular, skin, soft tissue, cardiovascular and CNS (Box 2). Whether or not estrogen therapy can be used safely to prevent or slow these changes is an important underlying question addressed by this article.

Overall risks of estrogen therapy: looking at the WHI & other studies

The original studies published by the WHI study group identified increased risk for a number of diseases that have, in later publications, been substantially changed or clarified. Presentation of the risks as defined by the original WHI data are included in this section. A summary of the risks and benefits of hormone therapy from both the early and later WHI publications is shown in Table 1 .

Box 2.

Reported effects of short- and long-term estrogen deficiency.

Vascular

Hot flushes

Night sweats

Headaches

Rapid heart beat/palpitations

Urogenital: vaginal

Itching

Dryness

Bleeding

Infection/discharge

Loss of elasticity

Shrinking

Urogenital: bladder

Urinary frequency Incontinence Urgency Increased UTIs

Skeletal

Bone loss Osteoporosis Hip fracture Vertebral fracture Back pain Height loss Joint pain Immobility

Skin & soft tissue

Decreased collagen content and elasticity

Thinning

Wrinkling

Redistribution of fat (from hips and thighs to abdomen)

Psychological

Mood disturbance

Depression

Fatigue

Irritability

Insomnia

Sexual

Dyspareunia Decreased libido

Cardiovascular

Accelerated atherosclerosis Cardiovascular disease

CNS

Dementia Memory loss Parkinson's Macular degeneration

Breast

Breast pain Atrophy

In the original (estrogen plus progestin) WHI study, in the overall study population, women treated with estrogen and progestin had a significant increased risk of blood clots (≥18 per 10,000 women/year) and an increased risk of stroke (≥8 per 10,000/year). Treatment with estrogen plus progestin also resulted in a higher risk of heart disease (≥7 per 10,000/year) and breast cancer (≥8 per 10,000/year) (Table 1) [3,18,19]. Combined HRT did not increase endometrial cancer or ovarian cancer risk but did increase the risk of abnormal vaginal bleeding requiring further testing (Table 1).

In the original (estrogen only) WHI study, there was an increased risks of blood clots (+7 per 10,000/year) and stroke (+12 per 10,000/year), no increased risk cardiovascular disease, or ovarian cancer. The use of estrogen only resulted in a lower breast cancer risk (-6 per 10,000/year) that continued to be lower (statistically significant) in a 10-year follow-up study (Table 1) [20].

WHI substudy

In a separate substudy of the WHI Memory Study (WHIMS) women aged 65 years and older (average age of initiation 71 years of age) reported the combination hormones had a modestly increased risk of developing dementia, compared with those taking placebo (45 per 10,000 vs 22 per 10,000) [21]. These findings again clarify the importance of early initiation of therapy and the increased risk (early harm) that can occur when starting hormone therapy in women over 65 years of age.

WHI: follow-up studies

In an 11-year follow-up study, the death rate in participants who received estrogen plus progestin for 5 years was 2.6 per 10,000 versus 1.3 per 10,000 per year in the group that took placebo (hazard risk [HR]: 1.96; 95% CI: 1.00–4.04; p = .049). A total of 24 % of the breast cancer patients who took HRT had tumors that spread to the lymph nodes, compared with just 16% of women taking placebos [22].

Million Women Study

The Million Women Study reported an increased risk of breast cancer in women currently using HRT. Women on current combination hormone therapy were at twofold increased risk of developing breast cancer, and current users of estrogen-only therapy had a 1.3-fold risk. The effects were similar for all doses, patterns of use, delivery methods and types of estrogen and progestogen [23].

Slovenia study

In a case–control study carried out in Slovenia, hormone therapy was associated with a reduced risk of breast cancer. A total of 784 cases and 709 controls aged 50–69 years were enrolled in the study. The reduced risk was highest in women on estrogen-only replacement therapy (odds ratio [OR]: 0.51; 95% CI: 0.30–0.87). Longer duration of HRT use did not result in a significant change in risk (1–5 years of HRT use: OR: 0.44; 95% CI: 0.26–0.73; >5 years of HRT use: OR: 0.51; 95% CI: 0.30–0.87). Risk factors for breast cancer identified included obesity, smoking and any first-degree relative with breast or ovarian cancer (Box 3) [24].

WHI: reduced risks–benefits associated with estrogen or estrogen plus progestin therapy

The WHI reported a reduced risk of colon cancer in women on combination therapy; this equates to six women per 10,000 women [3]. In the WHI study group that received estrogen only, estrogen replacement therapy did not effect the risk of colorectal cancer (Table 1) [18]. Other studies have found a slightly lower risk of colorectal cancer in women who have used estrogen replacement therapy for many years.

The WHI reported reductions of bone fractures (45 total fractures and five hip fractures per 10,000 women/year on combined HRT and six fewer hip and spine fractures and overall 56 fewer osteoporotic-related fractures in the estrogen alone arm), reduction in breast cancer (six less per 10,000/year) and reduced cardiovascular disease risk (five less per 10,000/year) [3,18,19]. The overall number of deaths was reduced by six (49 in the estrogen only arm and 54 on placebo) (Table 1) [3,18,19].

The overall (reduced) risk for developing osteoporotic fracture in the combination therapy group, or (reduced) risk for osteoporotic fracture, breast cancer, and coronary heart disease (CHD) in women on estrogen alone in the WHI ranges between −0.45 and −0.67%.

Factors that affect the risk–benefit profile of hormone therapy

When evaluating the WHI or any study in regards to the risk–benefit profile for hormone therapy, there are important factors (Box 4) that should be considered as they have a profound effect on the risks and benefits.

The timing hypothesis simply says that timing of initiation is critical to understanding the therapeutic actions of estrogen. This theory is supported by large numbers and varieties of studies that consistently demonstrate an optimum therapeutic window for initiation of estrogen therapy [15 –17]. The risks are increased if hormone therapy is started after 60 years or after more than 10 years since menopause (Figure 1 & Table 1) [18,25,26]. Many studies, including trials on bone loss, urogenital atrophy, dementia and cardiovascular diseases, also demonstrate that the optimum benefit profile is achieved by initiation of estrogen therapy during this window.

Figure 1.

Overall risk and benefit are profoundly affected by age of initiation of therapy.

Another important factor to consider in an overall risk–benefit assessment is the dose of estrogen. There is substantial evidence that while low-dose estrogen is effective for menopausal symptoms [27] and for the prevention of bone loss [28] and other specific diseases associated with the low menopausal levels of estrogen, lower doses are associated with fewer side effects [27] and lowered risks.

Use of transdermal estrogen therapy adds a specific additional safety benefit as it avoids the hepatic ‘first pass’ effect thus avoiding changes in clotting factors and sex hormone-binding globulin. Multiple studies show no increased risk of blood clots and venous thromboembolism, even in high-risk postmenopausal women when transdermal estrogen is used [29,30].

Box 3.

Risks versus benefits of hormone therapy as defined by Women's Heath Initiative.

If the major risks of hormone therapy as reported in the Women's Health Initiative (WHI) are combined, the total number of affected women/year in the primary studies was 41/10,000 in the combination arm and 19/10,000 in the estrogen only arm. This is a very low number and confirms the low risk associated with hormone therapy. The overall increased risk of developing breast cancer, blood clots, stroke or coronary heart disease associated with estrogen or estrogen plus progestin therapy in the WHI is between 0.19 and 0.41%. These risks appear to be lower if hormone therapy is started in women within 10 years of their menopause or by 59 years of age, the risk of cardiovascular disease drops substantially. Use of low-dose therapy and transdermal therapy reduces the risks of venous thromboembolic problems

The benefits of hormone therapy are substantial when therapy is started within 10 years of menopause or by 59 years of age

Box 4.

Important factors to lower the risks and side effects of hormone therapy.

Age of initiation: ideally therapy begins within 10 years of menopause or by 60 years of age

Low dose: use of low-dose estrogen with low-dose progestin when appropriate

Route of administration: transdermal administration has reduced risk of blood clotting (venous thromboembolism risk) compared with oral administration

Consideration of progestin: side-effect profile of various progestins may play a clinical role in selecting the optimum treatment regimen. The newer progestin drosperinone (derivative of spironolactone) maybe a good consideration in hypertensive women

Benefits of estrogen treatment if started within a therapeutic window

As with the risk profile, the age of initiation plays a large part in maximizing the benefit profile. There is a therapeutic window where estrogen therapy is optimal. After many years of estrogen deficiency, the tissue changes may be advanced and the benefit of estrogen may be dramatically reduced. The primary beneficial action of estrogen is in prevention, that is protecting healthy tissue (Box 5).

Cardiovascular protection

A total of 40 years of trials support the cardiovascular protection of estrogen [2,4 –13,31 –37]. A few of the studies are highlighted below:

The Nurses Health Study followed over 70,000 women for over 30 years. They reported that the 0.3 mg dose of conjugated estrogen therapy was associated with a significant reduction in both major coronary disease 0.58 (95% CI: 0.37–0.92) and stroke 0.43 (95% CI: 0.22–0.83) [5,8];

Both arms of the WHI reported a major reduction in new cases of diabetes during the 7-year trial. This is an important morbidity that was inexplicably omitted from the arbitrary and invalidated ‘global index’ used by the WHI authors [3,18];

The WHI Coronary-Artery Calcification (CAC) studied 1064 women, randomized on the estrogen only arm of the WHI between age 50–59 years, with computed tomography of the heart. After 7.4 years on the study, the women who had taken estrogen had a significantly lower calcium score (30–40% reduction) compared with those taking placebo. (83.1 vs 123.1; p = 0.02). Women adherent to therapy or at least 5 years had a 64% reduction in score (p = 0.001) [2]. An accompanying editorial wrote “The results of WHI-CAC are clear and striking: women randomly assigned to receive estrogen had significantly less coronary-artery calcification than women randomly assigned to receive placebo” [38];

In a randomized study of 222 postmenopausal women 45 years of age or older without preexisting cardiovascular disease but with low-density lipoprotein cholesterol levels ≥130 mg/dl, the average rate of progression of subclinical atherosclerosis was lower in those taking estradiol compared with controls. (-0.0017 mm/year vs 0.0036 mm/year); the difference between average progression rates was 0.0053 mm/year (95% CI: 0.0001–0.0105 mm/year; p = 0.046). In women not on lipid-lowering medication (n = 77), the difference between average rates of progression between placebo versus estradiol was even greater at 0.0147 mm/year (95% CI: 0.0055–0.0240; p = 0.002) [9];

In a meta-analysis of 23 randomized controlled trials, women starting HRT <10 years after menopause or <60 years of age had significantly lowered risk of cardiovascular disease (Table 2) [33];

Data from 23 trials, with 39,049 participants followed for 191,340 patient-years, concluded that hormone therapy reduced the risk of CHD events in younger postmenopausal women (OR: 0.68; 95% C I: 0.48–0.96). For older women, hormone therapy increased the risk the first year (OR: 1.47; 95% CI: 1.12–1.92), then reduced events after 2 years (OR: 0.79; 95% CI: 0.67–0.93) [37].

Table 2.

Cardiovascular heart disease events associated with HRT in older and younger women.

Hormone replacement versus control	OR (95% CI)
>10 years since menopause >60 years of age	1.03 (0.91–1.16)
<10 years since menopause <60 years of age	0.68 (0.48–0.96)
All ages	0.99 (0.88–1.11)
Younger versus older	0.66 (0.46–0.95)

Meta-analysis of 34 randomized trials; 191,340 woman-years. OR: Odds ratio. Data taken from [33].

Prevention of dementia & Alzheimer's disease

A therapeutic window for protection from dementia and Alzheimer's disease is reported in a large number of studies [39 –45]. As with cardiovascular disease, estrogen therapy initiated within 10 years of the menopause or in women <60 years of age has a higher benefit profile. Starting hormone therapy after 60–65 years needs to be done with caution. Use of a very low dose of hormone therapy and consideration of a transdermal administration is recommended.

In a prospective study in incident dementia among 1357 men and 1889 women (mean age around 73–74 years), the incidence among women increased after age 80 years and exceeded men of similar age. Women who used HRT had approximately a 50% reduction in risk (HR: 0.59; 95% CI: 0.36–0.96). Risk varied with years of use of hormones. Prior HRT use is associated with reduced risk of Alzheimer's disease, but there was no benefit with current HRT use unless such use had exceeded 10 years [39].

Box 5.

Benefits associated with hormone therapy.

Established benefits

Protection from bone loss and osteoporotic fracture

HRT is effective in fracture prevention [3,17,18] in a population unscreened for osteoporosis. This is in contrast to the other therapies used for osteoporosis that have been shown to be effective in populations that have been selected for high risk of fracture

Protection from urogenital atrophy, menopausal symptoms and hot flashes (estrogen is gold standard)

Consider those with strong evidence

Cardiovascular disease prevention

Prevention of dementia and Alzheimer's disease

Decreased mortality

Consider those with multiple studies

Decreased arthritis, colon cancer, memory loss, fat redistribution, tooth loss, Parkinson's disease and collagen loss in skin/wrinkling

Reduced mortality

Misconceptions still exist that cardiovascular disease is not a real problem for women, although it is estimated that one in two women will eventually die of heart disease or stroke, compared with one in 25 who will eventually die of breast cancer. Cardiovascular disease, particularly CHD and stroke, remains the leading killer of women in the USA and most developed countries [46,47]. Evidence suggests that postmenopausal women on hormone therapy, if started within the therapeutic window, have a lowered mortality. This is largely thought to be due to estrogen's cardiovascular protection.

A 10 year follow-up of the Nurses' Health Study including 48,470 postmenopausal women, reported that the age-adjusted relative risk of mortality form all causes in women who used estrogen at any time was 0.81. For cardiovascular mortality it was 0.68. After adjustment for other risk factors, the relative risks remained significant. The age-adjusted relative risk for cardiovascular mortality was 0.52 for current estrogen users and 0.77 for former users [102].

In a study utilizing data from 30 trials with 26,708 participants, hormone therapy significantly reduced mortality in the younger age group (OR: 0.61; 95% CI: 0.39–0.95) (Table 2) [37]. A secondary analysis of the WHI was performed to determine whether the effects of hormone therapy on the risk of cardiovascular disease and mortality vary by age or years since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger compared with older women in both the estrogen only and estrogen plus progestin trial. However, if both studies are combined, there is a significant trend towards a reduced mortality in younger versus older women; p-value for trend = 0.2 (Table 1) [25].

Table 3 shows a comparison of overall mortality rate with HRT in younger versus older postmenopausal women [37]. Table 4 is a comparison of the overall mortality rates in first decade menopausal women with HRT compared with lipid-lowering medication and aspirin [26,32,37,48,49]. Hormone therapy has the only statistically significant reduction in mortality for younger postmenopausal women.

Table 3.

Meta-analysis of total mortality associated with HRT in younger versus older postmenopausal women.

Hormone therapy versus controls	OR (95% CI)
>60 years of age Mean age 66 years	1.03 (0.87–1.16)
<60 years of age Mean age 54 years	0.61 (0.35–0.95)
All ages	0.98 (0.97–1.18)

Meta-analysis of 30 randomized trials; 119,118 women-years. OR: Odds ratio. Data taken from [37].

Table 4.

Comparison of overall mortality rates in first decade menopausal women with HRT compared with lipid-lowering medication and aspirin.

Outcome	Hormone therapy relative risk (95% CI)	Lipid-lowering therapy relative risk (95% CI)	Aspirin therapy relative risk (95% CI)
CHD	0.68 (0.48–0.96)	0.89 (0.69–1.09)	0.91 (0.80–1.03)
Total mortality	0.61 (0.39–0.95)	0.95 (0.62–1.46)	0.95 (0.85–1.06)

Decline in mortality therapy in women <60 years old and/or <10 years since menopause. CHD: Coronary heart disease. Data taken from [26,33,37,48,49].

Summary for individualizing hormone therapy: start with an accurate analysis of the risks & benefits

Contrary to the 2002 media-driven hype surrounding the initial presentation of the WHI, there are new, better considered and much more reassuring consensus statements on HRT. The new consensus statements on HRT are based both on reanalyses of published data from the WHI and on other extensive studies that must be included in an accurate risk–benefits analyses of HRT. The North American Menopause Society, The American Menopause Society and the International Menopause Society now concur that the risk–benefit ratio is in favor of HRT when initiated near menopause.

Estrogen is a medication that is reported to decrease overall mortality, cardiovascular disease, decrease osteoporosis fracture, urogenital atrophy and dementia. When timing of administration, dose of therapy and route of administration are considered, estrogen is associated with low risks. The decision to take or to recommend low-dose estrogen therapy for either short or long term, should include an accurate risk–benefit analysis:

Estrogen/hormone therapy is FDA-approved for the prevention of bone loss and urogenital atrophy and is approved as a treatment of menopausal symptoms. Multiple other studies support the protective effect of estrogen therapy on cardiovascular disease, dementia and overall mortality. Data suggests that hormone therapy is singularly effective in preventing cardiovascular disease for women when therapy is started within 10 years of their menopause;

The risks associated with low-dose estrogen/hormone therapy are very low if started within 10 years of menopause or under 60 years of age;

Women with cardiovascular or thrombotic risk factors, those initiating therapy after age 60 or >10 years since menopause, or those with significant obesity should consider low-dose transdermal estrogen/hormone therapy;

Initiation of hormone therapy for treatment of menopausal symptoms in early menopause or perimenopause is associated with low risk. Decisions regarding long-term use of hormone therapy should be based on an accurate risk–benefit analysis.

Future perspective

Within the next 5 years, the results of both the Early Versus Late Intervention Trial With Estradiol (ELITE) and Kronos Early Estrogen Prevention Study (KEEPS) trial will be available [1,101]. These trials are designed to further clarify the cardiovascular protective effects of estrogen replacement when given to women in their early menopause years compared with those that have 10 years or more of menopause. If these trials demonstrate a protective effect of estrogen against atherosclerotic plaque formation, a very compelling argument for initiating estrogen therapy in the early menopause will be difficult to counter. Estrogen is already an established medication for preventing bone loss and treating menopausal symptoms in the early menopause. It is also expected that new low-dose estrogen only and combination products with new progestins will be introduced that will increase the choices for the large numbers of women entering the menopause. It is anticipated that within the next decade, healthcare providers and the general public will have a better and a more accurate understanding of the low risks associated with hormone therapy and that the accepted benefits associated with the initiation of hormone therapy for post-menopausal women within 10 years of their menopause will include protection from cardiovascular disease, prevention of bone loss, and effective treatment of menopausal symptoms.

Executive summary

A review of over 40 years of scientific studies demonstrates that estrogen is a medication that can decrease mortality, cardiovascular disease, osteoporosis fracture, urogenital atrophy, colon cancer and dementia.

When timing of administration, dose of therapy and route of administration are considered, estrogen is associated with low risks and substantial benefits.

Contrary to the exaggerated risks associated with HRT that developed after the initial press reports held by the WHI writing group, the recent approach to hormone therapy is more balanced and evidence based.

WHI has been heavily criticized as the study was conducted in mostly elderly, largely asymptomatic, obese, diseased women and this is not an appropriate population to extrapolate results to normal users of HRT who initiate therapy around menopause.

The decision on whether or not to take HRT for either short symptom relief or for long-term therapy, should be based on an accurate risk–benefit analysis.

The loss of estrogen has profound effects on a variety of tissues including urogenital, skeletal, vascular, skin, soft tissue, cardiovascular and the CNS.

Using a low dose of estrogen, adding a low dose of progestin in women with a uterus, and considering a transdermal approach in high-risk patients, are important considerations.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

Harman

Brinton

Cedars

. KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric 8, 3–12 (2005).

Very important ongoing study (along with the ELITE study) investigating the cardiovascular protective effects of estrogen therapy in menopausal women

Manson

Allison

Rossouw

. Estrogen therapy and coronary-artery calcification. N. Engl. J. Med. 356, 2591–2602 (2007).

A follow-up study of women in the Women's Health Initiative demonstrating the cardiovascular protective effect of estrogen replacement

Rossouw

Anderson

Prentice

. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002).

Grodstein

Stampfer

. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog. Cardiovasc. Dis. 38, 199–210 (1995).

10.

Stampfer

Colditz

Willett

. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses' health study. N. Engl. J. Med. 325(11), 756–762 (1991).

11.

Mendelsohn

Karas

. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 340, 1801–1811 (1999).

12.

Mikkola

Clarkson

. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc. Res. 53, 605–619 (2002).

13.

Grodstein

Manson

Colditz

Willett

Speizer

Stampfer

. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease HRT users compared with non-users. Ann. Intern. Med. 133(12), 933–941 (2000).

14.

Hodis

Mack

Lobo

. Estrogen in the prevention of atherosclerosis a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 135, 939–953 (2001).

15.

Schisterman

Gallagher

Bairey Merz

. The association of hormone replacement therapy and coronary calcium as determined by electron beam tomography. J. Womens Health Gend. Based Med. 11, 631–638 (2002).

16.

Akhrass

Evans

Wang

. Hormone replacement therapy is associated with less coronary atherosclerosis in postmenopausal women. J. Clin. Endocrinol. Metab. 88, 5611–5614 (2003).

17.

Waters

Alderman

Hsia

. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA 288, 2432–2440 (2002).

18.

Herrington

Reboussin

Brosnihan

. Effects of estrogen replacement on the progression of coronaryartery atherosclerosis. N. Engl. J. Med. 343, 522–529 (2000).

19.

Farquhar

Marjoribanks

Lethaby

Suckling

Lamberts

. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst. Rev. 15(2), CD004143 (2009).

20.

Grodstein

Manson

Stampfer

Willett

. The discrepancy between observational studies and randomized trials of menopausal hormone therapy Ann. Intern. Med. 140, 764–765 (2004).

21.

Highlights the importance of early initiation of estrogen therapy in menopausal women

22.

Phillips

Langer

. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil. Steril. 83, 558–566 (2005).

23.

Critically examines the differences between the findings of the observational trials and the Women's Health Initiative

24.

Grodstein

Clarkson

Manson

. Understanding the divergent data on postmenopausal hormone therapy. N. Engl. J. Med. 348, 645–650 (2003).

25.

Examines the reasons for the divergent data on postmenopausal hormone therapy

26.

Anderson

Limacher

Assaf

. Effects of conjugated equine estrogens in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004).

27.

Jackson

LaCroix

Gass

. Effects of estrogen plus progesin on risk of fracture and bone mineral density: WHI randomized trial. JAMA 290, 1729–1738 (2003).

28.

LaCroix

Chebowski

Manson

. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy. JAMA 305(13), 1305–1314 (2011).

29.

Rapp

Espeland

Hogan

Jones

Dugan

. Baseline experience with Modified mini mental state exam: the Women's Health Initiative memory study (WHIMS). Aging Ment. Health 7(3), 217–223 (2003).

30.

Rowan

Chlebowski

Anderson

. For the WHI investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304(15), 1684–1692 (2010).

31.

Gray

. Breast cancer and hormone-replacement therapy: the Million Women Study. Lancet 362(9392), 1332 (2003).

32.

Cerne

Ferk

Leskosek

Gersak

. Hormone replacement therapy and some risk factors for breast cancer among Slovenian postmenopausal women. Climacteric (2011) (Epub ahead of print).

33.

Rossouw

Prentice

Manson

. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297, 1465–1477 (2007).

34.

Hodis

Mack

. Postmenopausal hormone therapy and cardiovascular disease in perspective. Clin. Obstet. Gynecol. 51(3), 564–580 (2008).

35.

Highlights the importance of early initiation of estrogen therapy in menopausal women for the prevention of cardiovascular disease

36.

Langer

. Efficacy, safety, and tolerability of low-dose hormone therapy in managing menopausal symptoms J. Am. Board Fam. Med. 22, 563–573 (2009).

37.

McKeever

McIlwain

Greenwald

. An estradiol matrix transdermal system for the prevention of postmenopausal bone loss Clin. Ther. 22, 845–857 (2000).

38.

Demonstrates the effectiveness of low-dose transdermal estrogen therapy in preventing bone loss in postmenopausal women

39.

Scarabin

Oger

Plu-Bureau

, Estrogen and Thromboembolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362(9382), 428–432 (2003).

40.

Canonico

Oger

Plu-Bureau

. For the estrogen and thromboembolism risk (ESTHER) study group hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 115, 840–845 (2007).

41.

Grodstein

Manson

Colditz

Willett

Speizer

Stampfer

. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann. Intern. Med. 133(12), 933–941 (2000).

42.

Important prospective observational trial demonstrating a protective effect of estrogen therapy on primary cardiovascular disease

43.

Manson

Hsia

Johnson

. For the Women's Health Initiative investigators. estrogen plus progestin and the risk of coronary heart disease. N. Engl. J. Med. 349, 523–534 (2003).

44.

Salpeter

Walsh

Greyber

Salpeter

. Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J. Gen. Intern. Med. 21(4), 363–366 (2006).

45.

Meta-analysis of multiple studies demonstrating the importance of early initiation of estrogen therapy for cardiovascular disease protection

46.

Hsia

Langer

Manson

. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch. Intern. Med. 166, 357–365 (2006).

47.

Barrett-Connor

Laughlin

. Hormone therapy and coronary artery calcification in asymptomatic postmenopausal women: the Rancho bernardo study. Menopause 12, 40–48 (2005).

48.

Stampfer

Colditz

Willett

. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses' Health Study. N. Engl. J. Med. 325, 756 (1991).

49.

Salpeter

Walsh

Greyber

Ormiston

Salpeter

. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J. Gen. Intern. Med. (7), 791–804 (2004).

50.

Mendelsohn

Karas

. HRT and the young at heart N. Engl. J. Med. 356, 2639–2641 (2007).

51.

Zandi

Carlson

Plassman

. Hormone replacement therapy and incidence of Alzheimer Disease in older women the cache county study. JAMA 288, 2123–2129 (2002).

52.

Tang

Jacobs

Stern

. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 348, 429–432 (1996).

53.

Carlson

Zandi

Plassman

. Hormone replacement therapy and reduced cognitive decline in older women: the Cache county study. Neurology 57, 2210–2216 (2001).

54.

LeBlanc

Janowsky

Chan

Nelson

. Hormone replacement therapy and cognition. Systematic review and meta-analysis. JAMA 285, 1489–1499 (2001).

55.

Reviews the protective effect of estrogen replacement therapy on cognition in postmenopausal women

56.

Fillenbaum

Hanlon

Landerman

Schmader

. Impact of estrogen use on decline in cognitive function in a representative sample of older community-resident women. Am. J. Epidemiol. 153, 137–144 (2001).

57.

Kawas

Resnick

Morrison

. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore longitudinal study of aging. Neurology 48, 1517–1521 (1997).

58.

Seshadri

Zornberg

Derby

Myers

Jick

Drachman

. Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease. Arch. Neurol. 58, 435–440 (2001).

59.

Resnick

Henderson

. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA 288(17), 2170–2172 (2002).

60.

Demonstrates the importance of early initiation of estrogen therapy for reducing the risk of Alzheimer's disease

61.

Mosca

Manson

Sutehrland

Langer

Manolio

Barrett-Connor

. A statement for healthcare professionals from the American heart association. cardiovascular disease in women. Circulation 96, 2468–2482 (1997).

62.

Walsh

Pignone

. Drug treatment of hyperlipidemia in women. JAMA 291(18), 2243–2252 (2004).

63.

Ridker

Cook

Lee

. A randomized tiral of low-dose aspirin in the pirmary prevention of cardiovascular disease in women. N. Engl. J. Med. 352, 1293–1304 (2005).

64.

Anderson

Limacher

Assaf

. Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004).

65.

Early Versus Late Intervention Trial with Estradiol: ELITE. MD, USA: National Institute on Aging (2007) www.clinicaltrials.gov/show/NCT00114517

66.

Center for Injury Prevention and Control. Leading causes of death in females in the USA (2006) www.cdc.gov/women/lcod/.

Individualizing Hormone Therapy to Minimize Risk: Accurate Assessment of Risks and Benefits

Abstract

Keywords

Strategies to minimize risk

Accurate evaluation of the WHI: risks & benefits

Understanding menopause & the consequences of hypoestrogenism

Overall risks of estrogen therapy: looking at the WHI & other studies

WHI substudy

WHI: follow-up studies

Million Women Study

Slovenia study

WHI: reduced risks–benefits associated with estrogen or estrogen plus progestin therapy

Factors that affect the risk–benefit profile of hormone therapy

Benefits of estrogen treatment if started within a therapeutic window

Cardiovascular protection

Prevention of dementia & Alzheimer's disease

Reduced mortality

Summary for individualizing hormone therapy: start with an accurate analysis of the risks & benefits

Future perspective

Footnotes

References