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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Menopause. Author manuscript; available in PMC 2009 October 2.
Published in final edited form as:
PMCID: PMC2756246
NIHMSID: NIHMS104848

Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society

Abstract

Objective

To update for both clinicians and the lay public the evidence-based position statement published by The North American Menopause Society (NAMS) in March 2007 regarding its recommendations for menopausal hormone therapy (HT) for postmenopausal women, with consideration for the therapeutic benefit-risk ratio at various times through menopause and beyond.

Design

An Advisory Panel of clinicians and researchers expert in the field of women’s health was enlisted to review the March 2007 NAMS position statement, evaluate new evidence through an evidence-based analysis, and reach consensus on recommendations. The Panel’s recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement. The document was provided to other interested organizations to seek their endorsement.

Results

Current evidence supports a consensus regarding the role of HT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered. This paper lists all these areas along with explanatory comments. Conclusions that vary from the 2007 position statement are highlighted. Addenda include a discussion of risk concepts, a new component not included in the 2007 paper, and a recommended list of areas for future HT research. A suggested reading list of key references is also provided.

Conclusions

Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women.

Keywords: Menopause, Perimenopause, Estrogen, Progestogen, Hormone therapy, Hormone replacement therapy, Vasomotor symptoms, Vaginal atrophy, Sexual function, Urinary health, Quality of life, Osteoporosis, Coronary heart disease, Venous thromboembolism, Stroke, Total mortality, Diabetes mellitus, Endometrial cancer, Breast cancer, Mood, Depression, Dementia, Cognitive decline, Premature menopause, Premature ovarian failure, Bioidentical hormones, Postmenopause, Women’s Health Initiative, NAMS

The North American Menopause Society (NAMS), a nonprofit scientific organization, published position statements on the role of menopausal hormone therapy (HT) in October 2002 (Menopause 2003;10:6–12), September 2003 (Menopause 2003;10:497–506), October 2004 (Menopause 2004;11:589–600), and March 2007 (Menopause 2007;14:168–182). The goal of these position statements was to clarify the benefit-risk ratio of HT—as either estrogen therapy (ET) or combined estrogen-progestogen therapy (EPT) —for both treatment of menopause-related symptoms and disease prevention at various times through menopause and beyond.

Because of the rapidly evolving data affecting the benefit-risk ratio of HT and clinical management of aging women, the NAMS Board of Trustees recognized a need to update its position statement and convened a fifth Advisory Panel to provide recommendations and also place therapeutic risks into perspective for both clinicians and the lay public. The Panel’s recommendations were reviewed and approved by the 2007–2008 NAMS Board of Trustees.

The Society’s position statements provide expert analysis of the totality of the data, including the most recent scientific evidence, in an attempt to assist healthcare providers in their practices. They do not represent codified practice standards as defined by regulating bodies and insurance agencies.

METHODOLOGY

An Advisory Panel of clinicians and researchers expert in the field of women’s health was enlisted to review the March 2007 NAMS position statement, evaluate literature published subsequent to the previous position statement of 2007, conduct an evidence-based analysis, and attempt to reach consensus on recommendations.

A comprehensive literature search was conducted using the database MEDLINE with appropriate search words—including menopause, perimenopause, postmenopause, estrogen, progestogen, hormone therapy, hormone replacement therapy, vasomotor symptoms, vaginal atrophy, sexual function, urinary health, quality of life, osteoporosis, coronary heart disease, venous thromboembolism, stroke, total mortality, diabetes mellitus, endometrial cancer, breast cancer, mood, depression, dementia, cognitive decline, premature menopause, premature ovarian failure, natural hormones, bioidentical hormones, and Women’s Health Initiative—to identify all new papers published subsequent to the 2007 position statement. Some relevant papers were also provided by the panelists. Limitations included a scarcity of randomized prospective study data on the consequences of long-term use of HT when prescribed for symptom management or disease risk-reduction outcomes. In addition, evidence-based medicine implies that recommendations be limited to the women for whom the studies are relevant. Although this goal is ideal in principle, it is impossible in practice, given that there will never be adequate randomized, controlled trials (RCTs) to cover all populations, eventualities, drugs, and drug regimens. The practice of medicine is ultimately based on the interpretation at any one time of the entire body of evidence currently available.

NAMS recognizes that no trial data can be used to extrapolate clinical management recommendations for all women and that no single trial should be used to make public health recommendations. There are many observational studies, but, because the trials within the Women’s Health Initiative (WHI) are for some outcomes the only large, relatively long-term RCTs to date of postmenopausal women using HT, there was a necessity to give these findings prominent consideration among all the studies reviewed in the development of this paper. It is also recognized that the WHI trials have several characteristics that limit the ability to generalize the findings. These include the use of only one formulation of estrogen (conjugated estrogens [CE]), alone or with one progestin (medroxyprogesterone acetate [MPA]), and only one route of administration (oral). Moreover, women studied in the WHI were older (mean age, 63 y) —mostly more than 10 years beyond menopause, with more risk factors than younger women who typically use HT for menopause symptoms. They were also largely without menopause-related symptoms.

After considering all the evidence, the Panel provided its recommendations, which were reviewed and approved by the NAMS 2007–2008 Board of Trustees as an official NAMS position statement.

This position statement focuses on the use of HT products available by prescription in the United States and Canada. A current listing of these products is posted on the NAMS Web site (http://www.menopause.org/edumaterials/hormoneprimer.aspx). This paper does not include other hormones, such as estrogen agonists/antagonists (formerly called selective estrogen-receptor modulators), those available without a prescription (including phytoestrogens), and testosterone therapy, the latter having been addressed in a previous NAMS position statement (Menopause 2005;12:497–511).

The most current published references regarding HT use are found at the end of this statement.

Terminology

NAMS strongly recommends use of uniform and consistent terminology when describing HT (see Table 1). Definitions for additional potentially confusing terminology used in this paper are found in Table 2.

TABLE 1
NAMS Menopausal HT Terminology
TABLE 2
NAMS Menopause Terminology

Understanding risk

Confusion can arise among healthcare providers, the lay public, and the media when general concepts of risk are discussed. Understanding HT risks in particular is critical to clinical decision making around menopause and beyond. Since these issues are crucial to a discussion of the role of HT in an individual woman, this position statement addresses risk concepts in a special addendum to this paper (see Addendum A).

BENEFITS AND RISKS OF HT

Use of HT should be consistent with treatment goals, benefits, and risks for the individual woman. The benefit-risk ratio for an individual woman continually changes with her age and her menopause-related symptoms (eg, vasomotor symptoms, sleep disturbance, vaginal atrophy, dyspareunia, or diminished libido), any of which may have an adverse impact on quality of life (QOL). Risk factors are related to a woman’s baseline disease risks; her age; age at menopause; cause of menopause; time since menopause; prior use of any hormone; types, routes of administration, and doses of HT used; and emerging medical conditions during treatment. Potential benefits and risks are described below for the relevant clinical outcomes.

Vasomotor symptoms

ET, with or without the use of a progestogen, is the most effective treatment for menopause-related vasomotor symptoms (ie, hot flashes and night sweats) and their potential consequences (eg, diminished sleep quality, irritability, and reduced QOL). Treatment of moderate to severe vasomotor symptoms remains the primary indication for HT. Every systemic ET and EPT product has regulatory agency approval for this indication.

Vaginal symptoms

ET is the most effective treatment for moderate to severe symptoms of vulvar and vaginal atrophy (eg, vaginal dryness, dyspareunia, and atrophic vaginitis). Many systemic ET and EPT products and all local vaginal ET products have regulatory agency approval for treating these vaginal symptoms. When HT is considered solely for this indication, local vaginal ET is generally recommended.

Sexual function

Relief of moderate to severe vaginal atrophy with systemic ET/EPT or local ET can be effective in relieving dyspareunia, a common cause of intercourse avoidance. One oral systemic ET product is approved in the United States for the treatment of pain with intercourse. HT is not recommended as the sole treatment of other problems of sexual function, including diminished libido.

Urinary health

Local ET may benefit some women with urge incontinence who have vaginal atrophy. Whether ET by any route is effective in treating overactive bladder is unclear. There is controversy as to whether local ET can improve certain cases of pure stress incontinence. On the other hand, systemic HT may worsen or provoke stress incontinence, perhaps related to changes in uterine volume or periurethral collagen.

The use of local ET may help reduce the risk of recurrent urinary tract infection (UTI) by a direct proliferative effect on the urethra and bladder epithelia helping to restore the acidic environment and normal lactobacillus-predominant flora of the vagina, thus discouraging colonization of the vagina by pathogens associated with UTI. Clinically, only ET administered by the vaginal route has been shown in an RCT to be effective in reducing the risk of recurrent UTI. However, no ET/EPT product has regulatory agency approval for any urinary health indication.

Change in body weight/mass

Body mass index (BMI) increases with age in midlife, with the peak BMI occurring between ages 50 and 59. At this time of life, other factors may also contribute to weight gain, including a decrease in energy expenditure and an increase in energy intake coupled with a decrease in metabolic rate. In women, the hormonal changes associated with the menopause transition can affect body composition and add to the tendency to gain weight. No statistically significant difference in mean weight gain or BMI has been demonstrated between women who use HT and those who do not.

Quality of life

Although no HT product has regulatory agency approval for enhancing QOL, an improvement in health-related quality of life (HQOL) can result with HT use because of decreased menopause symptoms and perhaps other mechanisms, including a possible elevation of mood that leads to a feeling of well-being. Whether HT improves HQOL in asymptomatic women is unknown. Nor are data available to determine the effect of HT on global QOL, the sense of well-being whether symptoms or physical impairments are present or absent.

Osteoporosis

Bone strength depends on both bone quality and bone mineral density (BMD). Changes in BMD alone may not always reflect fracture risk. There is RCT evidence that HT reduces postmenopausal osteoporotic fractures, including hip fractures, even in women without osteoporosis, although no HT product has regulatory agency approval for treatment of osteoporosis. Many systemic ET-containing products have regulatory agency approval for prevention of postmenopausal osteoporosis through long-term treatment; a current list of these products can be found on the NAMS Web site (http://www.menopause.org/edumaterials/otcharts.pdf).

Extended use of HT is an option for women who have established reduction in bone mass, regardless of menopause symptoms, for prevention of further bone loss and/or reduction of osteoporotic fracture when alternate therapies are not appropriate or cause side effects, or when the benefit-risk ratio of the extended use of alternate therapies is unknown.

Cardiovascular effects

Three primary cardiovascular effects are discussed: coronary heart disease (CHD), stroke, and venous thromboembolism (VTE).

Coronary heart disease

Most observational and preclinical studies support the potential benefits of systemic ET/EPT in reducing the risk of CHD. Most RCTs do not. However, it is now understood that the characteristics of women participating in observational studies are markedly different from those of women enrolled in RCTs, and that these demographic or biologic differences, or both, influence baseline cardiovascular risks and the effects of HT on cardiovascular risk.

Timing of initiation

Data indicate that the disparity in findings between observational studies and RCTs is related in part to the timing of initiation of HT in relation to age and proximity to menopause. Most women studied in observational studies were younger than age 55 and within 2 to 3 years after menopause at the time HT was initiated. On the other hand, women enrolled in RCTs were an average of 63 to 64 years old and more than 10 years beyond menopause. When analyzed by age and time since menopause at initiation of HT, RCTs are in general agreement with observational studies indicating that HT may reduce CHD risk when initiated in younger and more recently postmenopausal women. In a secondary analysis of WHI data, there was a statistically significant reduction in the composite endpoint of myocardial infarction, coronary artery revascularization, and coronary death in women who were randomized to ET during ages 50 to 59. Combined data from both the ET and EPT trials of the WHI showed a statistical trend of an HT effect relative to placebo on CHD by time since menopause, indicating that women who initiate HT more than 10 years beyond menopause are at increased risk for CHD, and those women who initiate HT within 10 years of menopause tend to have a decreased risk for CHD.

Duration of therapy

Observational studies suggest that longer duration of HT use is associated with reduced risk of CHD and mortality. The WHI RCTs and the WHI observational study suggest a pattern of lower risk of CHD among women who used HT for 5 or more years, but this is not conclusive.

Analysis of age groups in the WHI indicates that women younger than age 70 at the time of initiating HT have no increased risk of CHD with HT relative to placebo for up to the years of follow-up provided in this study. Although observational studies show decreased risk of CHD with much longer HT use, it is unlikely that RCTs will be conducted for these long periods of time to confirm these findings. This is not unique to HT and is true for other therapies used to prevent CHD, such as statin therapy, for which there are RCT data in women up to an average of only 5 years of use.

In contrast, in the short term, HT may possibly be associated with an increase in CHD risk among women who are more distant from menopause at the time of HT initiation.

Coronary artery calcium

Observational studies show that long-term use of HT is associated with less accumulation of coronary artery calcium, which is strongly correlated with atheromatous plaque burden and future risk of clinical CHD events. In an ancillary substudy of younger women (<60 y) in the WHI ET trial, after an average of 7 years of treatment, women who had been randomized to ET had lower levels of coronary artery calcium than those randomized to placebo. These findings suggest that ET commenced in recently postmenopausal women may slow the development of atherosclerotic plaque.

Stroke

Results of observational studies of the risk of stroke with HT have been inconsistent. Several indicated an increased risk of ischemic stroke (including the Nurses’ Health Study [NHS], the largest prospective study of HT and stroke), whereas others showed no effect on stroke risk. The WHI EPT and ET trials demonstrated an increased risk of ischemic stroke and no effect on risk of hemorrhagic stroke. In these trials, there were 8 additional strokes per 10,000 women per year of EPT use and 11 additional strokes per 10,000 women per year of ET use when the entire cohort was analyzed. In recent analyses that combined results from the WHI EPT and ET trials, younger women aged 50 to 59 years at study entry had no significant increase in risk of stroke (relative risk [RR], 1.13; 95% confidence interval [CI], 0.73–1.76).

In women randomized in the WHI within 5 years of menopause, there were 3 strokes per 10,000 women per year of EPT, which is not statistically significant. The excess risk of stroke observed in the WHI studies would fall into the rare category of risk. Stroke risk was not increased in the Heart and Estrogen/progestin Replacement Study (HERS) and Women’s Estrogen for Stroke Trial (WEST) secondary prevention trials. These observations are largely driven by effects of HT on ischemic stroke as neither ET nor EPT seems to affect the risk of hemorrhagic stroke. However, with few women in that age group in the WHI trials, the CI was wide, which means that there was insignificant statistical power to reach a conclusion. In the NHS, among women aged 50 to 59 years, the relative risk of stroke for current EPT users was elevated (RR, 1.34; 95% CI, 0.84–2.13), and was significantly increased for current users of ET (RR, 1.58; 95% CI, 1.06–2.37). Lower doses of estrogen (eg, 0.3 mg CE) were not associated with an increased risk in the NHS, although this was based on the relatively few women who were taking lower doses.

All studies indicate that postmenopausal HT is not effective for reducing the risk of a recurrent stroke among women with established cardiovascular disease (CVD) or for prevention of a first stroke, and may increase the rate of first strokes. HT cannot be recommended for the primary or secondary prevention of stroke.

Venous thromboembolism

Data from both observational studies and RCTs suggest an increased risk of VTE with oral HT. In the WHI trials, there were 18 additional VTEs per 10,000 women per year of EPT use and 7 additional VTEs per 10,000 women per year of ET use when the entire cohort was analyzed. VTE risk in RCTs emerges soon after HT initiation (ie, during the first 1–2 y), and the magnitude of the excess risk seems to decrease somewhat over time. In the WHI trials, the absolute excess VTE risk associated with either EPT or ET was lower in women who were younger than age 60 when randomized to HT than in older women who initiated HT after age 60. There were 7 additional VTEs per 10,000 women per year of EPT use and 4 additional VTEs per 10,000 women per year of ET use in women aged 50 to 59 years when randomized to HT. These risks fall into the rare category of risk.

Growing evidence suggests that women with a prior history of VTE or women who possess factor V Leiden are at increased risk for VTE with HT use. There are limited observational data suggesting lower risks of VTE with transdermal than with oral ET, but there are no RCT data on this subject. Lower doses of oral ET may also confer less VTE risk than higher doses, but no RCT data are available to confirm this assumption.

Cardiovascular effects conclusion

Pending additional data, HT is currently not recommended as a sole or primary indication for coronary protection in women of any age. Initiation of HT by women aged 50 to 59 years or by those within 10 years of menopause to treat typical menopause symptoms (eg, vasomotor, vaginal) does not seem to increase the risk of CHD events. There is emerging evidence that initiation of HT in early postmenopause may reduce CHD risk.

Diabetes mellitus

Aging is associated with an increased risk of non-insulin-dependent diabetes mellitus (DM), also known as adult-onset DM or type 2 DM. Although no HT product has regulatory agency approval to treat DM, large RCTs suggest that HT use reduces the new onset of type 2 DM. Women who received active treatment in the WHI EPT arm had an annualized incidence of DM requiring treatment of 0.61% versus 0.76% in placebo-treated women. This translates into a 21% reduction (hazard ratio [HR], 0.79; 95% CI, 0.67–0.93) in incident-treated DM, or 15 fewer cases per 10,000 women per year of therapy. A similar risk reduction was also noted in the HERS trial (HR, 0.65; 95% CI, 0.48–0.89). In the WHI ET trial, there was a 12% reduction (HR, 0.88; 95% CI, 0.77–1.01) in incident DM, or 14 fewer cases per 10,000 women per year of ET use. It is presently unclear whether the mechanism for this benefit is through lesser centripetal weight gain, reduced insulin resistance in women receiving combined EPT, or some other factor. Meta-analysis data suggest that HT is associated with an improvement in insulin resistance in postmenopausal women. There is inadequate evidence to recommend HT as the sole or primary indication for the prevention of DM in peri- or postmenopausal women.

Optimal glucose control is a prime goal of therapy in postmenopausal women who have type 2 DM. Some data suggest that postmenopausal women with type 2 DM who use ET may require lower doses of medications for glycemic control.

In women with type 2 DM, measures to reduce CHD risk are probably of greatest concern. If HT is prescribed, the specific agent, dose, regimen, and route of administration are especially important. Transdermal ET administration may offer advantages over the oral route. Serum triglyceride levels, which are often increased in patients who have DM, are not increased further with transdermal HT. Moreover, adverse alterations in blood pressure in both nonhypertensive and hypertensive women (although viewed as being a rare, if not idiosyncratic, reaction) have been reported only with oral therapy.

Endometrial cancer

The use of unopposed systemic ET in postmenopausal women with an intact uterus is associated with increased endometrial cancer risk related to the ET dose and duration of use. Standard-dose therapy (0.625 mg/d CE or the equivalent), when used for more than 3 years, is associated with up to a fivefold increased risk of endometrial cancer; if used for 10 years, the risk increases up to tenfold. This increased risk persists for several years after ET discontinuation. Because abnormal uterine bleeding usually brings the disease to medical attention early in its course, most cases do not reduce life expectancy. To negate this increased risk, adequate concomitant progestogen use is recommended for women with an intact uterus (see Progestogen indication, below, for more). There is limited evidence to support the use of HT in women with a history of early-stage (stages I and II) endometrial cancer.

Breast cancer

Diagnosis of breast cancer increases with EPT use beyond 3 to 5 years. In the WHI, this increased risk, in absolute terms, was in the rare category, being four to six additional invasive cancers per 10,000 women per year of EPT use for 5 or more years. In this trial, the increase in breast cancer risk was significantly related to EPT use before enrollment in the trial. Studies have not clarified whether the risk differs between continuous and sequential use of progestogen. Women in the ET arm of the WHI demonstrated no increase in risk of breast cancer after an average of 7.1 years of use, with six fewer cases of invasive breast cancer per 10,000 women per year of ET use, which is not statistically significant. The decrease in risk was observed in all three age groups studied (ie, starting ET at 50–59, 60–69, and 70–79 y). Available evidence suggests that ET for fewer than 5 years has little impact on breast cancer risk. Specific subgroups may be affected in different ways.

EPT and, to a lesser extent, ET, increase breast cell proliferation, breast pain, and mammographic density, and EPT may impede the diagnostic interpretation of mammograms.

The question of HT use in women with a history of breast cancer is unresolved. The limited epidemiologic evidence is mixed; there are no completed long-term RCTs.

Mood and depression

Several, but not all, studies of midlife women suggest that depressive symptoms are no more common after the menopause transition than before, and most midlife women do not experience more depressive symptoms than younger women do. However, the menopause transition itself, as well as early postmenopause, may be times of heightened vulnerability for a subgroup of women. For women without a history of prior depression, several community-based longitudinal studies have observed an increased risk for the onset of major or minor depression during perimenopause or early postmenopause compared with premenopause.

For postmenopausal women without clinical depression, evidence is mixed concerning the effects of HT on mood. Several small, short-term trials among middle-aged women suggested that HT use improves mood, whereas other trial results showed no change.

Progestogens in EPT may worsen mood in some women, possibly in those with a history of premenstrual syndrome, premenstrual depressive disorder, or clinical depression.

Only a few RCTs have examined the effects of HT in middle-aged or older women who have depression. Two small RCTs support the antidepressant efficacy of short-term ET in depressed perimenopausal women, whereas one RCT failed to demonstrate the antidepressant efficacy of ET in depressed women who were 5 to 10 years postmenopause. It is controversial whether ET might in some circumstances augment antidepressant effects of selective serotonin reuptake inhibitors.

In conclusion, although HT might have a positive effect on mood and behavior, HT is not an antidepressant and should not be considered as such. Evidence is insufficient to support its use for the treatment of depression.

Cognitive aging/decline and dementia

The term “cognition” describes the group of mental processes by which knowledge is acquired or used. It encompasses such mental skills as concentration, learning and memory, language, spatial abilities, judgment, and reasoning. Cognitive abilities change throughout life. With advancing age, performance tends to decline on many, but not all, cognitive tests. Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal aging. Alzheimer’s disease (AD) is the most common cause of dementia.

Memory complaints are common in midlife, but findings from well-characterized cohorts suggest that natural menopause has little effect on memory performance or other areas of cognitive function.

Limited, short-term clinical trial data among younger postmenopausal women suggest that EPT does not have a substantial impact on cognition after natural menopause. As inferred from very small, short-term clinical trials, ET initiated promptly after bilateral oophorectomy may improve verbal memory. Several observational studies report no association between age at menopause and AD. However, a case-control study found that bilateral oophorectomy before menopause was associated with an elevated risk of cognitive impairment or dementia, and this risk increased with younger age at oophorectomy.

For postmenopausal women over age 60, findings from several large, well-designed clinical trials indicate that ET/EPT does not improve memory or other cognitive abilities. One trial within WHI—the Women’s Health Initiative Memory Study (WHIMS) —of women aged 65 to 79 reported an increase in dementia incidence with ET and EPT use. The estimate of dementia cases attributed to HT was 12 per 10,000 persons per year of ET use and 23 per 10,000 persons per year of EPT use.

By way of contrast, a number of observational studies have reported associations between HT use and reduced risk of developing AD. HT exposure in observational studies is more likely to involve use by younger women closer to the age of menopause than by women eligible for the WHIMS trial. Speculatively, this difference implies an early window during which HT use might reduce AD risk. However, recall bias and the healthy-user bias may account for protective associations in the observational studies, many of which are difficult to interpret because of fairly small numbers of study participants. The window of opportunity perspective is supported by limited evidence, but no clinical trial data address long-term cognitive consequences of ET/EPT exposure during the menopause transition and early postmenopause. For women with AD, limited clinical results suggest that ET has no substantial effect on dementia symptoms or progression.

Based on these considerations, HT cannot be recommended at any age for the sole or primary indication of preventing cognitive aging or dementia. HT seems to increase the incidence of dementia when initiated in women age 65 and older. Similarly, HT should not be used to enhance cognitive function in younger postmenopausal women with intact ovaries, although very small clinical trials support the use of ET initiated immediately after menopause induced by bilateral oophorectomy. Available data do not adequately address whether HT used soon after menopause increases or decreases later dementia risk. Limited data do not support the use of HT as treatment of AD.

Premature menopause and premature ovarian failure

Women experiencing premature menopause (≤40 y) or premature ovarian failure are a distinctly different group than women who reach menopause at the typical age of 51.3 years. Premature menopause and premature ovarian failure are associated with a lower risk of breast cancer and earlier onset of osteoporosis and CHD. There are inadequate data regarding HT in these populations. Most reports suggesting an increased risk of CHD with early natural or surgical menopause also suggest a protective effect of HT. The existing data regarding HT in women experiencing menopause at the typical age should not be extrapolated to women experiencing premature menopause and initiating HT at that time. The risks attributable to HT use by these young women receiving HT are likely smaller and the benefits potentially greater than those in older women who commence HT at or beyond the typical age of menopause, although no trial data exist.

Total mortality

The WHI trials are consistent with observational studies indicating that HT may reduce total mortality when initiated soon after menopause. The WHI suggests that both ET and EPT reduce total mortality by 30% when initiated in women younger than age 60, and when data from the ET and EPT WHI RCTs were combined, that reduction with HT use was statistically significant. In contrast, HT was not associated with mortality reduction among women who initiated HT at age 60 or older.

PRACTICAL THERAPEUTIC ISSUES

Class versus specific product effect

Estrogens and progestogens share some common features and effects as well as potentially different properties. However, the current gold standard for determining the net clinical outcome for any given agent (alone or in combination) is through RCTs. In the absence of rigorous, head-to-head RCTs of various estrogens and progestogens, which are unlikely to be conducted, clinicians will be required to generalize the clinical trial results for one agent to all agents within the same hormonal family. On a theoretical basis, however, there are likely to be differences within each family based on factors such as relative potency of the compound, androgenicity, glucocorticoid effects, bioavailability, and route of administration.

Progestogen indication

The primary menopause-related indication for progestogen use is to negate the increased risk of endometrial cancer from systemic ET use. All women with an intact uterus who use systemic ET should also be prescribed adequate progestogen. Postmenopausal women without a uterus should generally not be prescribed a progestogen with systemic ET. A progestogen is generally not indicated when ET at the recommended low doses is administered locally for vaginal atrophy. Concomitant progestogen may improve the efficacy of low-dose ET in treating vasomotor symptoms. Some women who use EPT may experience undesirable side effects from the progestogen component.

Dosages

The lowest effective dose of estrogen consistent with treatment goals, benefits, and risks for the individual woman should be the therapeutic goal, with a corresponding low dose of progestogen added to counter the adverse effects of systemic ET on the uterus. Lower ET and EPT doses are better tolerated and may have a more favorable benefit-risk ratio than standard doses. However, lower doses have not been tested in long-term trials. Among the lower daily doses typically used when initiating systemic ET are 0.3 mg oral CE, 0.5 mg oral micronized 17β–estradiol, and 0.014 to 0.025 mg transdermal 17β-estradiol patch. The progestogen dose varies based on the progestogen used and the estrogen dose, typically starting at the lowest effective doses of 1.5 mg MPA, 0.1 mg norethindrone acetate, 0.5 mg drospirenone, or 50 to 100 mg micronized progesterone. Different doses may have different health outcomes. Some women may require additional local ET for persistent vaginal symptoms.

Routes of administration

There is currently no clear benefit of one route of administration versus another for systemic ET. Nonoral routes of administration may offer both advantages and disadvantages compared with the oral route, but the long-term benefit-risk ratio has not been demonstrated. Differences would be related to the role of the first-pass hepatic effect, the hormone concentrations in the blood achieved by a given route, and the biologic activity of ingredients. There is observational evidence that transdermal ET may be associated with a lower risk of deep vein thrombosis (DVT) than oral administration but no RCT evidence. Local ET administration is preferred when treating solely vaginal symptoms. Although minimal systemic absorption is possible, there are no reports of adverse effects.

Systemic progestogen is required for endometrial protection from unopposed ET. Topical progesterone is not recommended. (For more, see Progestogen indication, above.)

Regimens

There are multiple dosing regimen options for endometrial safety when adding progestogen to estrogen (see Table 3). Research is inadequate to endorse one regimen over another. Current data support the recommendation to minimize progestogen exposure through one of various options. There is insufficient evidence regarding endometrial safety to recommend as an alternative to standard EPT regimens the off-label use of long-cycle regimens, vaginal administration of progesterone, the contraceptive levonorgestrel-releasing intrauterine system, or low-dose estrogen without progestogen. If any of these approaches is used, close surveillance of the endometrium is recommended pending more definitive research, much of which is currently in progress.

TABLE 3
Terminology defining some types of EPT regimens

There are also multiple dosing regimen options from which to choose when using ET alone for women after hysterectomy; no data provide guidance on which regimen is best for all women.

“Bioidentical” hormones

NAMS recognizes that one area of confusion in clinical practice is so-called “bioidentical” hormone preparations. This term has been used to refer to many well-tested, regulatory agency–approved, brand-name HT products containing hormones chemically identical to hormones produced by women (primarily in the ovaries), such as 17β-estradiol or progesterone. However, the term is most often used to describe custom-made HT formulations (called “bioidentical hormone therapy,” or BHT) that are compounded for an individual according to a healthcare provider’s prescription.

Custom-compounding of HT may provide different doses, ingredients (eg, estriol), and routes of administration (eg, subdermal implants) that are not commercially available, and therapies without nonhormonal ingredients (eg, dyes, preservatives) that some women cannot tolerate. Use of BHT has escalated in recent years, often with the dose determined by salivary hormone testing, a procedure that has not been proven accurate or reliable. There may be risks to the patient. Custom-compounded formulations, including BHT, have not been tested for efficacy or safety; safety information is not consistently provided to patients with their prescription, as is required with commercially available HT; and batch standardization and purity may be uncertain. Custom-compounded drug formulations are not approved by any regulatory agency, although some active ingredients meet the specifications of the United States Pharmacopeia. Expense is also an issue, as many custom-compounded preparations are viewed as experimental drugs and are not covered by third-party payers, resulting in higher cost to the patient.

The US Food and Drug Administration (FDA) has ruled that compounding pharmacies have made claims about the safety and effectiveness of BHT unsupported by medical evidence and considered to be false and misleading (see statement at: www.fda.gov/cder/pharmcomp/default.htm). Pharmacies may not compound drugs containing estriol without an investigational new drug authorization. The FDA also states that there is no scientific basis for using saliva testing to adjust hormone levels.

NAMS recommends that filled prescriptions for BHT should have a patient package insert identical to that required for products that have regulatory agency approval. In the absence of efficacy and safety data for any specific prescription, the generalized benefit-risk ratio data of commercially available HT products should apply equally to BHT. There are individual women for whom the positives outweigh the negatives, but for the vast majority of women, regulatory agency–approved HT will provide appropriate therapy without assuming the risks and cost of custom preparations.

TREATMENT ISSUES

Pretreatment evaluation

HT should be considered only when an indication for therapy has been clearly identified, contraindications ruled out, and the potential individual benefits and risks adequately discussed with the woman so that an informed decision can be made. Before initiating HT, a comprehensive history and physical examination are essential. Mammography should be performed according to national guidelines and age, but preferably within the 12 months before initiation of therapy. Other specific examinations, such as bone densitometry, may be considered on a case-by-case basis.

Timing of initiation

Emerging data reveal that the timing of HT initiation in relation to proximity to menopause is important. How soon treatment is begun after menopause seems to have a strong impact on long-term health outcomes (eg, early initiation may reduce total mortality rates and CHD risk; see Coronary heart disease and Total mortality).

Women older than age 60 who experienced natural menopause at the typical age and have never used HT will have elevated baseline risks of CHD, stroke, VTE, and breast cancer, and HT should therefore not be initiated in this population without a compelling indication and only after appropriate counseling.

Premature menopause and premature ovarian failure are conditions associated with a lower risk of breast cancer and earlier onset of osteoporosis and CHD, but there are no clear data as to whether ET or EPT will affect morbidity or mortality from these conditions. Despite this, it is logical and considered safe to recommend HT for these younger women, at least until the typical age of natural menopause. Younger women with premature menopause might also require higher doses of HT for menopause symptom relief than the doses currently recommended for women aged 50 to 59 years.

Duration of use

One of the most challenging issues regarding HT is the duration of use. Existing data do not provide a clear indication as to whether longer duration of therapy improves or worsens the benefit-risk ratio.

Since the effects of HT on risk of breast cancer, CHD, stroke, total CVD, and osteoporotic fracture in perimenopausal women with moderate to severe menopause symptoms have not been established in RCTs, the findings from trials in different populations should, therefore, be extrapolated with caution. For example, data from large studies such as WHI and HERS should not be extrapolated to symptomatic postmenopausal women who initiate HT younger than age 50, as these women were not studied in those trials. WHI and HERS involved predominantly asymptomatic postmenopausal women aged 50 years and older (with mean ages of 63 y and 67 y, respectively), most of whom were 10 years or more beyond menopause, and HERS was conducted solely among women with known coronary artery disease. Results obtained from RCTs among women with established disease should not be extrapolated to women without such conditions. The data also should not be extrapolated to women experiencing premature menopause (≤40 y) and initiating HT at that time.

Extending HT use beyond the years around menopause may be a concern for healthcare providers and their patients. The benefits outweigh the risks in some women, whereas the reverse is true for others. Treatment recommendations are different for women experiencing premature menopause, those who are first users of HT, or women who are in their 60s and have previously used HT for several years.

Provided that the lowest effective dose is used, that the woman is well aware of the potential benefits and risks, and that there is clinical supervision, extending HT use for an individual woman’s treatment goals is acceptable under some circumstances, including:

  • The woman for whom, in her own opinion, the benefits of menopause symptom relief outweigh risks, notably after failing an attempt to stop HT
  • Regardless of symptoms, for further prevention of osteoporotic fracture and/or preservation of bone mass in the woman with established reduction in bone mass when alternate therapies are not appropriate, cause unacceptable side effects, or when the benefit-risk ratio of the extended use of alternate therapies is unknown.

Symptom recurrence

Vasomotor symptoms have an approximately 50% chance of recurring when HT is discontinued, independent of age and duration of use. The decision to continue HT should be individualized on the basis of severity of symptoms and current benefit-risk ratio considerations, provided the woman in consultation with her healthcare provider believes that continuation of therapy is warranted.

Discontinuance

Current data suggest that the rates of vasomotor symptom recurrence are similar when HT is either tapered or abruptly discontinued.

Data regarding breast cancer incidence after discontinuance are conflicting. An initial analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registries showed that the age-adjusted incidence rate of breast cancer in women in the United States fell sharply (by 6.7%) in 2003, as compared with the rate in 2002. The decrease was evident only in women who were aged 50 years or older and was more evident in cancers that were estrogen-receptor positive than in those that were estrogen-receptor negative. It was theorized that the drop could be related to the large number of women discontinuing HT following the termination of the EPT arm of the WHI. However, women in the WHI who had been assigned to EPT had an equivalent rate of cardiovascular events, fractures, and colon cancers as women who had been assigned to placebo when followed for 3 years after stopping HT. The only statistical difference was an increase in the rates of all cancer in women who had been assigned to EPT, with an excess of 30 cancers per 10,000 women per year of EPT, including a number of fatal lung cancers. There is an obvious disparity in these two reports; in the absence of any current conclusion, neither report should influence clinical decisions regarding current HT usage beyond those reported in this NAMS position statement.

Individualization of therapy is key

An individual risk profile is essential for every woman contemplating any regimen of EPT or ET. Women should be informed of known risks, but it cannot be assumed that benefits and risks of HT apply to all age ranges and durations of therapy. Women’s willingness to accept risks of HT will vary depending on their individual situations, particularly whether HT is being considered to treat existing symptoms or to lower risk for osteoporotic fractures that may or may not occur. Moreover, because incidence of disease outcomes increases with age and time since menopause, the benefit-risk ratio for HT is more likely to be acceptable for short-term use for symptom reduction in a younger population. In contrast, long-term HT or HT initiation in older women may have a less acceptable ratio. Women experiencing premature menopause, whether natural or induced, have a different situation, including increased risk of osteoporosis and CVD, and often more intense symptoms, than women reaching menopause at the typical age. Recommendations would be different for women who are first users of HT or women who are in their sixties and have previously used HT for several years. Each woman is unique, having her own risk profile and preferences. When HT is desired by patients, individualization of therapy is key to bringing health benefits with minimal risks, thereby enhancing QOL.

Variations from the May 2007 position statement

Each section of the May 2007 position statement has been updated using new studies and findings. The outline and contents have been reorganized, and the statement has been expanded to include additional areas of attention as indicated below.

  • Benefits and risks of HT
    • Vaginal symptoms (new)
    • Sexual function (new)
    • Urinary health (new)
    • Change in body weight/mass (new)
    • Cardiovascular effects (expanded and modified)
    • Breast cancer (expanded and modified)
    • Endometrial cancer (new)
    • Mood and depression (new and expanded)
    • Cognitive aging/decline and dementia (expanded)
    • Total mortality (new)
  • Practical therapeutic issues
    • Dosages (new)
    • Routes of administration (new)
    • Regimens (new)
    • “Bioidentical” hormones (expanded)
  • Treatment issues
    • Timing of initiation (new)
    • Duration of use (new)
    • Discontinuance (new)
    • Individualization of therapy (new)
  • Explaining HT risk (new)

Summary

The potential absolute risks published thus far for use of HT are low, particularly for the WHI ET trial, which provided evidence of considerable safety for 0.625 mg/day of oral CE. The risks in the WHI EPT trial were rare by the criteria of the Council for International Organizations of Medical Sciences (CIOMS), except for stroke, which was above the rare category. For women younger than age 50 or those at low risk of CHD, stroke, osteoporosis, breast cancer, or colon cancer, the absolute risk or benefit from ET or EPT is likely to be even smaller than that demonstrated in the WHI, although the relative risk at different ages may be similar. There is a growing body of evidence that each type of estrogen and progestogen, route of administration, and timing of therapy have distinct beneficial and adverse effects. Further research remains essential.

ADDENDUM A: EXPLAINING HT RISK

One lesson learned since the first announcement of WHI results is that healthcare providers see how vulnerable patients are to fear, leading to mistrust of healthcare providers and pharmaceutical products. Any fear is difficult to reason away, but ongoing communication of accurate information is essential to assist women in navigating the maze of information.

It is mandatory that clinicians caring for postmenopausal women understand the basic concepts of risk in order to communicate the potential benefits and risks of HT and other therapies. Risk is defined as the possibility or chance of harm; it does not indicate that harm will occur.

Calculating risk

Studies comparing outcomes with exposures attempt to identify or calculate the degree to which the outcome is associated with the exposure. But a statistical association between an exposure and an outcome does not necessarily mean that the exposure caused the outcome. A weak association or an association found only in a single study, particularly if it is not an RCT, should not be taken as concrete evidence of a true cause-and-effect relationship. For example, if a woman using EPT for a short length of time is diagnosed with breast cancer, EPT is unlikely to be the initiator of the breast cancer. It has been postulated that EPT may stimulate a preexisting cancer to grow more quickly, thereby being diagnosed earlier than if no hormone is used.

Risk calculations provide a basis by which healthcare providers and patients can weigh the pros and cons of initiating or continuing therapy. Understanding the concepts “relative risk,” “absolute risk,” and “statistical significance” is essential to interpreting risk.

Relative risk

Relative risk (RR) is a ratio—the rate of disease or of the outcome of interest in a group exposed to a potential risk factor or treatment divided by the rate of disease or outcome of interest in an unexposed group.

Rate describes the number of events, per number of individuals, per time interval (eg, 50/10,000/year). For example, if the annual rate of DVT in postmenopausal women who use oral ET is 22 per 10,000, and the annual rate in those who do not use ET is 11 per 10,000, the RR associated with ET use is:

equation M1

This means that compared with postmenopausal women not using ET, the risk of DVT for those using ET is twice that of a nonuser in the study.

RR less than 1.0 suggests that the exposure lowers risk. For example, an RR of 0.50 means there is a 50% less chance (or risk) of the outcome studied for those with versus those without the exposure. An RR of 0.3 means a 70% lower risk for the exposed group.

RR greater than 1.0 suggests the exposure increases risk. For example, an RR of 1.2 means there is a 20% increase in risk in the group with the exposure versus the group without the exposure. An RR of 2.0 means double the risk.

RR equal to 1.0 suggests that the exposure is associated with neither harm nor benefit versus the group without the exposure.

Absolute risk

The impact of RR on both a population and an individual basis depends on incidence (ie, the number of new cases). This can be quantified by the absolute risk (AR), which is the difference between the incidence rates in the exposed and unexposed groups—in other words, the risk difference. The AR quantifies the effect of an exposure on a population basis, providing a measure of its public health impact. AR is more clinically useful than RR in explaining risk to patients. For example, for the calculation presented above about the risk of DVT in women using oral ET, the AR is:

equation M2

This means that for every 10,000 postmenopausal women who use ET, there would be 11 additional cases of DVTs per year of ET use.

Statistical significance

When the statistical significance is, for example, P = 0.05, this means that there is a 5% chance that the study’s results are due to chance or coincidence and a 95% chance that they are truly related to the intervention being studied. Practical (or clinical) significance—whether the results are worth acting on—is entirely different. For example, a 6-month study of a weight loss treatment that includes a large number of patients might show statistically significant weight loss of 1 pound, which is not practically significant for someone who needs to lose 30 pounds. Thus, statistical significance does not always imply clinical relevance.

Risk levels

These numbers are often difficult to place in practical and personal perspective for many women and even for health professionals. The World Health Organization convened a panel of experts to develop standardized nomenclature for the description of risk for adverse events in recognition of this problem. In 1998, the CIOMS Task Force provided a strict form of risk categorization to assist healthcare professionals and the public when interpreting risk. CIOMS definitions are as follows:

  • Rare = Less than or equal to 10 per 10,000 per year
  • Very rare = Less than or equal to 1 per 10,000 per year

Numerical data

Using numerical data to understand and explain health risks can be extremely helpful, but can also be very confusing. Consider the following suggestions:

  • Instead of saying to the patient that there is a 20% chance of a side effect, say that 2 of every 10 women experience the side effect.
  • Avoid presenting data with different denominators (eg, “Headache developed in 6 of 500 women without the drug versus 20 in 1,000 with the drug”). Use the same denominator, such as 1,000 or 10,000 (eg, “Headache developed in 12 of every 1,000 women without the drug, compared to 20 of 1,000 women with the drug”).
  • Be aware of the hazard for the condition in the baseline population. Two times a very rare event is still a very rare event.
  • Recognize that even in the absence of an exposure (eg, HT use), there is a risk of development of all the diseases and other adverse health outcomes under consideration. In RCTs, that background inherent risk is represented by the rate of occurrence of the adverse health outcome in the placebo group.
  • Be careful not to overstate the risk, especially if the studied population has a low rate. Try to use the AR, not the RR (eg, instead of saying that a drug increases the risk of heart attack about twofold, say that 4 out of every 1,000 drug users have a heart attack per year compared to 2 out of every 1,000 nonusers).
  • Be aware that the meanings of high, moderate, low, very low, and minimal risk are not universal, so using these terms can lead to confusion.
  • Recognize that a woman’s values, education, needs, preferences, and emotions affect the way she considers risk, so data alone may not influence her. She may, for instance, view menopause as a natural event not calling for any medical intervention.
  • Understand that different adverse health outcomes may have the same risk, but women may fear certain outcomes more. For example, the risks of stroke and breast cancer from EPT are similar. However, although stroke may be more disabling, some women will fear breast cancer more.
  • Recognize that media reports of new medical research can lead to possible misunderstanding of the reported risks, often due to the practice of delivering news in small incomplete portions. Reported risks are often difficult to interpret by the media, sometimes because the findings are not clearly written by the researchers. Use tables or diagrams to help patients put risk into perspective.
  • Learn to communicate to different patients in different ways. Be sensitive as to whether patients seek numerical information, the healthcare provider’s honest opinion, or both.

ADDENDUM B: FUTURE RESEARCH

During this review, the following areas requiring further research were identified:

Pharmacology

  • Head-to-head comparison of different formulations, regimens, and doses of both estrogens and progestogens
  • Mechanism for the possible early harm from HT, including pharmacogenomics, polymorphisms, and prothrombotic markers
  • Endometrial effects from alternatives to standard progestogen regimens, such as a progestin-releasing intrauterine system or long-cycle progestogen regimens
  • Role of progestogens (eg, type and regimen) in breast cancer, CHD, and other disease outcomes
  • Benefits and risks of the most commonly used formulations of custom-compounded hormone therapy
  • Identification of the mechanisms that lead to the differential effects of HT on cardiovascular risk in younger, recently postmenopausal women versus older women well past menopause
  • Comparison of health outcomes of HT to other common long-term therapies

HT for women with underlying disease

  • Effects of estrogen on mood and interactions of estrogens with mood-altering drugs
  • Effect of simultaneous use of some estrogen agonists/antagonists with ET to modulate the long-term safety profile of ET
  • Incidence and course of potential influence of HT on CHD, breast cancer, dementia, and other health outcomes in women experiencing premature menopause
  • Short- and long-term effects of HT on neuropsychiatric disorders, such as Parkinson’s disease, depression, and schizophrenia
  • Short- and long-term effects of HT on sleep in general and sleep disorders, such as sleep apnea
  • Long-term effects of HT on primary and secondary prevention and progression of hearing loss and ophthalmologic disorders, such as cataract and age-related macular degeneration
  • Role of HT in postmenopausal women with underlying disease, such as DM and hypertension, and evaluation of the effects of HT on the adverse events associated with the disease itself
  • Factoring of other health outcomes, including QOL issues, into the composite benefit-risk ratio for HT
  • Determination of how women at risk of DVT and pulmonary embolism can best be identified as well as how hypercoagulability responsiveness to estrogens in general can be measured
  • Determination of any relationship between the menopause transition, HT, and various forms of arthritis and joint pain
  • Stricter evaluation of and potential influence of HT on domains of QOL through the menopause transition
  • Treatment of symptomatic perimenopause

Health outcomes for HT over the long term (>10 y)

  • Timing of initiation of HT relative to menopause with regard to cardiovascular, cognitive, and other health outcomes
  • Cause of the increase in stroke with HT and of increased CHD and breast cancer with EPT to better understand the pathophysiology of these events, to identify potential new treatments and ways to prevent their occurrence, and to identify a subgroup for whom HT would be less toxic
  • Long-term effects of HT on risk of AD and other forms of dementia, particularly when therapy is initiated before age 65
  • Health outcomes with osteoporosis drugs over the long term (>10 y)
  • Identification of subgroups of women for whom ET or EPT might be beneficial with regard to cardiovascular, DM, cognitive, and overall health outcomes
  • Creation of validated instruments for determining the impact of HT on both overall QOL and HQOL

Discontinuance

  • Benefit-risk ratio associated with an abrupt versus a tapering discontinuation of HT regimens, including the impact on bone density in the first 2 or 3 years after termination
  • Effects of HT discontinuation on health outcomes influenced by HT
  • Identification of the outcomes with differing schedules of withdrawal from HT (ie, abrupt vs tapered) and predictors of adverse effects of HT discontinuation

Acknowledgments

NAMS appreciates the contributions of the following members of the Advisory Panel: Wulf H. Utian, MD, PhD, DSc(Med) (Advisory Panel Chair), Consultant in Obstetrics, Gynecology, and Women’s Health Institute; Arthur H. Bill Professor Emeritus of Reproductive Biology, Case Western Reserve University School of Medicine, Consultant in Obstetrics, Gynecology, and Women’s Health Institute, Cleveland Clinic, Executive Director, The North American Menopause Society, Cleveland, OH; David F. Archer, MD, Professor of Obstetrics and Gynecology, Director, Conrad Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA; Gloria A. Bachmann, MD, Associate Dean for Women’s Health, Director of the Women’s Health Institute, Interim Chair, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ; J. Christopher Gallagher, MD, Professor of Medicine and Endocrinology, Creighton University Medical Center, Omaha, NE; Francine Grodstein, ScD, Associate Professor of Medicine, Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Julia R. Heiman, PhD, ABPP, Director, The Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, IN; Victor W. Henderson, MD, MS, Professor of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA; Howard N. Hodis, MD, Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology, Professor of Medicine and Preventive Medicine, Professor of Molecular Pharmacology and Toxicology, Director, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; Richard H. Karas, MD, PhD, Professor of Medicine, Vice Chairman, Department of Medicine, Associate Director, Molecular Cardiology Research Institute, Director, Women’s Heart Center, Tufts University School of Medicine, Tufts-New England Medical Center, Boston, MA; Rogerio A. Lobo, MD, Professor of Obstetrics and Gynecology, Columbia University, College of Physicians and Surgeons, New York, NY; JoAnn E. Manson, MD, DrPH, Professor of Medicine and Elizabeth F. Brigham Professor of Women’s Health, Harvard Medical School, Chief, Division of Preventive Medicine, Co-Director of the Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital, Boston, MA; Robert L. Reid, MD, Professor of Obstetrics and Gynecology, Chair, Division of Reproductive Endocrinology and Infertility, Queen’s University, Kingston, ON, Canada; Peter J. Schmidt, MD, Acting Chief, Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, MD; and Cynthia A. Stuenkel, MD, Clinical Professor of Medicine, University of California, San Diego, La Jolla, CA. The Society also acknowledges the editorial contributions of Charles L. Loprinzi, MD, Professor of Oncology, Mayo Clinic, Rochester, MN; Susan Wysocki, RNC, NP, FAANP, President and CEO, National Association of Nurse Practitioners in Women’s Health, Washington, DC; Pamela P. Boggs, MBA, NAMS Director of Education and Development; Kathryn J. Wisch, NAMS Managing Editor; and Angela M. Bilancini, NAMS Assistant Medical Editor. The position statement was reviewed and approved by the 2007–2008 NAMS Board of Trustees: Victor W. Henderson, MD, MS (President), Professor of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA; JoAnn V. Pinkerton, MD (President-elect), Professor of Obstetrics and Gynecology, Vice Chair for Academic Affairs, Director, Midlife Health Center, University of Virginia Health Sciences Center, Charlottesville, VA; Steven R. Goldstein, MD (Treasurer), Professor of Obstetrics and Gynecology, New York University School of Medicine, New York, NY; Cynthia A. Stuenkel, MD, (Secretary), Clinical Professor of Medicine, University of California, San Diego, La Jolla, CA; Thomas B. Clarkson, DVM, Professor of Comparative Medicine, Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC; Elizabeth Contestabile, RN, BScN, Nurse Educator, Shirley E. Greenberg Women’s Health Centre, The Ottawa Hospital, Riverside Campus, Ottawa, ON, Canada; Robert R. Freedman, PhD, Professor of Psychiatry and Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Risa Kagan, MD, Clinical Professor of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, East Bay Physicians Medical Group, Berkeley, CA; Nancy K. Reame, MSN, PhD, FAAN, Mary Dickey Lindsay Professor of Nursing and Director of DNSc Program, Columbia University School of Nursing, New York, NY; Marilyn L. Rothert, PhD, RN, FAAN, Professor Emerita and Dean Emerita, College of Nursing, Michigan State University, East Lansing, MI; Isaac Schiff, MD (Ex Officio), Joe Vincent Meigs Professor of Gynecology, Harvard Medical School, Chief, Vincent Memorial Ob/Gyn Service, Massachusetts General Hospital, Editor-in-chief, Menopause, Boston, MA; Leon Speroff, MD, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR; Wulf H. Utian, MD, PhD, DSc(Med) (Ex Officio), Arthur H. Bill Professor Emeritus of Reproductive Biology, Case Western Reserve University School of Medicine, Consultant in Obstetrics, Gynecology, and Women’s Health Institute Cleveland Clinic, Executive Director, The North American Menopause Society, Cleveland, OH; and Michelle P. Warren, MD, Medical Director, Center for Menopause, Hormonal Disorders, and Women’s Health, Professor of Medicine, Obstetrics and Gynecology, Wyeth Professor of Women’s Health, Columbia Presbyterian Medical Center, New York, NY.

Footnotes

This NAMS position statement has been endorsed by the American Medical Women’s Association, The Endocrine Society, the National Association of Nurse Practitioners in Women’s Health, the National Women’s Health Resource Center, and the Society for Obstetricians and Gynaecologists of Canada.

Disclosure: For the Advisory Panel, Dr. Archer reports: Consultant—Agile, Berlex, Johnson & Johnson, Novo Nordisk, Organon, Ortho-McNeil, Pfizer, Solvay TAP, Wyeth; Research support—Barr/Duramed, Berlex, Organon, Solvay, Warner Chilcott, Wyeth; Speaker—Novo Nordisk, Organon, Wyeth. Dr. Bachmann reports: Research support—Bayer, Boehringer-Ingelheim, Boston Scientific, Duramed, GlaxoSmithKline, Johnson & Johnson, Novartis, Novo Nordisk, Pfizer, Procter & Gamble, Roche, Wyeth, Xanodyne. Dr. Gallagher reports: Research support—Pfizer, Wyeth; Speaker—Wyeth. Dr. Grodstein reports: No significant financial relationships. Dr. Heiman reports: Consultant—Bayer, Boehringer-Ingelheim; Research support—Bayer, Pfizer. Dr. Henderson reports: No significant financial relationships. Dr. Hodis reports: No significant financial relationships. Dr. Karas reports: Consultant, Speaker—Wyeth. Dr. Lobo reports: Consultant—Bayer, Organon, Ortho, Solvay, Wyeth. Dr. Manson reports: No significant financial relationships. Dr. Reid reports: Advisory board—Wyeth Canada; Consultant—Bayer Canada, Procter & Gamble; Speaker—Bayer Canada, Wyeth Canada. Dr. Schmidt reports: Research support—Novogen, Watson. Dr. Stuenkel reports: Consultant—Upsher-Smith, Wyeth; Speaker—Upsher-Smith, Eli Lilly. Dr. Utian reports: Advisory board/consultant— GlaxoSmithKline, Merck, Orcas; Consultant—Barr/Duramed, Berlex, Bionovo, Bradley, Depomed, KV Pharmaceuticals, Novo Nordisk, Organon, Pfizer, Gerson Lehman, Goldman Sachs, Johnson & Johnson, McKinsey, Wyeth.

For members of the NAMS Board of Trustees who are not serving on the Advisory Panel, Dr. Clarkson reports: Member—Council on Hormone Education; Speaker—Wyeth; Advisory board—Wyeth. Ms. Contestabile reports: No significant financial relationships. Dr. Freedman reports: Consultant—Alexza, Duramed, GlaxoSmithKline, Novartis, Organon, Pfizer, Vela, Wyeth; Research support—Glaxo-SmithKline, National Institutes of Health, Organon. Dr. Goldstein reports: Advisory board—Eli Lilly, GlaxoSmithKline, Merck, Pfizer, Procter & Gamble. Dr. Kagan reports: Advisory board—Merck; Consultant—Merck, Roche/GlaxoSmithKline; Research support—Amgen, Aventis, Eli Lilly, Novartis, Procter & Gamble, Roche/GlaxoSmithKline, Wyeth; Speaker—Merck, Roche/GlaxoSmithKline. Dr. Pinkerton reports: Consultant—Boehringer-Ingelheim, Duramed, Merck, Novo Nordisk; Research support—Solvay, Wyeth; Speaker—Merck. Dr. Reame reports: Consultant—Cypress Bioscience, Procter & Gamble; Research support—Novo Nordisk, Procter & Gamble. Dr. Rothert reports: No significant financial relationships. Dr. Schiff reports: Advisory Board—Pause, the consumer magazine of the American College of Obstetricians and Gynecologists; Editor-in-chief-Menopause, the official journal of The North American Menopause Society. Dr. Speroff reports: Consultant—Warner Chilcott; Research support—Barr, Berlex, Organon, Wyeth. Dr.Warren reports: Research support—GlaxoSmithKline, Novartis, Solvay, Wyeth; Speaker—Bayer, Bradley, Wyeth.

For additional contributors not previously mentioned, Ms. Bilancini reports: No significant financial relationships. Ms. Boggs reports: No significant financial reltionships. Dr. Loprinzi reports: No significant financial relationships. Ms. Wisch reports: No significant financial relationships. Ms. Wysocki reports: Advisory Board—Berlex, Digene, Duramed, Esprit, Eli Lilly, Merck, Organon, Ortho Women’s Health, Wyeth.

SUGGESTED READING

Suggested Reading is categorized into primary headings.

Position statements and guidelines

  • AACE Menopause Guidelines Revision Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract. 2006;12:315–337. [PubMed]
  • Council for International Organizations of Medical Sciences (CIOMS) Guidelines for Preparing Core Clinical-Safety Information on Drugs. 2nd ed. Geneva, Switzerland: CIOMS; 1998.
  • The North American Menopause Society. Recommendations for estrogen and progestogen use in peri- and postmenopausal women: October 2004 position statement of The North American Menopause Society. Menopause. 2004;11:589–600. [PubMed]
  • The North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause. 2007;14:357–369. [PubMed]
  • The North American Menopause Society. The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society. Menopause. 2005;12:497–511. [PubMed]

Menopause-related symptoms

  • Anderson GL, Limacher M, Assaf AR, et al. for the 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. 2004;291:1701–1712. [PubMed]
  • Aslan E, Bagis T, Kilicdag EB, Tarim E, Erkanli S, Kuscu E. How best is to discontinue postmenopausal hormone therapy: immediate or tapered? Maturitas. 2007;56:78–83. [PubMed]
  • Barnabei VM, Cochrane BB, Aragaki AK, et al. for the Women’s Health Initiative Investigators. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol. 2005;105:1063–1073. [PubMed]
  • Barnabei VM, Grady D, Stovall DW, et al. Menopausal symptoms in older women and the effects of treatment with hormone therapy. Obstet Gynecol. 2002;100:1209–1218. [PubMed]
  • Brunner RL, Gass M, Aragaki A, et al. for the Women’s Health Initiative Investigators. Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized clinical trial. Arch Intern Med. 2005;165:1976–1986. [PubMed]
  • Cirillo DJ, Wallace RB, Rodabough RJ, et al. Effect of estrogen therapy on gallbladder disease. JAMA. 2005;293:330–339. [PubMed]
  • Danforth KN, Townsend MK, Lifford K, Curhan GC, Resnick NM, Grodstein F. Risk factors for urinary incontinence among middle-aged women. Am J Obstet Gynecol. 2006;194:339–345. [PMC free article] [PubMed]
  • Genazzani AR, Gambacciani M. Effect of climacteric transition and hormone replacement therapy on body weight and body fat distribution. Gynecol Endocrinol. 2006;22:145–150. [PubMed]
  • Greenspan SL, Resnick NM, Parker RA. The effect of hormone replacement on physical performance in community-dwelling elderly women. Am J Med. 2005;118:1232–1239. [PubMed]
  • Haimov-Kochman R, Barak-Glantz E, Arbel R, et al. Gradual discontinuation of hormone therapy does not prevent the reappearance of climacteric symptoms: a randomized prospective study. Menopause. 2006;13:370–376. [PubMed]
  • Hays J, Ockene JK, Brunner RL, et al. for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003;348:1839–1854. [PubMed]
  • Hendrix SL, Cochrane BB, Nygaard IE, et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA. 2005;293:935–948. [PubMed]
  • Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and responses to recent evidence. JAMA. 2004;291:47–53. [PubMed]
  • Hlatky MA, Boothroyd D, Vittinghoff E, Sharp P, Whooley MA. for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. JAMA. 2002;287:591–597. [PubMed]
  • Holzer G, Riegler E, Honigsmann H, Farokhnia S, Schmidt JB. Effects and side-effects of 2% progesterone cream on the skin of peri-and postmenopausal women: results from a double-blind, vehicle-controlled, randomized study. Br J Dermatol. 2005;153:626–634. [PubMed]
  • Leiblum SR, Koochaki PE, Rodenberg CA, et al. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women’s International Study of Health and Sexuality (WISHeS) Menopause. 2006;13:46–56. [PubMed]
  • National Institutes of Health. State-of-the-Science Panel. National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann Intern Med. 2005;142:1003–1013. [PubMed]
  • Nielsen TF, Ravn P, Pitkin J, Christiansen C. Pulsed estrogen therapy improves postmenopausal quality of life: a 2-year placebo-controlled study. Maturitas. 2006;53:184–190. [PubMed]
  • Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA. 2005;294:183–193. [PubMed]
  • Ohayon MM. Severe hot flashes are associated with chronic insomnia. Arch Intern Med. 2006;166:1262–1268. [PubMed]
  • Paganini-Hill A, Corrada MM, Kawas CH. Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study. Menopause. 2006;13:12–18. [PMC free article] [PubMed]
  • Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med. 2004;19:791–804. [PMC free article] [PubMed]
  • Sowers M, Zheng H, Tomey K. Changes in body composition in women over six years at midlife: ovarian and chronological aging. J Clin Endocrinol Metab. 2007;92:895–901. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Wolff EF, Narayan D, Taylor HS. Long-term effects of hormone therapy on skin rigidity and wrinkles. Fertil Steril. 2005;84:285–288. [PubMed]

Skeletal effects

  • Barrett-Connor E, Wehren LE, Siris ES, et al. Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study. Menopause. 2003;10:412–419. [PubMed]
  • Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. 2008;336:262–266. [PMC free article] [PubMed]
  • Cirillo DJ, Wallace RB, Wu L, Yood RA. Effect of hormone therapy on risk of hip and knee joint replacement in the Women’s Health Initiative. Arthritis Rheum. 2006;54:3194–3204. [PubMed]
  • Cauley JA, Robbins J, Chen Z, et al. for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1729–1738. [PubMed]
  • Chen Z, Bassford T, Green SB, et al. Postmenopausal hormone therapy and body composition—a substudy of the estrogen plus progestin trial of the Women’s Health Initiative. Am J Clin Nutr. 2005;82:651–656. [PubMed]
  • Ettinger B, Ensrud KE, Wallace R, et al. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol. 2004;104:443–451. [PubMed]
  • Gallagher JC, Rapuri PB, Haynatzki G, Detter JR. Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. J Clin Endocrinol Metab. 2002;87:4914–4923. [PubMed]
  • Greendale GA, Espeland M, Slone S, Marcus R, Barrett-Connor E. for the PEPI Safety Follow-up Study (PSFS) Investigators. Bone mass response to discontinuation of long-term hormone replacement therapy: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Safety Follow-Up Study. Arch Intern Med. 2002;162:665–672. [PubMed]
  • Greenspan SL, Emkey RD, Bone HG, et al. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137:875–883. [PubMed]
  • Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. J Bone Miner Res. 2006;21:817–828. [PubMed]
  • The North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause. 2006;13:340–367. [PubMed]
  • Thorneycroft IH, Lindsay R, Pickar JH. Body composition during treatment with conjugated estrogens with and without medroxyprogesterone acetate: analysis of the women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial. Am J Obstet Gynecol. 2007;137:e1–e7. [PubMed]
  • The Writing Group for the PEPI trial. Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/ Progestin Interventions (PEPI) trial. JAMA. 1996;276:1389–1396. [PubMed]
  • Yates J, Barrett-Connor E, Barlas S, Chen YT, Miller PD, Siris ES. Rapid loss of hip fracture protection after estrogen cessation: evidence from the National Osteoporosis Risk Assessment. Obstet Gynecol. 2004;103:440–446. [PubMed]

Cardiovascular effects and diabetes

  • Angerer P, Kothny W, Stork S, von Schacky C. Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial. J Am Coll Cardiol. 2000;36:1786–1796. [PubMed]
  • Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized, controlled trial. Arterioscler Thromb Vasc Biol. 2001;21:262–268. [PubMed]
  • Bairey Merz CN, Johnson BD, Sharaf BL, et al. for the WISE Study Group. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE Study. J Am Coll Cardiol. 2003;41:413–419. [PubMed]
  • Barrett-Connor E, Mosca L, Collins P, et al. for the Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–137. [PubMed]
  • Bonds DE, Lasser N, Qi L, et al. The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial. Diabetologia. 2006;49:459–468. [PubMed]
  • Canonico M, Oger E, Plu-Bureau G, et al. for the Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women. Circulation. 2007;115:840–845. [PubMed]
  • Cherry N, Gilmour K, Hannaford P, et al. The ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomized placebo controlled trial. Lancet. 2002;360:2001–2008. [PubMed]
  • Clarke SC, Kelleher J, Lloyd-Jones H, Slack M, Schofiel PM. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study. Br J Obstet Gynaecol. 2002;109:1056–1062. [PubMed]
  • Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med. 2006;166:772–780. [PubMed]
  • Cushman M, Kuller LH, Prentice R, et al. for the Women’s Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573–1580. [PubMed]
  • de Lecinana MA, Egido JA, Fernandez C, et al. for the PIVE Study Investigators of the Stroke Project of the Spanish Cerebrovascular Diseases Study Group. Risk of ischemic stroke and lifetime estrogen exposure. Neurology. 2007;68:33–38. [PubMed]
  • Ferrara A, Quesenberry CP, Karter AJ, Njoroge CW, Jacobson AS, Selby JV. for the Northern California Kaiser Permanente Diabetes Registry. Current use of unopposed estrogen and estrogen plus progestin and the risk of acute myocardial infarction among women with diabetes: the Northern California Kaiser Permanente Diabetes Registry, 1995–1998. Circulation. 2003;107:43–48. [PubMed]
  • Grady D, Herrington D, Bittner V, et al. for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II) JAMA. 2002;288:49–57. [PubMed]
  • Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933–941. [PubMed]
  • Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on stroke in the Women’s Health Initiative: a randomized trial. Circulation. 2006;113:2425–2434. [PubMed]
  • Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522–529. [PubMed]
  • Herrington DM, Vittinghoff E, Lin F, et al. for the HERS Study Group. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS) Circulation. 2002;105:2962–2967. [PubMed]
  • Hodis HN, Mack WJ, Azen SP, et al. for the Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group. Hormone therapy and the progression of coronary artery atherosclerosis in postmenopausal women. N Engl J Med. 2003;349:535–545. [PubMed]
  • Hodis HN, Mack WJ, Lobo RA, et al. for Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939–953. [PubMed]
  • Hsia J, Langer RD, Manson JE, et al. fop the Women’s Health Initiative Investigators. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357–365. [PubMed]
  • Hsia J, Simon JA, Lin F, et al. Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study. Circulation. 2000;102:2228–2232. [PubMed]
  • Hu FB, Grodstein F, Hannekens CH, et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med. 1999;159:1061–1066. [PubMed]
  • Hulley S, Furberg C, Barrett-Connor E, et al. for the HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II) JAMA. 2002;288:58–66. [PubMed]
  • Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med. 2002;137:273–284. [PubMed]
  • Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1–19. [PubMed]
  • Lemaitre RN, Weiss NS, Smith NL, et al. Esterified estrogen and conjugated equine estrogen and the risk of incident myocardial infarction and stroke. Arch Intern Med. 2006;166:399–404. [PubMed]
  • Lobo RA. Evaluation of cardiovascular event rates with hormone therapy in healthy early postmenopausal women. Arch Intern Med. 2004;164:482–484. [PubMed]
  • Lokkegaard E, Jovanovic Z, Heitmann BL, et al. The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy. Maturitas. 2006;53:226–233. [PubMed]
  • Mack WJ, Hameed AB, Xiang M, et al. Does elevated body mass modify the influence of postmenopausal estrogen replacement on atherosclerosis progression: results from the Estrogen in the Prevention of Atherosclerosis Trial. Atherosclerosis. 2003;168:91–98. [PubMed]
  • Mack WJ, Slater CC, Xiang M, Shoupe D, Lobo RA, Hodis HN. Elevated subclinical atherosclerosis associated with oophorectomy is related to time since menopause rather than type of menopause. Fertil Steril. 2004;82:391–397. [PubMed]
  • Manson JE, Allison MA, Rossouw JE, et al. for the WHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602. [PubMed]
  • Manson JE, Bassuk SS. Invited commentary: hormone therapy and risk of coronary heart disease—why renew the focus on the early years of menopause? Am J Epidemiol. 2007;166:511–517. [PubMed]
  • Manson JE, Hsia J, Johnson KC, et al. for the Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523–534. [PubMed]
  • Margolis KL, Bonds DE, Rodabough RJ, et al. for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. [PubMed]
  • Ouyang P, Michos ED, Karas RH. Hormone replacement therapy and the cardiovascular system lessons learned and unanswered questions. J Am Coll Cardiol. 2006;47:1741–1753. [PubMed]
  • Prentice RL, Langer RD, Stefanick ML, et al. for the Women’s Health Initiative Investigators. Combined analysis of Women’s Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. Am J Epidemiol. 2006;163:589–599. [PubMed]
  • Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477. [PubMed]
  • Salpeter SR, Walsh JM, Greyber E, Salpeter EE. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006;21:363–366. [PMC free article] [PubMed]
  • Salpeter SR, Walsh JM, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab. 2006;8:538–554. [PubMed]
  • Scarabin P-Y, Oger E, Plu-Bureau G. for the EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428–432. [PubMed]
  • Simon JA, Hsia J, Cauley JA, et al. Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS) Circulation. 2001;103:638–642. [PubMed]
  • Smith NL, Heckbert SR, Lemaitre RN, et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA. 2004;292:1581–1587. [PubMed]
  • Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345:1243–1249. [PubMed]
  • for the Heart and Estrogen/progestin Replacement Study research group. Vittinghoff E, Shlipak MG, Varosy PD, et al. Risk factors and secondary prevention in women with heart disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2003;138:81–89. [PubMed]
  • for the Women’s Health Initiative Investigators. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA. 2003;289:2673–2684. [PubMed]
  • Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288:2432–2440. [PubMed]
  • Yeboah J, Reboussin DM, Waters D, Kowalchuk G, Herrington DM. Effects of estrogen replacement with and without medroxyprogesterone acetate on brachial flow-mediated vasodilator responses in postmenopausal women with coronary artery disease. Am Heart J. 2007;153:439–444. [PubMed]
  • Yosefy C, Feingold M. Continuation of hormone replacement therapy during acute myocardial infarction after the Women’s Health Initiative study. Is it the time for change? Int J Cardiol. 2006;107:293–298. [PubMed]

Cancers

  • American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion. No. 337: noncontraceptive uses of the levonorgestrel intrauterine system. Obstet Gynecol. 2006;107:1479–1482. [PubMed]
  • Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006;55:103–115. [PubMed]
  • for the Women’s Health Initiative Investigators. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1739–1748. [PubMed]
  • Ayhan A, Taskiran C, Simsek S, Sever A. Does immediate hormone replacement therapy affect the oncologic outcome in endometrial cancer survivors? Int J Gynecol Canc. 2006;16:805–808. [PubMed]
  • for the Gynecologic Oncology Group Study. Barakat RR, Bundy BN, Spirtos NM, Bell J, Mannel RS. Randomized double-blind trial of estrogen replacement therapy versus placebo in stage I or II endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2006;24:587–592. [PubMed]
  • for the Million Women Study Collaborators. Beral V, Bull D, Reeves G. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005;365:1543–1551. [PubMed]
  • for the Million Women Study Collaborators. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–427. [PubMed]
  • for the Million Women Study Collaborators. Beral V. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet. 2007;369:1703–1710. [PubMed]
  • Bernstein L. The risk of breast, endometrial and ovarian cancer in users of hormonal preparations. Basic Clin Pharmacol Toxicol. 2006;98:288–296. [PubMed]
  • Chan JA, Meyerhardt JA, Chan AT, Giovannucci EL, Colditz GA, Fuchs CS. Hormone replacement therapy and survival after colorectal cancer diagnosis. J Clin Oncol. 2006;24:5680–5686. [PubMed]
  • Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med. 2006;166:1027–1032. [PubMed]
  • for the Women’s Health Initiative Investigators. Chlebowski RT, Anderson G, Pettinger M, et al. Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy. Arch Intern Med. 2008;68:370–377. [PubMed]
  • for the Women’s Health Initiative Investigators. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA. 2003;289:3243–3253. [PubMed]
  • for the Women’s Health Initiative Investigators. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med. 2004;350:991–1004. [PubMed]
  • Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 2005;11:545–560. [PubMed]
  • Conner P. Breast response to menopausal hormone therapy—aspects on proliferation apoptosis, and mammographic density. Ann Med. 2007;39:28–41. [PubMed]
  • Doherty JA, Cushing-Haugen KL, Saltzman BS, et al. Long-term use of postmenopausal estrogen and progestin hormone therapies and the risk of endometrial cancer. Am J Obstet Gynecol. 2007;197:139, e1–e7. [PubMed]
  • Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606–616. [PubMed]
  • Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114:448–454. [PubMed]
  • Glass AG, Lacey JV, Jr, Carreon JD, Hoover RN. Breast cancer incidence, 1980–2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst. 2007;99:1152–1161. [PubMed]
  • Grady D, Vittinghoff E, Lin F, et al. Effect of ultra-low-dose transdermal estradiol on breast density in postmenopausal women. Menopause. 2007;14(3 pt 1):391–396. [PubMed]
  • Greendale GA, Reboussin BA, Sie A, et al. Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Ann Intern Med. 1999;130:262–269. [PubMed]
  • Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med. 1999;106:574–582. [PubMed]
  • Lacey JV, Jr, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer [erratum in: JAMA 2002;288:2544] JAMA. 2002;288:334–341. [PubMed]
  • Li CI, Daling JR. Changes in breast cancer incidence rates in the United States by histologic subtype and race/ethnicity, 1995 to 2004. Cancer Epidemiol Biomarkers Prev. 2007;16:2773–2780. [PubMed]
  • Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA. 2003;289:3254–3263. [PubMed]
  • Li CI, Malone KE, Porter PL, et al. Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas. Cancer Epidemiol Biomarkers Prev. 2008;17:43–50. [PubMed]
  • Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estrogen-only therapy. Obstet Gynecol. 2006;108:1354–1360. [PubMed]
  • for the Women’s Health Initiative Mammogram Density Study Investigators. McTiernan A, Martin CF, Peck JD, et al. Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women’s Health Initiative randomized trial. J Natl Cancer Inst. 2005;97:1366–1376. [PubMed]
  • 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. [PubMed]
  • Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670–1674. [PubMed]
  • Shantakumar S, Terry MB, Paykin A, et al. Age and menopausal effects of hormonal birth control and hormone replacement therapy in relation to breast cancer risk. Am J Epidemiol. 2007;165:1187–1198. [PubMed]
  • for the WHI Investigators. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295:1647–1657. [PubMed]
  • Tamimi RM, Byrne C, Colditz GA, Hankinson SE. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2007;99:1178–1187. [PubMed]
  • Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med. 2006;166:1483–1489. [PubMed]
  • Van Duijnhoven FJB, Peeters PHM, Warren RML, et al. Postmenopausal hormone therapy and changes in mammographic density. J Clin Oncol. 2007;25:1323–1328. [PubMed]
  • Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonor-gestrel-releasing hormone system (LNG-IUS)—a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol. 2006;125:9–28. [PubMed]
  • for the Stockholm Breast Cancer Study Group. von Schoultz E, Rutqvist LE. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97:533–535. [PubMed]
  • Weiss LK, Burkman RT, Cushing-Hauger KL, et al. Hormone-replacement therapy regimens and breast cancer risk. Obstet Gynecol. 2002;100:1148–1158. [PubMed]

Brain effects

  • Almeida OP, Lautenschlager NT, Vasikaran S, Leedman P, Gelavis A, Flicker L. A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life. Neurobiol Aging. 2006;27:141–149. [PubMed]
  • Archer JS, Love-Geffen TE, Herbst-Damm KL, Swinney DA, Chang JR. Effect of estradiol versus estradiol and testosterone on brain-activation patterns in postmenopausal women. Menopause. 2006;13:528–537. [PubMed]
  • for the PERF Study Group. Bagger YZ, Tanko LB, Alexandersen P, Qin G, Christiansen C. Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause. 2005;12:12–17. [PubMed]
  • Brandes JL. The influence of estrogen on migraine: a systematic review. JAMA. 2006;295:1824–1830. [PubMed]
  • Bromberger JT, Matthews KA, Schott LL, et al. Depressive symptoms during the menopausal transition: the Study of Women’s Health Across the Nation (SWAN) J Affect Disord. 2007;103:267–272. [PMC free article] [PubMed]
  • Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health. 2001;91:1435–1442. [PubMed]
  • Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006;63:385–390. [PubMed]
  • for the Women’s Health Initiative Memory Study Investigators. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women:Women’s Health Initiative Memory Study. JAMA. 2004;291:2959–2968. [PubMed]
  • Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006;63:375–382. [PubMed]
  • Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry. 2004;61:62–70. [PubMed]
  • Fuh JL, Wang SJ, Lee SJ, Lu SR, Juang KD. A longitudinal study of cognition change during early menopausal transition in a rural community. Maturitas. 2006;53:447–453. [PubMed]
  • 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. [PubMed]
  • Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry. 2005;76:103–105. [PMC free article] [PubMed]
  • Henderson VW, Espeland MA, Hogan PE, et al. Prior use of hormone therapy and incidence of Alzheimer’s disease in the Women’s Health Initiative Memory Study. Neurology. 2007;68 Suppl 1:A205.
  • Henderson VW, Guthrie JR, Dudley EC, Burger HG, Dennerstein L. Estrogen exposures and memory at midlife: a population-based study of women. Neurology. 2003;60:1369–1371. [PubMed]
  • Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology. 2000;54:295–301. [PubMed]
  • Henderson VW, Sherwin BB. Surgical versus natural menopause: cognitive issues. Menopause. 2007;14(Part 2 of 2):572–579. [PubMed]
  • Henderson VW. Estrogen-containing hormone therapy and Alzheimer’s disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience. 2006;138:1031–1039. [PubMed]
  • Herlitz A, Thilers P, Habib R. Endogenous estrogen is not associated with cognitive performance before, during, or after menopause. Menopause. 2007;14(3 pt 1):425–431. [PubMed]
  • Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience. 2000;101:485–512. [PubMed]
  • Kang JH, Weuve J, Grodstein F. Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology. 2004;63:101–107. [PubMed]
  • Lebrun CE, van der Schouw YT, de Jong FH, Pols HA, Grobbee DE, Lamberts SW. Endogenous oestrogens are related to cognition in healthy elderly women. Clin Endocrinol (Oxf) 2005;63:50–55. [PubMed]
  • Lord C, Buss C, Lupien SJ, Pruessner JC. Hippocampal volumes are larger in postmenopausal women using estrogen compared with past users, never users and men: a possible window of opportunity effect. Neurobiol Aging. 2008;29:95–101. [PubMed]
  • Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2008:CD003122. [PubMed]
  • MacLennan AH, Henderson VW, Paine BJ, et al. Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study. Menopause. 2006;13:28–36. [PubMed]
  • Maki PM, Gast MJ, Vieweg AJ, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology. 2007;69:1322–1330. [PubMed]
  • Maki PM. A systematic review of clinical trials of hormone therapy on cognitive function: effects of age at initiation and progestin use. Ann NY Acad Sci. 2005;1052:182–197. [PubMed]
  • Meyer PM, Powell LH, Wilson RS, et al. A population-based longitudinal study of cognitive functioning in the menopausal transition. Neurology. 2003;61:801–806. [PubMed]
  • Morrison MF, Kallan MJ, Ten Have T, Katz I, Tweedy K, Battistini M. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry. 2004;55:406–412. [PubMed]
  • Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41:338–343. [PubMed]
  • Women’s Health Initiative Study of Cognitive Aging Investigators. Resnick SM, Maki PM, Rapp SR, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab. 2006;91:1802–1810. [PubMed]
  • Schiff R, Bulpitt CJ, Wesnes KA, Rajkumar C. Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo controlled pilot cross-over study. Psychoneuroendocrinology. 2005;30:309–315. [PubMed]
  • Schmidt PJ, Haq NA, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry. 2004;161:2238–2244. [PubMed]
  • Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol. 2000;183:414–420. [PubMed]
  • Sherwin BB. Surgical menopause, estrogen, and cognitive function in women: what do the findings tell us? Ann NY Acad Sci. 2005;1052:3–10. [PubMed]
  • for the Women’s Health Initiative Memory Study Investigators. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004;291:2947–2958. [PubMed]
  • Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58:529–534. [PubMed]
  • Soares CN, Arsenio H, Joffe H, et al. Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life. Menopause. 2006;13:780–786. [PubMed]
  • Stewart DE, Rolfe DE, Robertson E. Depression, estrogen, and the Women’s Health Initiative. Psychosomatics. 2004;45:445–447. [PubMed]
  • Thurston RC, Joffe H, Soares CN, Harlow BL. Physical activity and risk of vasomotor symptoms in women with and without a history of depression: results from the Harvard Study of Moods and Cycles. Menopause. 2006;13:553–560. [PubMed]
  • Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. Estrogen therapy and risk of cognitive decline: results from the Women’s Estrogen for Stroke Trial (WEST) Am J Obstet Gynecol. 2005;192:387–393. [PubMed]
  • Yaffe K, Krueger K, Cummings SR, et al. Effect of raloxifene on the prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry. 2005;162:683–690. [PubMed]
  • for the Cache County Memory Study Investigators. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002;288:2123–2129. [PubMed]

Dosages

  • Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril. 2001;75:1080–1087. [PubMed]
  • Bachmann GA, Schaefers M, Uddin A, Utian WH. Lowest effective transdermal 17β-estradiol dose for relief of hot flushes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2007;110:771–779. [PubMed]
  • Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet. 2002;360:942–944. [PubMed]
  • Brynhildsen J, Hammar M. Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women. Menopause. 2002;9:137–144. [PubMed]
  • Diem S, Grady D, Quan J, et al. Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years. Menopause. 2006;13:130–138. [PubMed]
  • Cochrane HT Study Group. Farquhar CM, Marjoribanks J, Lethaby A, Lamberts Q, Suckling JA. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2005:CD004143. [PubMed]
  • Hashimoto M, Miyao M, Akishita M, et al. Effects of long-term and reduced-dose hormone replacement therapy on endothelial function and intima-media thickness in postmenopausal women. Menopause. 2002;9:58–64. [PubMed]
  • Johnson SR, Ettinger B, Macer JL, Ensrud KE, Quan J, Grady D. Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol. Obstet Gynecol. 2005;105:779–787. [PubMed]
  • 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. JAMA. 2002;287:2668–2676. [PubMed]
  • Pickar JH, Yeh I-T, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril. 2003;80:1234–1240. [PubMed]
  • Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17β-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA. 2003;290:1042–1048. [PubMed]
  • Simon JA, Bouchard C, Waldbaum A, Utian W, Zborowski J, Snabes MC. Low dose of transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2007;109:588–596. [PubMed]
  • Speroff L, Whitcomb RW, Kempfert NJ, Boyd RA, Paulissen JB, Rowan JP. Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms. Obstet Gynecol. 1996;88:587–592. [PubMed]
  • Utian WH, Burry KA, Archer DF, et al. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients: the Esclim Study Group. Am J Obstet Gynecol. 1999;181:71–79. [PubMed]
  • Utian WH, Gass MLS, Pickar JH. Body mass index does not influence response to treatment, nor does body weight change with lower doses of conjugated estrogens and medroxyprogesterone acetate in younger, postmenopausal women. Menopause. 2004;11:306–314. [PubMed]
  • 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. [PubMed]
  • Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in women’s international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007;335:239–251. [PMC free article] [PubMed]
  • Waetjen LE, Brown JS, Vittinghoff E, et al. The effect of ultralow-dose transdermal estradiol on urinary incontinence in postmenopausal women. Obstet Gynecol. 2005;106:946–952. [PMC free article] [PubMed]
  • Yaffe K, Vittinghoff E, Ensrud KE, et al. Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life. Arch Neurol. 2006;63:945–950. [PubMed]

Evaluating HT risk

  • for the WHI Investigators. Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036–1045. [PubMed]
  • Hodis HN, Mack WJ. Postmenopausal hormone therapy in clinical perspective. Menopause. 2007;14:944–957. [PubMed]
  • for the Writing Group for the Women’s Health Initiative Investigators. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initaitive randomized controlled trial. JAMA. 2002;288:321–333. [PubMed]
  • Trussell J, Jordan B. Reproductive health risks in perspective. Contraception. 2006;73:437–439. [PubMed]
  • US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med. 2005;142:855–860. [PubMed]
  • 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. JAMA. 2002;288:321–333. [PubMed]