Menopause and the Impact of Hormone Replacement on Chronic Disease: Current Controversies and Findings
December 2014
Volume 5, Issue 4


Welcome from Tamara L. Wexler, MD, PhD

Menopause, and Its Symptoms and Sequelae
Menopause refers to the time when ovarian reproductive function ends—when a woman’s ovaries stop producing eggs and making the hormones estrogen and progesterone. Menopause tends to occur in a woman’s late 40s to early 50s, but varies by country, with an average age of 51 years in the United States; it is retrospectively diagnosed 1 year after a woman’s last menstrual period. (This EndoScan does not include studies related to premature ovarian failure nor to menopause that occurs abruptly after oophorectomy, chemotherapy or radiation.)

During the years leading up to menopause, vasomotor symptoms such as hot flashes and night sweats often occur. A host of other symptoms have been reported in association with perimenopause (see Perimenopause and Menopause Overview). The hormone changes that occur after menopause increase the risk for osteoporosis and fracture, and heart disease.

A Brief History of Hormone Replacement Therapy
For a period of time, hormone replacement therapy (HRT) was widely recommended for its use in helping prevent not only symptoms of perimenopause but also chronic conditions such as osteoporosis, dementia, and heart disease. This changed with the publication of the Heart and Estrogen/Progestin Replacement Study (HERS), and, particularly, reports from the Women’s Health Initiative (WHI) in 2002.

Prior to reports from the WHI, it was thought that hormone treatment after menopause not only alleviated vasomotor and other symptoms, but reduced the risk of cardiovascular disease, osteoporosis, dementia, some cancers, and sexual dysfunction, based on existing (largely basic and epidemiological) evidence.1

HERS was the first large randomized controlled trial (RCT) to investigate the impact of HRT on women with preexisting heart disease. HERS examined the result of combined estrogen plus progestin (E+P) treatment in 2,763 women (average age 67) over 4 years.2 Given previous observations, it was expected that HRT would show a protective effect. However, the study found that HRT did not reduce the incidence of myocardial infarction or coronary heart disease-related death (though cholesterol profiles improved); furthermore, the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) increased.

The WHI was designed to look at the impact of estrogen plus progestin (E+P) or estrogen alone in 27,000 women without known coronary heart disease (CHD), over 9 years.3 In 2002, the E+P study was terminated early due to evidence that the risks of treatment outweighed the benefits; an increase in CHD, stroke, and PE (and, in 2003, dementia and breast cancer) was seen.4-6 In 2004, the E alone study was stopped due to lack of evidence for cardioprotection, as well as an increase risk of stroke.7 With the reports from the WHI that HRT was associated with an increased risk of heart disease, stroke, breast cancer (for combined treatment), and cognitive decline, research and clinical practice dramatically changed.

The studies did find benefits to hormone replacement, including prevention of osteoporosis and alleviation of symptoms. Further study and analysis has led to the current recommendation that HRT not be used for chronic disease prevention, but that short-term use for symptomatic relief (such as of vasomotor symptoms) is indicated in certain patients. Current indications approved by the U.S. Food and Drug Administration for HRT are treatment of symptoms such as vasomotor symptoms, and prevention of osteoporosis, with the warning that HRT be prescribed at the lowest dose effective, and for the least amount of time indicated by individual patient situation.8

The topic of postmenopausal hormone therapy remains controversial, given the discrepancies between study results. Ongoing studies are investigating the benefits and risks of different types of HRT in particular populations, with a focus on which women will derive the most benefit, and whether timing and type of HRT affect the risk-benefit ratio.

Current Controversies and Effects on Chronic Disease
This EndoScan reviews current thinking and controversies regarding postmenopausal hormone therapy (referred to as postmenopausal HT or as HRT), focusing on the impact on cardiovascular health and coronary heart disease; breast cancer; and cognition and mood.a It is important to reiterate that, while symptomatic relief is not within the scope of this review, there is general agreement that HRT alleviates vasomotor symptoms, and the benefits of HRT may outweigh health risks in some patients at some times.

In this EndoScan, we discuss the current U.S. Preventive Services Task Force (USPSTF) guidelines for HRT use,9 a review of evidence for the timing hypothesis (Hodis et al, 2014),10 and 3 recent papers looking at the effect of HRT on markers for cardiovascular disease in recently postmenopausal women (Harman et al, 2014),11 the impact of baseline hormones on HRT-related breast cancer risk (Farhat et al, 2013),12 and a review of studies of the impact of HRT on cognition and mood (Fischer et al, 2014).13 Within the commentary on these papers, we review relevant literature within each area.

  • The Timing Hypothesis

There has been increasing attention paid to the timing and duration of HRT, and whether those factors account for some of the disparities between studies—ie, whether there is a window of time after menopause when HRT can decrease certain health risks in a way not seen later. The 2013 update to USPSTF recommendations on HRT concluded that studies suggesting increasing risks with older age at initiation and longer duration of treatment were not consistent and generally did not reach statistical significance.9 However, there remains interest in investigating potential benefits with earlier and shorter use of HRT, as is discussed in several of the papers we review; Hodis and Mack present evidence that earlier use of HRT may have a more favorable risk-benefit profile,10 and the ongoing randomized controlled Early versus Late Intervention Trial with Estradiol (ELITE) is designed to test the timing hypothesis on cardiovascular risk.14

  • Cardiovascular Disease

There has been much interest in the impact of HRT on cardiac disease, as it remains the primary cause of mortality in women. Hodis and Mack focus on the impact of treatment timing on cardiac risk and overall mortality, reviewing a host of studies to support their hypothesis that the risk-benefit profile of HRT (and other treatments) is related to the timing of treatment.10 In the randomized Kronos Early Estrogen Prevention Study (KEEPS; summarized below), Harman and colleagues report that biomarkers for atherosclerosis in a relatively young and healthy population within 36 months of last menses are not significantly improved with HRT.11

  • Breast Cancerb

The association between E+P (though not unopposed E) and increased rates of breast cancer has been well described.4,15 We review here a study by Farhat and colleagues investigating how preexisting sex hormone levels may influence the risk of breast cancer with E+P treatment.12

  • Cognition and Mood

While early studies suggested that postmenopausal hormone therapy provides a measure of neuroprotection, HERS, WHI, and other studies noted a link between HRT and poorer cognitive performance. These later studies (WHI and HERS) looked at women over 65 years old, and used oral estrogen (versus transdermal) in the combined hormone treatment arm. Fischer and colleagues posited that these factors might impact study results, and set out to review studies published since 2000 to better characterize the effect of HRT on cognition and on mood.13

Important Considerations in Interpreting Study Results
As we review recent publications regarding CHD, breast cancer, and cognition and mood, it is important to note study design characteristics that may impact the interpretation of results. As always, this includes the particular cohort of interest—age, health (eg, preexisting heart disease), and years since onset of menopause. Both the timing of HRT initiation (ie, years since menopause) and duration of use may impact the health effects of treatment.

Of particular importance is the specific hormone treatment regime used. It is essential to distinguish between combined hormone treatment—an estrogen and a progesterone—and unopposed estrogen. Unopposed estrogen is only used in women who have had a hysterectomy, given its association with endometrial cancer; there is evidence that this risk is attenuated by progesterone or progestin, and, thus, combined treatment with E+P is used in any woman with a uterus. The effects of E+P are different than effects of unopposed E, and study results must be considered based on the exact type of hormone replacement.

Type of estrogen and of progesterone, and route of administration, may be relevant. There has been some suggestion that HRT effects vary depending on estrogen type and route of administration. For example, 17β-estradiol is the predominant endogenous estrogen prior to menopause, and has higher potency (higher receptor binding) than estrone, the predominant postmenopausal estrogen. The widely used oral CEE is estrone-based, with a post-hepatic metabolism estrone:estradiol ratio of 5-7:1.1 Transdermal administration of 17β-estradiol, which does not undergo hepatic metabolism and results in a 1:1 estrone:estradiol ratio, may thus more closely approximate the premenopausal hormone state.1,13 Progesterone preparation also may be relevant. For example, Fischer and colleagues cite evidence that the commonly prescribed synthetic progestin medroxyprogesterone acetate (MPA) may modify the cognitive benefit of estradiol and that micronized progesterone may more closely mimic endogenous progesterone.13

WHI Summary and Update, and the Ongoing KEEPS Trials
Given the impact of the WHI studies, and the importance of understanding the precise cohort and intervention studied, we summarize briefly here the WHI design and results, and a recent update to the WHI. We also describe the ongoing KEEPS trials, designed to answer some of the questions posed by WHI and subsequent studies.

  • WHI Studies

The WHI studied postmenopausal women (age 50-79 years) across 40 U.S. centers. A total of 68,132 women were entered into 4 randomized clinical trials; 93,176 (those ineligible for or uninterested in the RCTs) were followed in an observational study.4-7,16 The study required a 3-month wash-out of any preexisting HT prior to randomization;3 thus, some of the non-HRT group may have been previously exposed.

Also of note, the WHI cohort was older than subjects previously studied; mean age was 63 years at onset of (study-related) HRT, and it has been suggested that there may thus have been a higher rate of preexisting subclinical cardiovascular disease due to age and time since menopause.

An update regarding lessons from the WHI trials of hormone replacement therapy, by authors including those of the original studies, proposes that some of the disagreement in impact on CHD may derive from a time-dependent effect: HRT (particularly E+P) was associated with an initial increase in CHD risk, followed by a trend towards decreased risk.17 In analyses of shorter randomized clinical trials, early effects predominate (examples given are the primary prevention WHI and secondary prevention HERS trials, and WHI trial of estrogen therapy). In longer observational studies, in which women may have already been on HRT for a time, later effects predominate (eg, in the WHI observational study, the majority of the cohort had been on E+P for >2 years at baseline). The authors do mention the results of short-term trials of the timing hypothesis and KEEPS study, as well as the interest in the ongoing ELITE trial, but conclude that these trials are too small and short-termed to determine the impact on clinical disease.

There was an extended follow-up period through September of 2010, and the WHI continues to publish updates and new data. In 2013, an article on the extended post-termination phase of the WHI RCTs gave an overview of the risks found during the trials as well as those that persisted after discontinuing all interventions, noting that the majority of health risks and benefits did not persist during the extended follow-up phase (one exception being elevated risk of breast cancer for women in the E+P trial).18 While the authors note that quality of life results were mixed, they also again underscore that HRT is not recommended for chronic disease prevention but may be appropriate for short-term symptomatic relief.

  • KEEPS Trials

While initial findings from the Women’s Health Initiative did not demonstrate cardiovascular or cognitive benefits of hormone therapy in menopausal women, further analysis of this data and findings from other studies suggested benefits in a subset of women with earlier HRT use. Given both the older age of the WHI E+P cohort, and the use of oral (versus transdermal) estrogen+MPA as sole hormone treatment, the randomized controlled KEEPS was designed to investigate the effects of combined HRT in women within 36 months of last menses. KEEPS also was designed to study whether the type of estrogen affects outcomes: the 3 arms used oral CEE+P, transdermal 17b-estradiol+P, and placebo. The main trial looked at progression of atherosclerosis in 727 women (age 42-58 years) within 36 months of their last menses; we include a report of early results in this EndoScan (Harman et al, 2014).11 An ancillary trial, KEEPS-Cog, was designed to determine the impact of early HRT on cognitive function and mood, with the hypothesis that transdermal (versus oral) E would be beneficial to cognitive function.1,13 It is hoped that the KEEPS trials will provide more definitive insights into the effects of HRT and the impact of type of estrogen in recently postmenopausal women.


  • There is not full agreement on whether HRT provides a benefit or risk in terms of coronary heart disease, and factors including the timing of HRT may impact its effect.
  • Results of all studies should be considered in light of the cohort and intervention studied, namely:

-Cohort characteristics, including age, preexisting conditions including cardiovascular                       disease and risk factors, and prior hormone treatment exposure

-Timing of HRT initiation following menopause, and duration of treatment

-Type of HRT (combined or unopposed treatment; oral or transdermal estrogen)

  • Individual patient characteristics should drive treatment decisions
  • We summarize here some of what is known regarding the impact of postmenopausal HT on risks for cardiovascular disease, breast cancer, and cognitive decline. It is generally accepted that HRT provides benefit for vasomotor symptoms, as well as for osteoporosis and colorectal cancer. 
  • Ongoing studies examine the role of combined HRT (with oral and transdermal estrogen) on coronary artery disease and cognition.

aThere are non-estrogen/progesterone postmenopausal treatments, which include androgens, supplements, and selective serotonin reuptake inhibitors/cognitive therapy; we do not discuss non-HRT interventions in this EndoScan, nor do we touch on the use of bioidenticals (currently not recommended for use per the FDA and many medical associations.) These topics will be discussed in an upcoming issue of EndoScan.

bWhile RCTs showed an increase in breast cancer and mortality with combined HRT, observational studies found an association between E+P and breast cancers with more favorable prognoses. Chlebowski and colleagues designed a study to address the difference seen between WHI randomized clinical trials and observational studies15—the former tying combined HRT to increased breast cancer and mortality,6 and the latter to breast cancer with more favorable outcomes.16 In a subanalysis of WHI observational study participants (41,449 women with 2 years of normal mammograms, 16,121 on E+P, and 25,328 not currently on HT), use of E+P conferred an additional risk of developing breast cancer (HR 1.55, 95% CI 1.41-1.70, P<0.001), particularly with earlier post-menopause initiation of HT; survival after breast cancer was similar whether or not the women had been on HT.15 Of note, some of the non-HT group had used HT; the WHI required only 3 months not on HT prior to randomization.3

1. Wharton W, Gleason CE, Miller VM, Asthana S. Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective sub study (KEEPS Cog). Brain Res. 2013;1514:12-17.

2. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280(7):605-613.

3. Hays J, Hunt JR, Hubbell FA, et al. The Women's Health Initiative recruitment methods and results. Ann Epidemiol. 2003;13(9 Suppl):S18-77.

4. 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 Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

5. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651-2662.

6. 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(24):3243-3253.

7. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.

8. U.S. Food and Drug Administration. FDA Updates Hormone Therapy Information for Post Menopausal Women. February, 2014. Accessed December 12, 2014.

9. Moyer VA. Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158(1):47-54.

10. Hodis HN, Mack WJ. Hormone replacement therapy and the association with coronary heart disease and overall mortality: clinical application of the timing hypothesis. J Steroid Biochem Mol Biol. 2014;142:68-75.

11. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014;161(4):249-260.

12. Farhat GN, Parimi N, Chlebowski RT, et al. Sex hormone levels and risk of breast cancer with estrogen plus progestin. J Natl Cancer Inst. 2013;105(19):1496-1503.

13. Fischer B, Gleason C, Asthana S. Effects of hormone therapy on cognition and mood. Fertil Steril. 2014;101(4):898-904.

14. Hodis HN, Mack WJ, Shoupe D, et al. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause. 2014 [Epub ahead of print].

15. Chlebowski RT, Manson JE, Anderson GL, et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study. J Natl Cancer Inst. 2013;105(8):526-535.

16. Anderson GL, Manson J, Wallace R, et al. Implementation of the Women's Health Initiative study design. Ann Epidemiol. 2003;13(9 Suppl):S5-17.

17. Rossouw JE, Manson JE, Kaunitz AM, Anderson GL. Lessons learned from the Women's Health Initiative trials of menopausal hormone therapy. Obstet Gynecol. 2013;121(1):172-176.

18. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

First Article:
U.S. Preventive Services Task Force Does Not Recommend Hormone Therapy for Prevention of Chronic Disease in Postmenopausal Women
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