Is Timing Everything? A Meeting Report of the Society for Women's Health Research Roundtable on Menopausal Hormone Therapy

Abstract

The Society for Women's Health Research (SWHR) is a national, nonprofit organization based in Washington DC that is dedicated to transforming women's health through science, advocacy, and education. For more than 10 years, women and the physicians who treat them have been concerned about the safety of menopausal hormone therapy, largely since the early termination of two large federally funded studies. Considerable confusion remains despite decades of accumulated evidence from observational studies, clinical trials, and meta-analyses. In November 2012, SWHR convened 18 of the foremost experts within the field for a roundtable event to discuss the collective evidence related to the risks and benefits of hormone therapy. This report includes a synopsis of those discussions, the clinical statements that were generated and agreed upon, and the research recommendations suggested by the assembled experts.

Introduction

Women's fertile decades are characterized by regular ovulation and subsequent shedding of the uterine endometrial lining during menstruation in response to the cycle of estrogen and progesterone produced by the ovaries. As a woman approaches her midlife years, ovarian function gradually decreases, resulting in a drastic reduction in the release of these sex hormones, irregular menstrual periods, and eventually, the permanent cessation of menstruation.¹ The decline in female hormones and menstrual disruption may be accompanied by physical and psychological symptoms such as hot flushes and night sweats (vasomotor symptoms), vaginal dryness, irritability, and depression.^2,3 Hormone therapy (HT) is the most effective treatment for the reduction of vasomotor symptoms and aims to reduce other menopause-related symptoms and downstream consequences such as vulvovaginal atrophy and osteoporosis with resulting bone fracture. But, how safe is HT for disease prevention?

In 1991, the National Institutes of Health initiated the Women's Health Initiative (WHI), a 15-year set of clinical trials and observational studies of women aged 50–79 years, to address the most common causes of morbidity and mortality in postmenopausal women, including cardiovascular disease (CVD), cancer, and osteoporosis.⁴ Reversing prior conceptions in the field concerning the safety and utility of HT,^5,6 the WHI investigators reported that, with an average of 5.2 years of follow-up, HT with combined, continuous estrogen and progestogen (E+P) led to statistically significant increases in coronary heart disease (CHD), stroke, and venous thromboembolism (VTE). The study also showed significant decreases in hip fracture and colorectal cancer. Increased risks of breast cancer and decreased risks for endometrial cancer were reported but did not meet statistical significance.⁴ The WHI reported, in a concurrent study on the effects of estrogen alone (WHI-E), with an average of 6.8 years of randomized treatment, a significant increase in the risk of stroke and a significant decrease in the risk of hip fracture. Decreased risks in the development of CHD and breast cancer were reported but failed to meet statistical significance.⁷ It is important to note that neither WHI trial was designed to test the effect of HT on early postmenopausal women because the average age of women included in the studies was 64 years and 12 years postmenopausal.

The effects of these studies were far reaching in terms of both medicine and policy. The WHI Data Safety and Monitoring Board called a early stop to the WHI-E+P study based on concerns over the increased risk of CHD and a trend towards increase in breast cancer risk among study participants, although the risk of breast cancer did not reach statistical significance. The publication from the WHI-E+P study recommended that HT not be initiated or continued for the prevention of CHD.⁴ The WHI-E trial was also terminated by the National Institutes of Health in 2004, 1 year early, due to concern over increased risk of stroke, although no increased risks in either CHD or breast cancer were reported.

The following decade was punctuated with controversy and conservative policy decisions, starting with the U.S. Food and Drug Administration (FDA) Black Box warning in 2003 on risks of developing CVD with HT and recommendations that HT not be used for chronic disease prevention but rather only in a dose- and time-limited manner for the management of moderate-to-severe vasomotor symptoms. Policy decisions recommending against the use of HT continue today with the recent publication of the 2012 U.S. Preventative Services Task Force recommendations against using HT for chronic disease prevention.^8,9 These policy recommendations were set against a backdrop of often conflicting and confusing reports from the scientific community regarding interpretations and reanalyses of the original WHI studies, subsequent clinical trials, and observational studies.

In the 10 years since the publication of the unexpected findings from the WHI study and the subsequent media and policy reaction, the rate of HT use in menopausal women sharply declined globally. In the United States alone, the number of women using HT fell precipitously from 20% in 1999 to less than 5% in 2010.¹⁰ In an effort to clear up the confusion and to examine the totality of the evidence on the risks and benefits of HT, the Society for Women's Health Research (SWHR) convened a scientific roundtable event in Washington, DC, in November 2012: the SWHR Menopause Hormone Therapy Roundtable. Eighteen international experts were invited to discuss the scientific evidence concerning HT and the effects of HT on five chronic health conditions: (1) cardiovascular disease, (2) osteoporosis, (3) cognitive aging and Alzheimer's disease, (4) cancer, and 5) quality of life. Roundtable participants were assigned to subgroups based on their expertise and asked to summarize the scientific evidence for the relationship between HT and the chronic conditions. Following the subgroups' synopses of the current state of research, the experts debated and discussed the quality and interpretations of the data, both as they related to specific chronic conditions and in context of other conditions. Following this dynamic, moderated exchange, the experts created a set of clinical statements, reflecting a consensus or majority of those present, which were generated through the discussion. It is hoped that publication of these clinical statements will facilitate the development of future, formal clinical guidelines to create clarity for the management of menopausal symptoms and chronic diseases. Finally, roundtable participants were asked to compose a set of research recommendations for the future. This paper summarizes the discussions held at the SWHR Menopause Hormone Therapy Roundtable, the clinical statements proposed, and the recommended directions for future research. The roundtable participants (Appendix 1) reviewed this article for accuracy prior to submission.

Discussion Summaries

Cardiovascular Disease

As the first group to speak at the roundtable, the CVD subgroup began by discussing the challenges in evaluating studies that span a wide spectrum of methodologies, including observational studies, randomized clinical trials (RCTs), and meta-analyses of published data. Study populations vary in terms of the number of participants, age, time since menopause, and prior medical histories. Participants' ages and number of years postmenopause for the initiation of treatment are especially important in the evaluation of HT effects on long-term outcomes. Studies of HT also vary by the dosing, schedule, duration, and formulation of HT, which may use estrogen, such as conjugated equine estrogen (CEE) or oral or transdermal 17β-estradiol, with (E+P) or without (E) progestogen, such as medroxyprogesterone acetate (MPA), norethisterone acetate, or micronized progesterone. Further, the progestogen may be administered in either a continuous or sequential manner, with sequential administration typically involving E alone and then 12–14 days of added P. Finally, various studies differ in the outcomes measured and the length of follow-up.

The CVD subgroup noted that data from dozens of observational studies on the effects of estrogen or the effect of combined estrogen and progestogen on CHD showed a 40%–50% reduction in risk of developing CHD.^6,11
–13 Similar reductions in biomarker studies and animal models of CHD provided biological correlation to the observed effects.^14,15 The WHI clinical trials were designed as large RCTs powered to provide statistically robust experimental evidence on the effect of continuous, combined estrogen (CEE) and progestogen (MPA) (WHI-E+P) or estrogen alone (WHI-E) on the primary outcome of CHD.⁴ Contrary to the observational studies, the WHI E+P trials, conducted in women with an average age of 64 years and with HT initiation at 12 years postmenopause, initially reported an increased risk for developing CHD in women treated with estrogen and progestogen.⁴ Interestingly, the WHI-E trial reported no increased risk of developing CHD in women treated with estrogen alone.⁷

Next, the CVD subgroup discussed the likelihood that participant age and time since menopause at HT initiation contributed to the discrepancies in findings between the WHI study and earlier observational studies. The average age of the WHI women was 64 years and 12 years postmenopause, whereas women enrolled in the observational studies were between 30 and 55 years old and less than 2 years postmenopause at the start of treatment.^4,16 A large meta-analysis of 23 RCTs, representing 39,000 women, showed a 32% reduction in CHD in women starting HT at less than 60 years of age or less than 10 years postmenopause.¹⁷ This risk reduction was lost in women older than 60 years or more than 10 years postmenopause.¹⁷ These results, along with animal studies in nonhuman primates,¹⁸ support the timing hypothesis, which posits that women respond differentially with respect to CHD based on the timing of HT initiation relative to age and/or time since menopause.¹⁶

The CVD subgroup went on to summarize results from RCTs that were designed or reanalyzed to look at the effects of HT differentially, based on the age and/or time postmenopause for treatment initiation. In a reanalysis of the WHI E+P study, cohorts were assembled based on age and times since menopause. Women who started HT closer to menopause had no significant increased risk for developing CHD compared to placebo. Women who started HT 20 or more years after menopause had a significantly increased risk.¹⁹

Finally, the CVD subgroup summarized the Danish Osteoporosis Prevention Study (DOPS), the only prospective, longitudinal RCT specifically designed to examine clinical outcomes in 1006 women who were specifically a priori randomized to oral 17β-estradiol (E) alone or with sequential norethisterone acetate for 12 days (E+P) in the peri- or early postmenopausal period.²⁰ While the primary objective was to evaluate the effect of HT on the incidence of fractures in early postmenopausal women, the study also investigated the long-term effects of hormone replacement therapy on a composite endpoint of mortality, heart failure, and myocardial infarction. After 10 years of receiving either HT or placebo, significantly fewer women (52%) in the treatment group died, developed heart failure, or experienced a myocardial infarction. This reduction in risk was still present after 16 years of follow-up.²⁰

The CVD subgroup next discussed data for the risk of stroke with the use of HT, noting that conclusions from observational studies were highly inconsistent. The WHI-E+P and WHI-E trials both reported an increased risk of stroke with HT treatment, contributing to an additional 8 or 11 strokes, respectively, per 10,000 women treated annually.^4,7,21 The effect of HT on the risk of stroke in the WHI studies was independent of time and age since menopause.¹⁹ An increased risk in VTE was also reported in the WHI-E+P trial, with an absolute risk of 18 additional cases/10,000 women/year of E+P therapy.⁴ The WHI-E trial also reported a slight increased risk between E and placebo (an additional 7 cases/10,000 women/year), which lacked statistical significance.⁷ However, DOPS reported no increased risk in either stroke or VTE with HT treatment compared to placebo.²⁰ It is important to recognize, however, that DOPS might not have had sufficient power to detect the more rare events, such as stroke and VTE.

In summary, the original WHI-E+P study reported an increased risk of CHD, VTE, and stroke for women on HT.⁴ Reanalysis of these data, based on age, reported that the increased risk of CHD is limited to women who initiate HT therapy 20 years or later postmenopause.¹⁹ This timing effect is supported by observational trials and other RCTs, suggesting that HT with E+P does not increase the risk of CHD, and may actually decrease the risk in more recently postmenopausal women.^17,20 HT treatment with E alone was not associated with an increased risk in CHD.⁷ The WHI also reports risks of increased VTE and stroke in women,⁴ associated with both E alone and E+P therapy. While the results from DOPS again suggest a possible age effect for these risks, the study may have lacked sufficient power to assess these outcomes.²⁰ Thus, this is an area that requires future study.

Cognitive aging and Alzheimer's disease

The cognitive aging and Alzheimer ‘s disease (CogA/AD) subgroup discussed the relationship between HT and the progression of CogA and the development of AD. The complex network of neurons, synapses, receptors, and signaling pathways associated with the aging brain presents challenges for researchers interested in mechanisms associated with the influence of HT. The massive network of excitable neurons communicate with one another via receptors on tree-like dendrites or spines that receive and transmit signals to other such structures on nearby neurons. Loss of dendritic spines in the synapses of the prefrontal cortex is correlated with cognitive decline and may precede AD as well, though this is still a matter of intense study and investigation.^22,23 Estrogen receptors are present in excitatory synapses in the prefrontal cortex,²⁴ and it has been shown that estradiol enhances cognitive performance in nonhuman primates through partial restoration of the thin spines.²⁴ Thus, estrogen receptors and related signaling pathways may provide therapeutic targets for cognitive decline. Further, if synaptic alterations associated with CogA precede those associated with AD, then this may be an appropriate therapeutic window to halt AD progression. It is conceivable that by protecting the synapses and promoting plasticity, possibly through treatment with estradiol, the progression of CogA and possibly AD²⁵ could be slowed or halted. However, since the link between CogA and AD has not yet been firmly established, the effect of HT on both outcomes was discussed separately by the CogA/AD subgroup.

Recent observational studies and results from RCTs on CogA have produced conflicting results. The six observational studies discussed (Nurses' Health Study,²⁶ LAW,²⁷ Three Cities [3C],²⁸ SWAN,²⁹ Swedish Twin Study,³⁰ and REMEMBER Study³¹) varied greatly in their findings on cognitive outcomes and varied depending on the formulation (E vs. E+P), timing, dosage, and duration of treatment. The results of the various observational studies were far from congruent, with both risks and benefits attributed to HT across the studies. The results from RCTs on cognitive function were somewhat less difficult to interpret, particularly among older postmenopausal women without dementia. In general, the studies in early postmenopausal women (<65 years old) showed widely inconsistent results.³² Studies of older postmenopausal women (>65 years old) showed neutral effects with E alone and either neutral or small adverse effects with E+P.³² Further work is necessary on the risks and benefits of HT on CogA outcomes.

The CogA/AD subgroup next addressed the effects of HT on the progression and development of AD. Controversy arises from the idea that HT can prevent AD among healthy women. A meta-analysis of observational studies described a 30% reduction in AD risk.^33,34 This meta-analysis opposes the WHI Memory Study (WHIMS), the only randomized study of HT for the primary prevention of dementia, which showed a doubling of the risk for dementia in older women treated with E+P.^33,34 The discrepancy between the observational studies and the WHIM study may be due, once again, to the age of participants and the length of time following the onset of menopause before treatment initiation.³⁵

Three observational studies to date have explicitly examined whether the effects of HT on AD risk depends on the timing of initiation. In the Kaiser Permanente Study, investigators reported a decreased risk of developing AD in women who use HT only at midlife (mean age, 48.7 years) and an increased risk in women who began HT in late life (mean age, 76 years).³⁶ These results were supported in the Cache County Cohort, in which either E or E+P initiated within 5 years of menopause was associated with reduced risk, whereas HT initiated later than 5 years after menopause was associated with neither risk nor benefit.³⁷ Lastly, the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study found a lower risk of AD among recently postmenopausal women.³⁵ Thus, based on these observational studies, the timing of initiation of HT appeared to influence the risk, with less risk associated with HT initiation closer to menopause.

In summary, the literature is mixed on the effects of HT on CogA in early postmenopausal women and neutral or tending towards adverse effects in older postmenopausal women. The literature is also mixed on the effects of HT on AD. Observational studies showed a decreased risk in the development of AD when HT was initiated early postmenopause, but an increased risk in older, postmenopausal women.

Osteoporosis

The osteoporosis subgroup highlighted recent studies that collectively show the effectiveness of HT for the prevention of osteoporosis and fracture. Bone density losses begin in the year preceding a woman's final menstrual period (FMP) and continue for 2 years post-FMP, at which time bone loss decelerates, but does not cease.³⁸ This loss in bone density is likely due to the decrease in estrogen because any decline in estrogen, such as in amenorrheic athletes, is associated with a corresponding decrease in bone density.³⁹ Estrogen treatment in menopausal women has the effect of increasing bone density.⁴⁰ Evidence that low-dose HT might protect against bone loss⁴¹ led the Women's Health, Osteoporosis, Progestogen, Estrogen (Women's HOPE) trial to investigate the efficacy of lower doses of CEE alone (E) and with continuous MPA (E+P) in early postmenopausal women (within 4 years post FMP).⁴² E at all doses led to significant increases in both spinal and hip bone density. Further, E+P significantly increased spine bone density, relative to E alone. These data show that low doses of E and E+P slow early postmenopausal bone loss in the hip and spine.⁴² A comparison of results from clinical trials of HT and other FDA-approved therapies for the prevention of bone loss (bisphosphonates and raloxifene) in early postmenopausal women demonstrate that, while all of the therapies provided some protection from early postmenopausal bone loss in the spine and hip, HT provides greater protection.⁴³

The osteoporosis subgroup stated that fracture was the most clinically significant physical manifestation of postmenopausal osteoporosis. The WHI study provided RCT evidence for the efficacy of E and E+P in reducing the incidence of hip, vertebral, nonvertebral, and total fractures.^4,44 The subgroup confirmed that these results were consistent with results from both observational studies and other RCTs showing protection from fracture and improvement in bone density, respectively, in women assigned to HT.

Unfortunately, the beneficial effect of HT for the prevention of osteoporosis and subsequent bone fractures is not sustained following the cessation of HT. In the STOP IT RCT, postmenopausal women were treated with E or E+P for 3 years with continued evaluation for 2 years after cessation of treatment. Discontinuation led to rapid bone loss to levels similar to those in untreated women.⁴⁵ Studies following the cessation of HT treatment in women enrolled in the WHI-E and WHI-E+P studies show an increase in hip, vertebral, and total fractures with the fracture rates returning to those found in untreated women^4,46,47 including a threefold higher risk of suffering a hip fracture compared with women who continued HT.⁴⁸

Quality of life

Quality of life refers to an individual's sense of well-being. Menopause-specific quality of life (MSQOL) measures the impact of symptoms experienced during the menopausal transition, such as hot flashes, night sweats, vaginal dryness or pain, and changes in mood, on daily life. Health-related QOL (HRQOL) instruments focus on patients' perceptions of their overall health, not restricted to menopause-specific symptoms. Global QOL (GQOL) instruments refer to the global sense of well-being and self-satisfaction (beyond the presence or absence of symptoms) to reflect how a peri- or postmenopausal woman feels generally, and specifically, regarding interest in life, ability to complete a day's work with satisfaction, maintenance of good interpersonal relationships, sexuality, and a general feeling of wellness. A number of instruments have been developed to measure various types of QOL. These instruments are questionnaires specifically designed to provide comparable measures of MSQOL, HRQOL, or GQOL. The QOL subgroup emphasized that a (QOL) instrument needs to be validated for specific populations or circumstances to be appropriately utilized.

The QOL subgroup summarized results from 10 clinical trials addressing the effect of HT on MSQOL, HRQOL, and GQOL. Four studies examined the effect of various hormone treatments on MSQOL and reported improvements in MSQOL with HT. The effect of HT on HRQOL in healthy women was studied in five clinical trials. Overall, there were no significant differences reported in HRQOL with one exception, showing an improvement in some HRQOL measures in women who were experiencing hot flashes at baseline.^{4,7,49

–52} It is important to note, however, that the average age of participants in the HRQOL studies was higher than in the MSQOL studies. Finally, there was only one published study addressing GQOL, which did not report any significant changes based on HT.⁵¹

The QOL subgroup next presented the results of a quality-adjusted-life-years (QALYs) model. QALYs measure both the quality and quantity of life lived and are useful for the assessment of interventions. In the model discussed by the subgroup, data for midlife and older women were compiled separately and cost-effectiveness assumptions were drawn from the available literature. The model predicts that HT initiated in midlife women (around age 50) would significantly increase QALYs, mainly through improvement in QOL measures. However, the model predicts HT started in later years would not significantly improve QOL, QALYs, or life expectancy.⁵³ This QALY study concluded that the timing of HT initiation was a major determinant on the effects of HT on quality of life.

Cancer

The role of HT on the risk of breast cancer is one of the most controversial areas of the HT debate. The cancer subgroup focused primarily on breast cancer, though other types of cancer, including endometrial, colorectal, cervical, and ovarian cancers, were also discussed.

Endogenous female hormones are carcinogenic as demonstrated by the sex differences in the incidence of breast cancer and the elevated estrogen levels in women with breast cancer.⁵⁴ Endogenous estrogen levels are also highly associated with uterine cancer and hyperplasia.⁵⁴ The cancer subgroup argued that this effect by endogenous hormones may not be directly extrapolated to exogenous female hormones. While there is considerable evidence that unopposed estrogen therapy (E alone) causes endometrial cancer,⁵⁵ inclusion of progestogens may negate this risk.⁵⁵ Further, HT has been found to reduce the risk of cancer of the large bowel.^55,56 There have been over 50 observational studies conducted to assess the impact of HT on the risk of developing breast cancer.^55,56 However, despite the number of studies, clear causality between HT and breast cancer has been difficult to prove. The reported increased risk of developing breast cancer with E+P in the WHI trial failed to reach statistical significance.^4,57 The Million Women Study (MWS) found that women who self-reported current use of E+P had an increased risk of developing breast cancer, while women who had stopped E+P therapy were not at an elevated risk.⁵⁸ Treatment with E alone did not increase the risk of breast cancer,⁷ and later studies suggested that E may actually reduce the risk.^47,59 The cancer subgroup further highlighted data from the recent DOPS showing data that, while not statistically significant, showed treatment with E or E+P trends towards a decrease in breast cancer for up to 16 years of follow-up.²⁰ In summary, the subgroup emphasized that risk, if any, of developing breast cancer in response to HT was small, with the absolute risk ranging from an additional 3 to 12 cases of breast cancer per 10,000 women per year attributable to E+P.

Next, the cancer subgroup addressed the relationship between HT and other types of cancers. As mentioned previously, the relationship between E and the risk of developing endometrial cancer has been well established.⁵⁵ There are scant data on the effect of E+P on endometrial cancer in older women, though preliminary studies thus far show no reduction in risk with the addition of P. Few studies have examined the link between HT and ovarian cancer, however, MWS reported an increased risk of ovarian cancers in patients receiving HT, especially among hysterectomized women.⁶⁰ Finally, there is currently no evidence to indicate that E or E+P increases or decreases the risk of cervical cancer. The paucity of data on the effect of HT on the risk of developing these cancers suggests that further research is needed in these areas. Finally, there are consistent data from a number of cohort and case–control studies, including the WHI studies, that report a decreased risk of developing colon or colorectal cancers in response to HT.^61

–64

Discussion

Many factors contribute to the different outcomes reported in the studies highlighted in this meeting report. The subgroups discussed the importance of considering study population size and age, especially in terms of the time when initiating HT. It is also necessary to consider the different HT doses, formulations, and schedules used in each study when assessing the literature. The discussions at the roundtable often centered on the pivotal WHI studies. The group emphasized the importance of considering the collective entirety of the data when drawing conclusions because each study represents an important facet of the overall body of knowledge on the effects of HT. Thus, no one study should be either overgeneralized or excluded from consideration.

The risks and benefits of HT will, undoubtedly, continue to be debated for years to come. Evidence is mounting that HT, delivered early in the postmenopausal period (10 years or less since FMP), reduces total mortality and risk for CHD. Any increase in breast cancer for these younger women was considered small. However, no protective effect for HT was found for mortality or CHD in older postmenopausal women. So, timing definitely matters. Women older than 60 years or more than 10 years from menopause may have missed the window of opportunity for benefit from HT.

In conclusion, the SWHR Menopause Roundtable provided an exceedingly informative and thought-provoking discussion on the data that relate to the effects of HT on chronic health conditions. SWHR asked the roundtable to provide consensus clinical statements that reflect the current literature and could potentially facilitate the development of formal clinical guidelines in the future. These clinical statements are included in Table 1, as dictated and voted upon by the roundtable participants on the day of the event. The consensus statements were generated after considerable discussion and debate of available data concerning the relationship between HT and a particular chronic condition. Clearly, a woman's entire health history should be taken into account in an appropriate benefit–risk evaluation. Additionally, the roundtable participants highlighted key research gaps that need to be addressed in order to better understand the effects of HT on chronic health conditions (Table 2). There is a need for continued dialogue among researchers, clinicians, and patients on the complicated issues surrounding HT. Further, continued research is necessary to produce the science to better inform clinicians and women on the risks and benefits of HT. There will be no “one size fits all” solution to HT—it will be incumbent upon each clinician and patient to weigh the risks and benefits when considering individualized patient care.

Table 1.

Consensus Clinical Statements ^a

Clinical recommendation	Vote	Difference from the USPTF recommendations^8,9
Overall health benefits
1. The benefit–risk profile of HT is more favorable for younger, newly menopausal, women.	Unanimous	The SWHR roundtable recommendation provides guidance on duration that is acceptable based on literature. USPTF did not address HT for symptom management.
2. In younger, symptomatic postmenopausal women, the benefits of E+P for at least 5 years outweigh the risks.	2 abstain	The SWHR Roundtable recommendation provides guidance on duration that is acceptable based on literature.
3. In younger, postmenopausal women with hysterectomy, the benefits of unopposed estrogen treatment for at least 10 years outweigh the risks.	Unanimous	The SWHR Roundtable recommendation provides risk information for younger individuals.
4. Patients with premature ovarian insufficiency benefit from hormone therapy and should be treated until at least the age of menopause, based on expert opinions and available observational data.	Unanimous	The SWHR Roundtable recommendation applies to women less than 50 years old.
5. There is consistent evidence that in early postmenopausal women, hormone therapy reduces total mortality.	5 opposed^b	The SWHR Roundtable recommendation provides guidance on total mortality and age difference with respect to the effects of HT initiation and effect
Quality of life
6. Hormone therapy is the most effective treatment for vasomotor symptoms.	Unanimous
7. Hormone therapy provides a significant benefit on MS-QOL (HRQOL) in early postmenopausal women, mainly through the relief of symptoms, but treatment also may result in a global increase in sense of wellbeing (GQOL).	Unanimous	The SWHR Roundtable recommendation shows improvement in QOL for younger women.
Osteoporosis
8. Estrogen can be used for the prevention of osteoporosis (an FDA approved indication) in early postmenopausal women at increased risk of fracture. The optimal duration for treatment is not known. However, if HT is discontinued the benefits dissipate. Therefore, in patients at high risk for osteoporotic fractures, continued estrogen treatment or other alternative treatments should be considered.	2 abstain	The SWHR Roundtable recommendation advocates for the use of HT for the prevention of a chronic disease, osteoporosis.
Breast cancer
9. Available evidence suggests that unopposed estrogen appears not to increase the risk of breast cancer and may possibly reduce the risk in postmenopausal women with hysterectomy.	Unanimous
Dementia
10. There is insufficient evidence to recommend hormone therapy after menopause for the prevention of dementia or enhancement of cognition.	Unanimous
Vascular disease
11. HT in early postmenopausal women does not increase the risk for CHD, and may reduce it. However, there is insufficient evidence for the use of HT in the primary prevention of CHD.	1 opposed^c	The SWHR Roundtable recommendation provides guidance concerning CHD in younger women.
12. Hormone therapy should not be used for the secondary prevention of CHD or stroke.	3 abstain
13. HT in early postmenopausal women may slightly increase the risk of stroke although the absolute increase in risk, if present, is very small.	3 opposed^d

Roundtable participants were asked to draw up consensus statements, based on the best evidence available, which includes both observational and clinical trial data. Unanimous agreement was reached on several topic areas, however, where necessary, the dissenting opinions are presented as well. Most of the consensus statements are based on studies of estrogen (conjugated equine estrogen) alone or with medroxyprogesterone acetate as continuous combined therapy. Each of the consensus statements is based on available data concerning the relationship between HT and a particular chronic condition. More research is necessary in each area. When considering the use of the following, a benefit–risk evaluation should be performed to include the entirety of a woman's health history.

All present agreed that HT does not pose a risk on total mortality. However, 10 members wanted the stronger wording that HT “reduces” total mortality, while five members wanted to state that HT “may reduce” total mortality.

The opposing vote supported a stronger statement and did not want the inclusion of “insufficient” in this statement.

The three opposing votes wanted a stronger statement that the risk, if present, is “rare” as opposed to “very small.”

HT, hormone therapy; USPTF, U.S. Preventative Services Task Force; E+P, estrogen and progestogen; SWHR, Society for Women's Health Research; MS-QOL, menopause-specific quality of life; HRQOL, health-related quality of life; GQOL, global quality of life; FDA, U.S. Food and Drug Administration; CHD, coronary heart disease.

Table 2.

Research Recommendations and Priorities From the Society for Women's Health Research Menopause Hormone Therapy Roundtable

Additional human trials and animal and laboratory studies are needed to understand the following:

1. The biological mechanisms of action of different estrogens and progestogens in specific tissues

2. The effect of cyclic versus continuous estrogen in clinical outcomes

3. The effect of cyclic versus continuous progestogens in clinical outcomes

4. Estrogen receptors and the signaling cascades activated by different receptors

5. The effect of different formulations, doses and routes of deliveries of estrogen and progestin

6. Reanalysis of Women's Health Initiative data—both for younger women and based on proximity to menopause among women who remain blinded and adherent

7. Comparative effectiveness research for different hormone therapy regimens

8. The effect of hormone therapy in newly menopausal women with no prior use of hormone use

9. Appropriate, validated instruments for measurement of quality of life in all clinical studies

10. Efficacy and safety data on hormone therapy treatment for primary ovarian insufficiency (POI)

11. Worst case estimates of outcomes related to HT use, for all implicated outcomes

12. Novel agents as alternatives to hormones, such as selective estrogen receptor modulators, psychoactive drugs, and phytoestrogens

13. Cognitive outcomes of HT during the perimenopause and POI

14. Additional effects of midlife HT on Alzheimer's disease in later life

15. Epidemiological studies of cancer risk based on biological insights relative to cancer risk

Footnotes

Appendix 1.

Society for Women's Health Research Menopause Hormone Therapy Roundtable Participants

Participant	Affiliation
Sanjay Asthana, MD^a	Professor and Head of the Division of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health
Jane A. Cauley, DrPH	Professor, Department of Epidemiology University of Pittsburgh
J. Christopher Gallagher, MD	Professor, Creighton University School of Medicine Director, Bone Metabolism Unit, Division of Endocrinology, Creighton University Medical Center
S. Mitchell Harman, MD, PhD	Director and President, Kronos Longevity Research Institute
Victor W. Henderson, MD, MS	Professor, Health Research & Policy – Epidemiology Professor, Neurology & Neurological Sciences Stanford University School of Medicine
Howard N. Hodis, MD	Professor of Medicine, University of Southern California Keck School of Medicine Director, USC Atherosclerosis Research Unit
Richard H. Karas, MD, PhD	Professor, Tufts University School of Medicine Vice-Chairman of Medicine, Tufts Medical Center Co-Director, Women's Heart Center
Robert Lindsay, MBChB, PhD, FRCP	Chief of Internal Medicine, Helen Hayes Hospital Professor of Clinical Medicine, Columbia University
Roger A. Lobo, MD	Professor of Obstetrics and Gynecology and Fellowship Director, Center for Women's Reproductive Care, Columbia University Medical Center
Pauline Maki, PhD	Professor of Psychiatry and Psychology, University of Illinois at Chicago Director of Women's Mental Health Research
JoAnn E. Manson, MD, DrPH	Professor of Medicine, Harvard Medical School Chief, Division of Preventive Medicine, Brigham and Women's Hospital Professor in the Department of Epidemiology, Harvard School of Public Health
John H. Morrison, PhD	Dean of Basic Sciences and the Graduate School of Biological Sciences Professor, Department of Neuroscience Willard T.C. Johnson Professor of Geriatrics and Palliative Medicine (Neurobiology of Aging) Mount Sinai School of Medicine
Shelley Salpeter, MD, FACP	Clinical Professor of Medicine, Stanford University
Louise Lind Schierbeck, MD	Registrar, Department of Cardiology, Bispebjerg Hospital Hvidovre Hospital
Samuel Shapiro, MB, FCP(SA), FRCP(E)	Professor, Department of Public Health and Family Medicine, University of Cape Town Medical School
John C. Stevenson, MB BS, FRCP, FESC, MFSEM	Consultant Physician and Endocrinologist, Royal Brompton Hospital, London; Imperial College London Reader in Metabolic Medicine, Imperial College of Medicine, London Honorary Principal Research Fellow, National Heart & Lung Institute
Wulf H. Utian, MD, PhD, DSc	Consultant, Gynecology and Women's Health, The Cleveland Clinic Chair Scientific Board, RMR Inc. Professor Emeritus, Case Western Reserve University
Nancy Fugate Woods, PhD, RN, FAAN	Professor of Bio-behavioral Nursing and Health Systems, University of Washington

Dr. Asthana was unable to attend the roundtable event, though he participated in discussions, document, and presentation preparation prior to the roundtable.

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