Margery Gass, MD

In March 2007, the North American Menopause Society (NAMS) issued an updated evidence-based position statement on the risks and benefits of hormone therapy (HT) in peri- and post-menopausal women.¹ This article will briefly review the major conclusions of that position statement and review three new reports from the Women’s Health Initiative (WHI) published after the NAMS position statement.^2–4 The objective is to update clinicians on current recommendations on the use of HT and to assess, together with the preceding article in this supplement by Hodis, emerging data that will inform future recommendations.

TAKE-HOME POINTS FROM THE UPDATED NAMS POSITION STATEMENT

The 2007 NAMS position statement on HT was developed by 14 expert clinicians and researchers who used previous NAMS position statements on the topic from 2002, 2003, and 2004 as a basis. The experts then reviewed all relevant subsequent evidence from a comprehensive literature search to determine areas of consensus and nonconsensus. Twenty-four areas of consensus and two areas of nonconsensus were identified, which represented a clear increase in consensus relative to the prior NAMS position statements. Thirty-two areas were identified as requiring further research.

Key recommendations and observations from the 2007 NAMS position statement are cited below, in many cases verbatim or near verbatim to preserve the intent.¹

Highlights of the NAMS position statement

Terminology

NAMS proposes adoption of the following terminology:

• Estrogen therapy (ET) for use of unopposed estrogen
• Estrogen-progestogen therapy (EPT) for combined use of estrogen and progestogen
• Hormone therapy (HT) to include both ET and EPT
• Progestogen to include both progesterone and progestins.

Indications for HT

• Treatment of moderate to severe vasomotor symptoms
• Treatment of moderate to severe vulvovaginal symptoms. When ET is being used only for this symptom, NAMS recommends local (vaginal) delivery.

Use of a progestogen

• Because the primary purpose of progestogen use is to prevent the endometrial cancer associated with unopposed estrogen, only women with a uterus should take a progestogen along with estrogen.
• Lack of endometrial safety data prevents NAMS from recommending long-cycle progestogen (eg, 12 to 14 days every 3 to 6 months), progestogen intrauterine systems, or low-dose estrogen without progestogen.
• A progestogen is usually not necessary with use of low-dose vaginal estrogen.⁵ However, separate from the NAMS statement is a Cochrane review of the use of vaginally administered estrogens that recommends further investigation of long-term endometrial safety with use of vaginal estrogen beyond 6 months.⁶

Cardiac and cerebrovascular disease

• HT is not recommended for prevention of coronary heart disease (CHD) at any age, pending new data to the contrary.
• HT should not be used for prevention of stroke and should be discouraged in women who have an increased risk of stroke.

Venous thromboembolism

• HT increases the risk of venous thrombosis and venous thromboembolism (VTE).

Diabetes mellitus

• Both ET and EPT reduced the risk of incident diabetes mellitus requiring treatment (by 12% and 21%, respectively, relative to placebo in the WHI).
• Evidence is insufficient to recommend HT solely for the prevention of diabetes mellitus.

Breast cancer

• EPT increased the risk of breast cancer in the WHI, but ET did not.
• Both ET and EPT increase breast cell proliferation, breast pain, and mammographic density. Diagnosis of cancer may be delayed.

Osteoporosis

• Both ET and EPT reduce the risk of postmenopausal fractures.
• HT is an option for reducing the risk of osteoporosis after the risks and benefits are weighed against those of other therapies.

Premature menopause and premature ovarian failure

• The absolute risks posed by ET and EPT may be lower in women with premature menopause or premature ovarian failure because of the lower incidence of CHD, stroke, and VTE in younger women. The risk-benefit ratio of HT is likely to be more favorable in this younger age group, but this has not yet been demonstrated.

Extended use of HT

• Extended use of HT may be considered in women who decide that menopausal symptom relief out­weighs the risks of HT, particularly after an attempt to stop HT has failed.
• Extended use may be appropriate for women with vasomotor symptoms at high risk of osteoporosis-related fracture.
• Extended use may be considered for the prevention of further bone loss in women with established low bone mass when other therapies are contraindicated or are not well tolerated.

Caution on use of “bioidentical” hormones

• In the absence of further data, compounded “bioidentical” hormone preparations should be presumed to carry the known risks and benefits of HT.
• The lack of regulatory oversight with regard to purity and consistency of bioidenticals prompts caution in their use.

Areas of nonconsensus

The NAMS panel did not reach consensus on the best way to discontinue HT or on the relative safety of continuous versus sequential use of progestogen along with estrogen. Lack of data and conflicting data prevented consensus in these two areas.

 

 

UPDATES FROM THE WOMEN’S HEALTH INITIATIVE

Since the publication of the 2007 NAMS position statement, three additional important analyses have emerged from the WHI randomized trial. The first report, by Rossouw et al, examined the effects of HT on the risk of cardiovascular disease (CVD) and other outcomes according to age and time since menopause.² The second analysis, by Manson et al, was a post hoc study of the extent of coronary artery calcification in the 50- to 59-year-old group in the ET arm of the WHI.³ The third analysis, by Heiss et al, reported health outcomes at 2.4 years after treatment was stopped in the EPT arm of the WHI.⁴

Cardiovascular results

The analysis by Rossouw et al of the CVD effects of HT by age and years since menopause has been reported in detail in the preceding paper by Hodis. In brief, the authors concluded that the data confirm a very low risk for women in their 50s who use HT for menopausal symptoms. The authors cautioned that the low risk from ages 50 to 59 does not guarantee lack of harm with prolonged use into older ages. Stroke and thrombosis risk were not dependent on years since menopause.

The WHI Coronary Artery Calcium Study was conducted in the ET arm approximately 1.3 years after the intervention (ET or placebo) was discontinued.3 Participants had completed a mean 7.4 years of intervention. The 1,064 eligible and available participants were aged 50 to 59 at WHI baseline. They underwent computed tomography of the heart. More than half of the women had a coronary artery calcium (CAC) score of 0. Overall, the mean CAC score was 83.1 among those randomized to ET and 123.1 among those randomized to placebo (P = .02). Classic CVD risk factors such as smoking, diabetes, hypertension, and high cholesterol were also associated with increased CAC scores, but they did not significantly modify the effect of ET on CAC. The authors cautioned that because of the multiple and complex effects of estrogen in the cardiovascular system, further study should be completed before ET is used for prevention of CAC.

Postintervention assessment

The third key HT-related WHI paper⁴ published since the 2007 NAMS position statement is the first to report the health events that occurred in the EPT arm since discontinuation of the study drugs.

Design and end points. The intervention phase of the WHI trial of EPT included 16,608 postmenopausal women (with intact uterus) aged 50 to 79 years at baseline who were randomized to treatment with EPT or placebo for a mean of 5.6 years before the treatment intervention was discontinued in July 2002 because the overall health risks of EPT were found to exceed the health benefits. Of these original participants, 15,730 women (95%) completed a planned postintervention follow-up consisting of semi-annual monitoring for adjudicated outcomes from July 2002 through March 2005. The mean duration of postintervention follow-up was 2.4 years.⁴

The primary outcomes of this postintervention analysis were CVD events and invasive breast cancer. These end points, together with endometrial cancer, colorectal cancer, stroke, pulmonary embolism, hip fracture, and death, were also factored into a global index of risks versus benefits with EPT.

Results. CVD. There was neither an elevated risk nor a decreased risk of CHD after discontinuation of EPT (hazard ratio [HR] = 0.95; 95% CI, 0.73 to 1.26). Risks that were elevated in the intervention phase, such as deep vein thrombosis (DVT) and stroke, disappeared after EPT was stopped. Women originally randomized to EPT had a similar rate of all CVD events compared with those who had been randomized to placebo (HR = 1.04; 95% CI, 0.89 to 1.21).

Breast and other cancers. The annualized incidence of invasive breast cancer in the postintervention period was 0.42% in the group that had been randomized to EPT versus 0.33% in the group randomized to placebo. This translated to a nonsignificant HR of 1.27 (95% CI, 0.91 to 1.78) for the postintervention period. In contrast, the annualized rate of all cancers (endometrial, colorectal, and breast combined) in the postintervention period was significantly higher in the EPT group (1.56%) than in the placebo group (1.26%) (HR = 1.24; 95% CI, 1.04 to 1.48). More extensive analysis of this finding is under way.

The cancer findings from this 2.4-year postintervention phase of the WHI parallel those from the 2.7-year postintervention phase of the Heart and Estrogen/progestin Replacement Study (HERS), in which between-group differences in the rates of breast and colon cancers approached null as the incidences of lung and other cancers increased in the group that had been randomized to EPT.⁷

Fractures. During the intervention phase, EPT was associated with a significant reduction in fractures; however, the EPT fracture benefit disappeared within the 2.4-year follow-up period.

Mortality. There was little difference in all-cause mortality between the treatment groups in the intervention phase. Although the difference was not statistically significant, there was a 15% higher mortality rate in the EPT group during the postintervention phase (HR = 1.15; 95% CI, 0.95 to 1.39). Contributing in part to this difference was an increased risk of mortality from lung cancer that requires further exploration.

Global index. The global index of risks versus benefits from enrollment to the present analysis remained significantly elevated (HR = 1.12; 95% CI, 1.03 to 1.21), suggesting more risk than benefit from use of EPT. The increase in the global index loses significance when the postintervention phase is considered alone (HR = 1.11; 95% CI, 0.99 to 1.27).

Conclusions. The researchers concluded that a number of outcome patterns observed with EPT in the intervention period of the WHI randomized trial did not persist during the 3-year postintervention follow-up:

• CHD, DVT, and stroke risks disappeared
• Hip fracture and total fracture benefits disappeared
• The composite risk of all cancers increased and was statistically significant in the postintervention phase, although the elevated risk of breast cancer was no longer statistically significant in the postintervention phase.

Summary of the new WHI reports

These three recent papers from the WHI suggest lower risks with short-term use of EPT in women ages 50 to 59 compared with older women. A delay in atherosclerosis and a decrease in all-cause mortality were also noted in this age group. The postintervention follow-up findings of a rapid disappearance of most risks and benefits of EPT will be of interest to patients who want to know what to expect when they discontinue HT. The late development (in years 5 to 8) of an increase in the composite risk of all cancers merits further investigation.

In March 2007, the North American Menopause Society (NAMS) issued an updated evidence-based position statement on the risks and benefits of hormone therapy (HT) in peri- and post-menopausal women.¹ This article will briefly review the major conclusions of that position statement and review three new reports from the Women’s Health Initiative (WHI) published after the NAMS position statement.^2–4 The objective is to update clinicians on current recommendations on the use of HT and to assess, together with the preceding article in this supplement by Hodis, emerging data that will inform future recommendations.

TAKE-HOME POINTS FROM THE UPDATED NAMS POSITION STATEMENT

The 2007 NAMS position statement on HT was developed by 14 expert clinicians and researchers who used previous NAMS position statements on the topic from 2002, 2003, and 2004 as a basis. The experts then reviewed all relevant subsequent evidence from a comprehensive literature search to determine areas of consensus and nonconsensus. Twenty-four areas of consensus and two areas of nonconsensus were identified, which represented a clear increase in consensus relative to the prior NAMS position statements. Thirty-two areas were identified as requiring further research.

Key recommendations and observations from the 2007 NAMS position statement are cited below, in many cases verbatim or near verbatim to preserve the intent.¹

Highlights of the NAMS position statement

Terminology

NAMS proposes adoption of the following terminology:

• Estrogen therapy (ET) for use of unopposed estrogen
• Estrogen-progestogen therapy (EPT) for combined use of estrogen and progestogen
• Hormone therapy (HT) to include both ET and EPT
• Progestogen to include both progesterone and progestins.

Indications for HT

• Treatment of moderate to severe vasomotor symptoms
• Treatment of moderate to severe vulvovaginal symptoms. When ET is being used only for this symptom, NAMS recommends local (vaginal) delivery.

Use of a progestogen

• Because the primary purpose of progestogen use is to prevent the endometrial cancer associated with unopposed estrogen, only women with a uterus should take a progestogen along with estrogen.
• Lack of endometrial safety data prevents NAMS from recommending long-cycle progestogen (eg, 12 to 14 days every 3 to 6 months), progestogen intrauterine systems, or low-dose estrogen without progestogen.
• A progestogen is usually not necessary with use of low-dose vaginal estrogen.⁵ However, separate from the NAMS statement is a Cochrane review of the use of vaginally administered estrogens that recommends further investigation of long-term endometrial safety with use of vaginal estrogen beyond 6 months.⁶

Cardiac and cerebrovascular disease

• HT is not recommended for prevention of coronary heart disease (CHD) at any age, pending new data to the contrary.
• HT should not be used for prevention of stroke and should be discouraged in women who have an increased risk of stroke.

Venous thromboembolism

• HT increases the risk of venous thrombosis and venous thromboembolism (VTE).

Diabetes mellitus

• Both ET and EPT reduced the risk of incident diabetes mellitus requiring treatment (by 12% and 21%, respectively, relative to placebo in the WHI).
• Evidence is insufficient to recommend HT solely for the prevention of diabetes mellitus.

Breast cancer

• EPT increased the risk of breast cancer in the WHI, but ET did not.
• Both ET and EPT increase breast cell proliferation, breast pain, and mammographic density. Diagnosis of cancer may be delayed.

Osteoporosis

• Both ET and EPT reduce the risk of postmenopausal fractures.
• HT is an option for reducing the risk of osteoporosis after the risks and benefits are weighed against those of other therapies.

Premature menopause and premature ovarian failure

• The absolute risks posed by ET and EPT may be lower in women with premature menopause or premature ovarian failure because of the lower incidence of CHD, stroke, and VTE in younger women. The risk-benefit ratio of HT is likely to be more favorable in this younger age group, but this has not yet been demonstrated.

Extended use of HT

• Extended use of HT may be considered in women who decide that menopausal symptom relief out­weighs the risks of HT, particularly after an attempt to stop HT has failed.
• Extended use may be appropriate for women with vasomotor symptoms at high risk of osteoporosis-related fracture.
• Extended use may be considered for the prevention of further bone loss in women with established low bone mass when other therapies are contraindicated or are not well tolerated.

Caution on use of “bioidentical” hormones

• In the absence of further data, compounded “bioidentical” hormone preparations should be presumed to carry the known risks and benefits of HT.
• The lack of regulatory oversight with regard to purity and consistency of bioidenticals prompts caution in their use.

Areas of nonconsensus

The NAMS panel did not reach consensus on the best way to discontinue HT or on the relative safety of continuous versus sequential use of progestogen along with estrogen. Lack of data and conflicting data prevented consensus in these two areas.

 

 

UPDATES FROM THE WOMEN’S HEALTH INITIATIVE

Since the publication of the 2007 NAMS position statement, three additional important analyses have emerged from the WHI randomized trial. The first report, by Rossouw et al, examined the effects of HT on the risk of cardiovascular disease (CVD) and other outcomes according to age and time since menopause.² The second analysis, by Manson et al, was a post hoc study of the extent of coronary artery calcification in the 50- to 59-year-old group in the ET arm of the WHI.³ The third analysis, by Heiss et al, reported health outcomes at 2.4 years after treatment was stopped in the EPT arm of the WHI.⁴

Cardiovascular results

The analysis by Rossouw et al of the CVD effects of HT by age and years since menopause has been reported in detail in the preceding paper by Hodis. In brief, the authors concluded that the data confirm a very low risk for women in their 50s who use HT for menopausal symptoms. The authors cautioned that the low risk from ages 50 to 59 does not guarantee lack of harm with prolonged use into older ages. Stroke and thrombosis risk were not dependent on years since menopause.

The WHI Coronary Artery Calcium Study was conducted in the ET arm approximately 1.3 years after the intervention (ET or placebo) was discontinued.3 Participants had completed a mean 7.4 years of intervention. The 1,064 eligible and available participants were aged 50 to 59 at WHI baseline. They underwent computed tomography of the heart. More than half of the women had a coronary artery calcium (CAC) score of 0. Overall, the mean CAC score was 83.1 among those randomized to ET and 123.1 among those randomized to placebo (P = .02). Classic CVD risk factors such as smoking, diabetes, hypertension, and high cholesterol were also associated with increased CAC scores, but they did not significantly modify the effect of ET on CAC. The authors cautioned that because of the multiple and complex effects of estrogen in the cardiovascular system, further study should be completed before ET is used for prevention of CAC.

Postintervention assessment

The third key HT-related WHI paper⁴ published since the 2007 NAMS position statement is the first to report the health events that occurred in the EPT arm since discontinuation of the study drugs.

Design and end points. The intervention phase of the WHI trial of EPT included 16,608 postmenopausal women (with intact uterus) aged 50 to 79 years at baseline who were randomized to treatment with EPT or placebo for a mean of 5.6 years before the treatment intervention was discontinued in July 2002 because the overall health risks of EPT were found to exceed the health benefits. Of these original participants, 15,730 women (95%) completed a planned postintervention follow-up consisting of semi-annual monitoring for adjudicated outcomes from July 2002 through March 2005. The mean duration of postintervention follow-up was 2.4 years.⁴

The primary outcomes of this postintervention analysis were CVD events and invasive breast cancer. These end points, together with endometrial cancer, colorectal cancer, stroke, pulmonary embolism, hip fracture, and death, were also factored into a global index of risks versus benefits with EPT.

Results. CVD. There was neither an elevated risk nor a decreased risk of CHD after discontinuation of EPT (hazard ratio [HR] = 0.95; 95% CI, 0.73 to 1.26). Risks that were elevated in the intervention phase, such as deep vein thrombosis (DVT) and stroke, disappeared after EPT was stopped. Women originally randomized to EPT had a similar rate of all CVD events compared with those who had been randomized to placebo (HR = 1.04; 95% CI, 0.89 to 1.21).

Breast and other cancers. The annualized incidence of invasive breast cancer in the postintervention period was 0.42% in the group that had been randomized to EPT versus 0.33% in the group randomized to placebo. This translated to a nonsignificant HR of 1.27 (95% CI, 0.91 to 1.78) for the postintervention period. In contrast, the annualized rate of all cancers (endometrial, colorectal, and breast combined) in the postintervention period was significantly higher in the EPT group (1.56%) than in the placebo group (1.26%) (HR = 1.24; 95% CI, 1.04 to 1.48). More extensive analysis of this finding is under way.

The cancer findings from this 2.4-year postintervention phase of the WHI parallel those from the 2.7-year postintervention phase of the Heart and Estrogen/progestin Replacement Study (HERS), in which between-group differences in the rates of breast and colon cancers approached null as the incidences of lung and other cancers increased in the group that had been randomized to EPT.⁷

Fractures. During the intervention phase, EPT was associated with a significant reduction in fractures; however, the EPT fracture benefit disappeared within the 2.4-year follow-up period.

Mortality. There was little difference in all-cause mortality between the treatment groups in the intervention phase. Although the difference was not statistically significant, there was a 15% higher mortality rate in the EPT group during the postintervention phase (HR = 1.15; 95% CI, 0.95 to 1.39). Contributing in part to this difference was an increased risk of mortality from lung cancer that requires further exploration.

Global index. The global index of risks versus benefits from enrollment to the present analysis remained significantly elevated (HR = 1.12; 95% CI, 1.03 to 1.21), suggesting more risk than benefit from use of EPT. The increase in the global index loses significance when the postintervention phase is considered alone (HR = 1.11; 95% CI, 0.99 to 1.27).

Conclusions. The researchers concluded that a number of outcome patterns observed with EPT in the intervention period of the WHI randomized trial did not persist during the 3-year postintervention follow-up:

• CHD, DVT, and stroke risks disappeared
• Hip fracture and total fracture benefits disappeared
• The composite risk of all cancers increased and was statistically significant in the postintervention phase, although the elevated risk of breast cancer was no longer statistically significant in the postintervention phase.

Summary of the new WHI reports

These three recent papers from the WHI suggest lower risks with short-term use of EPT in women ages 50 to 59 compared with older women. A delay in atherosclerosis and a decrease in all-cause mortality were also noted in this age group. The postintervention follow-up findings of a rapid disappearance of most risks and benefits of EPT will be of interest to patients who want to know what to expect when they discontinue HT. The late development (in years 5 to 8) of an increase in the composite risk of all cancers merits further investigation.

In March 2007, the North American Menopause Society (NAMS) issued an updated evidence-based position statement on the risks and benefits of hormone therapy (HT) in peri- and post-menopausal women.¹ This article will briefly review the major conclusions of that position statement and review three new reports from the Women’s Health Initiative (WHI) published after the NAMS position statement.^2–4 The objective is to update clinicians on current recommendations on the use of HT and to assess, together with the preceding article in this supplement by Hodis, emerging data that will inform future recommendations.

TAKE-HOME POINTS FROM THE UPDATED NAMS POSITION STATEMENT

The 2007 NAMS position statement on HT was developed by 14 expert clinicians and researchers who used previous NAMS position statements on the topic from 2002, 2003, and 2004 as a basis. The experts then reviewed all relevant subsequent evidence from a comprehensive literature search to determine areas of consensus and nonconsensus. Twenty-four areas of consensus and two areas of nonconsensus were identified, which represented a clear increase in consensus relative to the prior NAMS position statements. Thirty-two areas were identified as requiring further research.

Key recommendations and observations from the 2007 NAMS position statement are cited below, in many cases verbatim or near verbatim to preserve the intent.¹

Highlights of the NAMS position statement

Terminology

NAMS proposes adoption of the following terminology:

• Estrogen therapy (ET) for use of unopposed estrogen
• Estrogen-progestogen therapy (EPT) for combined use of estrogen and progestogen
• Hormone therapy (HT) to include both ET and EPT
• Progestogen to include both progesterone and progestins.

Indications for HT

• Treatment of moderate to severe vasomotor symptoms
• Treatment of moderate to severe vulvovaginal symptoms. When ET is being used only for this symptom, NAMS recommends local (vaginal) delivery.

Use of a progestogen

• Because the primary purpose of progestogen use is to prevent the endometrial cancer associated with unopposed estrogen, only women with a uterus should take a progestogen along with estrogen.
• Lack of endometrial safety data prevents NAMS from recommending long-cycle progestogen (eg, 12 to 14 days every 3 to 6 months), progestogen intrauterine systems, or low-dose estrogen without progestogen.
• A progestogen is usually not necessary with use of low-dose vaginal estrogen.⁵ However, separate from the NAMS statement is a Cochrane review of the use of vaginally administered estrogens that recommends further investigation of long-term endometrial safety with use of vaginal estrogen beyond 6 months.⁶

Cardiac and cerebrovascular disease

• HT is not recommended for prevention of coronary heart disease (CHD) at any age, pending new data to the contrary.
• HT should not be used for prevention of stroke and should be discouraged in women who have an increased risk of stroke.

Venous thromboembolism

• HT increases the risk of venous thrombosis and venous thromboembolism (VTE).

Diabetes mellitus

• Both ET and EPT reduced the risk of incident diabetes mellitus requiring treatment (by 12% and 21%, respectively, relative to placebo in the WHI).
• Evidence is insufficient to recommend HT solely for the prevention of diabetes mellitus.

Breast cancer

• EPT increased the risk of breast cancer in the WHI, but ET did not.
• Both ET and EPT increase breast cell proliferation, breast pain, and mammographic density. Diagnosis of cancer may be delayed.

Osteoporosis

• Both ET and EPT reduce the risk of postmenopausal fractures.
• HT is an option for reducing the risk of osteoporosis after the risks and benefits are weighed against those of other therapies.

Premature menopause and premature ovarian failure

• The absolute risks posed by ET and EPT may be lower in women with premature menopause or premature ovarian failure because of the lower incidence of CHD, stroke, and VTE in younger women. The risk-benefit ratio of HT is likely to be more favorable in this younger age group, but this has not yet been demonstrated.

Extended use of HT

• Extended use of HT may be considered in women who decide that menopausal symptom relief out­weighs the risks of HT, particularly after an attempt to stop HT has failed.
• Extended use may be appropriate for women with vasomotor symptoms at high risk of osteoporosis-related fracture.
• Extended use may be considered for the prevention of further bone loss in women with established low bone mass when other therapies are contraindicated or are not well tolerated.

Caution on use of “bioidentical” hormones

• In the absence of further data, compounded “bioidentical” hormone preparations should be presumed to carry the known risks and benefits of HT.
• The lack of regulatory oversight with regard to purity and consistency of bioidenticals prompts caution in their use.

Areas of nonconsensus

The NAMS panel did not reach consensus on the best way to discontinue HT or on the relative safety of continuous versus sequential use of progestogen along with estrogen. Lack of data and conflicting data prevented consensus in these two areas.

 

 

UPDATES FROM THE WOMEN’S HEALTH INITIATIVE

Since the publication of the 2007 NAMS position statement, three additional important analyses have emerged from the WHI randomized trial. The first report, by Rossouw et al, examined the effects of HT on the risk of cardiovascular disease (CVD) and other outcomes according to age and time since menopause.² The second analysis, by Manson et al, was a post hoc study of the extent of coronary artery calcification in the 50- to 59-year-old group in the ET arm of the WHI.³ The third analysis, by Heiss et al, reported health outcomes at 2.4 years after treatment was stopped in the EPT arm of the WHI.⁴

Cardiovascular results

The analysis by Rossouw et al of the CVD effects of HT by age and years since menopause has been reported in detail in the preceding paper by Hodis. In brief, the authors concluded that the data confirm a very low risk for women in their 50s who use HT for menopausal symptoms. The authors cautioned that the low risk from ages 50 to 59 does not guarantee lack of harm with prolonged use into older ages. Stroke and thrombosis risk were not dependent on years since menopause.

The WHI Coronary Artery Calcium Study was conducted in the ET arm approximately 1.3 years after the intervention (ET or placebo) was discontinued.3 Participants had completed a mean 7.4 years of intervention. The 1,064 eligible and available participants were aged 50 to 59 at WHI baseline. They underwent computed tomography of the heart. More than half of the women had a coronary artery calcium (CAC) score of 0. Overall, the mean CAC score was 83.1 among those randomized to ET and 123.1 among those randomized to placebo (P = .02). Classic CVD risk factors such as smoking, diabetes, hypertension, and high cholesterol were also associated with increased CAC scores, but they did not significantly modify the effect of ET on CAC. The authors cautioned that because of the multiple and complex effects of estrogen in the cardiovascular system, further study should be completed before ET is used for prevention of CAC.

Postintervention assessment

The third key HT-related WHI paper⁴ published since the 2007 NAMS position statement is the first to report the health events that occurred in the EPT arm since discontinuation of the study drugs.

Design and end points. The intervention phase of the WHI trial of EPT included 16,608 postmenopausal women (with intact uterus) aged 50 to 79 years at baseline who were randomized to treatment with EPT or placebo for a mean of 5.6 years before the treatment intervention was discontinued in July 2002 because the overall health risks of EPT were found to exceed the health benefits. Of these original participants, 15,730 women (95%) completed a planned postintervention follow-up consisting of semi-annual monitoring for adjudicated outcomes from July 2002 through March 2005. The mean duration of postintervention follow-up was 2.4 years.⁴

The primary outcomes of this postintervention analysis were CVD events and invasive breast cancer. These end points, together with endometrial cancer, colorectal cancer, stroke, pulmonary embolism, hip fracture, and death, were also factored into a global index of risks versus benefits with EPT.

Results. CVD. There was neither an elevated risk nor a decreased risk of CHD after discontinuation of EPT (hazard ratio [HR] = 0.95; 95% CI, 0.73 to 1.26). Risks that were elevated in the intervention phase, such as deep vein thrombosis (DVT) and stroke, disappeared after EPT was stopped. Women originally randomized to EPT had a similar rate of all CVD events compared with those who had been randomized to placebo (HR = 1.04; 95% CI, 0.89 to 1.21).

Breast and other cancers. The annualized incidence of invasive breast cancer in the postintervention period was 0.42% in the group that had been randomized to EPT versus 0.33% in the group randomized to placebo. This translated to a nonsignificant HR of 1.27 (95% CI, 0.91 to 1.78) for the postintervention period. In contrast, the annualized rate of all cancers (endometrial, colorectal, and breast combined) in the postintervention period was significantly higher in the EPT group (1.56%) than in the placebo group (1.26%) (HR = 1.24; 95% CI, 1.04 to 1.48). More extensive analysis of this finding is under way.

The cancer findings from this 2.4-year postintervention phase of the WHI parallel those from the 2.7-year postintervention phase of the Heart and Estrogen/progestin Replacement Study (HERS), in which between-group differences in the rates of breast and colon cancers approached null as the incidences of lung and other cancers increased in the group that had been randomized to EPT.⁷

Fractures. During the intervention phase, EPT was associated with a significant reduction in fractures; however, the EPT fracture benefit disappeared within the 2.4-year follow-up period.

Mortality. There was little difference in all-cause mortality between the treatment groups in the intervention phase. Although the difference was not statistically significant, there was a 15% higher mortality rate in the EPT group during the postintervention phase (HR = 1.15; 95% CI, 0.95 to 1.39). Contributing in part to this difference was an increased risk of mortality from lung cancer that requires further exploration.

Global index. The global index of risks versus benefits from enrollment to the present analysis remained significantly elevated (HR = 1.12; 95% CI, 1.03 to 1.21), suggesting more risk than benefit from use of EPT. The increase in the global index loses significance when the postintervention phase is considered alone (HR = 1.11; 95% CI, 0.99 to 1.27).

Conclusions. The researchers concluded that a number of outcome patterns observed with EPT in the intervention period of the WHI randomized trial did not persist during the 3-year postintervention follow-up:

• CHD, DVT, and stroke risks disappeared
• Hip fracture and total fracture benefits disappeared
• The composite risk of all cancers increased and was statistically significant in the postintervention phase, although the elevated risk of breast cancer was no longer statistically significant in the postintervention phase.

Summary of the new WHI reports

These three recent papers from the WHI suggest lower risks with short-term use of EPT in women ages 50 to 59 compared with older women. A delay in atherosclerosis and a decrease in all-cause mortality were also noted in this age group. The postintervention follow-up findings of a rapid disappearance of most risks and benefits of EPT will be of interest to patients who want to know what to expect when they discontinue HT. The late development (in years 5 to 8) of an increase in the composite risk of all cancers merits further investigation.

Dr. Holly Thacker: In light of the updates that Drs. Hodis and Gass have presented on hormone therapy (HT) for menopausal women and that Drs. Jenkins and Sikon have presented on nonhormonal options for menopausal management, let’s start our roundtable by considering a couple of case studies that will give us the chance to apply the latest data in a practical way.

CASE 1: A SYMPTOMATIC 67-YEAR-OLD IN WHOM HORMONE THERAPY WAS ABRUPTLY STOPPED

Dr. Margaret McKenzie: A 67-year-old menopausal woman presents for the evaluation of hot flashes, vaginal dryness causing dyspareunia, and decreased libido. She was previously on estrogen-progestogen therapy (EPT), consisting of daily conjugated equine estrogens and medroxyprogesterone acetate, for 15 years starting at the time of natural menopause. Her gynecologist discontinued this HT abruptly at the time of the initial release of data from the Women’s Health Initiative trial, and the patient is now seeking another opinion about resuming HT. When she presents, she has been off HT for less than 6 months. Would you restart HT in this patient?

Dr. Andrea Sikon: The abrupt discontinuation certainly contributes to her symptoms. The short duration of time off HT is important, and would lead me to restart HT after an updated review of risk factors. She had been on it for 15 years and has done fine, so she appears to be an ideal candidate to restart.

Dr. McKenzie: What specific questions would you ask when doing your risk assessment? How would you evaluate this patient to determine whether she is a good candidate to continue HT?

Dr. Thacker: I would obtain a family history. Using a population-based risk assessment such as the Gail model, I would calculate her absolute risk of breast cancer based on her duration of EPT use. I might offer her a lower-dose regimen. A conjugated equine estrogen dosage of 0.3 mg/day may be as effective in a 67-year-old woman as 0.625 mg/day is in a younger woman in terms of relieving vasomotor symptoms, depending on individual metabolism. We do have evidence from the HOPE trial that 0.3 mg/day is effective for relief of vasomotor symptoms.¹ In addition, data from the Nurses’ Health Study show no increased risk of stroke with 0.3 mg/day, as opposed to the increased risk with 0.625 mg/day, and there are other data showing that the risk of stroke is possibly related to dosage.²

At the same time, we do not yet have long-term data to show that the lower dose is necessarily safer and we do not have data on bone fracture risk with the lower dose, so I would want to know this patient’s bone mineral density (BMD). I would also want to know about her cardiovascular risk profile, including her lipid profile, and I would want more details about her sexual function.

Dr. McKenzie: I will supply a few more case details. This patient’s body mass index (BMI) was 24 kg/m². She exercised regularly. Her BMD was normal for her age. She was taking a statin to treat hyperlipidemia. She was a nonsmoker, and her family history was unremarkable. Does any of this information change the way that you would counsel her?

Dr. Howard Hodis: Knowing her BMI and that she was on a statin, I would have even less of a problem reinitiating HT.

Case continued

Dr. McKenzie: Well, EPT was reinitiated in this patient at a lower dose (0.45/1.5 mg), and she was satisfied. At her most recent visit, several years later, the possibility of reducing her dose of HT was offered; however, the patient is happy with her quality of life and accepts whatever risk that continued HT may bring. She inquired about transdermal testosterone to restore her sex drive, and it was agreed that if it receives US marketing approval for women with decreased libido, a 24-week trial would be attempted.

Dr. Hodis: If you look at the data, this patient not only may enhance her quality of life by continuing HT but might extend it as well.

Dr. Thacker: Many patients inquire about using testosterone only, without estrogen, for treating dyspareunia and low libido. Clinicians must understand that testosterone is aromatized to estrogen. If a patient is on a high dose of oral estrogen, I would consider switching to transdermal estrogen before trying testosterone, whose use in women remains off-label in the United States. But the patient in our case has been doing well for several years on low-dose estrogen and she still has her ovaries.

Dr. Margery Gass: Some colleagues and I completed a study, which was presented at a recent Endocrine Society meeting,³ in which transdermal testosterone was just as effective without estrogen in increasing libido. But this remains moot for general clinical practice unless the transdermal testosterone patch is approved in this country (as it is already approved for use in women in Europe).

Dr. Hodis: Would any of you be worried about this patient’s fracture risk after having HT stopped following 15 years of use? Data show that the rate of bone loss after abrupt cessation of HT is just as great as when a woman is going through menopause.

Dr. Gass: Yes, and that is exactly the point. The woman should be assessed under these circumstances just as she would be at menopause, using the same risk factors.

Dr. Thacker: I think that underscores that there is risk in stopping treatment, just as there is in taking treatment or not taking treatment, and all of these risks should be considered. Many times, once a patient is off HT, some clinicians forget to check the patient’s BMD or to do a complete genital examination.

Dr. Sikon: Many providers who do not specialize in women’s health may forget that when HT is stopped, it is as if a newly menopausal state is being created. Providers need to think about ensuing changes in bone and genitourinary status as well as quality-of-life concerns.

Dr. McKenzie: In today’s clinical environment, there is awareness of the importance of long-term bone health because patients are living longer. The use of BMD measurements in practice is clearly expanding.

Dr. Thacker: It is worth noting that all of the drugs used to treat osteoporosis have been studied primarily in women who already have osteoporosis. The therapy with the most data to support a reduction in the risk of all types of fracture is HT. These data are very impressive, and although fracture prevention would not be the sole reason for using HT, it can make the overall risk-benefit assessment easier, particularly if it can be determined whether or not an individual patient is at high risk of venous thromboembolism (VTE).

 

 

CASE 2: A SYMPTOMATIC 47-YEAR-OLD WITH A HISTORY OF BREAST CANCER

Dr. McKenzie: A 47-year-old postmenopausal woman with a 7-year history of breast cancer presents for the management of hot flashes, irritability, and reduced sleep. In addition, recent onset of vaginal dryness is causing dyspareunia that is not alleviated by lubricants. Her breast cancer was estrogen receptor (ER)/progesterone receptor (PR)–positive, and she received tamoxifen therapy for 5 years (now completed) following the initial diagnosis and management. How would you approach the management of this patient?

Dr. Marjorie Jenkins: I would first try to determine the severity of her hot flashes and how much her symptoms are affecting her quality of life. She may say that she is still having hot flashes, but how frequent are they? Do they cause nighttime awakening and subsequent fatigue?

Dr. McKenzie: The reason this patient presented was to ask for some form of relief because her symptoms were affecting her quality of life. Her dyspareunia was getting worse. She was trying various lubricants without success. At the same time, she expressed fear because her tumor was ER/PR-positive. Most cancer survivors have recurrence in the back of their mind even though they are in remission.

Dr. Jenkins: Was she asking specifically about HT or about help to relieve her symptoms?

Dr. McKenzie: She was asking for help for her symptoms.

Dr. Jenkins: I would consider low-dose vaginal estrogen to address her dyspareunia. I would also consider a serotonin-norepinephrine reuptake inhibitor, such as venlafaxine, to treat her hot flashes and irritability, along with lifestyle modifications, although the latter do not have evidence-based support. If these measures failed to offer relief, I would reconsider the risks and benefits of low-dose HT. I would call her oncologist for input if I planned to start vaginal estrogen, low-dose topical testosterone, or any type of hormonal treatment. I would make sure that the patient knew that her oncologist was working as part of the team responsible for her management.

Dr. Thacker: I concur. When I see hormonally sensitive breast cancer patients with vaginal symptoms, particularly when they are taking tamoxifen, I often talk to them about local estrogen before vaginal atrophy becomes severe. Once the atrophy becomes severe, local estrogen, even in low doses, may be absorbed systemically (increasing the risk of endometrial hyperplasia) until the the vagina becomes re-estrogenized and stratified with healthy squamous epithelium. Once this restratification takes place, there are generally no systemic hormonal effects with low-dose local vaginal estrogen, but it is best to avoid severe atrophy in the first place. I like to start local estrogen early if I know that the oncologist wants to use an aromatase inhibitor in a breast cancer survivor. I prescribe the low-dose vaginal form frequently in my practice, and order transvaginal ultrasonography liberally if there is concern about the endometrium.

Additionally, I would offer this patient venlafaxine or, more specifically, desvenlafaxine, as the literature has shown that the latter agent is associated with an improvement in sleep.⁴ (Currently, desvenlafaxine has been approved by the US Food and Drug Administration [FDA] solely to treat major depression; however, it has been studied in nondepressed women with hot flashes and is expected to be the first nonhormonal agent to receive FDA approval specifically to treat hot flashes.)

Dr. Gass: This patient still has her uterus in place. Data show that estrogens have a first-pass uterine effect, and this gives me pause because estrogen levels could well be higher in the uterus than in the bloodstream. Because of those data, as well as the absence of long-term safety data, the use of estrogen in this patient would cause me concern.

With breast cancer patients in particular, I try everything else to treat vaginal dryness before adding estrogen. I believe that if a patient is having dyspareunia despite the use of adequate lubricants, something else is the problem. In many cases these women have not had intercourse for months because they have been undergoing treatment for breast cancer, and they can have hallmark pain syndromes or constriction of the vagina that may require treatments besides just estrogen. If all else failed, I would prescribe vaginal estrogen on a temporary basis. Women who stay sexually active after menopause can do perfectly fine without treatment, but those who have periods of abstinence and then try to resume sexual activity typically run into problems.

Dr. Hodis: Would you have concern about breast cancer recurrence with estrogen reinitiation, based on the literature?

Dr. Gass: I have seen recurrences out to 20 years after the initial cancer. If the cancer does recur, the woman will always have a nagging doubt that it could have been avoided if she had not used estrogen.

Dr. Thacker: We have many breast cancer survivors in our practice. It is an easier decision to give estrogen to women who have had bilateral mastectomy with reconstruction for a stage I breast cancer and have already had a hysterectomy or bilateral salpingo­oophorectomy. But we otherwise try to avoid it unless the patient has first tried everything else and is miserable from her vaginal symptoms.

Dr. Gass: When a patient is diagnosed with breast cancer, I gently encourage her to continue sexual activity through the course of treatment, explaining that she may be far better off later. It may avoid a lot of problems if we can proactively get that message across.

Dr. Jenkins: That is a great point, and there is evidence that increased sexual activity decreases vaginal atrophy and assists in maintaining vaginal elasticity and the ability of urogenital congestion with arousal. Although lubricants and moisturizers do work well, they may require repeated application, and inelasticity is still a problem for some patients. It is somewhat of a “use it or lose it” proposition.

Dr. Thacker: Recurrent urinary tract infections (UTIs) are a problem as well. Patients see urologists, undergo multiple endoscopies, and are treated with antibiotics, sometimes chronically, yet often they are not even offered local vaginal estrogen, which reduces recurrent UTIs. Local estrogen should be considered in any woman with vaginal atrophy and recurrent UTIs.

Case continued

Dr. McKenzie: To return to our case, this patient’s vagina was, in fact, severely constricted because she had not been sexually active for a while. Her BMI was initially greater than 25 kg/m², but she lost weight and became more symptomatic as she did so. She then stopped having sex because it was painful.

When she presented initially, she had a package of black cohosh with her and was willing to try it for her symptoms but was apprehensive after reading the disclaimers in the package. A 47-year-old who has already been diagnosed with ER-positive breast cancer is generally anxious about using any therapies that may be associated with an increased risk of breast cancer.

After examination of her vagina, her oncologist was consulted and suggested that her serum estradiol levels be measured; they were less than 20 pg/mL. We then agreed to a trial of estradiol vaginal tablets, vaginal dilators, and an increase in her sexual activity. She has been on vaginal estradiol for 2 years and is functioning very well. Her hot flashes improved spontaneously as her body adapted to her new weight.

 

 

BEYOND THE CASES: OTHER CHALLENGES IN MENOPAUSAL MANAGEMENT

HT discontinuation, dose reduction in real-world practice

Dr. Thacker: The first case we covered touched on both discontinuation of HT and HT dosage reduction. These are issues that come up often in clinical practice; what lessons does the panel have to share on these issues?

Dr. Gass: I find that there is a small subset of women who are highly symptomatic and are probably always going to be miserable whenever they try to go off HT. For some, if they are highly symptomatic at menopause, they tend to stay that way. They may try to go off, but a year later, they come back and say, “I am just too miserable.”

Dr. McKenzie: In my practice, I have noticed patients who end up staying on higher doses of HT for a long period because they do not tolerate weaning. If you take them down to 0.625 mg of estrogen, their hot flashes resume, so they seem to require 0.9 mg.

Dr. Thacker: I have a very small subset of those women too. I wonder if their metabolism is different; maybe 0.9 mg of conjugated equine estrogens is to them what 0.3 mg is to other women. As women get older, perhaps metabolic changes are one reason that many can reduce their hormone dosage. It is very challenging. I tell my students that it is much easier trying to determine how much thyroid hormone replacement to give a patient than how much estrogen.

When does transdermal estrogen make sense?

Dr. Sikon: I would be interested in the rest of the panel’s views on management of a woman in her early postmenopausal years who is symptomatic and has been on oral HT and is also a smoker. Would you switch her to transdermal estrogen or continue her oral HT and continue aggressive smoking cessation counseling?

Dr. Thacker: Many practitioners think that a smoker cannot take any type of HT because they equate it to oral/hormonal contraceptives, which increase the risk of heart attack in smokers over age 35, but hormonal contraceptives are different in that they involve a much higher dose of hormone. In my practice, the cases when I will offer transdermal estrogen are generally when a patient has gastrointestinal upset, known gallbladder disease, elevated triglycerides, or a prior deep vein thrombosis (DVT), even though I will tell the patient that the HT-associated risks are still possible with transdermal therapies. Many women are inappropriately and inaccurately told that compounded transdermal therapies are “risk free.”

Dr. McKenzie: Transdermal estrogen is also an option for patients who are poor pill takers or are already taking too many pills. Many of my patients are on transdermal estrogen for the convenience that it offers. It is unfortunate that transdermal progesterone cream does not protect the endometrium in all patients; for women with a uterus, an oral progestogen needs to be prescribed. However, two transdermal patches containing progestogens have been shown to be efficacious in protecting the endometrium.

How should a history of DVT affect decision-making?

Dr. McKenzie: What do you do when a patient has a history of postoperative DVT and is already on HT? How many of the panel would discontinue the HT as opposed to continuing it?

Dr. Hodis: If it were a history of spontaneous DVT, I would feel uncomfortable continuing HT. A few years ago, a clinical trial was stopped early because women with a prior spontaneous DVT who were randomized to HT had a substantial increase in DVT incidence relative to those randomized to placebo.⁵ In the case of provoked or postoperative DVT, it may be a tougher call.

Dr. Thacker: I think that DVT is the greatest risk with HT, even though the media are more focused on breast cancer risk. The risk of breast cancer with estrogen alone is debatable, at least with oral conjugated estrogen, which was associated with a decreased risk in women who had undergone hysterectomy in the Women’s Health Initiative (WHI).⁶

When I see a woman with a history of DVT in my practice, I check her homocysteine levels and check for factor V Leiden and prothrombin gene mutation. If I find an inherited hypercoagulability disorder, I tell the patient that her risk of DVT with any type of hormone product is not just multiplicative, it is logarithmic. If the patient already requires lifelong anticoagulation, then I am a bit more comfortable with prescribing HT and I usually will try the transdermal route first; however, I always consider nonhormonal treatment alternatives first.

Dr. Gass: The WHI was supposed to have excluded women with a history of DVT, but a few such women were enrolled, and it was demonstrated that they were at higher risk of DVT recurrence if randomized to HT. The majority of DVT episodes in the WHI were spontaneous, not related to surgical procedures.

Dr. Jenkins: I have a patient who had been on low-dose HT for 30 years and underwent lumbar spine surgery. She had a somewhat prolonged recovery, so her lack of mobility and her age clearly increased her risk of DVT. So she was taken off HT and became miserable from the resulting hot flashes and sleep disturbance. We thoroughly discussed the risks and benefits of restarting HT, and because she was taking warfarin, we felt comfortable restarting the HT.

Women with spontaneous DVT are a different case, however, and I have an issue with restarting oral or transdermal HT in those cases. However, if we discuss the data with these patients and document the significant risks of HT in their cases, some may want to accept the increased risk in order to improve their quality of life, and that may be reasonable if they are truly fully informed.

Dr. Thacker: What about a woman who has been on oral contraceptives for several years and has not had a DVT? Is the safe use of oral/ hormonal contraceptives something you take into account, Dr. Gass, in your decision whether to prescribe HT?

Dr. Gass: Yes, that can be reassuring. Twenty-seven percent of EPT participants and 49% of estrogen therapy (ET) participants in the WHI randomized trial had used hormones in the past, so it was as if they were already tested for an early risk of blood clots.⁷

What role for SERMs (estrogen agonists/antagonists)?

Dr. Thacker: I would like to discuss the use of estrogen agonists/estogen antagonists, formerly known as selective estrogen receptor modulators (SERMs), such as raloxifene. Raloxifene now has an indication for breast cancer prevention as well as for reduction of vertebral fractures. I don’t know if there is adequate recognition among practitioners that SERMs appear to be associated with the same risk of DVT that estrogen is, and a greater risk of fatal stroke.

Dr. Jenkins: I find the lack of hip fracture data with raloxifene concerning, because hip fracture carries the highest 5-year mortality of any type of fracture. Raloxifene therefore is not a first-line agent for bone loss in my practice. But we also have to consider the patient’s risk of breast cancer and whether or not she has been on tamoxifen and now needs an agent to protect her against fracture. The question is whether we should consider starting these patients on raloxifene versus a bisphosphonate.

Dr. Thacker: Dr. Gass, do you think that raloxifene is safe for the endometrium? For years, we did not know the full effects of tamoxifen on the endometrium; it took experience with millions of patients to find out that tamoxifen increases the risk of endometrial cancer.

Dr. Gass: I do think that raloxifene is safer. I use it in my practice primarily for women younger than age 65 who are not yet at high risk for hip fracture but are still concerned about breast cancer. Although this concern diminishes as women age without having developed breast cancer, for younger women, who may see their friends getting breast cancer, it is a major concern. So if a patient is a good candidate for a bone loss agent and also has concern about breast cancer, raloxifene can be a good option, especially since we do not know what the implications are of taking bisphosphonates for 30 years. Questions about that are starting to be raised, so I think it is good to consider a sequential approach for some of these patients. A sequential approach might involve use of HT in a symptomatic menopausal woman, followed by use of raloxifene after the woman no longer has menopausal symptoms but is concerned about spine fracture protection and breast cancer risk reduction, followed by bisphosphonate use as she gets older and is at increased risk for stroke/VTE and for hip fracture.

 

 

The challenge of educating younger doctors about HT

Dr. Thacker: I think we need to find ways to translate the data on HT to younger generations of physicians, because the closer one is to graduating from medical school, the less likely he or she is to offer HT to an otherwise healthy, severely symptomatic woman younger than age 60.

Dr. McKenzie: Absolutely, and I think the real challenge is to reach younger physicians who go into private practice, who generally have the fewest opportunities to stay on top of the latest evidence. We must offer evidence-based education programs on this topic to physicians in the community to ensure that they are equipped to understand and explain the real risks and benefits of HT in order to individualize treatment decisions.

As a physician at a tertiary care center, I am surprised at the number of women referred to me who should have already been on HT for menopausal symptoms, but their physicians were unduly influenced by the initial WHI publication. They need to thoroughly evaluate their patients, assess their risks, assess any new medical problems, try to educate them, and then tailor therapy to improve their patients’ quality of life.

Correcting misperceptions: WHI was not a treatment trial

Dr. Thacker: I believe that many practitioners and especially students do not realize that the WHI was a trial designed to assess prevention of chronic diseases. It was not a menopausal treatment trial, and often its data are being misapplied to women who are different from the ones enrolled in the WHI, in that they are younger and more symptomatic.

Dr. Gass: It is correct that the WHI was not a treatment trial, but that was how HT was being used by some physicians and patients prior to the WHI. Physicians in this country were giving some 65-year-old women HT for osteoporosis and dementia. These practices needed to be supported with data, and that was the impetus behind the trial. Along the same lines, it is important how we present the risks to patients. If HT is being used as a therapy for a woman suffering from menopausal symptoms, she might be willing to accept more risk than if it is being used like a vitamin pill, to promote general health, in which case the risks should be virtually nil because the woman is healthy and without complaints.

Dr. Thacker: Yes, and that is why I think the earlier discussion of comparable risks of breast cancer, stroke, and VTE with aspirin, SERMs, fibric acid derivatives, and statins helps to put the risks of HT in perspective. It appears that physicians and patients tolerate very similar risks with commonly used nonhormonal medicines in women but do not tolerate any risks with HT, even in symptomatic women. In my opinion, this is a medical travesty. It is important to recognize that there are few absolutes in medicine that apply to all patients. The only universal recommendations I make to all patients are to wear seatbelts and not to smoke.

Dr. Hodis: What I find notable is that with HT we see a reduction in mortality regardless of the risks that we have described. As the observational data show, if we start HT and continue it, there is a reduction in mortality of 30% or even greater, and the clinical trial data tend to support this benefit. So why do we shy away from HT? Because we are worried about a small increase in breast cancer diagnoses or a small increase in DVT? That is an issue I am grappling with.

Dr. Thacker: Similarly, how do you reconcile the observational data with aspirin? In the Nurses’ Health Study, the aspirin users had lower mortality, but in all of the randomized controlled trials in midlife women, we do not see a reduction in cardiovascular risk with aspirin, let alone a reduction in mortality. So, the people who self-select for treatment are obviously different from those enrolled in randomized trials. The randomized controlled trial may be our gold standard, but it is not necessarily the only evidence to consider.

Dr. Hodis: But there is a concordance between observational studies and randomized trials with respect to overall mortality and HT. The data from a meta-analysis of 30 randomized trials⁸ are consistent with the data from observational studies, even though they do identify risks. I wonder how many more women would select HT if we told them about the 30% reduction in mortality despite the possibility of breast cancer diagnosis and DVT risks.

Dr. Gass: Women will select according to their own agenda.

Dr. Hodis: Yes, in the end, it is all individualized.

Dr. Gass: Indeed, because women have specific concerns, such as breast cancer, fracture risk, or Alzheimer disease, and they base their personal decisions on these specific concerns. I educate them about the risks and benefits, and they pretty much decide for themselves. They know their priorities.

Age and the risk-benefit assessment with HT

Dr. Thacker: Does the panel have any comments on the recent position statement from the American Association of Clinical Endocrinologists concluding that the benefits of HT exceed the risks in symptomatic women younger than age 60?

Dr. Hodis: My only comment is to ask why it took them so long to come to that conclusion.

Dr. Thacker: We could say the same for the North American Menopause Society (NAMS). It was not until its 2007 position statement on the use of ET and EPT in perimenopausal and postmenopausal women that NAMS moved beyond the issue of a time limit for HT—the “lowest dose for the shortest amount of time” mantra—and recommended the type of reevaluation used with any other treatment.

It seems as if practitioners are less willing to tolerate the risks of HT in older women than to tolerate the risks of hormonal contraceptives in younger women. Perhaps that is because hormonal contraceptives prevent pregnancy and the risks associated with it, yet this same value is not afforded to the symptoms and other effects suffered by postmenopausal women. I think we did afford HT similar value as hormonal contraceptives in the 1980s and 1990s, when we were trying to promote the potential health benefits of HT before we had bisphosphonates and statins and before we realized the risks of VTE with HT, risks that were identified much sooner with hormonal contraceptives. Since then the medical community has overcorrected by too often dismissing HT, overemphasizing the risks and ignoring very important quality-of-life issues, including sex and sleep disturbances, in the process.

Dr. Jenkins: Also, too many people associate menopause only with hot flashes, without taking into account the increased risk of serious diseases that may occur at this time, such as osteoporosis and heart disease.

Dr. Thacker: That may be because menopause is a normal event. It can be a great time of life for many women; in fact, it is associated with lower rates of depression, unless there is a prolonged symptomatic perimenopause. Menopause is certainly not a disease, and NAMS has been very good at recognizing and promoting it as a normal phase of life. But to neglect treating a woman going through menopausal symptoms just because menopause is a normal life event would be akin to withholding assistance for women during childbirth, which is another natural event.

We fail from a medical perspective if we do not take care of symptomatic women, because they will then turn to people who are not physicians and who offer unregulated therapies. These people may deliver the right message—that menopausal women deserve to feel well and look good—but the way they tell women to treat menopausal symptoms is not science-based.

At one time, we were overtreating women and not individualizing therapy, but to me it is even more worrisome to withhold therapies unless women are so highly symptomatic that they consider ending their life. We are continuing to discover the risks and benefits of HT and how to further tailor it. We have many newer, lower-dose HT options, and we are expecting the first nonhormonal therapy for menopausal vasomotor symptoms, desvenlafaxine. We are fortunate to have bone agents and local vaginal therapies for women without vasomotor symptoms. With both hormonal and nonhormonal options, we must keep the risks and benefits of any therapy in perspective.

CONCLUSIONS

Dr. Thacker: This has been a great discussion, and although we do not all agree on every point, I would like to conclude by summarizing some key points on which I think we do all agree (see sidebar above). Menopause is a normal life event, but for some women who are symptomatic, and for a smaller percentage who will be symptomatic for the rest of their lives, HT is the gold standard, although it does not treat all symptoms and has some well-defined risks. We do have other options on the horizon for relief of vasomotor symptoms, for bone health, and for urogenital atrophy.

Following the data on the effects of HT on cardiovascular health will be particularly interesting. Although there is not support for using HT specifically for cardiovascular prevention, there are provocative data that in the symptomatic woman who has self-selected it, HT has cardiovascular benefit and reduces the risk of diabetes.

A woman on HT who has not had “early harm” does not need to arbitrarily discontinue therapy based on any time limit, as long as she is being periodically reevaluated and is offered individualized options.

Dr. Holly Thacker: In light of the updates that Drs. Hodis and Gass have presented on hormone therapy (HT) for menopausal women and that Drs. Jenkins and Sikon have presented on nonhormonal options for menopausal management, let’s start our roundtable by considering a couple of case studies that will give us the chance to apply the latest data in a practical way.

CASE 1: A SYMPTOMATIC 67-YEAR-OLD IN WHOM HORMONE THERAPY WAS ABRUPTLY STOPPED

Dr. Margaret McKenzie: A 67-year-old menopausal woman presents for the evaluation of hot flashes, vaginal dryness causing dyspareunia, and decreased libido. She was previously on estrogen-progestogen therapy (EPT), consisting of daily conjugated equine estrogens and medroxyprogesterone acetate, for 15 years starting at the time of natural menopause. Her gynecologist discontinued this HT abruptly at the time of the initial release of data from the Women’s Health Initiative trial, and the patient is now seeking another opinion about resuming HT. When she presents, she has been off HT for less than 6 months. Would you restart HT in this patient?

Dr. Andrea Sikon: The abrupt discontinuation certainly contributes to her symptoms. The short duration of time off HT is important, and would lead me to restart HT after an updated review of risk factors. She had been on it for 15 years and has done fine, so she appears to be an ideal candidate to restart.

Dr. McKenzie: What specific questions would you ask when doing your risk assessment? How would you evaluate this patient to determine whether she is a good candidate to continue HT?

Dr. Thacker: I would obtain a family history. Using a population-based risk assessment such as the Gail model, I would calculate her absolute risk of breast cancer based on her duration of EPT use. I might offer her a lower-dose regimen. A conjugated equine estrogen dosage of 0.3 mg/day may be as effective in a 67-year-old woman as 0.625 mg/day is in a younger woman in terms of relieving vasomotor symptoms, depending on individual metabolism. We do have evidence from the HOPE trial that 0.3 mg/day is effective for relief of vasomotor symptoms.¹ In addition, data from the Nurses’ Health Study show no increased risk of stroke with 0.3 mg/day, as opposed to the increased risk with 0.625 mg/day, and there are other data showing that the risk of stroke is possibly related to dosage.²

At the same time, we do not yet have long-term data to show that the lower dose is necessarily safer and we do not have data on bone fracture risk with the lower dose, so I would want to know this patient’s bone mineral density (BMD). I would also want to know about her cardiovascular risk profile, including her lipid profile, and I would want more details about her sexual function.

Dr. McKenzie: I will supply a few more case details. This patient’s body mass index (BMI) was 24 kg/m². She exercised regularly. Her BMD was normal for her age. She was taking a statin to treat hyperlipidemia. She was a nonsmoker, and her family history was unremarkable. Does any of this information change the way that you would counsel her?

Dr. Howard Hodis: Knowing her BMI and that she was on a statin, I would have even less of a problem reinitiating HT.

Case continued

Dr. McKenzie: Well, EPT was reinitiated in this patient at a lower dose (0.45/1.5 mg), and she was satisfied. At her most recent visit, several years later, the possibility of reducing her dose of HT was offered; however, the patient is happy with her quality of life and accepts whatever risk that continued HT may bring. She inquired about transdermal testosterone to restore her sex drive, and it was agreed that if it receives US marketing approval for women with decreased libido, a 24-week trial would be attempted.

Dr. Hodis: If you look at the data, this patient not only may enhance her quality of life by continuing HT but might extend it as well.

Dr. Thacker: Many patients inquire about using testosterone only, without estrogen, for treating dyspareunia and low libido. Clinicians must understand that testosterone is aromatized to estrogen. If a patient is on a high dose of oral estrogen, I would consider switching to transdermal estrogen before trying testosterone, whose use in women remains off-label in the United States. But the patient in our case has been doing well for several years on low-dose estrogen and she still has her ovaries.

Dr. Margery Gass: Some colleagues and I completed a study, which was presented at a recent Endocrine Society meeting,³ in which transdermal testosterone was just as effective without estrogen in increasing libido. But this remains moot for general clinical practice unless the transdermal testosterone patch is approved in this country (as it is already approved for use in women in Europe).

Dr. Hodis: Would any of you be worried about this patient’s fracture risk after having HT stopped following 15 years of use? Data show that the rate of bone loss after abrupt cessation of HT is just as great as when a woman is going through menopause.

Dr. Gass: Yes, and that is exactly the point. The woman should be assessed under these circumstances just as she would be at menopause, using the same risk factors.

Dr. Thacker: I think that underscores that there is risk in stopping treatment, just as there is in taking treatment or not taking treatment, and all of these risks should be considered. Many times, once a patient is off HT, some clinicians forget to check the patient’s BMD or to do a complete genital examination.

Dr. Sikon: Many providers who do not specialize in women’s health may forget that when HT is stopped, it is as if a newly menopausal state is being created. Providers need to think about ensuing changes in bone and genitourinary status as well as quality-of-life concerns.

Dr. McKenzie: In today’s clinical environment, there is awareness of the importance of long-term bone health because patients are living longer. The use of BMD measurements in practice is clearly expanding.

Dr. Thacker: It is worth noting that all of the drugs used to treat osteoporosis have been studied primarily in women who already have osteoporosis. The therapy with the most data to support a reduction in the risk of all types of fracture is HT. These data are very impressive, and although fracture prevention would not be the sole reason for using HT, it can make the overall risk-benefit assessment easier, particularly if it can be determined whether or not an individual patient is at high risk of venous thromboembolism (VTE).

 

 

CASE 2: A SYMPTOMATIC 47-YEAR-OLD WITH A HISTORY OF BREAST CANCER

Dr. McKenzie: A 47-year-old postmenopausal woman with a 7-year history of breast cancer presents for the management of hot flashes, irritability, and reduced sleep. In addition, recent onset of vaginal dryness is causing dyspareunia that is not alleviated by lubricants. Her breast cancer was estrogen receptor (ER)/progesterone receptor (PR)–positive, and she received tamoxifen therapy for 5 years (now completed) following the initial diagnosis and management. How would you approach the management of this patient?

Dr. Marjorie Jenkins: I would first try to determine the severity of her hot flashes and how much her symptoms are affecting her quality of life. She may say that she is still having hot flashes, but how frequent are they? Do they cause nighttime awakening and subsequent fatigue?

Dr. McKenzie: The reason this patient presented was to ask for some form of relief because her symptoms were affecting her quality of life. Her dyspareunia was getting worse. She was trying various lubricants without success. At the same time, she expressed fear because her tumor was ER/PR-positive. Most cancer survivors have recurrence in the back of their mind even though they are in remission.

Dr. Jenkins: Was she asking specifically about HT or about help to relieve her symptoms?

Dr. McKenzie: She was asking for help for her symptoms.

Dr. Jenkins: I would consider low-dose vaginal estrogen to address her dyspareunia. I would also consider a serotonin-norepinephrine reuptake inhibitor, such as venlafaxine, to treat her hot flashes and irritability, along with lifestyle modifications, although the latter do not have evidence-based support. If these measures failed to offer relief, I would reconsider the risks and benefits of low-dose HT. I would call her oncologist for input if I planned to start vaginal estrogen, low-dose topical testosterone, or any type of hormonal treatment. I would make sure that the patient knew that her oncologist was working as part of the team responsible for her management.

Dr. Thacker: I concur. When I see hormonally sensitive breast cancer patients with vaginal symptoms, particularly when they are taking tamoxifen, I often talk to them about local estrogen before vaginal atrophy becomes severe. Once the atrophy becomes severe, local estrogen, even in low doses, may be absorbed systemically (increasing the risk of endometrial hyperplasia) until the the vagina becomes re-estrogenized and stratified with healthy squamous epithelium. Once this restratification takes place, there are generally no systemic hormonal effects with low-dose local vaginal estrogen, but it is best to avoid severe atrophy in the first place. I like to start local estrogen early if I know that the oncologist wants to use an aromatase inhibitor in a breast cancer survivor. I prescribe the low-dose vaginal form frequently in my practice, and order transvaginal ultrasonography liberally if there is concern about the endometrium.

Additionally, I would offer this patient venlafaxine or, more specifically, desvenlafaxine, as the literature has shown that the latter agent is associated with an improvement in sleep.⁴ (Currently, desvenlafaxine has been approved by the US Food and Drug Administration [FDA] solely to treat major depression; however, it has been studied in nondepressed women with hot flashes and is expected to be the first nonhormonal agent to receive FDA approval specifically to treat hot flashes.)

Dr. Gass: This patient still has her uterus in place. Data show that estrogens have a first-pass uterine effect, and this gives me pause because estrogen levels could well be higher in the uterus than in the bloodstream. Because of those data, as well as the absence of long-term safety data, the use of estrogen in this patient would cause me concern.

With breast cancer patients in particular, I try everything else to treat vaginal dryness before adding estrogen. I believe that if a patient is having dyspareunia despite the use of adequate lubricants, something else is the problem. In many cases these women have not had intercourse for months because they have been undergoing treatment for breast cancer, and they can have hallmark pain syndromes or constriction of the vagina that may require treatments besides just estrogen. If all else failed, I would prescribe vaginal estrogen on a temporary basis. Women who stay sexually active after menopause can do perfectly fine without treatment, but those who have periods of abstinence and then try to resume sexual activity typically run into problems.

Dr. Hodis: Would you have concern about breast cancer recurrence with estrogen reinitiation, based on the literature?

Dr. Gass: I have seen recurrences out to 20 years after the initial cancer. If the cancer does recur, the woman will always have a nagging doubt that it could have been avoided if she had not used estrogen.

Dr. Thacker: We have many breast cancer survivors in our practice. It is an easier decision to give estrogen to women who have had bilateral mastectomy with reconstruction for a stage I breast cancer and have already had a hysterectomy or bilateral salpingo­oophorectomy. But we otherwise try to avoid it unless the patient has first tried everything else and is miserable from her vaginal symptoms.

Dr. Gass: When a patient is diagnosed with breast cancer, I gently encourage her to continue sexual activity through the course of treatment, explaining that she may be far better off later. It may avoid a lot of problems if we can proactively get that message across.

Dr. Jenkins: That is a great point, and there is evidence that increased sexual activity decreases vaginal atrophy and assists in maintaining vaginal elasticity and the ability of urogenital congestion with arousal. Although lubricants and moisturizers do work well, they may require repeated application, and inelasticity is still a problem for some patients. It is somewhat of a “use it or lose it” proposition.

Dr. Thacker: Recurrent urinary tract infections (UTIs) are a problem as well. Patients see urologists, undergo multiple endoscopies, and are treated with antibiotics, sometimes chronically, yet often they are not even offered local vaginal estrogen, which reduces recurrent UTIs. Local estrogen should be considered in any woman with vaginal atrophy and recurrent UTIs.

Case continued

Dr. McKenzie: To return to our case, this patient’s vagina was, in fact, severely constricted because she had not been sexually active for a while. Her BMI was initially greater than 25 kg/m², but she lost weight and became more symptomatic as she did so. She then stopped having sex because it was painful.

When she presented initially, she had a package of black cohosh with her and was willing to try it for her symptoms but was apprehensive after reading the disclaimers in the package. A 47-year-old who has already been diagnosed with ER-positive breast cancer is generally anxious about using any therapies that may be associated with an increased risk of breast cancer.

After examination of her vagina, her oncologist was consulted and suggested that her serum estradiol levels be measured; they were less than 20 pg/mL. We then agreed to a trial of estradiol vaginal tablets, vaginal dilators, and an increase in her sexual activity. She has been on vaginal estradiol for 2 years and is functioning very well. Her hot flashes improved spontaneously as her body adapted to her new weight.

 

 

BEYOND THE CASES: OTHER CHALLENGES IN MENOPAUSAL MANAGEMENT

HT discontinuation, dose reduction in real-world practice

Dr. Thacker: The first case we covered touched on both discontinuation of HT and HT dosage reduction. These are issues that come up often in clinical practice; what lessons does the panel have to share on these issues?

Dr. Gass: I find that there is a small subset of women who are highly symptomatic and are probably always going to be miserable whenever they try to go off HT. For some, if they are highly symptomatic at menopause, they tend to stay that way. They may try to go off, but a year later, they come back and say, “I am just too miserable.”

Dr. McKenzie: In my practice, I have noticed patients who end up staying on higher doses of HT for a long period because they do not tolerate weaning. If you take them down to 0.625 mg of estrogen, their hot flashes resume, so they seem to require 0.9 mg.

Dr. Thacker: I have a very small subset of those women too. I wonder if their metabolism is different; maybe 0.9 mg of conjugated equine estrogens is to them what 0.3 mg is to other women. As women get older, perhaps metabolic changes are one reason that many can reduce their hormone dosage. It is very challenging. I tell my students that it is much easier trying to determine how much thyroid hormone replacement to give a patient than how much estrogen.

When does transdermal estrogen make sense?

Dr. Sikon: I would be interested in the rest of the panel’s views on management of a woman in her early postmenopausal years who is symptomatic and has been on oral HT and is also a smoker. Would you switch her to transdermal estrogen or continue her oral HT and continue aggressive smoking cessation counseling?

Dr. Thacker: Many practitioners think that a smoker cannot take any type of HT because they equate it to oral/hormonal contraceptives, which increase the risk of heart attack in smokers over age 35, but hormonal contraceptives are different in that they involve a much higher dose of hormone. In my practice, the cases when I will offer transdermal estrogen are generally when a patient has gastrointestinal upset, known gallbladder disease, elevated triglycerides, or a prior deep vein thrombosis (DVT), even though I will tell the patient that the HT-associated risks are still possible with transdermal therapies. Many women are inappropriately and inaccurately told that compounded transdermal therapies are “risk free.”

Dr. McKenzie: Transdermal estrogen is also an option for patients who are poor pill takers or are already taking too many pills. Many of my patients are on transdermal estrogen for the convenience that it offers. It is unfortunate that transdermal progesterone cream does not protect the endometrium in all patients; for women with a uterus, an oral progestogen needs to be prescribed. However, two transdermal patches containing progestogens have been shown to be efficacious in protecting the endometrium.

How should a history of DVT affect decision-making?

Dr. McKenzie: What do you do when a patient has a history of postoperative DVT and is already on HT? How many of the panel would discontinue the HT as opposed to continuing it?

Dr. Hodis: If it were a history of spontaneous DVT, I would feel uncomfortable continuing HT. A few years ago, a clinical trial was stopped early because women with a prior spontaneous DVT who were randomized to HT had a substantial increase in DVT incidence relative to those randomized to placebo.⁵ In the case of provoked or postoperative DVT, it may be a tougher call.

Dr. Thacker: I think that DVT is the greatest risk with HT, even though the media are more focused on breast cancer risk. The risk of breast cancer with estrogen alone is debatable, at least with oral conjugated estrogen, which was associated with a decreased risk in women who had undergone hysterectomy in the Women’s Health Initiative (WHI).⁶

When I see a woman with a history of DVT in my practice, I check her homocysteine levels and check for factor V Leiden and prothrombin gene mutation. If I find an inherited hypercoagulability disorder, I tell the patient that her risk of DVT with any type of hormone product is not just multiplicative, it is logarithmic. If the patient already requires lifelong anticoagulation, then I am a bit more comfortable with prescribing HT and I usually will try the transdermal route first; however, I always consider nonhormonal treatment alternatives first.

Dr. Gass: The WHI was supposed to have excluded women with a history of DVT, but a few such women were enrolled, and it was demonstrated that they were at higher risk of DVT recurrence if randomized to HT. The majority of DVT episodes in the WHI were spontaneous, not related to surgical procedures.

Dr. Jenkins: I have a patient who had been on low-dose HT for 30 years and underwent lumbar spine surgery. She had a somewhat prolonged recovery, so her lack of mobility and her age clearly increased her risk of DVT. So she was taken off HT and became miserable from the resulting hot flashes and sleep disturbance. We thoroughly discussed the risks and benefits of restarting HT, and because she was taking warfarin, we felt comfortable restarting the HT.

Women with spontaneous DVT are a different case, however, and I have an issue with restarting oral or transdermal HT in those cases. However, if we discuss the data with these patients and document the significant risks of HT in their cases, some may want to accept the increased risk in order to improve their quality of life, and that may be reasonable if they are truly fully informed.

Dr. Thacker: What about a woman who has been on oral contraceptives for several years and has not had a DVT? Is the safe use of oral/ hormonal contraceptives something you take into account, Dr. Gass, in your decision whether to prescribe HT?

Dr. Gass: Yes, that can be reassuring. Twenty-seven percent of EPT participants and 49% of estrogen therapy (ET) participants in the WHI randomized trial had used hormones in the past, so it was as if they were already tested for an early risk of blood clots.⁷

What role for SERMs (estrogen agonists/antagonists)?

Dr. Thacker: I would like to discuss the use of estrogen agonists/estogen antagonists, formerly known as selective estrogen receptor modulators (SERMs), such as raloxifene. Raloxifene now has an indication for breast cancer prevention as well as for reduction of vertebral fractures. I don’t know if there is adequate recognition among practitioners that SERMs appear to be associated with the same risk of DVT that estrogen is, and a greater risk of fatal stroke.

Dr. Jenkins: I find the lack of hip fracture data with raloxifene concerning, because hip fracture carries the highest 5-year mortality of any type of fracture. Raloxifene therefore is not a first-line agent for bone loss in my practice. But we also have to consider the patient’s risk of breast cancer and whether or not she has been on tamoxifen and now needs an agent to protect her against fracture. The question is whether we should consider starting these patients on raloxifene versus a bisphosphonate.

Dr. Thacker: Dr. Gass, do you think that raloxifene is safe for the endometrium? For years, we did not know the full effects of tamoxifen on the endometrium; it took experience with millions of patients to find out that tamoxifen increases the risk of endometrial cancer.

Dr. Gass: I do think that raloxifene is safer. I use it in my practice primarily for women younger than age 65 who are not yet at high risk for hip fracture but are still concerned about breast cancer. Although this concern diminishes as women age without having developed breast cancer, for younger women, who may see their friends getting breast cancer, it is a major concern. So if a patient is a good candidate for a bone loss agent and also has concern about breast cancer, raloxifene can be a good option, especially since we do not know what the implications are of taking bisphosphonates for 30 years. Questions about that are starting to be raised, so I think it is good to consider a sequential approach for some of these patients. A sequential approach might involve use of HT in a symptomatic menopausal woman, followed by use of raloxifene after the woman no longer has menopausal symptoms but is concerned about spine fracture protection and breast cancer risk reduction, followed by bisphosphonate use as she gets older and is at increased risk for stroke/VTE and for hip fracture.

 

 

The challenge of educating younger doctors about HT

Dr. Thacker: I think we need to find ways to translate the data on HT to younger generations of physicians, because the closer one is to graduating from medical school, the less likely he or she is to offer HT to an otherwise healthy, severely symptomatic woman younger than age 60.

Dr. McKenzie: Absolutely, and I think the real challenge is to reach younger physicians who go into private practice, who generally have the fewest opportunities to stay on top of the latest evidence. We must offer evidence-based education programs on this topic to physicians in the community to ensure that they are equipped to understand and explain the real risks and benefits of HT in order to individualize treatment decisions.

As a physician at a tertiary care center, I am surprised at the number of women referred to me who should have already been on HT for menopausal symptoms, but their physicians were unduly influenced by the initial WHI publication. They need to thoroughly evaluate their patients, assess their risks, assess any new medical problems, try to educate them, and then tailor therapy to improve their patients’ quality of life.

Correcting misperceptions: WHI was not a treatment trial

Dr. Thacker: I believe that many practitioners and especially students do not realize that the WHI was a trial designed to assess prevention of chronic diseases. It was not a menopausal treatment trial, and often its data are being misapplied to women who are different from the ones enrolled in the WHI, in that they are younger and more symptomatic.

Dr. Gass: It is correct that the WHI was not a treatment trial, but that was how HT was being used by some physicians and patients prior to the WHI. Physicians in this country were giving some 65-year-old women HT for osteoporosis and dementia. These practices needed to be supported with data, and that was the impetus behind the trial. Along the same lines, it is important how we present the risks to patients. If HT is being used as a therapy for a woman suffering from menopausal symptoms, she might be willing to accept more risk than if it is being used like a vitamin pill, to promote general health, in which case the risks should be virtually nil because the woman is healthy and without complaints.

Dr. Thacker: Yes, and that is why I think the earlier discussion of comparable risks of breast cancer, stroke, and VTE with aspirin, SERMs, fibric acid derivatives, and statins helps to put the risks of HT in perspective. It appears that physicians and patients tolerate very similar risks with commonly used nonhormonal medicines in women but do not tolerate any risks with HT, even in symptomatic women. In my opinion, this is a medical travesty. It is important to recognize that there are few absolutes in medicine that apply to all patients. The only universal recommendations I make to all patients are to wear seatbelts and not to smoke.

Dr. Hodis: What I find notable is that with HT we see a reduction in mortality regardless of the risks that we have described. As the observational data show, if we start HT and continue it, there is a reduction in mortality of 30% or even greater, and the clinical trial data tend to support this benefit. So why do we shy away from HT? Because we are worried about a small increase in breast cancer diagnoses or a small increase in DVT? That is an issue I am grappling with.

Dr. Thacker: Similarly, how do you reconcile the observational data with aspirin? In the Nurses’ Health Study, the aspirin users had lower mortality, but in all of the randomized controlled trials in midlife women, we do not see a reduction in cardiovascular risk with aspirin, let alone a reduction in mortality. So, the people who self-select for treatment are obviously different from those enrolled in randomized trials. The randomized controlled trial may be our gold standard, but it is not necessarily the only evidence to consider.

Dr. Hodis: But there is a concordance between observational studies and randomized trials with respect to overall mortality and HT. The data from a meta-analysis of 30 randomized trials⁸ are consistent with the data from observational studies, even though they do identify risks. I wonder how many more women would select HT if we told them about the 30% reduction in mortality despite the possibility of breast cancer diagnosis and DVT risks.

Dr. Gass: Women will select according to their own agenda.

Dr. Hodis: Yes, in the end, it is all individualized.

Dr. Gass: Indeed, because women have specific concerns, such as breast cancer, fracture risk, or Alzheimer disease, and they base their personal decisions on these specific concerns. I educate them about the risks and benefits, and they pretty much decide for themselves. They know their priorities.

Age and the risk-benefit assessment with HT

Dr. Thacker: Does the panel have any comments on the recent position statement from the American Association of Clinical Endocrinologists concluding that the benefits of HT exceed the risks in symptomatic women younger than age 60?

Dr. Hodis: My only comment is to ask why it took them so long to come to that conclusion.

Dr. Thacker: We could say the same for the North American Menopause Society (NAMS). It was not until its 2007 position statement on the use of ET and EPT in perimenopausal and postmenopausal women that NAMS moved beyond the issue of a time limit for HT—the “lowest dose for the shortest amount of time” mantra—and recommended the type of reevaluation used with any other treatment.

It seems as if practitioners are less willing to tolerate the risks of HT in older women than to tolerate the risks of hormonal contraceptives in younger women. Perhaps that is because hormonal contraceptives prevent pregnancy and the risks associated with it, yet this same value is not afforded to the symptoms and other effects suffered by postmenopausal women. I think we did afford HT similar value as hormonal contraceptives in the 1980s and 1990s, when we were trying to promote the potential health benefits of HT before we had bisphosphonates and statins and before we realized the risks of VTE with HT, risks that were identified much sooner with hormonal contraceptives. Since then the medical community has overcorrected by too often dismissing HT, overemphasizing the risks and ignoring very important quality-of-life issues, including sex and sleep disturbances, in the process.

Dr. Jenkins: Also, too many people associate menopause only with hot flashes, without taking into account the increased risk of serious diseases that may occur at this time, such as osteoporosis and heart disease.

Dr. Thacker: That may be because menopause is a normal event. It can be a great time of life for many women; in fact, it is associated with lower rates of depression, unless there is a prolonged symptomatic perimenopause. Menopause is certainly not a disease, and NAMS has been very good at recognizing and promoting it as a normal phase of life. But to neglect treating a woman going through menopausal symptoms just because menopause is a normal life event would be akin to withholding assistance for women during childbirth, which is another natural event.

We fail from a medical perspective if we do not take care of symptomatic women, because they will then turn to people who are not physicians and who offer unregulated therapies. These people may deliver the right message—that menopausal women deserve to feel well and look good—but the way they tell women to treat menopausal symptoms is not science-based.

At one time, we were overtreating women and not individualizing therapy, but to me it is even more worrisome to withhold therapies unless women are so highly symptomatic that they consider ending their life. We are continuing to discover the risks and benefits of HT and how to further tailor it. We have many newer, lower-dose HT options, and we are expecting the first nonhormonal therapy for menopausal vasomotor symptoms, desvenlafaxine. We are fortunate to have bone agents and local vaginal therapies for women without vasomotor symptoms. With both hormonal and nonhormonal options, we must keep the risks and benefits of any therapy in perspective.

CONCLUSIONS

Dr. Thacker: This has been a great discussion, and although we do not all agree on every point, I would like to conclude by summarizing some key points on which I think we do all agree (see sidebar above). Menopause is a normal life event, but for some women who are symptomatic, and for a smaller percentage who will be symptomatic for the rest of their lives, HT is the gold standard, although it does not treat all symptoms and has some well-defined risks. We do have other options on the horizon for relief of vasomotor symptoms, for bone health, and for urogenital atrophy.

Following the data on the effects of HT on cardiovascular health will be particularly interesting. Although there is not support for using HT specifically for cardiovascular prevention, there are provocative data that in the symptomatic woman who has self-selected it, HT has cardiovascular benefit and reduces the risk of diabetes.

A woman on HT who has not had “early harm” does not need to arbitrarily discontinue therapy based on any time limit, as long as she is being periodically reevaluated and is offered individualized options.

Dr. Holly Thacker: In light of the updates that Drs. Hodis and Gass have presented on hormone therapy (HT) for menopausal women and that Drs. Jenkins and Sikon have presented on nonhormonal options for menopausal management, let’s start our roundtable by considering a couple of case studies that will give us the chance to apply the latest data in a practical way.

CASE 1: A SYMPTOMATIC 67-YEAR-OLD IN WHOM HORMONE THERAPY WAS ABRUPTLY STOPPED

Dr. Margaret McKenzie: A 67-year-old menopausal woman presents for the evaluation of hot flashes, vaginal dryness causing dyspareunia, and decreased libido. She was previously on estrogen-progestogen therapy (EPT), consisting of daily conjugated equine estrogens and medroxyprogesterone acetate, for 15 years starting at the time of natural menopause. Her gynecologist discontinued this HT abruptly at the time of the initial release of data from the Women’s Health Initiative trial, and the patient is now seeking another opinion about resuming HT. When she presents, she has been off HT for less than 6 months. Would you restart HT in this patient?

Dr. Andrea Sikon: The abrupt discontinuation certainly contributes to her symptoms. The short duration of time off HT is important, and would lead me to restart HT after an updated review of risk factors. She had been on it for 15 years and has done fine, so she appears to be an ideal candidate to restart.

Dr. McKenzie: What specific questions would you ask when doing your risk assessment? How would you evaluate this patient to determine whether she is a good candidate to continue HT?

Dr. Thacker: I would obtain a family history. Using a population-based risk assessment such as the Gail model, I would calculate her absolute risk of breast cancer based on her duration of EPT use. I might offer her a lower-dose regimen. A conjugated equine estrogen dosage of 0.3 mg/day may be as effective in a 67-year-old woman as 0.625 mg/day is in a younger woman in terms of relieving vasomotor symptoms, depending on individual metabolism. We do have evidence from the HOPE trial that 0.3 mg/day is effective for relief of vasomotor symptoms.¹ In addition, data from the Nurses’ Health Study show no increased risk of stroke with 0.3 mg/day, as opposed to the increased risk with 0.625 mg/day, and there are other data showing that the risk of stroke is possibly related to dosage.²

At the same time, we do not yet have long-term data to show that the lower dose is necessarily safer and we do not have data on bone fracture risk with the lower dose, so I would want to know this patient’s bone mineral density (BMD). I would also want to know about her cardiovascular risk profile, including her lipid profile, and I would want more details about her sexual function.

Dr. McKenzie: I will supply a few more case details. This patient’s body mass index (BMI) was 24 kg/m². She exercised regularly. Her BMD was normal for her age. She was taking a statin to treat hyperlipidemia. She was a nonsmoker, and her family history was unremarkable. Does any of this information change the way that you would counsel her?

Dr. Howard Hodis: Knowing her BMI and that she was on a statin, I would have even less of a problem reinitiating HT.

Case continued

Dr. McKenzie: Well, EPT was reinitiated in this patient at a lower dose (0.45/1.5 mg), and she was satisfied. At her most recent visit, several years later, the possibility of reducing her dose of HT was offered; however, the patient is happy with her quality of life and accepts whatever risk that continued HT may bring. She inquired about transdermal testosterone to restore her sex drive, and it was agreed that if it receives US marketing approval for women with decreased libido, a 24-week trial would be attempted.

Dr. Hodis: If you look at the data, this patient not only may enhance her quality of life by continuing HT but might extend it as well.

Dr. Thacker: Many patients inquire about using testosterone only, without estrogen, for treating dyspareunia and low libido. Clinicians must understand that testosterone is aromatized to estrogen. If a patient is on a high dose of oral estrogen, I would consider switching to transdermal estrogen before trying testosterone, whose use in women remains off-label in the United States. But the patient in our case has been doing well for several years on low-dose estrogen and she still has her ovaries.

Dr. Margery Gass: Some colleagues and I completed a study, which was presented at a recent Endocrine Society meeting,³ in which transdermal testosterone was just as effective without estrogen in increasing libido. But this remains moot for general clinical practice unless the transdermal testosterone patch is approved in this country (as it is already approved for use in women in Europe).

Dr. Hodis: Would any of you be worried about this patient’s fracture risk after having HT stopped following 15 years of use? Data show that the rate of bone loss after abrupt cessation of HT is just as great as when a woman is going through menopause.

Dr. Gass: Yes, and that is exactly the point. The woman should be assessed under these circumstances just as she would be at menopause, using the same risk factors.

Dr. Thacker: I think that underscores that there is risk in stopping treatment, just as there is in taking treatment or not taking treatment, and all of these risks should be considered. Many times, once a patient is off HT, some clinicians forget to check the patient’s BMD or to do a complete genital examination.

Dr. Sikon: Many providers who do not specialize in women’s health may forget that when HT is stopped, it is as if a newly menopausal state is being created. Providers need to think about ensuing changes in bone and genitourinary status as well as quality-of-life concerns.

Dr. McKenzie: In today’s clinical environment, there is awareness of the importance of long-term bone health because patients are living longer. The use of BMD measurements in practice is clearly expanding.

Dr. Thacker: It is worth noting that all of the drugs used to treat osteoporosis have been studied primarily in women who already have osteoporosis. The therapy with the most data to support a reduction in the risk of all types of fracture is HT. These data are very impressive, and although fracture prevention would not be the sole reason for using HT, it can make the overall risk-benefit assessment easier, particularly if it can be determined whether or not an individual patient is at high risk of venous thromboembolism (VTE).

 

 

CASE 2: A SYMPTOMATIC 47-YEAR-OLD WITH A HISTORY OF BREAST CANCER

Dr. McKenzie: A 47-year-old postmenopausal woman with a 7-year history of breast cancer presents for the management of hot flashes, irritability, and reduced sleep. In addition, recent onset of vaginal dryness is causing dyspareunia that is not alleviated by lubricants. Her breast cancer was estrogen receptor (ER)/progesterone receptor (PR)–positive, and she received tamoxifen therapy for 5 years (now completed) following the initial diagnosis and management. How would you approach the management of this patient?

Dr. Marjorie Jenkins: I would first try to determine the severity of her hot flashes and how much her symptoms are affecting her quality of life. She may say that she is still having hot flashes, but how frequent are they? Do they cause nighttime awakening and subsequent fatigue?

Dr. McKenzie: The reason this patient presented was to ask for some form of relief because her symptoms were affecting her quality of life. Her dyspareunia was getting worse. She was trying various lubricants without success. At the same time, she expressed fear because her tumor was ER/PR-positive. Most cancer survivors have recurrence in the back of their mind even though they are in remission.

Dr. Jenkins: Was she asking specifically about HT or about help to relieve her symptoms?

Dr. McKenzie: She was asking for help for her symptoms.

Dr. Jenkins: I would consider low-dose vaginal estrogen to address her dyspareunia. I would also consider a serotonin-norepinephrine reuptake inhibitor, such as venlafaxine, to treat her hot flashes and irritability, along with lifestyle modifications, although the latter do not have evidence-based support. If these measures failed to offer relief, I would reconsider the risks and benefits of low-dose HT. I would call her oncologist for input if I planned to start vaginal estrogen, low-dose topical testosterone, or any type of hormonal treatment. I would make sure that the patient knew that her oncologist was working as part of the team responsible for her management.

Dr. Thacker: I concur. When I see hormonally sensitive breast cancer patients with vaginal symptoms, particularly when they are taking tamoxifen, I often talk to them about local estrogen before vaginal atrophy becomes severe. Once the atrophy becomes severe, local estrogen, even in low doses, may be absorbed systemically (increasing the risk of endometrial hyperplasia) until the the vagina becomes re-estrogenized and stratified with healthy squamous epithelium. Once this restratification takes place, there are generally no systemic hormonal effects with low-dose local vaginal estrogen, but it is best to avoid severe atrophy in the first place. I like to start local estrogen early if I know that the oncologist wants to use an aromatase inhibitor in a breast cancer survivor. I prescribe the low-dose vaginal form frequently in my practice, and order transvaginal ultrasonography liberally if there is concern about the endometrium.

Additionally, I would offer this patient venlafaxine or, more specifically, desvenlafaxine, as the literature has shown that the latter agent is associated with an improvement in sleep.⁴ (Currently, desvenlafaxine has been approved by the US Food and Drug Administration [FDA] solely to treat major depression; however, it has been studied in nondepressed women with hot flashes and is expected to be the first nonhormonal agent to receive FDA approval specifically to treat hot flashes.)

Dr. Gass: This patient still has her uterus in place. Data show that estrogens have a first-pass uterine effect, and this gives me pause because estrogen levels could well be higher in the uterus than in the bloodstream. Because of those data, as well as the absence of long-term safety data, the use of estrogen in this patient would cause me concern.

With breast cancer patients in particular, I try everything else to treat vaginal dryness before adding estrogen. I believe that if a patient is having dyspareunia despite the use of adequate lubricants, something else is the problem. In many cases these women have not had intercourse for months because they have been undergoing treatment for breast cancer, and they can have hallmark pain syndromes or constriction of the vagina that may require treatments besides just estrogen. If all else failed, I would prescribe vaginal estrogen on a temporary basis. Women who stay sexually active after menopause can do perfectly fine without treatment, but those who have periods of abstinence and then try to resume sexual activity typically run into problems.

Dr. Hodis: Would you have concern about breast cancer recurrence with estrogen reinitiation, based on the literature?

Dr. Gass: I have seen recurrences out to 20 years after the initial cancer. If the cancer does recur, the woman will always have a nagging doubt that it could have been avoided if she had not used estrogen.

Dr. Thacker: We have many breast cancer survivors in our practice. It is an easier decision to give estrogen to women who have had bilateral mastectomy with reconstruction for a stage I breast cancer and have already had a hysterectomy or bilateral salpingo­oophorectomy. But we otherwise try to avoid it unless the patient has first tried everything else and is miserable from her vaginal symptoms.

Dr. Gass: When a patient is diagnosed with breast cancer, I gently encourage her to continue sexual activity through the course of treatment, explaining that she may be far better off later. It may avoid a lot of problems if we can proactively get that message across.

Dr. Jenkins: That is a great point, and there is evidence that increased sexual activity decreases vaginal atrophy and assists in maintaining vaginal elasticity and the ability of urogenital congestion with arousal. Although lubricants and moisturizers do work well, they may require repeated application, and inelasticity is still a problem for some patients. It is somewhat of a “use it or lose it” proposition.

Dr. Thacker: Recurrent urinary tract infections (UTIs) are a problem as well. Patients see urologists, undergo multiple endoscopies, and are treated with antibiotics, sometimes chronically, yet often they are not even offered local vaginal estrogen, which reduces recurrent UTIs. Local estrogen should be considered in any woman with vaginal atrophy and recurrent UTIs.

Case continued

Dr. McKenzie: To return to our case, this patient’s vagina was, in fact, severely constricted because she had not been sexually active for a while. Her BMI was initially greater than 25 kg/m², but she lost weight and became more symptomatic as she did so. She then stopped having sex because it was painful.

When she presented initially, she had a package of black cohosh with her and was willing to try it for her symptoms but was apprehensive after reading the disclaimers in the package. A 47-year-old who has already been diagnosed with ER-positive breast cancer is generally anxious about using any therapies that may be associated with an increased risk of breast cancer.

After examination of her vagina, her oncologist was consulted and suggested that her serum estradiol levels be measured; they were less than 20 pg/mL. We then agreed to a trial of estradiol vaginal tablets, vaginal dilators, and an increase in her sexual activity. She has been on vaginal estradiol for 2 years and is functioning very well. Her hot flashes improved spontaneously as her body adapted to her new weight.

 

 

BEYOND THE CASES: OTHER CHALLENGES IN MENOPAUSAL MANAGEMENT

HT discontinuation, dose reduction in real-world practice

Dr. Thacker: The first case we covered touched on both discontinuation of HT and HT dosage reduction. These are issues that come up often in clinical practice; what lessons does the panel have to share on these issues?

Dr. Gass: I find that there is a small subset of women who are highly symptomatic and are probably always going to be miserable whenever they try to go off HT. For some, if they are highly symptomatic at menopause, they tend to stay that way. They may try to go off, but a year later, they come back and say, “I am just too miserable.”

Dr. McKenzie: In my practice, I have noticed patients who end up staying on higher doses of HT for a long period because they do not tolerate weaning. If you take them down to 0.625 mg of estrogen, their hot flashes resume, so they seem to require 0.9 mg.

Dr. Thacker: I have a very small subset of those women too. I wonder if their metabolism is different; maybe 0.9 mg of conjugated equine estrogens is to them what 0.3 mg is to other women. As women get older, perhaps metabolic changes are one reason that many can reduce their hormone dosage. It is very challenging. I tell my students that it is much easier trying to determine how much thyroid hormone replacement to give a patient than how much estrogen.

When does transdermal estrogen make sense?

Dr. Sikon: I would be interested in the rest of the panel’s views on management of a woman in her early postmenopausal years who is symptomatic and has been on oral HT and is also a smoker. Would you switch her to transdermal estrogen or continue her oral HT and continue aggressive smoking cessation counseling?

Dr. Thacker: Many practitioners think that a smoker cannot take any type of HT because they equate it to oral/hormonal contraceptives, which increase the risk of heart attack in smokers over age 35, but hormonal contraceptives are different in that they involve a much higher dose of hormone. In my practice, the cases when I will offer transdermal estrogen are generally when a patient has gastrointestinal upset, known gallbladder disease, elevated triglycerides, or a prior deep vein thrombosis (DVT), even though I will tell the patient that the HT-associated risks are still possible with transdermal therapies. Many women are inappropriately and inaccurately told that compounded transdermal therapies are “risk free.”

Dr. McKenzie: Transdermal estrogen is also an option for patients who are poor pill takers or are already taking too many pills. Many of my patients are on transdermal estrogen for the convenience that it offers. It is unfortunate that transdermal progesterone cream does not protect the endometrium in all patients; for women with a uterus, an oral progestogen needs to be prescribed. However, two transdermal patches containing progestogens have been shown to be efficacious in protecting the endometrium.

How should a history of DVT affect decision-making?

Dr. McKenzie: What do you do when a patient has a history of postoperative DVT and is already on HT? How many of the panel would discontinue the HT as opposed to continuing it?

Dr. Hodis: If it were a history of spontaneous DVT, I would feel uncomfortable continuing HT. A few years ago, a clinical trial was stopped early because women with a prior spontaneous DVT who were randomized to HT had a substantial increase in DVT incidence relative to those randomized to placebo.⁵ In the case of provoked or postoperative DVT, it may be a tougher call.

Dr. Thacker: I think that DVT is the greatest risk with HT, even though the media are more focused on breast cancer risk. The risk of breast cancer with estrogen alone is debatable, at least with oral conjugated estrogen, which was associated with a decreased risk in women who had undergone hysterectomy in the Women’s Health Initiative (WHI).⁶

When I see a woman with a history of DVT in my practice, I check her homocysteine levels and check for factor V Leiden and prothrombin gene mutation. If I find an inherited hypercoagulability disorder, I tell the patient that her risk of DVT with any type of hormone product is not just multiplicative, it is logarithmic. If the patient already requires lifelong anticoagulation, then I am a bit more comfortable with prescribing HT and I usually will try the transdermal route first; however, I always consider nonhormonal treatment alternatives first.

Dr. Gass: The WHI was supposed to have excluded women with a history of DVT, but a few such women were enrolled, and it was demonstrated that they were at higher risk of DVT recurrence if randomized to HT. The majority of DVT episodes in the WHI were spontaneous, not related to surgical procedures.

Dr. Jenkins: I have a patient who had been on low-dose HT for 30 years and underwent lumbar spine surgery. She had a somewhat prolonged recovery, so her lack of mobility and her age clearly increased her risk of DVT. So she was taken off HT and became miserable from the resulting hot flashes and sleep disturbance. We thoroughly discussed the risks and benefits of restarting HT, and because she was taking warfarin, we felt comfortable restarting the HT.

Women with spontaneous DVT are a different case, however, and I have an issue with restarting oral or transdermal HT in those cases. However, if we discuss the data with these patients and document the significant risks of HT in their cases, some may want to accept the increased risk in order to improve their quality of life, and that may be reasonable if they are truly fully informed.

Dr. Thacker: What about a woman who has been on oral contraceptives for several years and has not had a DVT? Is the safe use of oral/ hormonal contraceptives something you take into account, Dr. Gass, in your decision whether to prescribe HT?

Dr. Gass: Yes, that can be reassuring. Twenty-seven percent of EPT participants and 49% of estrogen therapy (ET) participants in the WHI randomized trial had used hormones in the past, so it was as if they were already tested for an early risk of blood clots.⁷

What role for SERMs (estrogen agonists/antagonists)?

Dr. Thacker: I would like to discuss the use of estrogen agonists/estogen antagonists, formerly known as selective estrogen receptor modulators (SERMs), such as raloxifene. Raloxifene now has an indication for breast cancer prevention as well as for reduction of vertebral fractures. I don’t know if there is adequate recognition among practitioners that SERMs appear to be associated with the same risk of DVT that estrogen is, and a greater risk of fatal stroke.

Dr. Jenkins: I find the lack of hip fracture data with raloxifene concerning, because hip fracture carries the highest 5-year mortality of any type of fracture. Raloxifene therefore is not a first-line agent for bone loss in my practice. But we also have to consider the patient’s risk of breast cancer and whether or not she has been on tamoxifen and now needs an agent to protect her against fracture. The question is whether we should consider starting these patients on raloxifene versus a bisphosphonate.

Dr. Thacker: Dr. Gass, do you think that raloxifene is safe for the endometrium? For years, we did not know the full effects of tamoxifen on the endometrium; it took experience with millions of patients to find out that tamoxifen increases the risk of endometrial cancer.

Dr. Gass: I do think that raloxifene is safer. I use it in my practice primarily for women younger than age 65 who are not yet at high risk for hip fracture but are still concerned about breast cancer. Although this concern diminishes as women age without having developed breast cancer, for younger women, who may see their friends getting breast cancer, it is a major concern. So if a patient is a good candidate for a bone loss agent and also has concern about breast cancer, raloxifene can be a good option, especially since we do not know what the implications are of taking bisphosphonates for 30 years. Questions about that are starting to be raised, so I think it is good to consider a sequential approach for some of these patients. A sequential approach might involve use of HT in a symptomatic menopausal woman, followed by use of raloxifene after the woman no longer has menopausal symptoms but is concerned about spine fracture protection and breast cancer risk reduction, followed by bisphosphonate use as she gets older and is at increased risk for stroke/VTE and for hip fracture.

 

 

The challenge of educating younger doctors about HT

Dr. Thacker: I think we need to find ways to translate the data on HT to younger generations of physicians, because the closer one is to graduating from medical school, the less likely he or she is to offer HT to an otherwise healthy, severely symptomatic woman younger than age 60.

Dr. McKenzie: Absolutely, and I think the real challenge is to reach younger physicians who go into private practice, who generally have the fewest opportunities to stay on top of the latest evidence. We must offer evidence-based education programs on this topic to physicians in the community to ensure that they are equipped to understand and explain the real risks and benefits of HT in order to individualize treatment decisions.

As a physician at a tertiary care center, I am surprised at the number of women referred to me who should have already been on HT for menopausal symptoms, but their physicians were unduly influenced by the initial WHI publication. They need to thoroughly evaluate their patients, assess their risks, assess any new medical problems, try to educate them, and then tailor therapy to improve their patients’ quality of life.

Correcting misperceptions: WHI was not a treatment trial

Dr. Thacker: I believe that many practitioners and especially students do not realize that the WHI was a trial designed to assess prevention of chronic diseases. It was not a menopausal treatment trial, and often its data are being misapplied to women who are different from the ones enrolled in the WHI, in that they are younger and more symptomatic.

Dr. Gass: It is correct that the WHI was not a treatment trial, but that was how HT was being used by some physicians and patients prior to the WHI. Physicians in this country were giving some 65-year-old women HT for osteoporosis and dementia. These practices needed to be supported with data, and that was the impetus behind the trial. Along the same lines, it is important how we present the risks to patients. If HT is being used as a therapy for a woman suffering from menopausal symptoms, she might be willing to accept more risk than if it is being used like a vitamin pill, to promote general health, in which case the risks should be virtually nil because the woman is healthy and without complaints.

Dr. Thacker: Yes, and that is why I think the earlier discussion of comparable risks of breast cancer, stroke, and VTE with aspirin, SERMs, fibric acid derivatives, and statins helps to put the risks of HT in perspective. It appears that physicians and patients tolerate very similar risks with commonly used nonhormonal medicines in women but do not tolerate any risks with HT, even in symptomatic women. In my opinion, this is a medical travesty. It is important to recognize that there are few absolutes in medicine that apply to all patients. The only universal recommendations I make to all patients are to wear seatbelts and not to smoke.

Dr. Hodis: What I find notable is that with HT we see a reduction in mortality regardless of the risks that we have described. As the observational data show, if we start HT and continue it, there is a reduction in mortality of 30% or even greater, and the clinical trial data tend to support this benefit. So why do we shy away from HT? Because we are worried about a small increase in breast cancer diagnoses or a small increase in DVT? That is an issue I am grappling with.

Dr. Thacker: Similarly, how do you reconcile the observational data with aspirin? In the Nurses’ Health Study, the aspirin users had lower mortality, but in all of the randomized controlled trials in midlife women, we do not see a reduction in cardiovascular risk with aspirin, let alone a reduction in mortality. So, the people who self-select for treatment are obviously different from those enrolled in randomized trials. The randomized controlled trial may be our gold standard, but it is not necessarily the only evidence to consider.

Dr. Hodis: But there is a concordance between observational studies and randomized trials with respect to overall mortality and HT. The data from a meta-analysis of 30 randomized trials⁸ are consistent with the data from observational studies, even though they do identify risks. I wonder how many more women would select HT if we told them about the 30% reduction in mortality despite the possibility of breast cancer diagnosis and DVT risks.

Dr. Gass: Women will select according to their own agenda.

Dr. Hodis: Yes, in the end, it is all individualized.

Dr. Gass: Indeed, because women have specific concerns, such as breast cancer, fracture risk, or Alzheimer disease, and they base their personal decisions on these specific concerns. I educate them about the risks and benefits, and they pretty much decide for themselves. They know their priorities.

Age and the risk-benefit assessment with HT

Dr. Thacker: Does the panel have any comments on the recent position statement from the American Association of Clinical Endocrinologists concluding that the benefits of HT exceed the risks in symptomatic women younger than age 60?

Dr. Hodis: My only comment is to ask why it took them so long to come to that conclusion.

Dr. Thacker: We could say the same for the North American Menopause Society (NAMS). It was not until its 2007 position statement on the use of ET and EPT in perimenopausal and postmenopausal women that NAMS moved beyond the issue of a time limit for HT—the “lowest dose for the shortest amount of time” mantra—and recommended the type of reevaluation used with any other treatment.

It seems as if practitioners are less willing to tolerate the risks of HT in older women than to tolerate the risks of hormonal contraceptives in younger women. Perhaps that is because hormonal contraceptives prevent pregnancy and the risks associated with it, yet this same value is not afforded to the symptoms and other effects suffered by postmenopausal women. I think we did afford HT similar value as hormonal contraceptives in the 1980s and 1990s, when we were trying to promote the potential health benefits of HT before we had bisphosphonates and statins and before we realized the risks of VTE with HT, risks that were identified much sooner with hormonal contraceptives. Since then the medical community has overcorrected by too often dismissing HT, overemphasizing the risks and ignoring very important quality-of-life issues, including sex and sleep disturbances, in the process.

Dr. Jenkins: Also, too many people associate menopause only with hot flashes, without taking into account the increased risk of serious diseases that may occur at this time, such as osteoporosis and heart disease.

Dr. Thacker: That may be because menopause is a normal event. It can be a great time of life for many women; in fact, it is associated with lower rates of depression, unless there is a prolonged symptomatic perimenopause. Menopause is certainly not a disease, and NAMS has been very good at recognizing and promoting it as a normal phase of life. But to neglect treating a woman going through menopausal symptoms just because menopause is a normal life event would be akin to withholding assistance for women during childbirth, which is another natural event.

We fail from a medical perspective if we do not take care of symptomatic women, because they will then turn to people who are not physicians and who offer unregulated therapies. These people may deliver the right message—that menopausal women deserve to feel well and look good—but the way they tell women to treat menopausal symptoms is not science-based.

At one time, we were overtreating women and not individualizing therapy, but to me it is even more worrisome to withhold therapies unless women are so highly symptomatic that they consider ending their life. We are continuing to discover the risks and benefits of HT and how to further tailor it. We have many newer, lower-dose HT options, and we are expecting the first nonhormonal therapy for menopausal vasomotor symptoms, desvenlafaxine. We are fortunate to have bone agents and local vaginal therapies for women without vasomotor symptoms. With both hormonal and nonhormonal options, we must keep the risks and benefits of any therapy in perspective.

CONCLUSIONS

Dr. Thacker: This has been a great discussion, and although we do not all agree on every point, I would like to conclude by summarizing some key points on which I think we do all agree (see sidebar above). Menopause is a normal life event, but for some women who are symptomatic, and for a smaller percentage who will be symptomatic for the rest of their lives, HT is the gold standard, although it does not treat all symptoms and has some well-defined risks. We do have other options on the horizon for relief of vasomotor symptoms, for bone health, and for urogenital atrophy.

Following the data on the effects of HT on cardiovascular health will be particularly interesting. Although there is not support for using HT specifically for cardiovascular prevention, there are provocative data that in the symptomatic woman who has self-selected it, HT has cardiovascular benefit and reduces the risk of diabetes.

A woman on HT who has not had “early harm” does not need to arbitrarily discontinue therapy based on any time limit, as long as she is being periodically reevaluated and is offered individualized options.