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Hormone therapy’s protection against endometrial cancer persists in Women’s Health Initiative follow-up study

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Hormone therapy’s protection against endometrial cancer persists in Women’s Health Initiative follow-up study

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Rowan T. Chlebowski

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

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AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Rowan T. Chlebowski

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.

Dr. Rowan T. Chlebowski

Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

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Hormone therapy’s protection against endometrial cancer persists in Women’s Health Initiative follow-up study
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AT THE EUROPEAN CANCER CONGRESS 2013

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Major finding: HT was associated with a 35% reduction in the risk for endometrial cancer (P = .007) when compared with placebo.

Data source: The Women’s Health Initiative, randomized, double-blind clinical trial of 16,608 postmenopausal women treated with hormone therapy or placebo.

Disclosures: The National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.

Breast cancer hormone therapy may affect cognitive function

Differentiating the impacts of distress and interventions
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Breast cancer hormone therapy may affect cognitive function

SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

 

Dr. Hope Rugo

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

[email protected]

On Twitter @sherryboschert

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While the relationship between chemotherapy and neurocognitive changes is increasingly well described, cognitive changes associated with hormone therapy for breast cancer has proven to be somewhat complex. Chemotherapy can confound this. There are questions about different reports of outcomes for different drugs, for selective estrogen-receptor modulators and aromatase inhibitors, as well as how menopausal status, prior oophorectomy, and hormone therapy all affect cognitive changes in women.

 


Dr. Julia White

 

The important points of this study are that there are measurements at baseline, 1 month, and 18 months for a longitudinal picture. In addition, both comprehensive neuropsychological testing and patient-reported outcomes are available at each of those time points.

Previous studies have assessed these relationships, including a small study of memory impairment with anastrozole vs. tamoxifen in 31 patients treated for a minimum of 3 months. There was no difference between groups in depression, anxiety and fatigue, but researchers found that those on anastrozole had significantly poorer performance on learning and memory measures than those taking tamoxifen (Menopause 2007;14:995-8).

Another small substudy compared 94 patients enrolled in the ATAC (Arimidex, Tamoxifen Alone or in Combination) study to 35 noncancer controls. There were no differences in working memory, attention and visual memory, but those on endocrine therapy had poorer performance on tests of verbal memory and processing speed compared with controls.

The IBIS II (International Breast Cancer Intervention II) prevention study comparing anastrozole vs. placebo showed no overall difference in cognitive function with the addition of anastrozole. At 6 months, those on anastrozole had poorer memory, but this finding resolved by 24 months.

In a subset of 179 patients in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) phase III adjuvant study, comparing exemestane with tamoxifen then exemestane, there was little change from baseline to 1 year in all domains of cognitive function with the addition of exemestane.

A substudy done from the BIG 1-98 (Breast International Group 1-98) trial indicated significant improvement in cognitive function from year 5 of therapy to year 6 after cessation of hormone therapies. Interestingly, perceived cognition did not change in the patients.

The current study looked at the relationship between perceived and measurable cognitive deficits in the same group of patients. Prior reports showed that patient-reported cognitive complaints post breast cancer treatment are common and are associated with persistent fatigue and depressive symptoms. It’s often difficult to sort out the etiology of those complaints.

In the current study, after controlling for depression and fatigue, decline on memory tests predicted perceived cognitive problems. Similarly, decline in verbal fluency predicted perceived verbal fluency problems.

This finding corroborates similar results from a prospective, longitudinal study of cognitive complaints and neuropsychological testing for verbal memory, psychomotor speed, and executive functioning in 189 patients who were beginning hormone therapy at the University of California, Los Angeles. (J. Natl. Cancer Inst. 2013;105:791-801).

Evaluations at baseline, 6 months, and 12 months showed that 23% had higher memory complaints and 19% had higher cognitive complaints after starting hormone therapy, slightly lower percentages than those seen in Dr. Rugo’s study.

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While the relationship between chemotherapy and neurocognitive changes is increasingly well described, cognitive changes associated with hormone therapy for breast cancer has proven to be somewhat complex. Chemotherapy can confound this. There are questions about different reports of outcomes for different drugs, for selective estrogen-receptor modulators and aromatase inhibitors, as well as how menopausal status, prior oophorectomy, and hormone therapy all affect cognitive changes in women.

 


Dr. Julia White

 

The important points of this study are that there are measurements at baseline, 1 month, and 18 months for a longitudinal picture. In addition, both comprehensive neuropsychological testing and patient-reported outcomes are available at each of those time points.

Previous studies have assessed these relationships, including a small study of memory impairment with anastrozole vs. tamoxifen in 31 patients treated for a minimum of 3 months. There was no difference between groups in depression, anxiety and fatigue, but researchers found that those on anastrozole had significantly poorer performance on learning and memory measures than those taking tamoxifen (Menopause 2007;14:995-8).

Another small substudy compared 94 patients enrolled in the ATAC (Arimidex, Tamoxifen Alone or in Combination) study to 35 noncancer controls. There were no differences in working memory, attention and visual memory, but those on endocrine therapy had poorer performance on tests of verbal memory and processing speed compared with controls.

The IBIS II (International Breast Cancer Intervention II) prevention study comparing anastrozole vs. placebo showed no overall difference in cognitive function with the addition of anastrozole. At 6 months, those on anastrozole had poorer memory, but this finding resolved by 24 months.

In a subset of 179 patients in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) phase III adjuvant study, comparing exemestane with tamoxifen then exemestane, there was little change from baseline to 1 year in all domains of cognitive function with the addition of exemestane.

A substudy done from the BIG 1-98 (Breast International Group 1-98) trial indicated significant improvement in cognitive function from year 5 of therapy to year 6 after cessation of hormone therapies. Interestingly, perceived cognition did not change in the patients.

The current study looked at the relationship between perceived and measurable cognitive deficits in the same group of patients. Prior reports showed that patient-reported cognitive complaints post breast cancer treatment are common and are associated with persistent fatigue and depressive symptoms. It’s often difficult to sort out the etiology of those complaints.

In the current study, after controlling for depression and fatigue, decline on memory tests predicted perceived cognitive problems. Similarly, decline in verbal fluency predicted perceived verbal fluency problems.

This finding corroborates similar results from a prospective, longitudinal study of cognitive complaints and neuropsychological testing for verbal memory, psychomotor speed, and executive functioning in 189 patients who were beginning hormone therapy at the University of California, Los Angeles. (J. Natl. Cancer Inst. 2013;105:791-801).

Evaluations at baseline, 6 months, and 12 months showed that 23% had higher memory complaints and 19% had higher cognitive complaints after starting hormone therapy, slightly lower percentages than those seen in Dr. Rugo’s study.

Body

While the relationship between chemotherapy and neurocognitive changes is increasingly well described, cognitive changes associated with hormone therapy for breast cancer has proven to be somewhat complex. Chemotherapy can confound this. There are questions about different reports of outcomes for different drugs, for selective estrogen-receptor modulators and aromatase inhibitors, as well as how menopausal status, prior oophorectomy, and hormone therapy all affect cognitive changes in women.

 


Dr. Julia White

 

The important points of this study are that there are measurements at baseline, 1 month, and 18 months for a longitudinal picture. In addition, both comprehensive neuropsychological testing and patient-reported outcomes are available at each of those time points.

Previous studies have assessed these relationships, including a small study of memory impairment with anastrozole vs. tamoxifen in 31 patients treated for a minimum of 3 months. There was no difference between groups in depression, anxiety and fatigue, but researchers found that those on anastrozole had significantly poorer performance on learning and memory measures than those taking tamoxifen (Menopause 2007;14:995-8).

Another small substudy compared 94 patients enrolled in the ATAC (Arimidex, Tamoxifen Alone or in Combination) study to 35 noncancer controls. There were no differences in working memory, attention and visual memory, but those on endocrine therapy had poorer performance on tests of verbal memory and processing speed compared with controls.

The IBIS II (International Breast Cancer Intervention II) prevention study comparing anastrozole vs. placebo showed no overall difference in cognitive function with the addition of anastrozole. At 6 months, those on anastrozole had poorer memory, but this finding resolved by 24 months.

In a subset of 179 patients in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) phase III adjuvant study, comparing exemestane with tamoxifen then exemestane, there was little change from baseline to 1 year in all domains of cognitive function with the addition of exemestane.

A substudy done from the BIG 1-98 (Breast International Group 1-98) trial indicated significant improvement in cognitive function from year 5 of therapy to year 6 after cessation of hormone therapies. Interestingly, perceived cognition did not change in the patients.

The current study looked at the relationship between perceived and measurable cognitive deficits in the same group of patients. Prior reports showed that patient-reported cognitive complaints post breast cancer treatment are common and are associated with persistent fatigue and depressive symptoms. It’s often difficult to sort out the etiology of those complaints.

In the current study, after controlling for depression and fatigue, decline on memory tests predicted perceived cognitive problems. Similarly, decline in verbal fluency predicted perceived verbal fluency problems.

This finding corroborates similar results from a prospective, longitudinal study of cognitive complaints and neuropsychological testing for verbal memory, psychomotor speed, and executive functioning in 189 patients who were beginning hormone therapy at the University of California, Los Angeles. (J. Natl. Cancer Inst. 2013;105:791-801).

Evaluations at baseline, 6 months, and 12 months showed that 23% had higher memory complaints and 19% had higher cognitive complaints after starting hormone therapy, slightly lower percentages than those seen in Dr. Rugo’s study.

Title
Differentiating the impacts of distress and interventions
Differentiating the impacts of distress and interventions

SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

 

Dr. Hope Rugo

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

 

Dr. Hope Rugo

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

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Major finding: The odds of any decline in cognitive function were significantly higher in patients on hormone therapy (OR, 7.7), compared with untreated patients in a multivariate conditional logistic regression analysis.

Data source: Prospective longitudinal study of 81 patients with breast cancer treated with hormone therapy (22 patients), chemotherapy (14), chemotherapy followed by hormone therapy (33), or no therapy (12).

Disclosures: NIH funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

In the hormone therapy fight, bioidenticals come out swinging

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With seemingly ageless celebrities touting the benefits of bioidentical, compounded hormones, and the cloud of the Women’s Health Initiative still obscuring the view, both physicians and patients want to know the truth about natural hormone replacement.

But as in so many areas of life, the truth can be many things to many people, Dr. Jan L. Shifren shared at the annual meeting of the North American Menopause Society (NAMS).

"For a woman with bothersome menopausal symptoms and concerns about potential hormone therapy [HT] risks, ‘bioHT’ may mean a formulation of hormones with all of the benefits and no risks, as it’s ‘natural’ and contains no package insert with a black box warning," said Dr. Shifren, director of the menopause program at Massachusetts General Hospital, Boston. "For a bioHT practitioner, it may mean a way of helping menopausal women disenfranchised with the medical establishment, while providing a steady source of income. For a clinician or pharmacist practicing within the current standard of care, an FDA inspector, or a lawyer for a women with endometrial cancer associated with its use, bioHT may mean something quite different!"

Dr. Jan L. Shifren

Bioidentical hormones are typically plant-based compounds with a molecular structure identical to that of the corresponding human hormone. Dosing is individual and based on a woman’s salivary hormone levels. Prescriptions are pharmacist compounded, typically in a topical preparation, but sometimes in an oral tablet or injected pellet.

All of this may sound reasonable at first glance, Dr. Shifren said. But science and money just keep getting in the way of the celebrity endorsements.

"Hormone therapy should be guided by symptoms. There are no data to support the use of blood or saliva measurements to improve treatment efficacy," Dr. Shifren said. Serum hormone levels constantly fluctuate – not only within the menstrual cycle, but also within a single day, "so it’s impossible to ‘match’ any individual woman’s ‘ideal’ hormone levels."

Additionally, Dr. Shifren said, salivary levels don’t even correspond to serum levels.

Safety is one of the biggest problems with such compounds. Because their manufacture is in the hands of a single individual, there’s no quality oversight. Women can’t count on getting the correct prescribed dose of hormone – and sometimes not even close to it.

A recent study commissioned by MORE magazine examined the exact hormone content in 12 bioHT prescriptions, which were filled by 12 pharmacies. Two pharmacies were retail stores and 10 were online companies.

Flora Research Labs analyzed the medications with mass spectrometry. The values varied widely: 96%-260% of the prescribed estrogen dose and 60%-80% of the prescribed progesterone dose.

"None of these would have met FDA standards," Dr. Shifren said. "The purity, bioavailability, and dose-to-dose consistency of any given prescription is an unknown."

Concern about the safety of conventional HT frequently drives women to seek out what they consider a more natural alternative. Although much more data have emerged, the original furor over the Women’s Health Initiative still casts HT in a negative light for many, Dr. Shifren said.

For women in good health, who start combination estrogen/progesterone HT early in menopause, at the lowest effective dose, the increased risks of cardiovascular disease and cancer are negligible. A 2010 British study of 15,710 cases and almost 60,000 controls found that low-dose transdermal HT had no effect on stroke risk. High-dose patch estrogen increased the risk by 89%, and both low- and high-dose oral estrogen increased the risk by 69%; however, each of those increases translated to an absolute increase of only about 1 stroke per year (BMJ 2010;340:c2519 [doi: 10.1136/bmj.c2519]).

A 2008 French study of almost 81,000 women found no significant associations between breast cancer and route of HT administration. However, the study did conclude that the combination of estrogen and progesterone was probably the safest, with a risk ratio of 1.0. Estrogen plus dydrogesterone resulted in a nonsignificant risk increase (relative risk, 1.16). Estrogen in combination with other progestogens carried a significant 69% risk increase (Breast Cancer Res. Treat. 2008;107:103-11).

Finally, Dr. Shifren said, it’s just about impossible to take profit out of the picture. Compounding HT sales are reaching more than $2 billion per year now.

"Many practitioners who prescribe compounded hormones also sell them, or benefit financially from relationships with compounders. This poses a potential conflict of interest and violates standards of professional ethical conduct," she said.

Dr. Shifren provides research consulting for New England Research Institutes.

[email protected]

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With seemingly ageless celebrities touting the benefits of bioidentical, compounded hormones, and the cloud of the Women’s Health Initiative still obscuring the view, both physicians and patients want to know the truth about natural hormone replacement.

But as in so many areas of life, the truth can be many things to many people, Dr. Jan L. Shifren shared at the annual meeting of the North American Menopause Society (NAMS).

"For a woman with bothersome menopausal symptoms and concerns about potential hormone therapy [HT] risks, ‘bioHT’ may mean a formulation of hormones with all of the benefits and no risks, as it’s ‘natural’ and contains no package insert with a black box warning," said Dr. Shifren, director of the menopause program at Massachusetts General Hospital, Boston. "For a bioHT practitioner, it may mean a way of helping menopausal women disenfranchised with the medical establishment, while providing a steady source of income. For a clinician or pharmacist practicing within the current standard of care, an FDA inspector, or a lawyer for a women with endometrial cancer associated with its use, bioHT may mean something quite different!"

Dr. Jan L. Shifren

Bioidentical hormones are typically plant-based compounds with a molecular structure identical to that of the corresponding human hormone. Dosing is individual and based on a woman’s salivary hormone levels. Prescriptions are pharmacist compounded, typically in a topical preparation, but sometimes in an oral tablet or injected pellet.

All of this may sound reasonable at first glance, Dr. Shifren said. But science and money just keep getting in the way of the celebrity endorsements.

"Hormone therapy should be guided by symptoms. There are no data to support the use of blood or saliva measurements to improve treatment efficacy," Dr. Shifren said. Serum hormone levels constantly fluctuate – not only within the menstrual cycle, but also within a single day, "so it’s impossible to ‘match’ any individual woman’s ‘ideal’ hormone levels."

Additionally, Dr. Shifren said, salivary levels don’t even correspond to serum levels.

Safety is one of the biggest problems with such compounds. Because their manufacture is in the hands of a single individual, there’s no quality oversight. Women can’t count on getting the correct prescribed dose of hormone – and sometimes not even close to it.

A recent study commissioned by MORE magazine examined the exact hormone content in 12 bioHT prescriptions, which were filled by 12 pharmacies. Two pharmacies were retail stores and 10 were online companies.

Flora Research Labs analyzed the medications with mass spectrometry. The values varied widely: 96%-260% of the prescribed estrogen dose and 60%-80% of the prescribed progesterone dose.

"None of these would have met FDA standards," Dr. Shifren said. "The purity, bioavailability, and dose-to-dose consistency of any given prescription is an unknown."

Concern about the safety of conventional HT frequently drives women to seek out what they consider a more natural alternative. Although much more data have emerged, the original furor over the Women’s Health Initiative still casts HT in a negative light for many, Dr. Shifren said.

For women in good health, who start combination estrogen/progesterone HT early in menopause, at the lowest effective dose, the increased risks of cardiovascular disease and cancer are negligible. A 2010 British study of 15,710 cases and almost 60,000 controls found that low-dose transdermal HT had no effect on stroke risk. High-dose patch estrogen increased the risk by 89%, and both low- and high-dose oral estrogen increased the risk by 69%; however, each of those increases translated to an absolute increase of only about 1 stroke per year (BMJ 2010;340:c2519 [doi: 10.1136/bmj.c2519]).

A 2008 French study of almost 81,000 women found no significant associations between breast cancer and route of HT administration. However, the study did conclude that the combination of estrogen and progesterone was probably the safest, with a risk ratio of 1.0. Estrogen plus dydrogesterone resulted in a nonsignificant risk increase (relative risk, 1.16). Estrogen in combination with other progestogens carried a significant 69% risk increase (Breast Cancer Res. Treat. 2008;107:103-11).

Finally, Dr. Shifren said, it’s just about impossible to take profit out of the picture. Compounding HT sales are reaching more than $2 billion per year now.

"Many practitioners who prescribe compounded hormones also sell them, or benefit financially from relationships with compounders. This poses a potential conflict of interest and violates standards of professional ethical conduct," she said.

Dr. Shifren provides research consulting for New England Research Institutes.

[email protected]

With seemingly ageless celebrities touting the benefits of bioidentical, compounded hormones, and the cloud of the Women’s Health Initiative still obscuring the view, both physicians and patients want to know the truth about natural hormone replacement.

But as in so many areas of life, the truth can be many things to many people, Dr. Jan L. Shifren shared at the annual meeting of the North American Menopause Society (NAMS).

"For a woman with bothersome menopausal symptoms and concerns about potential hormone therapy [HT] risks, ‘bioHT’ may mean a formulation of hormones with all of the benefits and no risks, as it’s ‘natural’ and contains no package insert with a black box warning," said Dr. Shifren, director of the menopause program at Massachusetts General Hospital, Boston. "For a bioHT practitioner, it may mean a way of helping menopausal women disenfranchised with the medical establishment, while providing a steady source of income. For a clinician or pharmacist practicing within the current standard of care, an FDA inspector, or a lawyer for a women with endometrial cancer associated with its use, bioHT may mean something quite different!"

Dr. Jan L. Shifren

Bioidentical hormones are typically plant-based compounds with a molecular structure identical to that of the corresponding human hormone. Dosing is individual and based on a woman’s salivary hormone levels. Prescriptions are pharmacist compounded, typically in a topical preparation, but sometimes in an oral tablet or injected pellet.

All of this may sound reasonable at first glance, Dr. Shifren said. But science and money just keep getting in the way of the celebrity endorsements.

"Hormone therapy should be guided by symptoms. There are no data to support the use of blood or saliva measurements to improve treatment efficacy," Dr. Shifren said. Serum hormone levels constantly fluctuate – not only within the menstrual cycle, but also within a single day, "so it’s impossible to ‘match’ any individual woman’s ‘ideal’ hormone levels."

Additionally, Dr. Shifren said, salivary levels don’t even correspond to serum levels.

Safety is one of the biggest problems with such compounds. Because their manufacture is in the hands of a single individual, there’s no quality oversight. Women can’t count on getting the correct prescribed dose of hormone – and sometimes not even close to it.

A recent study commissioned by MORE magazine examined the exact hormone content in 12 bioHT prescriptions, which were filled by 12 pharmacies. Two pharmacies were retail stores and 10 were online companies.

Flora Research Labs analyzed the medications with mass spectrometry. The values varied widely: 96%-260% of the prescribed estrogen dose and 60%-80% of the prescribed progesterone dose.

"None of these would have met FDA standards," Dr. Shifren said. "The purity, bioavailability, and dose-to-dose consistency of any given prescription is an unknown."

Concern about the safety of conventional HT frequently drives women to seek out what they consider a more natural alternative. Although much more data have emerged, the original furor over the Women’s Health Initiative still casts HT in a negative light for many, Dr. Shifren said.

For women in good health, who start combination estrogen/progesterone HT early in menopause, at the lowest effective dose, the increased risks of cardiovascular disease and cancer are negligible. A 2010 British study of 15,710 cases and almost 60,000 controls found that low-dose transdermal HT had no effect on stroke risk. High-dose patch estrogen increased the risk by 89%, and both low- and high-dose oral estrogen increased the risk by 69%; however, each of those increases translated to an absolute increase of only about 1 stroke per year (BMJ 2010;340:c2519 [doi: 10.1136/bmj.c2519]).

A 2008 French study of almost 81,000 women found no significant associations between breast cancer and route of HT administration. However, the study did conclude that the combination of estrogen and progesterone was probably the safest, with a risk ratio of 1.0. Estrogen plus dydrogesterone resulted in a nonsignificant risk increase (relative risk, 1.16). Estrogen in combination with other progestogens carried a significant 69% risk increase (Breast Cancer Res. Treat. 2008;107:103-11).

Finally, Dr. Shifren said, it’s just about impossible to take profit out of the picture. Compounding HT sales are reaching more than $2 billion per year now.

"Many practitioners who prescribe compounded hormones also sell them, or benefit financially from relationships with compounders. This poses a potential conflict of interest and violates standards of professional ethical conduct," she said.

Dr. Shifren provides research consulting for New England Research Institutes.

[email protected]

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Bone mineral density identifies fracture risk in women over 65

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Bone mineral density testing is an effective means of identifying women aged 65 years and older who are at high risk of fracture, according to Jane A. Cauley, Dr.P.H., an epidemiologist at the University of Pittsburgh.

All women aged 65 and over should have a BMD test. In a presentation at the annual meeting of the North American Menopause Society, she related the findings of a 2012 study conducted to determine when the test should be repeated. In that study of 4,957 women aged 67 years and older at baseline who underwent baseline T-score testing, the mean interval until 2% of participants had a hip or clinical vertebral fracture was 25 years for women whose baseline bone mineral density (BMD) T-score was greater than or equal to –1.00, 15.4 years for those whose T-score range was –1.01 to –1.49, 5.5 years for those whose T-score range was –1.50 to –1.99, and 5.4 years for those whose T-score was –2.00 to –2.49 (N. Engl. J. Med. 2012;366:225-33).

Also, in women with BMD T-scores greater than –1.50, osteoporosis developed in less than 10% during 15 years of follow-up.

Based on these findings, Dr. Cauley suggested that an initial BMD test should be recommended for all women aged 65 years and older, and that physicians should reassess the testing interval based on the initial result. If the T-score declines, so should the length of the testing interval.

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Bone mineral density testing is an effective means of identifying women aged 65 years and older who are at high risk of fracture, according to Jane A. Cauley, Dr.P.H., an epidemiologist at the University of Pittsburgh.

All women aged 65 and over should have a BMD test. In a presentation at the annual meeting of the North American Menopause Society, she related the findings of a 2012 study conducted to determine when the test should be repeated. In that study of 4,957 women aged 67 years and older at baseline who underwent baseline T-score testing, the mean interval until 2% of participants had a hip or clinical vertebral fracture was 25 years for women whose baseline bone mineral density (BMD) T-score was greater than or equal to –1.00, 15.4 years for those whose T-score range was –1.01 to –1.49, 5.5 years for those whose T-score range was –1.50 to –1.99, and 5.4 years for those whose T-score was –2.00 to –2.49 (N. Engl. J. Med. 2012;366:225-33).

Also, in women with BMD T-scores greater than –1.50, osteoporosis developed in less than 10% during 15 years of follow-up.

Based on these findings, Dr. Cauley suggested that an initial BMD test should be recommended for all women aged 65 years and older, and that physicians should reassess the testing interval based on the initial result. If the T-score declines, so should the length of the testing interval.

Bone mineral density testing is an effective means of identifying women aged 65 years and older who are at high risk of fracture, according to Jane A. Cauley, Dr.P.H., an epidemiologist at the University of Pittsburgh.

All women aged 65 and over should have a BMD test. In a presentation at the annual meeting of the North American Menopause Society, she related the findings of a 2012 study conducted to determine when the test should be repeated. In that study of 4,957 women aged 67 years and older at baseline who underwent baseline T-score testing, the mean interval until 2% of participants had a hip or clinical vertebral fracture was 25 years for women whose baseline bone mineral density (BMD) T-score was greater than or equal to –1.00, 15.4 years for those whose T-score range was –1.01 to –1.49, 5.5 years for those whose T-score range was –1.50 to –1.99, and 5.4 years for those whose T-score was –2.00 to –2.49 (N. Engl. J. Med. 2012;366:225-33).

Also, in women with BMD T-scores greater than –1.50, osteoporosis developed in less than 10% during 15 years of follow-up.

Based on these findings, Dr. Cauley suggested that an initial BMD test should be recommended for all women aged 65 years and older, and that physicians should reassess the testing interval based on the initial result. If the T-score declines, so should the length of the testing interval.

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In young hysterectomized women, does unopposed estrogen therapy increase overall survival?

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During the 1990s, more than 90% of hysterectomized women aged 50 to 59 years used ET following the procedure. When the initial findings of the WHI were published in 2002, they prompted many women to refuse or discontinue ET—despite the fact that the initial findings concerned the use of estrogen and progestin in combination in women with an intact uterus. Today, only some 30% of women use ET after hysterectomy.

When findings from the WHI estrogen-only arm were eventually published, they revealed that ET reduces mortality among women 50 to 59 years old, compared with placebo. Although most of the reduction in mortality relates to fewer deaths from coronary heart disease, a decline in deaths from breast cancer also was seen.2,3

Sarrel and colleagues calculated the excess mortality among US women aged 50 to 59 that could have been prevented by ET during the decade from 2002 through 2011. Their estimates ranged from approximately 19,000 deaths to as many as 92,000 deaths.

By calling attention to the negative health consequences of estrogen avoidance in young hysterectomized women, Sarrel and colleagues have performed a valuable public service.

Plethora of WHI data may have contributed to confusion

The WHI clinical trials have produced numerous analyses in various subsets of women. The sheer volume of data may be daunting in some cases, and likely has led to a failure to distinguish between estrogen-only and estrogen-progestin therapy, which have very different safety profiles.

Further, some clinicians and many patients have overlooked the fact that the risk-benefit profile of hormone therapy (both estrogen-only and estrogen-progestin therapy) is more favorable in younger, recently menopausal women than it is in older women.

I encounter evidence of this unwarranted fear of ET in my practice, with highly symptomatic, recently menopausal women who are appropriate candidates for hormone therapy electing to refuse the most effective treatment for menopausal symptoms.

Of course, hormone therapy, like all medications, has risks as well as benefits. For example, oral ET increases the risk of venous thrombosis and stroke, and long-term use of estrogen-progestin therapy increases the risk of breast cancer. However, the overblown fears of estrogen therapy have caused many appropriate candidates to miss out on symptom relief, prevention of osteoporosis, and treatment of symptomatic genital atrophy.

What this evidence means for practice
This provocative report demonstrates that wholesale avoidance of hormone therapy can have important negative public health consequence.
--Andrew M. Kaunitz, MD

We want to hear from you! Tell us what you think.

References

1. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.

2. LaCroix AZ, Chlebowski RT, Manson JE, et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305–1314.

3. Anderson GL, Chlebowski RI, Aragaki AK, et al. Conjugated equine estrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomized placebo-controlled trial. Lancet Oncol. 2012; 13(5):476–486.

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During the 1990s, more than 90% of hysterectomized women aged 50 to 59 years used ET following the procedure. When the initial findings of the WHI were published in 2002, they prompted many women to refuse or discontinue ET—despite the fact that the initial findings concerned the use of estrogen and progestin in combination in women with an intact uterus. Today, only some 30% of women use ET after hysterectomy.

When findings from the WHI estrogen-only arm were eventually published, they revealed that ET reduces mortality among women 50 to 59 years old, compared with placebo. Although most of the reduction in mortality relates to fewer deaths from coronary heart disease, a decline in deaths from breast cancer also was seen.2,3

Sarrel and colleagues calculated the excess mortality among US women aged 50 to 59 that could have been prevented by ET during the decade from 2002 through 2011. Their estimates ranged from approximately 19,000 deaths to as many as 92,000 deaths.

By calling attention to the negative health consequences of estrogen avoidance in young hysterectomized women, Sarrel and colleagues have performed a valuable public service.

Plethora of WHI data may have contributed to confusion

The WHI clinical trials have produced numerous analyses in various subsets of women. The sheer volume of data may be daunting in some cases, and likely has led to a failure to distinguish between estrogen-only and estrogen-progestin therapy, which have very different safety profiles.

Further, some clinicians and many patients have overlooked the fact that the risk-benefit profile of hormone therapy (both estrogen-only and estrogen-progestin therapy) is more favorable in younger, recently menopausal women than it is in older women.

I encounter evidence of this unwarranted fear of ET in my practice, with highly symptomatic, recently menopausal women who are appropriate candidates for hormone therapy electing to refuse the most effective treatment for menopausal symptoms.

Of course, hormone therapy, like all medications, has risks as well as benefits. For example, oral ET increases the risk of venous thrombosis and stroke, and long-term use of estrogen-progestin therapy increases the risk of breast cancer. However, the overblown fears of estrogen therapy have caused many appropriate candidates to miss out on symptom relief, prevention of osteoporosis, and treatment of symptomatic genital atrophy.

What this evidence means for practice
This provocative report demonstrates that wholesale avoidance of hormone therapy can have important negative public health consequence.
--Andrew M. Kaunitz, MD

We want to hear from you! Tell us what you think.

During the 1990s, more than 90% of hysterectomized women aged 50 to 59 years used ET following the procedure. When the initial findings of the WHI were published in 2002, they prompted many women to refuse or discontinue ET—despite the fact that the initial findings concerned the use of estrogen and progestin in combination in women with an intact uterus. Today, only some 30% of women use ET after hysterectomy.

When findings from the WHI estrogen-only arm were eventually published, they revealed that ET reduces mortality among women 50 to 59 years old, compared with placebo. Although most of the reduction in mortality relates to fewer deaths from coronary heart disease, a decline in deaths from breast cancer also was seen.2,3

Sarrel and colleagues calculated the excess mortality among US women aged 50 to 59 that could have been prevented by ET during the decade from 2002 through 2011. Their estimates ranged from approximately 19,000 deaths to as many as 92,000 deaths.

By calling attention to the negative health consequences of estrogen avoidance in young hysterectomized women, Sarrel and colleagues have performed a valuable public service.

Plethora of WHI data may have contributed to confusion

The WHI clinical trials have produced numerous analyses in various subsets of women. The sheer volume of data may be daunting in some cases, and likely has led to a failure to distinguish between estrogen-only and estrogen-progestin therapy, which have very different safety profiles.

Further, some clinicians and many patients have overlooked the fact that the risk-benefit profile of hormone therapy (both estrogen-only and estrogen-progestin therapy) is more favorable in younger, recently menopausal women than it is in older women.

I encounter evidence of this unwarranted fear of ET in my practice, with highly symptomatic, recently menopausal women who are appropriate candidates for hormone therapy electing to refuse the most effective treatment for menopausal symptoms.

Of course, hormone therapy, like all medications, has risks as well as benefits. For example, oral ET increases the risk of venous thrombosis and stroke, and long-term use of estrogen-progestin therapy increases the risk of breast cancer. However, the overblown fears of estrogen therapy have caused many appropriate candidates to miss out on symptom relief, prevention of osteoporosis, and treatment of symptomatic genital atrophy.

What this evidence means for practice
This provocative report demonstrates that wholesale avoidance of hormone therapy can have important negative public health consequence.
--Andrew M. Kaunitz, MD

We want to hear from you! Tell us what you think.

References

1. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.

2. LaCroix AZ, Chlebowski RT, Manson JE, et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305–1314.

3. Anderson GL, Chlebowski RI, Aragaki AK, et al. Conjugated equine estrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomized placebo-controlled trial. Lancet Oncol. 2012; 13(5):476–486.

References

1. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.

2. LaCroix AZ, Chlebowski RT, Manson JE, et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305–1314.

3. Anderson GL, Chlebowski RI, Aragaki AK, et al. Conjugated equine estrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomized placebo-controlled trial. Lancet Oncol. 2012; 13(5):476–486.

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Your postmenopausal patient reports a history of migraine

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Your postmenopausal patient reports a history of migraine

CASES IN MENOPAUSE
Brought to you by the menopause experts

Andrew M. Kaunitz, MD
Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. Dr. Kaunitz is a NAMS Board member and certified menopause practitioner. He also serves on the OBG Management Board of Editors.

JoAnn V. Pinkerton, MD
Professor, Department of Obstetrics and Gynecology, and Director, Division of Midlife Women’s Health, University of Virginia. Dr. Pinkerton is a North American Menopause Society (NAMS) past president and certified menopause practitioner. She also serves on the OBG Management Board of Editors.

James A. Simon, MD
Clinical Professor, Department of Obstetrics and Gynecology, George Washington University, and Medical Director, Women’s Health & Research Consultants, Washington, DC. Dr. Simon is a NAMS past president, a certified menopause practitioner, and a certified clinical densitometrist. He also serves on the OBG Management Board of Editors.

Disclosures
Dr. Kaunitz reports that his institution receives grant or research support from Bayer, Teva, Medical Diagnostic Laboratories, and Noven, and that he is a consultant to Bayer, Actavis, and Teva.

Dr. Pinkerton reports that her institution receives consulting fees from Pfizer, DepoMed, Shionogi, and Noven and multicenter research fees from DepoMed, Endoceutics, and Bionova.

Dr. Simon reports being a consultant to or on the advisory boards of Abbott Laboratories, Agile Therapeutics, Amgen, Ascend Therapeutics, BioSante, Depomed, Lelo, MD Therapeutics, Meda Pharmaceuticals, Merck, Noven, Novo Nordisk, Novogyne, Pfizer, Shionogi, Shippan Point Advisors LLC, Slate Pharmaceuticals, Sprout Pharmaceuticals, Teva, Warner Chilcott, and Watson. He also reports receiving (currently or in the past year) grant/research support from BioSante, EndoCeutics, Novo Nordisk, Novogyne, Palatin Technologies, Teva, and Warner Chilcott. He reports serving on the speakers bureaus of Amgen, Merck, Novartis, Noven, Novo Nordisk, Novogyne, Teva, and Warner Chilcott. Dr. Simon is currently the Chief Medical Officer for Sprout Pharmaceuticals.

CASE: Menopausal symptoms and a history of migraine with aura

Your new patient is a 52-year-old woman (G2P2) who reports a long history of two types of migraine: menstrually related migraine without aura and nonmenstrually related migraine with aura (usually involving visual scotomata). Other than the history of migraine, her health is good. Now postmenopausal, she has been referred to you by her primary care physician (PCP) for management of severe vasomotor symptoms and sleep disturbance.

Because of this patient’s history of migraine, her PCP declined to prescribe oral contraceptives (OCs) in the past over concern of increasing her risk of stroke. For her vasomotor symptoms, her PCP prescribed a trial of venlafaxine (Effexor) 75 mg daily, but her orgasms, which always had been difficult to achieve, became impossible. In addition, the patient began to perspire heavily unrelated to her hot flashes. As a result, she describes her mood as “terrible,” her energy level as “miniscule,” and she reports losing interest in sex completely (“I am just too tired”). She and her referring physician wonder whether it would be safe to try hormone therapy (HT).

A physical examination, including funduscopic assessment, reveals no abnormalities. Her blood pressure is 126/70 mm Hg, and blood chemistry results, including C-reactive protein, 25-hydroxy vitamin D, a complete blood count, and lipid profile, are all normal.

Would you offer this patient the option of HT?

Migraine affects roughly twice as many women as men.1 During the reproductive years, rapid fluctuations in ovarian hormones—both increases at midcycle and, to a greater extent, decreases during the premenstrual phase—are believed to be migraine “triggers.” Women who experience menstrually related migraine before menopause typically have an increased risk of migraine during perimenopause, with a significant reduction of migraine symptoms following menopause.2

Side effects of SSRIs and SNRIs
Most providers are aware that selective serotonin reuptake inhibitors (SSRIs) cause sexual side effects in as many as 80% of users. There is a dose-related pattern to reports of sexual problems among SSRI users, with higher doses causing more problems. The most common sexual symptoms associated with SSRIs are delayed ejaculation and absent or delayed orgasm.3

What is not as widely known is that even serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause sexual dysfunction. For example, in a prospective, multicenter study from Spain involving more than
1,000 outpatients, all of whom were taking an antidepressant, the overall rate of sexual dysfunction was 59%.4 Sexual dysfunction was most common among users of SSRIs and venlafaxine, an SNRI.5

Another common side effect of venlafaxine, sweating, is unrelated to hot flashes.5 So two of this patient’s concerns—orgasmic difficulties and profuse sweating unrelated to hot flashes—may have been caused or worsened by her antidepressant.

Another nonhormonal option
In June 2013, the US Food and Drug Administration (FDA) approved paroxetine mesylate (Brisdelle), an SSRI, for the treatment of moderate to severe menopausal vasomotor symptoms. Because the drug is a strong CYP2D6 inhibitor, it should not be given to women taking another medication that is metabolized by CYP2D6—most notably, tamoxifen.

Preliminary data on this drug suggest that, at the recommended dose (7.5 mg/d), it has no effect on sexual function.6 For this reason, it is another option for our patient to consider.

 

 

Related article: The gynecologist's role in managing menstrual migraine Anne H. Calhoun, MD 

Migraine and the risk of stroke
Migraine with aura has been associated with an increased risk of stroke and other cerebral vascular events,7 and that risk is further elevated in patients treated with OCs.8 Although migraine without aura also may be associated with an elevated risk of stroke, OCs do not further increase that risk.

Andrew M. Kaunitz, MD:
The elevated risk of stroke associated with use of OCs by women with migraine with aura appears to relate, in particular, to older, higher-dose OC formulations.9,10

Some practitioners assume that the data on the risk of stroke associated with OC use also applies to hormone therapy, but there is no evidence that HT, in which doses of estrogen are far lower than in OCs, increases the risk of stroke in migraineurs to any greater degree than would be expected in unselected populations (ie, as noted in the Women’s Health Initiative, Nurses Health Study, or other large investigations). Therefore, HT would be an appropriate option for this patient if her very slight risk of stroke on HT would be acceptable to the practitioner and patient.

JoAnn V. Pinkerton, MD:
The route of administration is critical here. In relatively healthy postmenopausal women (average age, 63), combined continuous oral HT significantly increased the risk of stroke. After 3 years of use, the absolute risk was 18 cases of stroke per 1,000 HT users (95% confidence interval [CI], 14–23). And oral estrogen-only therapy increased the risk of stroke after 7 years of use, with an absolute risk of 32 cases per 1,000 HT users (95% CI, 25–40).11

The limited clinical evidence available on the effects of tramsdermal estradiol on stroke risk indicates that the risk is not increased.12

Choosing an HT formulation

Consider the pharmacokinetic profile. Many oral estrogen HT products have rapid-release characteristics that make them likely to contribute to rapid rises and falls in the user’s estrogen level. Oral estrogens also are associated with procoagulant properties that may increase the risk of thrombosis and thromboembolism. Nonoral estrogens do not appear to increase these risks.13

Nonoral estrogens (patches, gels, sprays, lotions, and vaginal rings) provide a more stable pharmacokinetic profile, as do some oral products with controlled-release properties.

As for progestins, some formulations (medroxyprogesterone acetate) tend to cause vasoconstriction, whereas others (micronized progesterone) tend to be vasodilators. Whether these properties affect the rate of migraine or risk of stroke is unclear.

My management approach for this patient
In the absence of any systematic data on the use of HT in this clinical setting, and without any concrete suggestions from migraine experts, I would take the following three-step approach:

1. I would begin with a low-dose nonoral estradiol formulation, prescribing it without a progestin even in a woman who still has a uterus. My aim: to determine the lowest effective dose of HT for this particular patient. I would follow the patient on this dose for 3 months.

JoAnn V. Pinkerton, MD:
Another goal is to determine whether transdermal estradiol increases headaches. Before settling on a therapy, however, I would ask how long this patient has been postmenopausal, how long she has been experiencing vasomotor symptoms, and how severe those symptoms are. For example, is she having 7 or 8 hot flashes per day and waking from night sweats once or twice per night? I also would ask her how long she remained on the venlafaxine. The additional information would allow me to fine-tune her treatment.

 
2. If this formulation is tolerated, I would add micronized progesterone (oral or vaginal) for endometrial protection.

JoAnn V. Pinkerton, MD:
I would give oral progesterone if it is FDA approved for postmenopausal use, vaginal progesterone if it isn’t.

3. I would follow the patient’s clinical response—specifically, her vasomotor symptoms and rate of migraine with or without aura.

Hormone therapy is one option for postmenopausal migraineurs with bothersome vasomotor symptoms
Many women with a history of migraine move into menopause expecting their condition to improve, says headache expert Anne H. Calhoun, MD, a founder of the Carolina Headache Institute in Chapel Hill, North Carolina.

“Over the years, these women have heard that things get better with menopause.”

For women with a history of episodic migraine, that expectation is realistic, Calhoun says. “But for women with chronic migraine, who may experience a low-grade headache on a daily, or almost daily basis, with 10 or 12 severe headaches in a month, things usually get worse after menopause because the sleep issues of menopause are superimposed on the migraine.”

Dr. Calhoun observes that hormone therapy (HT) has never been contraindicated in women with migraine, although many neurologists are hesitant to prescribe any hormones for this population.

Before prescribing HT to a postmenopausal migraineur, Dr. Calhoun considers a range of variables, including sleep patterns, current medications, anxiety, frequency and severity of vasomotor symptoms, and any other problems the patient may be experiencing.

“It’s basically the same assessment as with any postmenopausal patient—to determine whether HT is a reasonable option,” she says.

And when she determines that HT is appropriate, “I almost exclusively use transdermal HT. I also am more likely to prescribe continuous use of a transdermal patch or skin gel, as I want to achieve very consistent hormone levels, day in and day out,” she says.

 

 

My bottom line

No systematic data on the use of HT in migraineurs has been published. In the absence of such data, some practitioners have extrapolated data on the use of OCs in this population and decline to prescribe HT to women with migraine. However, HT and OCs are vastly different in formulation, dose, and risks. Rather than make assumptions on the basis of irrelevant data, we should conduct studies of HT use in migraineurs.

Related article: Update on Menopause Andrew M. Kaunitz, MD (June 2013)

Women who have menstrually related migraine typically have an increased risk of migraine during perimenopause and a significant reduction in migraine following menopause. If hot flashes are bothersome, these women certainly can use HT. I recommend prescribing HT in a continuous fashion that maintains stable hormone levels in the blood, as fluctuating hormones tend to trigger migraines.

Andrew M. Kaunitz, MD:
I would just add that transdermal estradiol is preferred, to be given at the lowest effective dose.

Do you have a troubling case in menopause? Suggest it to the expert panel: [email protected]. They may address your management dilemma in a future issue.

We want to hear from you! Send us your Letter to the Editor 

References

1. Shuster LT, Faubion SS. Sood R, Casey PM. Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches. Curr Neurol Neurosci Rep. 2011;11(2):131–138.

2. Loder E, Rizzoli P, Golub J. Hormonal management of migraine associated with menses and the menopause: a clinical review. Headache. 2007;47(2):329–340.

3. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163:1504–1509.

4. Taylor MJ. Strategies for managing antidepressant-induced sexual dysfunction: a review. Curr Psychiatry Rep. 2006;8(6):431–436.

5. Effexor [package insert]. New York, NY: Pfizer; 2012.

6. Brisdelle [package insert]. Miami, FL: Noven Therapeutics; 2013.

7. Etminan M, Takkouche B, Isorna FC, Samli A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ. 2005;330(7482):63–65.

8. Becker WJ. Use of oral contraceptives in patients with migraine. Neurology. 1999;53(4 Suppl 1):S19–S25.

9. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet. 1996;348(9026): 498–505.

10. Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel HK. Stroke in users of low-dose oral contraceptives. N Engl J Med. 1996;335(1):8-15.

11. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7:CD004143. doi: 10.1002/14651858.CD004143.pub4

12. Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. 2010;340:c2519.

13. Kaunitz AM. Update on Menopause. OBG Manag. 2013;25(6):36–43, 49.

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Related Articles

CASES IN MENOPAUSE
Brought to you by the menopause experts

Andrew M. Kaunitz, MD
Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. Dr. Kaunitz is a NAMS Board member and certified menopause practitioner. He also serves on the OBG Management Board of Editors.

JoAnn V. Pinkerton, MD
Professor, Department of Obstetrics and Gynecology, and Director, Division of Midlife Women’s Health, University of Virginia. Dr. Pinkerton is a North American Menopause Society (NAMS) past president and certified menopause practitioner. She also serves on the OBG Management Board of Editors.

James A. Simon, MD
Clinical Professor, Department of Obstetrics and Gynecology, George Washington University, and Medical Director, Women’s Health & Research Consultants, Washington, DC. Dr. Simon is a NAMS past president, a certified menopause practitioner, and a certified clinical densitometrist. He also serves on the OBG Management Board of Editors.

Disclosures
Dr. Kaunitz reports that his institution receives grant or research support from Bayer, Teva, Medical Diagnostic Laboratories, and Noven, and that he is a consultant to Bayer, Actavis, and Teva.

Dr. Pinkerton reports that her institution receives consulting fees from Pfizer, DepoMed, Shionogi, and Noven and multicenter research fees from DepoMed, Endoceutics, and Bionova.

Dr. Simon reports being a consultant to or on the advisory boards of Abbott Laboratories, Agile Therapeutics, Amgen, Ascend Therapeutics, BioSante, Depomed, Lelo, MD Therapeutics, Meda Pharmaceuticals, Merck, Noven, Novo Nordisk, Novogyne, Pfizer, Shionogi, Shippan Point Advisors LLC, Slate Pharmaceuticals, Sprout Pharmaceuticals, Teva, Warner Chilcott, and Watson. He also reports receiving (currently or in the past year) grant/research support from BioSante, EndoCeutics, Novo Nordisk, Novogyne, Palatin Technologies, Teva, and Warner Chilcott. He reports serving on the speakers bureaus of Amgen, Merck, Novartis, Noven, Novo Nordisk, Novogyne, Teva, and Warner Chilcott. Dr. Simon is currently the Chief Medical Officer for Sprout Pharmaceuticals.

CASE: Menopausal symptoms and a history of migraine with aura

Your new patient is a 52-year-old woman (G2P2) who reports a long history of two types of migraine: menstrually related migraine without aura and nonmenstrually related migraine with aura (usually involving visual scotomata). Other than the history of migraine, her health is good. Now postmenopausal, she has been referred to you by her primary care physician (PCP) for management of severe vasomotor symptoms and sleep disturbance.

Because of this patient’s history of migraine, her PCP declined to prescribe oral contraceptives (OCs) in the past over concern of increasing her risk of stroke. For her vasomotor symptoms, her PCP prescribed a trial of venlafaxine (Effexor) 75 mg daily, but her orgasms, which always had been difficult to achieve, became impossible. In addition, the patient began to perspire heavily unrelated to her hot flashes. As a result, she describes her mood as “terrible,” her energy level as “miniscule,” and she reports losing interest in sex completely (“I am just too tired”). She and her referring physician wonder whether it would be safe to try hormone therapy (HT).

A physical examination, including funduscopic assessment, reveals no abnormalities. Her blood pressure is 126/70 mm Hg, and blood chemistry results, including C-reactive protein, 25-hydroxy vitamin D, a complete blood count, and lipid profile, are all normal.

Would you offer this patient the option of HT?

Migraine affects roughly twice as many women as men.1 During the reproductive years, rapid fluctuations in ovarian hormones—both increases at midcycle and, to a greater extent, decreases during the premenstrual phase—are believed to be migraine “triggers.” Women who experience menstrually related migraine before menopause typically have an increased risk of migraine during perimenopause, with a significant reduction of migraine symptoms following menopause.2

Side effects of SSRIs and SNRIs
Most providers are aware that selective serotonin reuptake inhibitors (SSRIs) cause sexual side effects in as many as 80% of users. There is a dose-related pattern to reports of sexual problems among SSRI users, with higher doses causing more problems. The most common sexual symptoms associated with SSRIs are delayed ejaculation and absent or delayed orgasm.3

What is not as widely known is that even serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause sexual dysfunction. For example, in a prospective, multicenter study from Spain involving more than
1,000 outpatients, all of whom were taking an antidepressant, the overall rate of sexual dysfunction was 59%.4 Sexual dysfunction was most common among users of SSRIs and venlafaxine, an SNRI.5

Another common side effect of venlafaxine, sweating, is unrelated to hot flashes.5 So two of this patient’s concerns—orgasmic difficulties and profuse sweating unrelated to hot flashes—may have been caused or worsened by her antidepressant.

Another nonhormonal option
In June 2013, the US Food and Drug Administration (FDA) approved paroxetine mesylate (Brisdelle), an SSRI, for the treatment of moderate to severe menopausal vasomotor symptoms. Because the drug is a strong CYP2D6 inhibitor, it should not be given to women taking another medication that is metabolized by CYP2D6—most notably, tamoxifen.

Preliminary data on this drug suggest that, at the recommended dose (7.5 mg/d), it has no effect on sexual function.6 For this reason, it is another option for our patient to consider.

 

 

Related article: The gynecologist's role in managing menstrual migraine Anne H. Calhoun, MD 

Migraine and the risk of stroke
Migraine with aura has been associated with an increased risk of stroke and other cerebral vascular events,7 and that risk is further elevated in patients treated with OCs.8 Although migraine without aura also may be associated with an elevated risk of stroke, OCs do not further increase that risk.

Andrew M. Kaunitz, MD:
The elevated risk of stroke associated with use of OCs by women with migraine with aura appears to relate, in particular, to older, higher-dose OC formulations.9,10

Some practitioners assume that the data on the risk of stroke associated with OC use also applies to hormone therapy, but there is no evidence that HT, in which doses of estrogen are far lower than in OCs, increases the risk of stroke in migraineurs to any greater degree than would be expected in unselected populations (ie, as noted in the Women’s Health Initiative, Nurses Health Study, or other large investigations). Therefore, HT would be an appropriate option for this patient if her very slight risk of stroke on HT would be acceptable to the practitioner and patient.

JoAnn V. Pinkerton, MD:
The route of administration is critical here. In relatively healthy postmenopausal women (average age, 63), combined continuous oral HT significantly increased the risk of stroke. After 3 years of use, the absolute risk was 18 cases of stroke per 1,000 HT users (95% confidence interval [CI], 14–23). And oral estrogen-only therapy increased the risk of stroke after 7 years of use, with an absolute risk of 32 cases per 1,000 HT users (95% CI, 25–40).11

The limited clinical evidence available on the effects of tramsdermal estradiol on stroke risk indicates that the risk is not increased.12

Choosing an HT formulation

Consider the pharmacokinetic profile. Many oral estrogen HT products have rapid-release characteristics that make them likely to contribute to rapid rises and falls in the user’s estrogen level. Oral estrogens also are associated with procoagulant properties that may increase the risk of thrombosis and thromboembolism. Nonoral estrogens do not appear to increase these risks.13

Nonoral estrogens (patches, gels, sprays, lotions, and vaginal rings) provide a more stable pharmacokinetic profile, as do some oral products with controlled-release properties.

As for progestins, some formulations (medroxyprogesterone acetate) tend to cause vasoconstriction, whereas others (micronized progesterone) tend to be vasodilators. Whether these properties affect the rate of migraine or risk of stroke is unclear.

My management approach for this patient
In the absence of any systematic data on the use of HT in this clinical setting, and without any concrete suggestions from migraine experts, I would take the following three-step approach:

1. I would begin with a low-dose nonoral estradiol formulation, prescribing it without a progestin even in a woman who still has a uterus. My aim: to determine the lowest effective dose of HT for this particular patient. I would follow the patient on this dose for 3 months.

JoAnn V. Pinkerton, MD:
Another goal is to determine whether transdermal estradiol increases headaches. Before settling on a therapy, however, I would ask how long this patient has been postmenopausal, how long she has been experiencing vasomotor symptoms, and how severe those symptoms are. For example, is she having 7 or 8 hot flashes per day and waking from night sweats once or twice per night? I also would ask her how long she remained on the venlafaxine. The additional information would allow me to fine-tune her treatment.

 
2. If this formulation is tolerated, I would add micronized progesterone (oral or vaginal) for endometrial protection.

JoAnn V. Pinkerton, MD:
I would give oral progesterone if it is FDA approved for postmenopausal use, vaginal progesterone if it isn’t.

3. I would follow the patient’s clinical response—specifically, her vasomotor symptoms and rate of migraine with or without aura.

Hormone therapy is one option for postmenopausal migraineurs with bothersome vasomotor symptoms
Many women with a history of migraine move into menopause expecting their condition to improve, says headache expert Anne H. Calhoun, MD, a founder of the Carolina Headache Institute in Chapel Hill, North Carolina.

“Over the years, these women have heard that things get better with menopause.”

For women with a history of episodic migraine, that expectation is realistic, Calhoun says. “But for women with chronic migraine, who may experience a low-grade headache on a daily, or almost daily basis, with 10 or 12 severe headaches in a month, things usually get worse after menopause because the sleep issues of menopause are superimposed on the migraine.”

Dr. Calhoun observes that hormone therapy (HT) has never been contraindicated in women with migraine, although many neurologists are hesitant to prescribe any hormones for this population.

Before prescribing HT to a postmenopausal migraineur, Dr. Calhoun considers a range of variables, including sleep patterns, current medications, anxiety, frequency and severity of vasomotor symptoms, and any other problems the patient may be experiencing.

“It’s basically the same assessment as with any postmenopausal patient—to determine whether HT is a reasonable option,” she says.

And when she determines that HT is appropriate, “I almost exclusively use transdermal HT. I also am more likely to prescribe continuous use of a transdermal patch or skin gel, as I want to achieve very consistent hormone levels, day in and day out,” she says.

 

 

My bottom line

No systematic data on the use of HT in migraineurs has been published. In the absence of such data, some practitioners have extrapolated data on the use of OCs in this population and decline to prescribe HT to women with migraine. However, HT and OCs are vastly different in formulation, dose, and risks. Rather than make assumptions on the basis of irrelevant data, we should conduct studies of HT use in migraineurs.

Related article: Update on Menopause Andrew M. Kaunitz, MD (June 2013)

Women who have menstrually related migraine typically have an increased risk of migraine during perimenopause and a significant reduction in migraine following menopause. If hot flashes are bothersome, these women certainly can use HT. I recommend prescribing HT in a continuous fashion that maintains stable hormone levels in the blood, as fluctuating hormones tend to trigger migraines.

Andrew M. Kaunitz, MD:
I would just add that transdermal estradiol is preferred, to be given at the lowest effective dose.

Do you have a troubling case in menopause? Suggest it to the expert panel: [email protected]. They may address your management dilemma in a future issue.

We want to hear from you! Send us your Letter to the Editor 

CASES IN MENOPAUSE
Brought to you by the menopause experts

Andrew M. Kaunitz, MD
Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. Dr. Kaunitz is a NAMS Board member and certified menopause practitioner. He also serves on the OBG Management Board of Editors.

JoAnn V. Pinkerton, MD
Professor, Department of Obstetrics and Gynecology, and Director, Division of Midlife Women’s Health, University of Virginia. Dr. Pinkerton is a North American Menopause Society (NAMS) past president and certified menopause practitioner. She also serves on the OBG Management Board of Editors.

James A. Simon, MD
Clinical Professor, Department of Obstetrics and Gynecology, George Washington University, and Medical Director, Women’s Health & Research Consultants, Washington, DC. Dr. Simon is a NAMS past president, a certified menopause practitioner, and a certified clinical densitometrist. He also serves on the OBG Management Board of Editors.

Disclosures
Dr. Kaunitz reports that his institution receives grant or research support from Bayer, Teva, Medical Diagnostic Laboratories, and Noven, and that he is a consultant to Bayer, Actavis, and Teva.

Dr. Pinkerton reports that her institution receives consulting fees from Pfizer, DepoMed, Shionogi, and Noven and multicenter research fees from DepoMed, Endoceutics, and Bionova.

Dr. Simon reports being a consultant to or on the advisory boards of Abbott Laboratories, Agile Therapeutics, Amgen, Ascend Therapeutics, BioSante, Depomed, Lelo, MD Therapeutics, Meda Pharmaceuticals, Merck, Noven, Novo Nordisk, Novogyne, Pfizer, Shionogi, Shippan Point Advisors LLC, Slate Pharmaceuticals, Sprout Pharmaceuticals, Teva, Warner Chilcott, and Watson. He also reports receiving (currently or in the past year) grant/research support from BioSante, EndoCeutics, Novo Nordisk, Novogyne, Palatin Technologies, Teva, and Warner Chilcott. He reports serving on the speakers bureaus of Amgen, Merck, Novartis, Noven, Novo Nordisk, Novogyne, Teva, and Warner Chilcott. Dr. Simon is currently the Chief Medical Officer for Sprout Pharmaceuticals.

CASE: Menopausal symptoms and a history of migraine with aura

Your new patient is a 52-year-old woman (G2P2) who reports a long history of two types of migraine: menstrually related migraine without aura and nonmenstrually related migraine with aura (usually involving visual scotomata). Other than the history of migraine, her health is good. Now postmenopausal, she has been referred to you by her primary care physician (PCP) for management of severe vasomotor symptoms and sleep disturbance.

Because of this patient’s history of migraine, her PCP declined to prescribe oral contraceptives (OCs) in the past over concern of increasing her risk of stroke. For her vasomotor symptoms, her PCP prescribed a trial of venlafaxine (Effexor) 75 mg daily, but her orgasms, which always had been difficult to achieve, became impossible. In addition, the patient began to perspire heavily unrelated to her hot flashes. As a result, she describes her mood as “terrible,” her energy level as “miniscule,” and she reports losing interest in sex completely (“I am just too tired”). She and her referring physician wonder whether it would be safe to try hormone therapy (HT).

A physical examination, including funduscopic assessment, reveals no abnormalities. Her blood pressure is 126/70 mm Hg, and blood chemistry results, including C-reactive protein, 25-hydroxy vitamin D, a complete blood count, and lipid profile, are all normal.

Would you offer this patient the option of HT?

Migraine affects roughly twice as many women as men.1 During the reproductive years, rapid fluctuations in ovarian hormones—both increases at midcycle and, to a greater extent, decreases during the premenstrual phase—are believed to be migraine “triggers.” Women who experience menstrually related migraine before menopause typically have an increased risk of migraine during perimenopause, with a significant reduction of migraine symptoms following menopause.2

Side effects of SSRIs and SNRIs
Most providers are aware that selective serotonin reuptake inhibitors (SSRIs) cause sexual side effects in as many as 80% of users. There is a dose-related pattern to reports of sexual problems among SSRI users, with higher doses causing more problems. The most common sexual symptoms associated with SSRIs are delayed ejaculation and absent or delayed orgasm.3

What is not as widely known is that even serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause sexual dysfunction. For example, in a prospective, multicenter study from Spain involving more than
1,000 outpatients, all of whom were taking an antidepressant, the overall rate of sexual dysfunction was 59%.4 Sexual dysfunction was most common among users of SSRIs and venlafaxine, an SNRI.5

Another common side effect of venlafaxine, sweating, is unrelated to hot flashes.5 So two of this patient’s concerns—orgasmic difficulties and profuse sweating unrelated to hot flashes—may have been caused or worsened by her antidepressant.

Another nonhormonal option
In June 2013, the US Food and Drug Administration (FDA) approved paroxetine mesylate (Brisdelle), an SSRI, for the treatment of moderate to severe menopausal vasomotor symptoms. Because the drug is a strong CYP2D6 inhibitor, it should not be given to women taking another medication that is metabolized by CYP2D6—most notably, tamoxifen.

Preliminary data on this drug suggest that, at the recommended dose (7.5 mg/d), it has no effect on sexual function.6 For this reason, it is another option for our patient to consider.

 

 

Related article: The gynecologist's role in managing menstrual migraine Anne H. Calhoun, MD 

Migraine and the risk of stroke
Migraine with aura has been associated with an increased risk of stroke and other cerebral vascular events,7 and that risk is further elevated in patients treated with OCs.8 Although migraine without aura also may be associated with an elevated risk of stroke, OCs do not further increase that risk.

Andrew M. Kaunitz, MD:
The elevated risk of stroke associated with use of OCs by women with migraine with aura appears to relate, in particular, to older, higher-dose OC formulations.9,10

Some practitioners assume that the data on the risk of stroke associated with OC use also applies to hormone therapy, but there is no evidence that HT, in which doses of estrogen are far lower than in OCs, increases the risk of stroke in migraineurs to any greater degree than would be expected in unselected populations (ie, as noted in the Women’s Health Initiative, Nurses Health Study, or other large investigations). Therefore, HT would be an appropriate option for this patient if her very slight risk of stroke on HT would be acceptable to the practitioner and patient.

JoAnn V. Pinkerton, MD:
The route of administration is critical here. In relatively healthy postmenopausal women (average age, 63), combined continuous oral HT significantly increased the risk of stroke. After 3 years of use, the absolute risk was 18 cases of stroke per 1,000 HT users (95% confidence interval [CI], 14–23). And oral estrogen-only therapy increased the risk of stroke after 7 years of use, with an absolute risk of 32 cases per 1,000 HT users (95% CI, 25–40).11

The limited clinical evidence available on the effects of tramsdermal estradiol on stroke risk indicates that the risk is not increased.12

Choosing an HT formulation

Consider the pharmacokinetic profile. Many oral estrogen HT products have rapid-release characteristics that make them likely to contribute to rapid rises and falls in the user’s estrogen level. Oral estrogens also are associated with procoagulant properties that may increase the risk of thrombosis and thromboembolism. Nonoral estrogens do not appear to increase these risks.13

Nonoral estrogens (patches, gels, sprays, lotions, and vaginal rings) provide a more stable pharmacokinetic profile, as do some oral products with controlled-release properties.

As for progestins, some formulations (medroxyprogesterone acetate) tend to cause vasoconstriction, whereas others (micronized progesterone) tend to be vasodilators. Whether these properties affect the rate of migraine or risk of stroke is unclear.

My management approach for this patient
In the absence of any systematic data on the use of HT in this clinical setting, and without any concrete suggestions from migraine experts, I would take the following three-step approach:

1. I would begin with a low-dose nonoral estradiol formulation, prescribing it without a progestin even in a woman who still has a uterus. My aim: to determine the lowest effective dose of HT for this particular patient. I would follow the patient on this dose for 3 months.

JoAnn V. Pinkerton, MD:
Another goal is to determine whether transdermal estradiol increases headaches. Before settling on a therapy, however, I would ask how long this patient has been postmenopausal, how long she has been experiencing vasomotor symptoms, and how severe those symptoms are. For example, is she having 7 or 8 hot flashes per day and waking from night sweats once or twice per night? I also would ask her how long she remained on the venlafaxine. The additional information would allow me to fine-tune her treatment.

 
2. If this formulation is tolerated, I would add micronized progesterone (oral or vaginal) for endometrial protection.

JoAnn V. Pinkerton, MD:
I would give oral progesterone if it is FDA approved for postmenopausal use, vaginal progesterone if it isn’t.

3. I would follow the patient’s clinical response—specifically, her vasomotor symptoms and rate of migraine with or without aura.

Hormone therapy is one option for postmenopausal migraineurs with bothersome vasomotor symptoms
Many women with a history of migraine move into menopause expecting their condition to improve, says headache expert Anne H. Calhoun, MD, a founder of the Carolina Headache Institute in Chapel Hill, North Carolina.

“Over the years, these women have heard that things get better with menopause.”

For women with a history of episodic migraine, that expectation is realistic, Calhoun says. “But for women with chronic migraine, who may experience a low-grade headache on a daily, or almost daily basis, with 10 or 12 severe headaches in a month, things usually get worse after menopause because the sleep issues of menopause are superimposed on the migraine.”

Dr. Calhoun observes that hormone therapy (HT) has never been contraindicated in women with migraine, although many neurologists are hesitant to prescribe any hormones for this population.

Before prescribing HT to a postmenopausal migraineur, Dr. Calhoun considers a range of variables, including sleep patterns, current medications, anxiety, frequency and severity of vasomotor symptoms, and any other problems the patient may be experiencing.

“It’s basically the same assessment as with any postmenopausal patient—to determine whether HT is a reasonable option,” she says.

And when she determines that HT is appropriate, “I almost exclusively use transdermal HT. I also am more likely to prescribe continuous use of a transdermal patch or skin gel, as I want to achieve very consistent hormone levels, day in and day out,” she says.

 

 

My bottom line

No systematic data on the use of HT in migraineurs has been published. In the absence of such data, some practitioners have extrapolated data on the use of OCs in this population and decline to prescribe HT to women with migraine. However, HT and OCs are vastly different in formulation, dose, and risks. Rather than make assumptions on the basis of irrelevant data, we should conduct studies of HT use in migraineurs.

Related article: Update on Menopause Andrew M. Kaunitz, MD (June 2013)

Women who have menstrually related migraine typically have an increased risk of migraine during perimenopause and a significant reduction in migraine following menopause. If hot flashes are bothersome, these women certainly can use HT. I recommend prescribing HT in a continuous fashion that maintains stable hormone levels in the blood, as fluctuating hormones tend to trigger migraines.

Andrew M. Kaunitz, MD:
I would just add that transdermal estradiol is preferred, to be given at the lowest effective dose.

Do you have a troubling case in menopause? Suggest it to the expert panel: [email protected]. They may address your management dilemma in a future issue.

We want to hear from you! Send us your Letter to the Editor 

References

1. Shuster LT, Faubion SS. Sood R, Casey PM. Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches. Curr Neurol Neurosci Rep. 2011;11(2):131–138.

2. Loder E, Rizzoli P, Golub J. Hormonal management of migraine associated with menses and the menopause: a clinical review. Headache. 2007;47(2):329–340.

3. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163:1504–1509.

4. Taylor MJ. Strategies for managing antidepressant-induced sexual dysfunction: a review. Curr Psychiatry Rep. 2006;8(6):431–436.

5. Effexor [package insert]. New York, NY: Pfizer; 2012.

6. Brisdelle [package insert]. Miami, FL: Noven Therapeutics; 2013.

7. Etminan M, Takkouche B, Isorna FC, Samli A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ. 2005;330(7482):63–65.

8. Becker WJ. Use of oral contraceptives in patients with migraine. Neurology. 1999;53(4 Suppl 1):S19–S25.

9. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet. 1996;348(9026): 498–505.

10. Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel HK. Stroke in users of low-dose oral contraceptives. N Engl J Med. 1996;335(1):8-15.

11. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7:CD004143. doi: 10.1002/14651858.CD004143.pub4

12. Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. 2010;340:c2519.

13. Kaunitz AM. Update on Menopause. OBG Manag. 2013;25(6):36–43, 49.

References

1. Shuster LT, Faubion SS. Sood R, Casey PM. Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches. Curr Neurol Neurosci Rep. 2011;11(2):131–138.

2. Loder E, Rizzoli P, Golub J. Hormonal management of migraine associated with menses and the menopause: a clinical review. Headache. 2007;47(2):329–340.

3. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163:1504–1509.

4. Taylor MJ. Strategies for managing antidepressant-induced sexual dysfunction: a review. Curr Psychiatry Rep. 2006;8(6):431–436.

5. Effexor [package insert]. New York, NY: Pfizer; 2012.

6. Brisdelle [package insert]. Miami, FL: Noven Therapeutics; 2013.

7. Etminan M, Takkouche B, Isorna FC, Samli A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ. 2005;330(7482):63–65.

8. Becker WJ. Use of oral contraceptives in patients with migraine. Neurology. 1999;53(4 Suppl 1):S19–S25.

9. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet. 1996;348(9026): 498–505.

10. Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel HK. Stroke in users of low-dose oral contraceptives. N Engl J Med. 1996;335(1):8-15.

11. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7:CD004143. doi: 10.1002/14651858.CD004143.pub4

12. Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. 2010;340:c2519.

13. Kaunitz AM. Update on Menopause. OBG Manag. 2013;25(6):36–43, 49.

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New option for treating menopausal vasomotor symptoms receives FDA approval

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A conjugated estrogen/bazedoxifene formulation (Duavee) was approved by the FDA in early October to treat moderate-to-severe menopausal vasomotor symptoms and prevent menopausal osteoporosis in women with an intact uterus.

“Endometrial safety studies up to 1 year in length suggest that the SERM (bazedoxifene) component of this combination formulation prevents the elevated risk of endometrial hyperplasia associated with estrogen-alone treatment,” said Andrew M. Kaunitz, MD.

“[The new drug] is an alternative to hormone therapy in women with a uterus who are experiencing bothersome vasomotor symptoms in menopause,” concluded JoAnn V. Pinkerton, MD, in a NAMS presentation entitled, “Beyond hormone therapy: Innovative options for treatment of hot flashes.” To hear Dr. Pinkerton describe how much relief from their symptoms (specifically hot flash frequency and severity) patients can expect, as well as advice on patient selection, click on the audio player below.  

“In clinical trials, the most commonly reported side effects [of Duavee] included muscle spasms, nausea, diarrhea, upset stomach, abdominal pain, throat pain, dizziness, and neck pain,” Dr. Kaunitz reported.

The manufacturer’s (Pfizer) Web site indicates that Duavee will be available in the first quarter of 2014. 

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A conjugated estrogen/bazedoxifene formulation (Duavee) was approved by the FDA in early October to treat moderate-to-severe menopausal vasomotor symptoms and prevent menopausal osteoporosis in women with an intact uterus.

“Endometrial safety studies up to 1 year in length suggest that the SERM (bazedoxifene) component of this combination formulation prevents the elevated risk of endometrial hyperplasia associated with estrogen-alone treatment,” said Andrew M. Kaunitz, MD.

“[The new drug] is an alternative to hormone therapy in women with a uterus who are experiencing bothersome vasomotor symptoms in menopause,” concluded JoAnn V. Pinkerton, MD, in a NAMS presentation entitled, “Beyond hormone therapy: Innovative options for treatment of hot flashes.” To hear Dr. Pinkerton describe how much relief from their symptoms (specifically hot flash frequency and severity) patients can expect, as well as advice on patient selection, click on the audio player below.  

“In clinical trials, the most commonly reported side effects [of Duavee] included muscle spasms, nausea, diarrhea, upset stomach, abdominal pain, throat pain, dizziness, and neck pain,” Dr. Kaunitz reported.

The manufacturer’s (Pfizer) Web site indicates that Duavee will be available in the first quarter of 2014. 

A conjugated estrogen/bazedoxifene formulation (Duavee) was approved by the FDA in early October to treat moderate-to-severe menopausal vasomotor symptoms and prevent menopausal osteoporosis in women with an intact uterus.

“Endometrial safety studies up to 1 year in length suggest that the SERM (bazedoxifene) component of this combination formulation prevents the elevated risk of endometrial hyperplasia associated with estrogen-alone treatment,” said Andrew M. Kaunitz, MD.

“[The new drug] is an alternative to hormone therapy in women with a uterus who are experiencing bothersome vasomotor symptoms in menopause,” concluded JoAnn V. Pinkerton, MD, in a NAMS presentation entitled, “Beyond hormone therapy: Innovative options for treatment of hot flashes.” To hear Dr. Pinkerton describe how much relief from their symptoms (specifically hot flash frequency and severity) patients can expect, as well as advice on patient selection, click on the audio player below.  

“In clinical trials, the most commonly reported side effects [of Duavee] included muscle spasms, nausea, diarrhea, upset stomach, abdominal pain, throat pain, dizziness, and neck pain,” Dr. Kaunitz reported.

The manufacturer’s (Pfizer) Web site indicates that Duavee will be available in the first quarter of 2014. 

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No weight gain or sexual dysfunction with first nonhormonal treatment for hot flashes

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“Since the 2002 publication of initial findings of the [Women’s Health Initiative], women and clinicians have been much more interested in nonhormonal treatment options for moderate to severe vasomotor symptoms,” said Andrew M. Kauntiz, MD, at NAMS 2013.

“Because of this interest, we have seen extensive trials of SSRIs [selective serotonin reuptake inhibitors] and SNRIs [selective norepinephrin reuptake inhibitors] for the treatment of bothersome hot flashes. We recognize that these agents do have efficacy greater than placebo in the treatment of these distressing symptoms among menopausal women. However, a concern among women and their providers has been that SSRIs and SNRIs can cause unwanted weight gain as well as sexual side effects,” Dr. Kaunitz said.

Low-dose mesylate salt of paroxetine (Brisdelle), an SSRI, was FDA-approved in June 2013 as 7.5-mg paroxetine tablets—the first nonhormonal treatment for moderate to severe vasomotor symptoms associated with menopause.

Dr. Kaunitz and colleagues pooled the data from two Phase 3 randomized, double-blind, placebo-controlled trials that demonstrated reduced frequency and severity of vasomotor symptoms and favorable tolerability with the 7.5-mg paroxetine formulation.

They found no clinically meaningful or statistically significant changes from baseline in weight or sexual function among the paroxetine group (median weight 74.5 kg) versus placebo (75.8 kg). The median body mass index (BMI) was 27.9 kg/m2 among women using paroxetine versus 28.2 kg/m2 in the placebo group. The Arizona Sexual Experience Scale (ASEX) score was 59% in the paroxetine group versus 58% in the placebo group.

In addition, no significant difference between treatment groups was observed in the proportion of patients who had a gain in body weight of 7% or greater at weeks 4, 12, or 24. The rates of adverse events suggestive of sexual dysfunction were low and were similar in both treatment groups.

“What’s encouraging with our clinical trial findings is that it is the first nonhormonal treatment for menopausal vasomotor symptoms and does not cause weight gain or sexual side effects," said Dr. Kaunitz.

Listen to Dr. Kaunitz’s round-up of this new drug:

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“Since the 2002 publication of initial findings of the [Women’s Health Initiative], women and clinicians have been much more interested in nonhormonal treatment options for moderate to severe vasomotor symptoms,” said Andrew M. Kauntiz, MD, at NAMS 2013.

“Because of this interest, we have seen extensive trials of SSRIs [selective serotonin reuptake inhibitors] and SNRIs [selective norepinephrin reuptake inhibitors] for the treatment of bothersome hot flashes. We recognize that these agents do have efficacy greater than placebo in the treatment of these distressing symptoms among menopausal women. However, a concern among women and their providers has been that SSRIs and SNRIs can cause unwanted weight gain as well as sexual side effects,” Dr. Kaunitz said.

Low-dose mesylate salt of paroxetine (Brisdelle), an SSRI, was FDA-approved in June 2013 as 7.5-mg paroxetine tablets—the first nonhormonal treatment for moderate to severe vasomotor symptoms associated with menopause.

Dr. Kaunitz and colleagues pooled the data from two Phase 3 randomized, double-blind, placebo-controlled trials that demonstrated reduced frequency and severity of vasomotor symptoms and favorable tolerability with the 7.5-mg paroxetine formulation.

They found no clinically meaningful or statistically significant changes from baseline in weight or sexual function among the paroxetine group (median weight 74.5 kg) versus placebo (75.8 kg). The median body mass index (BMI) was 27.9 kg/m2 among women using paroxetine versus 28.2 kg/m2 in the placebo group. The Arizona Sexual Experience Scale (ASEX) score was 59% in the paroxetine group versus 58% in the placebo group.

In addition, no significant difference between treatment groups was observed in the proportion of patients who had a gain in body weight of 7% or greater at weeks 4, 12, or 24. The rates of adverse events suggestive of sexual dysfunction were low and were similar in both treatment groups.

“What’s encouraging with our clinical trial findings is that it is the first nonhormonal treatment for menopausal vasomotor symptoms and does not cause weight gain or sexual side effects," said Dr. Kaunitz.

Listen to Dr. Kaunitz’s round-up of this new drug:

“Since the 2002 publication of initial findings of the [Women’s Health Initiative], women and clinicians have been much more interested in nonhormonal treatment options for moderate to severe vasomotor symptoms,” said Andrew M. Kauntiz, MD, at NAMS 2013.

“Because of this interest, we have seen extensive trials of SSRIs [selective serotonin reuptake inhibitors] and SNRIs [selective norepinephrin reuptake inhibitors] for the treatment of bothersome hot flashes. We recognize that these agents do have efficacy greater than placebo in the treatment of these distressing symptoms among menopausal women. However, a concern among women and their providers has been that SSRIs and SNRIs can cause unwanted weight gain as well as sexual side effects,” Dr. Kaunitz said.

Low-dose mesylate salt of paroxetine (Brisdelle), an SSRI, was FDA-approved in June 2013 as 7.5-mg paroxetine tablets—the first nonhormonal treatment for moderate to severe vasomotor symptoms associated with menopause.

Dr. Kaunitz and colleagues pooled the data from two Phase 3 randomized, double-blind, placebo-controlled trials that demonstrated reduced frequency and severity of vasomotor symptoms and favorable tolerability with the 7.5-mg paroxetine formulation.

They found no clinically meaningful or statistically significant changes from baseline in weight or sexual function among the paroxetine group (median weight 74.5 kg) versus placebo (75.8 kg). The median body mass index (BMI) was 27.9 kg/m2 among women using paroxetine versus 28.2 kg/m2 in the placebo group. The Arizona Sexual Experience Scale (ASEX) score was 59% in the paroxetine group versus 58% in the placebo group.

In addition, no significant difference between treatment groups was observed in the proportion of patients who had a gain in body weight of 7% or greater at weeks 4, 12, or 24. The rates of adverse events suggestive of sexual dysfunction were low and were similar in both treatment groups.

“What’s encouraging with our clinical trial findings is that it is the first nonhormonal treatment for menopausal vasomotor symptoms and does not cause weight gain or sexual side effects," said Dr. Kaunitz.

Listen to Dr. Kaunitz’s round-up of this new drug:

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Ospemifene for dyspareunia in postmenopausal women is well tolerated

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Oral ospemifene (Osphena) received FDA approval in February 2013 to treat moderate to severe dyspareunia that results from vulval and vaginal atrophy. This drug, a tissue-selective estrogen agonist/antagonist, is the first oral alternative to estrogen therapy, said Steven R. Goldstein, MD, who presented data on 12- and 52-week safety of ospemifene in Phase 2/3 placebo-controlled clinical trials at NAMS 2013.

Click on the audio player below to listen to Dr. Goldstein explain the available options for vulvar and vaginal atrophy and how oral ospemifene expands these options. In addition, he describes the tolerability and side effects of ospemifene that clinicians should be aware of.

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Oral ospemifene (Osphena) received FDA approval in February 2013 to treat moderate to severe dyspareunia that results from vulval and vaginal atrophy. This drug, a tissue-selective estrogen agonist/antagonist, is the first oral alternative to estrogen therapy, said Steven R. Goldstein, MD, who presented data on 12- and 52-week safety of ospemifene in Phase 2/3 placebo-controlled clinical trials at NAMS 2013.

Click on the audio player below to listen to Dr. Goldstein explain the available options for vulvar and vaginal atrophy and how oral ospemifene expands these options. In addition, he describes the tolerability and side effects of ospemifene that clinicians should be aware of.

Oral ospemifene (Osphena) received FDA approval in February 2013 to treat moderate to severe dyspareunia that results from vulval and vaginal atrophy. This drug, a tissue-selective estrogen agonist/antagonist, is the first oral alternative to estrogen therapy, said Steven R. Goldstein, MD, who presented data on 12- and 52-week safety of ospemifene in Phase 2/3 placebo-controlled clinical trials at NAMS 2013.

Click on the audio player below to listen to Dr. Goldstein explain the available options for vulvar and vaginal atrophy and how oral ospemifene expands these options. In addition, he describes the tolerability and side effects of ospemifene that clinicians should be aware of.

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Follow-up bone mineral density didn’t sharpen fracture risk assessment

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Performing a second bone mineral density measurement 4 years after an initial measurement was "of little value" in refining the estimation of fracture risk in osteoporosis, according to a report published online Sept. 24 in JAMA.

The finding calls into question the current practice of performing serial bone mineral density (BMD) tests at even shorter 2-year intervals to enhance fracture risk assessment, the study investigators noted.

In a secondary analysis of data from the Framingham Osteoporosis Study, BMD change during a 4-year interval "provided little additional information beyond baseline BMD for the clinical management of osteoporosis," said Dr. Sarah D. Berry of the Institute for Aging Research, Hebrew SeniorLife, Boston, and her associates (JAMA 2013;310:1256-62).

The appropriate interval between BMD assessments remains controversial, and studies of the issue have yielded mixed results.

Studies that reported a strong association between BMD loss during a short interval and subsequent fractures typically focused on the small subgroup of patients who had accelerated bone deterioration. Other studies primarily involving patients with low or normal bone loss have reported only a weak association between BMD loss and later fractures, the investigators said.

To determine whether repeat BMD testing is useful, Dr. Berry and her colleagues examined the rate of hip and major osteoporotic fracture among 310 men and 492 women in the prospective, population-based Framingham cohort.

The study patients underwent an initial BMD test of the femoral neck in 1987-1999, at a mean age of 74.8 years. None was receiving treatment for osteoporosis at that time. The patients then had at least one repeat BMD test a mean of 3.7 years later (range, 2.4-6.0 years later). The study participants then were followed for approximately 12 years or until they died.

During follow-up, 113 study patients (14.1%) had one or more major osteoporotic fractures. There were 88 hip, 24 spine, 5 shoulder, and 33 forearm fractures.

BMD loss during the interval between the first and second BMD assessments was associated with subsequent fracture. However, assessment of such loss provided little clinical value beyond that of the initial BMD test.

"The second BMD measure resulted in a small proportion of individuals [being] reclassified as [at] high risk of hip or major osteoporotic fracture," Dr. Berry and her associates said. But it remains unclear whether such a small number of reclassifications justifies the current practice of performing repeat BMD tests every 2 years, they added.

"We conclude that repeating a BMD test after 4 years would rarely change the clinical management of osteoporosis based on risk scores of hip fracture," the researchers explained. "Individuals with the greatest changes in risk scores were those who would have already been classified at high risk based on [the initial] BMD and [their] clinical characteristics."

Although some experts suggest that short rescreening intervals are warranted in high-risk patients, "we found no difference in the association between BMD change and fracture when stratified by sex, age, BMI, weight loss, T score, or fracture risk score," the study authors noted.

"Despite our findings, we recognize that detecting BMD loss would have been paramount for the small numbers of individuals reclassified by a second BMD test who went on to experience a fracture," Dr. Berry and her colleagues said. For those patients, a repeat screening test would allow physicians to give osteoporosis medications and reduce fracture risk, even among patients 75 years or older.

However, for the clear majority of patients who show normal or only mild bone loss at an initial screening, further study is needed to predict which patients are likely to transition to high risk of fracture and would therefore benefit from repeat BMD testing.

The study was limited in that almost all the patients were white. The usefulness of repeated BMD screening might be different in other racial and ethnic populations, the investigators said.

The National Institutes of Health, the National Heart, Lung, and Blood Institute, and the Friends of Hebrew SeniorLife supported the study. Dr. Berry reported no relevant financial conflicts of interest; one of her associates reported ties to Amgen, Ammonett Pharma, Eli Lilly, Hologic, Merck Sharpe & Dohme, Novartis, and Roche.

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Performing a second bone mineral density measurement 4 years after an initial measurement was "of little value" in refining the estimation of fracture risk in osteoporosis, according to a report published online Sept. 24 in JAMA.

The finding calls into question the current practice of performing serial bone mineral density (BMD) tests at even shorter 2-year intervals to enhance fracture risk assessment, the study investigators noted.

In a secondary analysis of data from the Framingham Osteoporosis Study, BMD change during a 4-year interval "provided little additional information beyond baseline BMD for the clinical management of osteoporosis," said Dr. Sarah D. Berry of the Institute for Aging Research, Hebrew SeniorLife, Boston, and her associates (JAMA 2013;310:1256-62).

The appropriate interval between BMD assessments remains controversial, and studies of the issue have yielded mixed results.

Studies that reported a strong association between BMD loss during a short interval and subsequent fractures typically focused on the small subgroup of patients who had accelerated bone deterioration. Other studies primarily involving patients with low or normal bone loss have reported only a weak association between BMD loss and later fractures, the investigators said.

To determine whether repeat BMD testing is useful, Dr. Berry and her colleagues examined the rate of hip and major osteoporotic fracture among 310 men and 492 women in the prospective, population-based Framingham cohort.

The study patients underwent an initial BMD test of the femoral neck in 1987-1999, at a mean age of 74.8 years. None was receiving treatment for osteoporosis at that time. The patients then had at least one repeat BMD test a mean of 3.7 years later (range, 2.4-6.0 years later). The study participants then were followed for approximately 12 years or until they died.

During follow-up, 113 study patients (14.1%) had one or more major osteoporotic fractures. There were 88 hip, 24 spine, 5 shoulder, and 33 forearm fractures.

BMD loss during the interval between the first and second BMD assessments was associated with subsequent fracture. However, assessment of such loss provided little clinical value beyond that of the initial BMD test.

"The second BMD measure resulted in a small proportion of individuals [being] reclassified as [at] high risk of hip or major osteoporotic fracture," Dr. Berry and her associates said. But it remains unclear whether such a small number of reclassifications justifies the current practice of performing repeat BMD tests every 2 years, they added.

"We conclude that repeating a BMD test after 4 years would rarely change the clinical management of osteoporosis based on risk scores of hip fracture," the researchers explained. "Individuals with the greatest changes in risk scores were those who would have already been classified at high risk based on [the initial] BMD and [their] clinical characteristics."

Although some experts suggest that short rescreening intervals are warranted in high-risk patients, "we found no difference in the association between BMD change and fracture when stratified by sex, age, BMI, weight loss, T score, or fracture risk score," the study authors noted.

"Despite our findings, we recognize that detecting BMD loss would have been paramount for the small numbers of individuals reclassified by a second BMD test who went on to experience a fracture," Dr. Berry and her colleagues said. For those patients, a repeat screening test would allow physicians to give osteoporosis medications and reduce fracture risk, even among patients 75 years or older.

However, for the clear majority of patients who show normal or only mild bone loss at an initial screening, further study is needed to predict which patients are likely to transition to high risk of fracture and would therefore benefit from repeat BMD testing.

The study was limited in that almost all the patients were white. The usefulness of repeated BMD screening might be different in other racial and ethnic populations, the investigators said.

The National Institutes of Health, the National Heart, Lung, and Blood Institute, and the Friends of Hebrew SeniorLife supported the study. Dr. Berry reported no relevant financial conflicts of interest; one of her associates reported ties to Amgen, Ammonett Pharma, Eli Lilly, Hologic, Merck Sharpe & Dohme, Novartis, and Roche.

Performing a second bone mineral density measurement 4 years after an initial measurement was "of little value" in refining the estimation of fracture risk in osteoporosis, according to a report published online Sept. 24 in JAMA.

The finding calls into question the current practice of performing serial bone mineral density (BMD) tests at even shorter 2-year intervals to enhance fracture risk assessment, the study investigators noted.

In a secondary analysis of data from the Framingham Osteoporosis Study, BMD change during a 4-year interval "provided little additional information beyond baseline BMD for the clinical management of osteoporosis," said Dr. Sarah D. Berry of the Institute for Aging Research, Hebrew SeniorLife, Boston, and her associates (JAMA 2013;310:1256-62).

The appropriate interval between BMD assessments remains controversial, and studies of the issue have yielded mixed results.

Studies that reported a strong association between BMD loss during a short interval and subsequent fractures typically focused on the small subgroup of patients who had accelerated bone deterioration. Other studies primarily involving patients with low or normal bone loss have reported only a weak association between BMD loss and later fractures, the investigators said.

To determine whether repeat BMD testing is useful, Dr. Berry and her colleagues examined the rate of hip and major osteoporotic fracture among 310 men and 492 women in the prospective, population-based Framingham cohort.

The study patients underwent an initial BMD test of the femoral neck in 1987-1999, at a mean age of 74.8 years. None was receiving treatment for osteoporosis at that time. The patients then had at least one repeat BMD test a mean of 3.7 years later (range, 2.4-6.0 years later). The study participants then were followed for approximately 12 years or until they died.

During follow-up, 113 study patients (14.1%) had one or more major osteoporotic fractures. There were 88 hip, 24 spine, 5 shoulder, and 33 forearm fractures.

BMD loss during the interval between the first and second BMD assessments was associated with subsequent fracture. However, assessment of such loss provided little clinical value beyond that of the initial BMD test.

"The second BMD measure resulted in a small proportion of individuals [being] reclassified as [at] high risk of hip or major osteoporotic fracture," Dr. Berry and her associates said. But it remains unclear whether such a small number of reclassifications justifies the current practice of performing repeat BMD tests every 2 years, they added.

"We conclude that repeating a BMD test after 4 years would rarely change the clinical management of osteoporosis based on risk scores of hip fracture," the researchers explained. "Individuals with the greatest changes in risk scores were those who would have already been classified at high risk based on [the initial] BMD and [their] clinical characteristics."

Although some experts suggest that short rescreening intervals are warranted in high-risk patients, "we found no difference in the association between BMD change and fracture when stratified by sex, age, BMI, weight loss, T score, or fracture risk score," the study authors noted.

"Despite our findings, we recognize that detecting BMD loss would have been paramount for the small numbers of individuals reclassified by a second BMD test who went on to experience a fracture," Dr. Berry and her colleagues said. For those patients, a repeat screening test would allow physicians to give osteoporosis medications and reduce fracture risk, even among patients 75 years or older.

However, for the clear majority of patients who show normal or only mild bone loss at an initial screening, further study is needed to predict which patients are likely to transition to high risk of fracture and would therefore benefit from repeat BMD testing.

The study was limited in that almost all the patients were white. The usefulness of repeated BMD screening might be different in other racial and ethnic populations, the investigators said.

The National Institutes of Health, the National Heart, Lung, and Blood Institute, and the Friends of Hebrew SeniorLife supported the study. Dr. Berry reported no relevant financial conflicts of interest; one of her associates reported ties to Amgen, Ammonett Pharma, Eli Lilly, Hologic, Merck Sharpe & Dohme, Novartis, and Roche.

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Follow-up bone mineral density didn’t sharpen fracture risk assessment
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Follow-up bone mineral density didn’t sharpen fracture risk assessment
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Major finding: A second bone mineral density test 4 years after an initial test was not useful in refining the prediction of major fractures and didn't change the clinical management of osteoporosis.

Data source: A secondary analysis of data from the prospective, population-based Framingham Osteoporosis Study involving 802 older men and women who underwent serial BMD testing and were followed for 12 years.

Disclosures: The National Institutes of Health, the National Heart, Lung, and Blood Institute, and the Friends of Hebrew SeniorLife supported the study. Dr. Berry reported no relevant financial conflicts of interest; one of her associates reported ties to Amgen, Ammonett Pharma, Eli Lilly, Hologic, Merck Sharpe & Dohme, Novartis, and Roche.