Menopause

Much has changed in the management of menopausal women. The Women’s Health Initiative (WHI) and other trials shed light on the risk-benefit ratio of hormone therapy (HT) and significantly altered patterns of usage. A new fracture risk-assessment tool devised by the World Health Organization is now available for widespread use; it continues to be refined so that it can be applied to specific populations with greater accuracy. And the management of low bone mass and osteoporosis has evolved so that we can determine with greater precision exactly who merits our attention.

This year, the Update on Menopause describes:

• a reanalysis of WHI data, focusing on the relationship between hormone therapy and the risk of coronary artery disease (CAD)
• a study from Finland that explores the risk of endometrial cancer associated with various progestin regimens in women who are taking estrogen and who have an intact uterus
• guidance from the North American Menopause Society and the National Osteoporosis Foundation on who, how, and when to evaluate for a likelihood of fracture
• insight into the benefits of and need for vitamin D among menopausal women
• information on a new selective estrogen-receptor modulator under development.

Hormone therapy and CAD: Is the glass half full…or half empty?

Toh S, Hernández-Díaz S, Logan R, Rossouw JE, Hernán MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear? A randomized trial. Ann Intern Med. 2010;152(4):211–217.

North American Menopause Society. Position Statement: Estrogen and progestogens use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17(2):242–255. DOI: 10.1097/gme.0b013e3181d0f6b9. http://www.menopause.org/PSht10.pdf. Accessed April 1, 2010.

When estrogen therapy is initiated within 10 years of menopause, it may reduce the risk of CAD, according to data from the WHI randomized trial and observational data.

The picture isn’t as clear in regard to estrogen-progestin HT. In a just-published study, Toh and colleagues reassessed data from the WHI trial of continuous oral conjugated equine estrogen plus medroxyprogesterone acetate versus placebo. They also compared the WHI findings with those of the large observational Nurses’ Health Study (NHS). Here are some of their findings:

• participants became less consistent in taking study medication over time—a finding of many long-term studies. This trend prompted Toh and colleagues to adjust their analysis for adherence
• among women who used HT within 10 years after the menopausal transition, the hazard ratio (HR) for CAD was 0.64 (95% confidence interval [CI], 0.21, 1.99) in the WHI and 0.68 (95% CI, 0.24, 1.91) in the NHS. Both hazard ratios suggest that the risk of CAD is lower in Ht users than in nonusers—although the difference is not significant
• when investigators pooled the WHI and NHS findings, the hazard ratio for CAD associated with combination HT was 0.66 (95% CI, 0.31, 1.42). Note that, as the number of participants increases, the confidence limits narrow.

Toh and colleagues concluded that their analysis demonstrated no diminished risk of CAD with HT use. My reading of these data is different: Combination HT does not increase the risk of CAD in women who have been postmenopausal for less than 10 years.

Focus on risk was unbalanced

The question of whether combination HT reduces the risk of CAD in younger women is somewhat moot. I am not aware of any ObGyn in the United States who uses HT to prevent CAD, and the great majority of symptomatic women who consider initiating HT have been menopausal for less than a decade. For these reasons, I find the conclusions drawn by Toh and colleagues a bit mystifying—and the title they chose for their study may be misleading:

Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear?

Nevertheless, fear that HT might increase the risk of CAD is common among symptomatic menopausal women and their physicians. What this important analysis can offer is reassurance to symptomatic women who have been menopausal for less than 10 years: namely, that HT—estrogen alone or estrogen plus progestin—does not increase the risk of myocardial infarction or death from CAD.

In women taking estrogen, sequential progestin therapy raises the risk of endometrial cancer

Jaakkola S, Lyytinen H, Pukkala E, Ylikorkala O. Endometrial cancer in postmenopausal women using estradiol-progestin therapy. Obstet Gynecol. 2009;114(6):1197–1204.

Because unopposed estrogen raises the risk of endometrial hyperplasia and adenocarcinoma, we prescribe progestational therapy when a menopausal woman who has an intact uterus decides to use estrogen.

Some ObGyns prescribe continuous progestin in this setting; others, sequential progestin (e.g., continuous estrogen along with 14 days of progestin each month). Still others prescribe “long-cycle” sequential regimens comprising continuous estrogen plus 2 weeks of progestin every 3 months. However, the long-term endometrial safety of these regimens has not been adequately explored.

In a national cohort study in Finland, Jaakkola and coworkers followed more than 200,000 menopausal women who used estrogen plus progestin (E+P) HT from 1994 to 2006. The incidence of endometrial cancer in these women was compared with that of all women in Finland. Overall, 1,400 newly diagnosed cases of endometrial cancer were identified.

Investigators found that, compared with the general population:

• E+P users overall had a 54% greater risk of endometrioid endometrial adenocarcinoma, the tumor most closely associated with use of unopposed estrogen
• monthly sequential E+P users had a 69% (5 years’ use) and 156% (10 years’ use) greater risk of this tumor
• at 5 and 10 years of use, long-cycle sequential HT was associated with a substantially higher risk of endometrial adenocarcinoma than was monthly sequential HT
• the endometrial safety profiles of transdermal and oral sequential HT were comparable; so were those of medroxyprogesterone acetate and norethindrone acetate
• in contrast to sequential HT regimens, continuous E+P was associated with a lower risk of endometrial cancer than that found in the overall population (76% risk reduction after 3 to 5 years of use).

These important findings clarify the safety profiles of long-term continuous E+P, which is protective, and sequential E+P, which substantially raises the risk of endometrial adenocarcinoma.

The authors estimate that, for every 1,000 women who use E+P for 10 years, eight additional cases of cancer will be diagnosed if that therapy is sequential and monthly; on the other hand, three or four fewer cases will be diagnosed if HT is continuous.

Guidance on who to assess for osteoporosis—and when to treat them

The North American Menopause Society. NAMS continuing medical education activity: Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17(1):23–24.

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, D.C.: NOF: 2008. http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf. Accessed April 1, 2010.

Kaunitz AM, McClung MR, Feldman RG, Wysocki S. Postmenopausal osteoporosis: fracture risk and prevention. OBG Management. 2009;21(10)(suppl):S1–6.

The North American Menopause Society (NAMS) has updated its position statement on the management of osteoporosis in postmenopausal women, incorporating many recommendations from guidelines issued in 2008 by the National Osteoporosis Foundation. You may find the recommendations on bone mineral density (BMD) assessment and use of medications to prevent fractures of particular interest.

BMD assessment should focus on women at high risk of fracture

In the United States, many women at low risk of fracture begin BMD assessment in their 50s via dual-energy x-ray absorptiometry (DXA) imaging of the lumbar spine and hip (FIGURE). As a result, many of these menopausal women are given a diagnosis of low bone mass (often termed “osteopenia” when in fact their DXA findings do not meet the criteria for osteoporosis) and are given a prescription for a bisphosphonate, often of indefinite duration.

FIGURE When DXA imaging reveals low BMD

DXA scan of the lumbar spine and both hips showing osteoporosis in a 69-year-old woman. The colored graphs show the range of bone mineral density (BMD) across eight decades. The blue bars represent normal bone density; the white squares within the orange and red bars denote this patient’s low BMD. NAMS’s latest position statement clarifies exactly which women should be assessed, concluding that BMD measurement is appropriate in postmenopausal women who are not only at least 50 years old, but who also have one or more of the following risk factors for fracture:

• a history of fracture after menopause
• body mass index (BMI) <21 kg/m² or weight <127 lb
• parental history of hip fracture
• current smoking, rheumatoid arthritis, or excessive alcohol intake (i.e., three or more drinks per day).

In the absence of these risk factors, BMD assessment should begin at 65 years of age.

Once initiated, treatment is usually long-term

The NAMS statement indicates that drug therapy—using bisphosphonates as first-line agents—is appropriate in postmenopausal women who have any of the following:

• a history of osteoporotic hip or vertebral fracture
• DXA-defined T-score lower than –2.5, indicating osteoporosis
• T-score from –1.0 to –2.5 (low bone mass) plus either a FRAX score that indicates a 10-year risk of hip fracture of at least 3% or a 10-year overall risk of osteoporotic fracture of at least 20%.

The World Health Organization (WHO) Fracture Risk Algorithm (FRAX) was developed to calculate the 10-year risk of hip fracture and the 10-year overall risk of osteoporotic fracture (online at http://www.shef.ac.uk/FRAX/). (For a description of two menopausal cases in which this Web site was used to determine appropriate clinical management, see the article by Kaunitz and colleagues cited above. Also, be aware that use of the FRAX Web site is inappropriate for making clinical decisions about women who are already using prescription antifracture therapy.)

NAMS points out that 1) treatment should usually span a period of years and 2) the risk of fracture after discontinuation of treatment has not been adequately studied.

BMD reassessment should be minimal

BMD assessment by means of DXA imaging to monitor the effects of therapy is appropriate after 1 or 2 years of treatment. Thereafter, repeat measurement is of little value in women whose BMD has stabilized or increased on therapy. A follow-up DXA scan is of limited use in predicting the effectiveness of antiresorptive therapy in lowering the risk of fracture. Moreover, changes in BMD can lag behind actual therapeutic benefits (i.e., fracture prevention).

In menopausal women who are not taking prescription antifracture therapy, the follow-up measurement of BMD is not useful until 2 to 5 years after initial testing. Although BMD may be lost rapidly in the initial years after menopause (or after discontinuation of HT), subsequently it plateaus or declines slowly.

If a woman is not using prescription antifracture therapy and is within 2 or 3 years of menopause (or if she has discontinued menopausal HT in the past 2 to 3 years), retesting in 2 years is prudent. However, if the same woman were 5 or more years post-menopausal and had not recently discontinued HT, follow-up BMD assessment can be deferred for 3 to 5 years.

This updated guidance from NAMS emphasizes that BMD need not be assessed in women younger than 65 years unless they have specific risk factors. FRAX evaluation also makes it possible to estimate the 10-year risk of fracture in women who have low bone mass but who do not meet criteria for osteoporosis. FRAX evaluation indicates that prescription therapy is rarely required for women in their 50s or 60s who have low bone mass (but not osteoporosis). For women in their 70s or 80s who have low bone mass (but not osteoporosis), however, FRAX evaluation often leads to a recommendation to initiate prescription antifracture treatment.

Many postmenopausal women who are in their 50s or 60s and who have T-scores of –1.0 to –2.5 are given bisphosphonates, despite being at low risk of fracture. Adherence to the NAMS guidelines will help prevent unnecessary assessment and treatment. In particular, the NAMS recommendations for follow-up BMD assessment—i.e., one-time evaluation 1 to 2 years after initiating therapy and no further assessment in women found to have stable BMD at the first follow-up DXA—should simplify clinical management in this setting.

Our menopausal patients should be taking more vitamin D supplements

Bischoff-Ferrari H. Vitamin D: what is an adequate vitamin D level and how much supplementation is necessary? Best Pract Res Clin Rheumatol. 2009;23(6):789.

Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.

Stewart JW, Alekel DL, Ritland LM, et al. Serum 25-hydroxyvitamin D is related to indicators of overall physical fitness in healthy postmenopausal women. Menopause. 2009;16(6):1093–1101.

Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. National Institutes of Health Web site. http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp. Updated November 13, 2009. Accessed April 2, 2010.

We have long recognized the important role vitamin D plays in promoting calcium absorption from the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal bone mineralization. Now, studies reveal that the vitamin also helps prevent falls and promotes overall fitness in menopausal women. It has also become clear that traditional targets for vitamin D supplementation are inadequate.

Two recent meta-analyses of double-blind, randomized trials concluded that vitamin D reduces the risk of falls in a dose-dependent manner. Dr. Heike Bischoff-Ferrari, a Swiss scientist and a leading vitamin D researcher, points out that 1) a minimum of 700 to 1,000 IU of vitamin D supplementation daily is appropriate in menopausal women and 2) a higher amount is indicated for those who are obese or deficient in vitamin D.

Compare the current recommended dietary allowance (RDA) for adults 51 to 70 years old: 400 IU daily. The federal Food and Nutrition Board is expected to update the vitamin D RDA this spring. The 2010 NAMS statement on osteoporosis recommends a daily vitamin D intake of 800 to 1,000 IU for menopausal women.

Much has changed in the management of menopausal women. The Women’s Health Initiative (WHI) and other trials shed light on the risk-benefit ratio of hormone therapy (HT) and significantly altered patterns of usage. A new fracture risk-assessment tool devised by the World Health Organization is now available for widespread use; it continues to be refined so that it can be applied to specific populations with greater accuracy. And the management of low bone mass and osteoporosis has evolved so that we can determine with greater precision exactly who merits our attention.

This year, the Update on Menopause describes:

• a reanalysis of WHI data, focusing on the relationship between hormone therapy and the risk of coronary artery disease (CAD)
• a study from Finland that explores the risk of endometrial cancer associated with various progestin regimens in women who are taking estrogen and who have an intact uterus
• guidance from the North American Menopause Society and the National Osteoporosis Foundation on who, how, and when to evaluate for a likelihood of fracture
• insight into the benefits of and need for vitamin D among menopausal women
• information on a new selective estrogen-receptor modulator under development.

Hormone therapy and CAD: Is the glass half full…or half empty?

Toh S, Hernández-Díaz S, Logan R, Rossouw JE, Hernán MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear? A randomized trial. Ann Intern Med. 2010;152(4):211–217.

North American Menopause Society. Position Statement: Estrogen and progestogens use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17(2):242–255. DOI: 10.1097/gme.0b013e3181d0f6b9. http://www.menopause.org/PSht10.pdf. Accessed April 1, 2010.

When estrogen therapy is initiated within 10 years of menopause, it may reduce the risk of CAD, according to data from the WHI randomized trial and observational data.

The picture isn’t as clear in regard to estrogen-progestin HT. In a just-published study, Toh and colleagues reassessed data from the WHI trial of continuous oral conjugated equine estrogen plus medroxyprogesterone acetate versus placebo. They also compared the WHI findings with those of the large observational Nurses’ Health Study (NHS). Here are some of their findings:

• participants became less consistent in taking study medication over time—a finding of many long-term studies. This trend prompted Toh and colleagues to adjust their analysis for adherence
• among women who used HT within 10 years after the menopausal transition, the hazard ratio (HR) for CAD was 0.64 (95% confidence interval [CI], 0.21, 1.99) in the WHI and 0.68 (95% CI, 0.24, 1.91) in the NHS. Both hazard ratios suggest that the risk of CAD is lower in Ht users than in nonusers—although the difference is not significant
• when investigators pooled the WHI and NHS findings, the hazard ratio for CAD associated with combination HT was 0.66 (95% CI, 0.31, 1.42). Note that, as the number of participants increases, the confidence limits narrow.

Toh and colleagues concluded that their analysis demonstrated no diminished risk of CAD with HT use. My reading of these data is different: Combination HT does not increase the risk of CAD in women who have been postmenopausal for less than 10 years.

Focus on risk was unbalanced

The question of whether combination HT reduces the risk of CAD in younger women is somewhat moot. I am not aware of any ObGyn in the United States who uses HT to prevent CAD, and the great majority of symptomatic women who consider initiating HT have been menopausal for less than a decade. For these reasons, I find the conclusions drawn by Toh and colleagues a bit mystifying—and the title they chose for their study may be misleading:

Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear?

Nevertheless, fear that HT might increase the risk of CAD is common among symptomatic menopausal women and their physicians. What this important analysis can offer is reassurance to symptomatic women who have been menopausal for less than 10 years: namely, that HT—estrogen alone or estrogen plus progestin—does not increase the risk of myocardial infarction or death from CAD.

In women taking estrogen, sequential progestin therapy raises the risk of endometrial cancer

Jaakkola S, Lyytinen H, Pukkala E, Ylikorkala O. Endometrial cancer in postmenopausal women using estradiol-progestin therapy. Obstet Gynecol. 2009;114(6):1197–1204.

Because unopposed estrogen raises the risk of endometrial hyperplasia and adenocarcinoma, we prescribe progestational therapy when a menopausal woman who has an intact uterus decides to use estrogen.

Some ObGyns prescribe continuous progestin in this setting; others, sequential progestin (e.g., continuous estrogen along with 14 days of progestin each month). Still others prescribe “long-cycle” sequential regimens comprising continuous estrogen plus 2 weeks of progestin every 3 months. However, the long-term endometrial safety of these regimens has not been adequately explored.

In a national cohort study in Finland, Jaakkola and coworkers followed more than 200,000 menopausal women who used estrogen plus progestin (E+P) HT from 1994 to 2006. The incidence of endometrial cancer in these women was compared with that of all women in Finland. Overall, 1,400 newly diagnosed cases of endometrial cancer were identified.

Investigators found that, compared with the general population:

• E+P users overall had a 54% greater risk of endometrioid endometrial adenocarcinoma, the tumor most closely associated with use of unopposed estrogen
• monthly sequential E+P users had a 69% (5 years’ use) and 156% (10 years’ use) greater risk of this tumor
• at 5 and 10 years of use, long-cycle sequential HT was associated with a substantially higher risk of endometrial adenocarcinoma than was monthly sequential HT
• the endometrial safety profiles of transdermal and oral sequential HT were comparable; so were those of medroxyprogesterone acetate and norethindrone acetate
• in contrast to sequential HT regimens, continuous E+P was associated with a lower risk of endometrial cancer than that found in the overall population (76% risk reduction after 3 to 5 years of use).

These important findings clarify the safety profiles of long-term continuous E+P, which is protective, and sequential E+P, which substantially raises the risk of endometrial adenocarcinoma.

The authors estimate that, for every 1,000 women who use E+P for 10 years, eight additional cases of cancer will be diagnosed if that therapy is sequential and monthly; on the other hand, three or four fewer cases will be diagnosed if HT is continuous.

Guidance on who to assess for osteoporosis—and when to treat them

The North American Menopause Society. NAMS continuing medical education activity: Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17(1):23–24.

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, D.C.: NOF: 2008. http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf. Accessed April 1, 2010.

Kaunitz AM, McClung MR, Feldman RG, Wysocki S. Postmenopausal osteoporosis: fracture risk and prevention. OBG Management. 2009;21(10)(suppl):S1–6.

The North American Menopause Society (NAMS) has updated its position statement on the management of osteoporosis in postmenopausal women, incorporating many recommendations from guidelines issued in 2008 by the National Osteoporosis Foundation. You may find the recommendations on bone mineral density (BMD) assessment and use of medications to prevent fractures of particular interest.

BMD assessment should focus on women at high risk of fracture

In the United States, many women at low risk of fracture begin BMD assessment in their 50s via dual-energy x-ray absorptiometry (DXA) imaging of the lumbar spine and hip (FIGURE). As a result, many of these menopausal women are given a diagnosis of low bone mass (often termed “osteopenia” when in fact their DXA findings do not meet the criteria for osteoporosis) and are given a prescription for a bisphosphonate, often of indefinite duration.

FIGURE When DXA imaging reveals low BMD

DXA scan of the lumbar spine and both hips showing osteoporosis in a 69-year-old woman. The colored graphs show the range of bone mineral density (BMD) across eight decades. The blue bars represent normal bone density; the white squares within the orange and red bars denote this patient’s low BMD. NAMS’s latest position statement clarifies exactly which women should be assessed, concluding that BMD measurement is appropriate in postmenopausal women who are not only at least 50 years old, but who also have one or more of the following risk factors for fracture:

• a history of fracture after menopause
• body mass index (BMI) <21 kg/m² or weight <127 lb
• parental history of hip fracture
• current smoking, rheumatoid arthritis, or excessive alcohol intake (i.e., three or more drinks per day).

In the absence of these risk factors, BMD assessment should begin at 65 years of age.

Once initiated, treatment is usually long-term

The NAMS statement indicates that drug therapy—using bisphosphonates as first-line agents—is appropriate in postmenopausal women who have any of the following:

• a history of osteoporotic hip or vertebral fracture
• DXA-defined T-score lower than –2.5, indicating osteoporosis
• T-score from –1.0 to –2.5 (low bone mass) plus either a FRAX score that indicates a 10-year risk of hip fracture of at least 3% or a 10-year overall risk of osteoporotic fracture of at least 20%.

The World Health Organization (WHO) Fracture Risk Algorithm (FRAX) was developed to calculate the 10-year risk of hip fracture and the 10-year overall risk of osteoporotic fracture (online at http://www.shef.ac.uk/FRAX/). (For a description of two menopausal cases in which this Web site was used to determine appropriate clinical management, see the article by Kaunitz and colleagues cited above. Also, be aware that use of the FRAX Web site is inappropriate for making clinical decisions about women who are already using prescription antifracture therapy.)

NAMS points out that 1) treatment should usually span a period of years and 2) the risk of fracture after discontinuation of treatment has not been adequately studied.

BMD reassessment should be minimal

BMD assessment by means of DXA imaging to monitor the effects of therapy is appropriate after 1 or 2 years of treatment. Thereafter, repeat measurement is of little value in women whose BMD has stabilized or increased on therapy. A follow-up DXA scan is of limited use in predicting the effectiveness of antiresorptive therapy in lowering the risk of fracture. Moreover, changes in BMD can lag behind actual therapeutic benefits (i.e., fracture prevention).

In menopausal women who are not taking prescription antifracture therapy, the follow-up measurement of BMD is not useful until 2 to 5 years after initial testing. Although BMD may be lost rapidly in the initial years after menopause (or after discontinuation of HT), subsequently it plateaus or declines slowly.

If a woman is not using prescription antifracture therapy and is within 2 or 3 years of menopause (or if she has discontinued menopausal HT in the past 2 to 3 years), retesting in 2 years is prudent. However, if the same woman were 5 or more years post-menopausal and had not recently discontinued HT, follow-up BMD assessment can be deferred for 3 to 5 years.

This updated guidance from NAMS emphasizes that BMD need not be assessed in women younger than 65 years unless they have specific risk factors. FRAX evaluation also makes it possible to estimate the 10-year risk of fracture in women who have low bone mass but who do not meet criteria for osteoporosis. FRAX evaluation indicates that prescription therapy is rarely required for women in their 50s or 60s who have low bone mass (but not osteoporosis). For women in their 70s or 80s who have low bone mass (but not osteoporosis), however, FRAX evaluation often leads to a recommendation to initiate prescription antifracture treatment.

Many postmenopausal women who are in their 50s or 60s and who have T-scores of –1.0 to –2.5 are given bisphosphonates, despite being at low risk of fracture. Adherence to the NAMS guidelines will help prevent unnecessary assessment and treatment. In particular, the NAMS recommendations for follow-up BMD assessment—i.e., one-time evaluation 1 to 2 years after initiating therapy and no further assessment in women found to have stable BMD at the first follow-up DXA—should simplify clinical management in this setting.

Our menopausal patients should be taking more vitamin D supplements

Bischoff-Ferrari H. Vitamin D: what is an adequate vitamin D level and how much supplementation is necessary? Best Pract Res Clin Rheumatol. 2009;23(6):789.

Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.

Stewart JW, Alekel DL, Ritland LM, et al. Serum 25-hydroxyvitamin D is related to indicators of overall physical fitness in healthy postmenopausal women. Menopause. 2009;16(6):1093–1101.

Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. National Institutes of Health Web site. http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp. Updated November 13, 2009. Accessed April 2, 2010.

We have long recognized the important role vitamin D plays in promoting calcium absorption from the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal bone mineralization. Now, studies reveal that the vitamin also helps prevent falls and promotes overall fitness in menopausal women. It has also become clear that traditional targets for vitamin D supplementation are inadequate.

Two recent meta-analyses of double-blind, randomized trials concluded that vitamin D reduces the risk of falls in a dose-dependent manner. Dr. Heike Bischoff-Ferrari, a Swiss scientist and a leading vitamin D researcher, points out that 1) a minimum of 700 to 1,000 IU of vitamin D supplementation daily is appropriate in menopausal women and 2) a higher amount is indicated for those who are obese or deficient in vitamin D.

Compare the current recommended dietary allowance (RDA) for adults 51 to 70 years old: 400 IU daily. The federal Food and Nutrition Board is expected to update the vitamin D RDA this spring. The 2010 NAMS statement on osteoporosis recommends a daily vitamin D intake of 800 to 1,000 IU for menopausal women.

Much has changed in the management of menopausal women. The Women’s Health Initiative (WHI) and other trials shed light on the risk-benefit ratio of hormone therapy (HT) and significantly altered patterns of usage. A new fracture risk-assessment tool devised by the World Health Organization is now available for widespread use; it continues to be refined so that it can be applied to specific populations with greater accuracy. And the management of low bone mass and osteoporosis has evolved so that we can determine with greater precision exactly who merits our attention.

This year, the Update on Menopause describes:

• a reanalysis of WHI data, focusing on the relationship between hormone therapy and the risk of coronary artery disease (CAD)
• a study from Finland that explores the risk of endometrial cancer associated with various progestin regimens in women who are taking estrogen and who have an intact uterus
• guidance from the North American Menopause Society and the National Osteoporosis Foundation on who, how, and when to evaluate for a likelihood of fracture
• insight into the benefits of and need for vitamin D among menopausal women
• information on a new selective estrogen-receptor modulator under development.

Hormone therapy and CAD: Is the glass half full…or half empty?

Toh S, Hernández-Díaz S, Logan R, Rossouw JE, Hernán MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear? A randomized trial. Ann Intern Med. 2010;152(4):211–217.

North American Menopause Society. Position Statement: Estrogen and progestogens use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17(2):242–255. DOI: 10.1097/gme.0b013e3181d0f6b9. http://www.menopause.org/PSht10.pdf. Accessed April 1, 2010.

When estrogen therapy is initiated within 10 years of menopause, it may reduce the risk of CAD, according to data from the WHI randomized trial and observational data.

The picture isn’t as clear in regard to estrogen-progestin HT. In a just-published study, Toh and colleagues reassessed data from the WHI trial of continuous oral conjugated equine estrogen plus medroxyprogesterone acetate versus placebo. They also compared the WHI findings with those of the large observational Nurses’ Health Study (NHS). Here are some of their findings:

• participants became less consistent in taking study medication over time—a finding of many long-term studies. This trend prompted Toh and colleagues to adjust their analysis for adherence
• among women who used HT within 10 years after the menopausal transition, the hazard ratio (HR) for CAD was 0.64 (95% confidence interval [CI], 0.21, 1.99) in the WHI and 0.68 (95% CI, 0.24, 1.91) in the NHS. Both hazard ratios suggest that the risk of CAD is lower in Ht users than in nonusers—although the difference is not significant
• when investigators pooled the WHI and NHS findings, the hazard ratio for CAD associated with combination HT was 0.66 (95% CI, 0.31, 1.42). Note that, as the number of participants increases, the confidence limits narrow.

Toh and colleagues concluded that their analysis demonstrated no diminished risk of CAD with HT use. My reading of these data is different: Combination HT does not increase the risk of CAD in women who have been postmenopausal for less than 10 years.

Focus on risk was unbalanced

The question of whether combination HT reduces the risk of CAD in younger women is somewhat moot. I am not aware of any ObGyn in the United States who uses HT to prevent CAD, and the great majority of symptomatic women who consider initiating HT have been menopausal for less than a decade. For these reasons, I find the conclusions drawn by Toh and colleagues a bit mystifying—and the title they chose for their study may be misleading:

Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Does the increased risk ever disappear?

Nevertheless, fear that HT might increase the risk of CAD is common among symptomatic menopausal women and their physicians. What this important analysis can offer is reassurance to symptomatic women who have been menopausal for less than 10 years: namely, that HT—estrogen alone or estrogen plus progestin—does not increase the risk of myocardial infarction or death from CAD.

In women taking estrogen, sequential progestin therapy raises the risk of endometrial cancer

Jaakkola S, Lyytinen H, Pukkala E, Ylikorkala O. Endometrial cancer in postmenopausal women using estradiol-progestin therapy. Obstet Gynecol. 2009;114(6):1197–1204.

Because unopposed estrogen raises the risk of endometrial hyperplasia and adenocarcinoma, we prescribe progestational therapy when a menopausal woman who has an intact uterus decides to use estrogen.

Some ObGyns prescribe continuous progestin in this setting; others, sequential progestin (e.g., continuous estrogen along with 14 days of progestin each month). Still others prescribe “long-cycle” sequential regimens comprising continuous estrogen plus 2 weeks of progestin every 3 months. However, the long-term endometrial safety of these regimens has not been adequately explored.

In a national cohort study in Finland, Jaakkola and coworkers followed more than 200,000 menopausal women who used estrogen plus progestin (E+P) HT from 1994 to 2006. The incidence of endometrial cancer in these women was compared with that of all women in Finland. Overall, 1,400 newly diagnosed cases of endometrial cancer were identified.

Investigators found that, compared with the general population:

• E+P users overall had a 54% greater risk of endometrioid endometrial adenocarcinoma, the tumor most closely associated with use of unopposed estrogen
• monthly sequential E+P users had a 69% (5 years’ use) and 156% (10 years’ use) greater risk of this tumor
• at 5 and 10 years of use, long-cycle sequential HT was associated with a substantially higher risk of endometrial adenocarcinoma than was monthly sequential HT
• the endometrial safety profiles of transdermal and oral sequential HT were comparable; so were those of medroxyprogesterone acetate and norethindrone acetate
• in contrast to sequential HT regimens, continuous E+P was associated with a lower risk of endometrial cancer than that found in the overall population (76% risk reduction after 3 to 5 years of use).

These important findings clarify the safety profiles of long-term continuous E+P, which is protective, and sequential E+P, which substantially raises the risk of endometrial adenocarcinoma.

The authors estimate that, for every 1,000 women who use E+P for 10 years, eight additional cases of cancer will be diagnosed if that therapy is sequential and monthly; on the other hand, three or four fewer cases will be diagnosed if HT is continuous.

Guidance on who to assess for osteoporosis—and when to treat them

The North American Menopause Society. NAMS continuing medical education activity: Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17(1):23–24.

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, D.C.: NOF: 2008. http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf. Accessed April 1, 2010.

Kaunitz AM, McClung MR, Feldman RG, Wysocki S. Postmenopausal osteoporosis: fracture risk and prevention. OBG Management. 2009;21(10)(suppl):S1–6.

The North American Menopause Society (NAMS) has updated its position statement on the management of osteoporosis in postmenopausal women, incorporating many recommendations from guidelines issued in 2008 by the National Osteoporosis Foundation. You may find the recommendations on bone mineral density (BMD) assessment and use of medications to prevent fractures of particular interest.

BMD assessment should focus on women at high risk of fracture

In the United States, many women at low risk of fracture begin BMD assessment in their 50s via dual-energy x-ray absorptiometry (DXA) imaging of the lumbar spine and hip (FIGURE). As a result, many of these menopausal women are given a diagnosis of low bone mass (often termed “osteopenia” when in fact their DXA findings do not meet the criteria for osteoporosis) and are given a prescription for a bisphosphonate, often of indefinite duration.

FIGURE When DXA imaging reveals low BMD

DXA scan of the lumbar spine and both hips showing osteoporosis in a 69-year-old woman. The colored graphs show the range of bone mineral density (BMD) across eight decades. The blue bars represent normal bone density; the white squares within the orange and red bars denote this patient’s low BMD. NAMS’s latest position statement clarifies exactly which women should be assessed, concluding that BMD measurement is appropriate in postmenopausal women who are not only at least 50 years old, but who also have one or more of the following risk factors for fracture:

• a history of fracture after menopause
• body mass index (BMI) <21 kg/m² or weight <127 lb
• parental history of hip fracture
• current smoking, rheumatoid arthritis, or excessive alcohol intake (i.e., three or more drinks per day).

In the absence of these risk factors, BMD assessment should begin at 65 years of age.

Once initiated, treatment is usually long-term

The NAMS statement indicates that drug therapy—using bisphosphonates as first-line agents—is appropriate in postmenopausal women who have any of the following:

• a history of osteoporotic hip or vertebral fracture
• DXA-defined T-score lower than –2.5, indicating osteoporosis
• T-score from –1.0 to –2.5 (low bone mass) plus either a FRAX score that indicates a 10-year risk of hip fracture of at least 3% or a 10-year overall risk of osteoporotic fracture of at least 20%.

The World Health Organization (WHO) Fracture Risk Algorithm (FRAX) was developed to calculate the 10-year risk of hip fracture and the 10-year overall risk of osteoporotic fracture (online at http://www.shef.ac.uk/FRAX/). (For a description of two menopausal cases in which this Web site was used to determine appropriate clinical management, see the article by Kaunitz and colleagues cited above. Also, be aware that use of the FRAX Web site is inappropriate for making clinical decisions about women who are already using prescription antifracture therapy.)

NAMS points out that 1) treatment should usually span a period of years and 2) the risk of fracture after discontinuation of treatment has not been adequately studied.

BMD reassessment should be minimal

BMD assessment by means of DXA imaging to monitor the effects of therapy is appropriate after 1 or 2 years of treatment. Thereafter, repeat measurement is of little value in women whose BMD has stabilized or increased on therapy. A follow-up DXA scan is of limited use in predicting the effectiveness of antiresorptive therapy in lowering the risk of fracture. Moreover, changes in BMD can lag behind actual therapeutic benefits (i.e., fracture prevention).

In menopausal women who are not taking prescription antifracture therapy, the follow-up measurement of BMD is not useful until 2 to 5 years after initial testing. Although BMD may be lost rapidly in the initial years after menopause (or after discontinuation of HT), subsequently it plateaus or declines slowly.

If a woman is not using prescription antifracture therapy and is within 2 or 3 years of menopause (or if she has discontinued menopausal HT in the past 2 to 3 years), retesting in 2 years is prudent. However, if the same woman were 5 or more years post-menopausal and had not recently discontinued HT, follow-up BMD assessment can be deferred for 3 to 5 years.

This updated guidance from NAMS emphasizes that BMD need not be assessed in women younger than 65 years unless they have specific risk factors. FRAX evaluation also makes it possible to estimate the 10-year risk of fracture in women who have low bone mass but who do not meet criteria for osteoporosis. FRAX evaluation indicates that prescription therapy is rarely required for women in their 50s or 60s who have low bone mass (but not osteoporosis). For women in their 70s or 80s who have low bone mass (but not osteoporosis), however, FRAX evaluation often leads to a recommendation to initiate prescription antifracture treatment.

Many postmenopausal women who are in their 50s or 60s and who have T-scores of –1.0 to –2.5 are given bisphosphonates, despite being at low risk of fracture. Adherence to the NAMS guidelines will help prevent unnecessary assessment and treatment. In particular, the NAMS recommendations for follow-up BMD assessment—i.e., one-time evaluation 1 to 2 years after initiating therapy and no further assessment in women found to have stable BMD at the first follow-up DXA—should simplify clinical management in this setting.

Our menopausal patients should be taking more vitamin D supplements

Bischoff-Ferrari H. Vitamin D: what is an adequate vitamin D level and how much supplementation is necessary? Best Pract Res Clin Rheumatol. 2009;23(6):789.

Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.

Stewart JW, Alekel DL, Ritland LM, et al. Serum 25-hydroxyvitamin D is related to indicators of overall physical fitness in healthy postmenopausal women. Menopause. 2009;16(6):1093–1101.

Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. National Institutes of Health Web site. http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp. Updated November 13, 2009. Accessed April 2, 2010.

We have long recognized the important role vitamin D plays in promoting calcium absorption from the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal bone mineralization. Now, studies reveal that the vitamin also helps prevent falls and promotes overall fitness in menopausal women. It has also become clear that traditional targets for vitamin D supplementation are inadequate.

Two recent meta-analyses of double-blind, randomized trials concluded that vitamin D reduces the risk of falls in a dose-dependent manner. Dr. Heike Bischoff-Ferrari, a Swiss scientist and a leading vitamin D researcher, points out that 1) a minimum of 700 to 1,000 IU of vitamin D supplementation daily is appropriate in menopausal women and 2) a higher amount is indicated for those who are obese or deficient in vitamin D.

Compare the current recommended dietary allowance (RDA) for adults 51 to 70 years old: 400 IU daily. The federal Food and Nutrition Board is expected to update the vitamin D RDA this spring. The 2010 NAMS statement on osteoporosis recommends a daily vitamin D intake of 800 to 1,000 IU for menopausal women.

Major Finding: Women who had ever used hormone therapy had a 14% higher risk for cataract extraction and current HT users had an 18% higher risk, compared with women who never used HT.

Data Source: A 98-month Swedish prospective study of 30,861 postmenopausal women.

Disclosures: Dr. Lindblad and her associates reported having no conflicts of interest related to the study, which was funded by Swedish government agencies and research foundations.

Women who used hormone therapy were more likely to need cataract surgery, a risk potentiated by drinking alcohol, a large Swedish prospective study found.

In a 98-month study of 30,861 postmenopausal women, those who had ever used hormone therapy (HT) had a 14% higher risk for cataract extraction and current HT users had an 18% higher risk, compared with women who had never used HT, in a multivariate adjusted analysis, Dr. Birgitta Ejdervik Lindblad and her associates reported. The study appears in the journal Ophthalmology (doi:10.1016/j.ophtha.2009.07.046).

Cataract extraction was even more likely in women who were using HT and drank alcohol. Among current HT users, any alcohol consumption was associated with a 29% higher risk for cataract extraction, and those who drank more than one alcoholic drink per day had a 42% higher risk, compared with women who were neither using HT nor drinking alcohol. (One drink was defined as about 13 g of alcohol, roughly equal to one glass of wine, bottle of beer, or drink of liquor.) Drinking alcohol has been associated with increased levels of plasma estrogen in postmenopausal women in prior studies.

Investigators collected data from women in the Swedish Mammography Cohort who completed questionnaires in September 1997 about hormone status, use of hormone therapy, and lifestyle factors. The researchers followed them through October 2005 and compared their names with those on Swedish registers of cataract surgeries, which identified 4,324 women who underwent cataract surgery during the study period.

Among women aged 65 years or older, the risk for cataract surgery was 73% higher in those using hormone therapy, compared with women who never used HT, after the researchers adjusted for the effects of alcohol consumption, smoking, diabetes, hypertension, steroid or vitamin use, body mass index, and education level.

Longer use of HT was associated with a higher risk for cataract extraction in a linear fashion, added Dr. Lindblad of the Karolinska Institute, Stockholm. Current users of hormone therapy reported a longer duration of HT (a mean of 6 years) compared with past users (4 years). Women who used HT for more than 10 years had a 20% higher risk of cataract extraction, compared with women who never used HT.

Dr. Lindblad and her associates advised caution in comparing their study with those conducted outside of Sweden because HT preparations and clinical practices vary between countries. Hormone therapy with estrogen alone is more common in the United States. And U.S. versions of HT for postmenopausal symptoms like hot flushes most commonly use conjugated estrogens alone or in combination with progesteronelike progestins, while in Sweden the predominant hormone therapy is a combination of estradiol with testosteronelike progestins. The different chemistries might have different effects on the body.

Major Finding: Women who had ever used hormone therapy had a 14% higher risk for cataract extraction and current HT users had an 18% higher risk, compared with women who never used HT.

Data Source: A 98-month Swedish prospective study of 30,861 postmenopausal women.

Disclosures: Dr. Lindblad and her associates reported having no conflicts of interest related to the study, which was funded by Swedish government agencies and research foundations.

Women who used hormone therapy were more likely to need cataract surgery, a risk potentiated by drinking alcohol, a large Swedish prospective study found.

In a 98-month study of 30,861 postmenopausal women, those who had ever used hormone therapy (HT) had a 14% higher risk for cataract extraction and current HT users had an 18% higher risk, compared with women who had never used HT, in a multivariate adjusted analysis, Dr. Birgitta Ejdervik Lindblad and her associates reported. The study appears in the journal Ophthalmology (doi:10.1016/j.ophtha.2009.07.046).

Cataract extraction was even more likely in women who were using HT and drank alcohol. Among current HT users, any alcohol consumption was associated with a 29% higher risk for cataract extraction, and those who drank more than one alcoholic drink per day had a 42% higher risk, compared with women who were neither using HT nor drinking alcohol. (One drink was defined as about 13 g of alcohol, roughly equal to one glass of wine, bottle of beer, or drink of liquor.) Drinking alcohol has been associated with increased levels of plasma estrogen in postmenopausal women in prior studies.

Investigators collected data from women in the Swedish Mammography Cohort who completed questionnaires in September 1997 about hormone status, use of hormone therapy, and lifestyle factors. The researchers followed them through October 2005 and compared their names with those on Swedish registers of cataract surgeries, which identified 4,324 women who underwent cataract surgery during the study period.

Among women aged 65 years or older, the risk for cataract surgery was 73% higher in those using hormone therapy, compared with women who never used HT, after the researchers adjusted for the effects of alcohol consumption, smoking, diabetes, hypertension, steroid or vitamin use, body mass index, and education level.

Longer use of HT was associated with a higher risk for cataract extraction in a linear fashion, added Dr. Lindblad of the Karolinska Institute, Stockholm. Current users of hormone therapy reported a longer duration of HT (a mean of 6 years) compared with past users (4 years). Women who used HT for more than 10 years had a 20% higher risk of cataract extraction, compared with women who never used HT.

Dr. Lindblad and her associates advised caution in comparing their study with those conducted outside of Sweden because HT preparations and clinical practices vary between countries. Hormone therapy with estrogen alone is more common in the United States. And U.S. versions of HT for postmenopausal symptoms like hot flushes most commonly use conjugated estrogens alone or in combination with progesteronelike progestins, while in Sweden the predominant hormone therapy is a combination of estradiol with testosteronelike progestins. The different chemistries might have different effects on the body.

Major Finding: Women who had ever used hormone therapy had a 14% higher risk for cataract extraction and current HT users had an 18% higher risk, compared with women who never used HT.

Data Source: A 98-month Swedish prospective study of 30,861 postmenopausal women.

Disclosures: Dr. Lindblad and her associates reported having no conflicts of interest related to the study, which was funded by Swedish government agencies and research foundations.

Women who used hormone therapy were more likely to need cataract surgery, a risk potentiated by drinking alcohol, a large Swedish prospective study found.

In a 98-month study of 30,861 postmenopausal women, those who had ever used hormone therapy (HT) had a 14% higher risk for cataract extraction and current HT users had an 18% higher risk, compared with women who had never used HT, in a multivariate adjusted analysis, Dr. Birgitta Ejdervik Lindblad and her associates reported. The study appears in the journal Ophthalmology (doi:10.1016/j.ophtha.2009.07.046).

Cataract extraction was even more likely in women who were using HT and drank alcohol. Among current HT users, any alcohol consumption was associated with a 29% higher risk for cataract extraction, and those who drank more than one alcoholic drink per day had a 42% higher risk, compared with women who were neither using HT nor drinking alcohol. (One drink was defined as about 13 g of alcohol, roughly equal to one glass of wine, bottle of beer, or drink of liquor.) Drinking alcohol has been associated with increased levels of plasma estrogen in postmenopausal women in prior studies.

Investigators collected data from women in the Swedish Mammography Cohort who completed questionnaires in September 1997 about hormone status, use of hormone therapy, and lifestyle factors. The researchers followed them through October 2005 and compared their names with those on Swedish registers of cataract surgeries, which identified 4,324 women who underwent cataract surgery during the study period.

Among women aged 65 years or older, the risk for cataract surgery was 73% higher in those using hormone therapy, compared with women who never used HT, after the researchers adjusted for the effects of alcohol consumption, smoking, diabetes, hypertension, steroid or vitamin use, body mass index, and education level.

Longer use of HT was associated with a higher risk for cataract extraction in a linear fashion, added Dr. Lindblad of the Karolinska Institute, Stockholm. Current users of hormone therapy reported a longer duration of HT (a mean of 6 years) compared with past users (4 years). Women who used HT for more than 10 years had a 20% higher risk of cataract extraction, compared with women who never used HT.

Dr. Lindblad and her associates advised caution in comparing their study with those conducted outside of Sweden because HT preparations and clinical practices vary between countries. Hormone therapy with estrogen alone is more common in the United States. And U.S. versions of HT for postmenopausal symptoms like hot flushes most commonly use conjugated estrogens alone or in combination with progesteronelike progestins, while in Sweden the predominant hormone therapy is a combination of estradiol with testosteronelike progestins. The different chemistries might have different effects on the body.

Major Finding: Six months of 70-minute aerobic exercise sessions three days per week significantly reduced the severity of menopausal symptoms while improving physical fitness.

Data Source: An uncontrolled study in 65 postmenopausal women.

Disclosures: None reported.

Postmenopausal women improved their physical fitness and reported reductions in the severity of menopausal symptoms after 12–24 weeks of aerobic exercise in three 70-minute sessions per week.

The 65 women (mean age, 50.1 years) rated the severity of menopausal symptoms on the self-administered Menopause Rating Scale questionnaire at baseline, 12 weeks, and 24 weeks in the uncontrolled study. The program of aerobic and calisthenic exercise aimed for 75%–80% of maximal heart rate according to the Karvonen method and consisted of 10 minutes of warm-up exercises; 40 minutes of aerobics; 15 minutes of exercise targeting the abdomen, hip, and leg muscles; and 5 minutes for cooldown and stretching.

Participants reported significant decreases in the severity of hot flushes, night sweats, cardiac symptoms, muscle and joint pain, sleeping disorder symptoms, depressive mood, irritability, anxiety, exhaustion, sexual problems, and urinary symptoms between the start and end of the study, Dr. Selma Karacan of Selcuk University in Konya, Turkey, reported (Sci. Sports 2009 [doi:10.1016/j.scispo.2009.07.004]).

Some of the symptoms showed improvement by 12 weeks and further significant improvements by 24 weeks, including vasomotor symptoms, muscle and joint pain, psychological symptoms, and sexual problems. The women reported no significant change in vaginal dryness.

Significant improvements also were seen in resting heart rate, systolic and diastolic blood pressures, flexibility, aerobic power, and the ability to perform sit-ups, push-ups, and right or left hand grips. Body weight, body mass index, body fat percentage, and fat weight decreased significantly, with no change in lean body mass values.

The findings support results from previous observational studies of physically active postmenopausal women compared with age-matched, sedentary control women. No randomized controlled trials have looked at the efficacy of exercise in managing hot flushes.

The current study suggests that a high level of cardiorespiratory fitness may help reduce menopausal symptoms, Dr. Karacan concluded.

Major Finding: Six months of 70-minute aerobic exercise sessions three days per week significantly reduced the severity of menopausal symptoms while improving physical fitness.

Data Source: An uncontrolled study in 65 postmenopausal women.

Disclosures: None reported.

Postmenopausal women improved their physical fitness and reported reductions in the severity of menopausal symptoms after 12–24 weeks of aerobic exercise in three 70-minute sessions per week.

The 65 women (mean age, 50.1 years) rated the severity of menopausal symptoms on the self-administered Menopause Rating Scale questionnaire at baseline, 12 weeks, and 24 weeks in the uncontrolled study. The program of aerobic and calisthenic exercise aimed for 75%–80% of maximal heart rate according to the Karvonen method and consisted of 10 minutes of warm-up exercises; 40 minutes of aerobics; 15 minutes of exercise targeting the abdomen, hip, and leg muscles; and 5 minutes for cooldown and stretching.

Participants reported significant decreases in the severity of hot flushes, night sweats, cardiac symptoms, muscle and joint pain, sleeping disorder symptoms, depressive mood, irritability, anxiety, exhaustion, sexual problems, and urinary symptoms between the start and end of the study, Dr. Selma Karacan of Selcuk University in Konya, Turkey, reported (Sci. Sports 2009 [doi:10.1016/j.scispo.2009.07.004]).

Some of the symptoms showed improvement by 12 weeks and further significant improvements by 24 weeks, including vasomotor symptoms, muscle and joint pain, psychological symptoms, and sexual problems. The women reported no significant change in vaginal dryness.

Significant improvements also were seen in resting heart rate, systolic and diastolic blood pressures, flexibility, aerobic power, and the ability to perform sit-ups, push-ups, and right or left hand grips. Body weight, body mass index, body fat percentage, and fat weight decreased significantly, with no change in lean body mass values.

The findings support results from previous observational studies of physically active postmenopausal women compared with age-matched, sedentary control women. No randomized controlled trials have looked at the efficacy of exercise in managing hot flushes.

The current study suggests that a high level of cardiorespiratory fitness may help reduce menopausal symptoms, Dr. Karacan concluded.

Major Finding: Six months of 70-minute aerobic exercise sessions three days per week significantly reduced the severity of menopausal symptoms while improving physical fitness.

Data Source: An uncontrolled study in 65 postmenopausal women.

Disclosures: None reported.

Postmenopausal women improved their physical fitness and reported reductions in the severity of menopausal symptoms after 12–24 weeks of aerobic exercise in three 70-minute sessions per week.

The 65 women (mean age, 50.1 years) rated the severity of menopausal symptoms on the self-administered Menopause Rating Scale questionnaire at baseline, 12 weeks, and 24 weeks in the uncontrolled study. The program of aerobic and calisthenic exercise aimed for 75%–80% of maximal heart rate according to the Karvonen method and consisted of 10 minutes of warm-up exercises; 40 minutes of aerobics; 15 minutes of exercise targeting the abdomen, hip, and leg muscles; and 5 minutes for cooldown and stretching.

Participants reported significant decreases in the severity of hot flushes, night sweats, cardiac symptoms, muscle and joint pain, sleeping disorder symptoms, depressive mood, irritability, anxiety, exhaustion, sexual problems, and urinary symptoms between the start and end of the study, Dr. Selma Karacan of Selcuk University in Konya, Turkey, reported (Sci. Sports 2009 [doi:10.1016/j.scispo.2009.07.004]).

Some of the symptoms showed improvement by 12 weeks and further significant improvements by 24 weeks, including vasomotor symptoms, muscle and joint pain, psychological symptoms, and sexual problems. The women reported no significant change in vaginal dryness.

Significant improvements also were seen in resting heart rate, systolic and diastolic blood pressures, flexibility, aerobic power, and the ability to perform sit-ups, push-ups, and right or left hand grips. Body weight, body mass index, body fat percentage, and fat weight decreased significantly, with no change in lean body mass values.

The findings support results from previous observational studies of physically active postmenopausal women compared with age-matched, sedentary control women. No randomized controlled trials have looked at the efficacy of exercise in managing hot flushes.

The current study suggests that a high level of cardiorespiratory fitness may help reduce menopausal symptoms, Dr. Karacan concluded.

CASE: Hysterectomy candidate asks about her ovaries

A 51-year-old premenopausal woman complains of severe menorrhagia that often causes her to miss work. Although she is taking an iron supplement, her hemoglobin level often drops below 10 g/dL. She has already been identified as having fibroids, with a uterine size of 14 weeks. You order ultra-sonography, which reveals an enlarged uterus with multiple fibroids and normal endometrial thickness, but no intracavitary lesions.

After you describe the treatment options, including uterine artery embolization, the patient requests a hysterectomy as a reasonably low-risk means of cure. During informed consent, she asks whether she should have her ovaries removed during the surgery. Further discussion reveals that her father died of a myocardial infarction when he was 64 years old, but there is no family or personal history of ovarian or breast cancer.

How do you advise this patient, based on her history and recent findings from medical research?

Many gynecologists have been trained to recommend bilateral oophorectomy for women older than 45 or 50 years who request a hysterectomy for benign disease. In these women, oophorectomy is recommended to prevent ovarian cancer and avert the potential for other ovarian pathology that might require later surgery.

In the United States, 78% of women 45 to 64 years old and 55% of women overall undergo bilateral oophorectomy at the time of hysterectomy.¹ These percentages mean that almost 300,000 women undergo bilateral oophorectomy each year.¹

Hysterectomy alone can sometimes lead to early ovarian failure, but this phenomenon is infrequent. A prospective study of premenopausal women found that, after 5 years of follow-up, 20% of women who underwent simple hysterectomy reached menopause, compared with 7% of matched women who did not undergo hysterectomy.²

In this article, I explore the risks and benefits associated with bilateral oophorectomy and present an algorithm to aid in deciding whether the patient should keep her ovaries—and when oophorectomy might be a better option ( FIGURE ).

Among the hazards associated with bilateral oophorectomy are:

• an increased risk of death from coronary artery disease (CAD), lung cancer, all cancers (except ovarian), and all causes^3,4
• an increased risk of osteoporosis and hip fracture⁵
• when performed before the onset of menopause, an increased risk of parkinsonism, cognitive impairment, dementia, anxiety, and depression.^6-8

Benefits include a reduced risk of ovarian cancer, particularly among women who have a BRCA gene mutation or strong family history of ovarian or breast cancer.

Although ovarian cancer causes 15,000 deaths each year in the United States, that figure pales when compared with heart disease, which accounts for 350,000 deaths. In addition, hip fracture may cause approximately 66,000 deaths each year, and dementia attributable to bilateral oophorectomy may affect 100,000 to 200,000 women.⁹ Reoperation for adnexal pathology or pain after hysterectomy is rare, occurring in only 2.8% of women. Therefore, the benefits of oophorectomy are often outweighed by the risks of CAD, hip fracture, and neurologic conditions.

FIGURE Conservation vs oophorectomy: A guide to decision-making

* Estrogen replacement is recommended for women younger than 45 years who opt for oophorectomy

Ovarian cancer is a real, but relatively low, risk

In 2008, an estimated 21,650 new cases of ovarian cancer were diagnosed (age at diagnosis: mean, 63 years), and 15,520 women died from the disease.¹⁰ Because we lack a reliable screening test to detect early-stage ovarian cancer in the general population, most women are given a diagnosis when disease is advanced and the 5-year survival rate is 15% to 25%.

There is agreement that women who are known to have a BRCA mutation, which increases the risk of ovarian and breast cancer, should strongly consider oophorectomy once childbearing is complete.¹¹ In the general population, however, the outlook is different.

In the United States, the lifetime risk of ovarian cancer is 1.4% overall. Among white women who have had three or more term pregnancies and who have used an oral contraceptive for at least 4 years, the lifetime risk of ovarian cancer drops to 0.3%.¹²

Need for reoperation is very low

The percentage of women who require reoperation after ovarian conservation—2.8%—may surprise you.¹³ That figure is lower than once thought because many studies were performed before asymptomatic, benign ovarian cysts were determined to be a fairly common phenomenon in postmenopausal women (prevalence, 6.6%). These cysts do not undergo transformation to cancer and, therefore, do not need to be removed.¹⁴

In addition, studies indicate that only 0.1% to 0.75% of women who retain their ovaries at the time of hysterectomy develop ovarian cancer.^15,16 Therefore, the rationale of performing oophorectomy to avoid future surgery appears to be unfounded.

CAD risk rises sharply after oophorectomy

A recent systematic review found mixed evidence concerning the risk of CAD following bilateral salpingo-oophorectomy.¹⁷ In observational studies, however, earlier age of surgical or natural menopause has been associated with a higher risk of cardiovascular mortality.^18-20 Early reports from the Nurses’ Health Study found that the risk of myocardial infarction doubled among women who underwent oophorectomy and never used estrogen, compared with age-matched premenopausal women (relative risk [RR], 2.2; 95% confidence interval [CI], 1.2, 4.2).³ Even after age 50, the risk of a first myocardial infarction is increased among oophorectomized women, compared with women who retain their ovaries (RR, 1.4; 95% CI, 1.0–2.0).²¹

A study by researchers from the Mayo Clinic, who examined all causes listed on the death certificate, found a significant association between bilateral oophorectomy before the age of 45 years and cardiovascular mortality (hazard ratio [HR], 1.44; 95% CI, 1.01–2.05).²² This risk was significantly increased among women who were not treated with estrogen through at least age 45, compared with estrogen-treated women.

Oophorectomy may impair bone health

After menopause, ovaries continue to produce significant amounts of the androgens testosterone and androstenedione, which are converted to estrone peripherally by skin, muscle, and fat cells.^23,24 The levels of these hormones remain consistent and have been documented to age 80.²⁵

Both estrogens and androgens inhibit bone resorption, and androgens also stimulate bone formation.²⁶ Low levels of androgens and estrogens are linked to lower bone density and a higher risk of hip and vertebral fracture in postmenopausal women.^27-29

Postmenopausal women who have been oophorectomized may have an even greater risk of osteoporosis. Over 16 years of follow-up, 340 women who had undergone oophorectomy at a median age of 62 years had 54% more osteoporotic fractures than women who had intact ovaries.⁵ Two other studies found no association between oophorectomy and bone loss or fracture risk, however.^30,31

Hip fracture is a well-documented cause of increased morbidity and mortality in older women. One study found that, before hip fracture, 28% of patients were housebound; 1 year after hip fracture, the percentage was 46%.³² Women older than 60 who underwent oophorectomy had a doubled risk of mortality after low-trauma hip fracture, compared with women who had intact ovaries (odds ratio [OR], 2.18; 95% CI, 2.03–2.32).⁵

Loss of ovaries may affect mental health and sexuality

In a premenopausal woman, oophorectomy causes a sudden loss of estrogen and often triggers hot flashes, mood changes, sleep disturbances, headaches, and a decline in feelings of well-being.^33,34 Over time, vaginal dryness, painful intercourse, loss of libido, bladder dysfunction, and depression may occur.^35,36

Evidence suggests that, in women, sexual desire, sexual sensation, and orgasmic response are influenced by androgens. After elective oophorectomy, declines in sexual desire have been reported.^37-39

Mental health and sexuality may rebound over time, however. One study found less improvement in mental health measures and body image 6 months after hysterectomy among women who were oophorectomized, compared with those who retained their ovaries. After 2 years, improvement levels were similar between groups.⁴⁰

Cognitive function may suffer

Analysis of data from the Mayo Clinic Cohort Study of Oophorectomy and Aging found that bilateral oophorectomy before the onset of menopause increased the risk of parkinsonism, cognitive impairment or dementia, and anxiety or depression, particularly if estrogen was not replaced.^6-8 These risks increased with younger age at oophorectomy.

The Women’s Health Initiative found an increased risk of dementia or mild cognitive impairment in women who were treated by estrogen alone or estrogen plus progestin after age 65.^41-44

These disparate conclusions suggest that estrogen may have a protective effect on the brain if it is given right after natural menopause or premenopausal oophorectomy, but deleterious effects if it is started years later.⁴⁵

Other studies of endogenous estrogen and cognitive function are few and yield inconsistent results.

Ovarian conservation boosts long-term survival

When there is no family history of ovarian cancer, ovarian conservation appears to maximize survival among healthy women 40 to 65 years old who undergo hysterectomy for benign disease.⁴⁶ Among healthy women hysterectomized before the age of 55, calculations suggest that 8.6% more would be alive at age 80 if their ovaries were conserved than if they were removed.⁴⁶

A study from the Mayo Clinic found that all-cause mortality was significantly higher among women who underwent prophylactic bilateral oophorectomy before the age of 45 than it was among women in the control group (HR, 1.67; 95% CI, 1.16–2.40); it was particularly high in women who did not receive estrogen treatment before age 45 (HR, 1.93; 95% CI, 1.25–2.96).²²

In a recent study, investigators used the Nurses’ Health Study database to explore the long-term health outcomes of 29,380 women who underwent hysterectomy.⁴ Of these women, 13,035 (44.4%) had their ovaries conserved, and 16,345 (55.6%) underwent bilateral oophorectomy. Follow-up was 24 years. Oophorectomy was associated with an increased risk of nonfatal CAD among all women (HR, 1.17; 95% CI, 1.02, 1.35), especially those who underwent the procedure before age 45 (HR, 1.26; 95% CI, 1.04, 1.54). Oophorectomy was associated with a markedly reduced risk of ovarian cancer but an increased risk of lung cancer (HR, 1.26; 95% CI, 1.02–1.56).

In regard to fatal events, oophorectomy increased the risk of death from all causes (HR, 1.12; 95% CI, 1.03, 1.21). Specifically, there was an increased risk of death from CAD (HR, 1.28; 95% CI, 1.00, 1.64), lung cancer (HR, 1.31; 95% CI, 1.02, 1.68), and all cancers (HR, 1.17; 95% CI, 1.04, 1.32). There was no overall difference in the risk of death from stroke, breast cancer, and colorectal cancer between women who underwent oophorectomy and those who retained their ovaries.

During the 24 years of follow-up, 37 women died from ovarian cancer, accounting for 1.2% of all deaths. At no age did oophorectomy show a survival benefit.

How this evidence should inform your practice

It is unfortunate that the entire body of evidence on the risks and benefits of bilateral salpingo-oophorectomy consists of observational studies, which have significant inherent limitations. Although the Nurses’ Health Study was the largest prospective study to examine the effect of oophorectomy on women’s health, and involved the longest follow-up, the study was observational, and oophorectomy and ovarian conservation were self-selected. Nevertheless, recent data suggest that a more detailed informed-consent process is warranted than the process in place. Informed consent should cover the risks and benefits of both oophorectomy and ovarian conservation.

Prophylactic oophorectomy is recommended only if a preponderance of the evidence establishes that it clearly benefits the patient. The studies described in this article suggest that bilateral oophorectomy does harm more often than it does good. Therefore, a cautious approach to oophorectomy at the time of hysterectomy is advised.

CASE RESOLVED

After you describe the risks and benefits of oophorectomy, and address the patient’s concerns about her family history of heart disease, she decides to keep her ovaries.

CASE: Hysterectomy candidate asks about her ovaries

A 51-year-old premenopausal woman complains of severe menorrhagia that often causes her to miss work. Although she is taking an iron supplement, her hemoglobin level often drops below 10 g/dL. She has already been identified as having fibroids, with a uterine size of 14 weeks. You order ultra-sonography, which reveals an enlarged uterus with multiple fibroids and normal endometrial thickness, but no intracavitary lesions.

After you describe the treatment options, including uterine artery embolization, the patient requests a hysterectomy as a reasonably low-risk means of cure. During informed consent, she asks whether she should have her ovaries removed during the surgery. Further discussion reveals that her father died of a myocardial infarction when he was 64 years old, but there is no family or personal history of ovarian or breast cancer.

How do you advise this patient, based on her history and recent findings from medical research?

Many gynecologists have been trained to recommend bilateral oophorectomy for women older than 45 or 50 years who request a hysterectomy for benign disease. In these women, oophorectomy is recommended to prevent ovarian cancer and avert the potential for other ovarian pathology that might require later surgery.

In the United States, 78% of women 45 to 64 years old and 55% of women overall undergo bilateral oophorectomy at the time of hysterectomy.¹ These percentages mean that almost 300,000 women undergo bilateral oophorectomy each year.¹

Hysterectomy alone can sometimes lead to early ovarian failure, but this phenomenon is infrequent. A prospective study of premenopausal women found that, after 5 years of follow-up, 20% of women who underwent simple hysterectomy reached menopause, compared with 7% of matched women who did not undergo hysterectomy.²

In this article, I explore the risks and benefits associated with bilateral oophorectomy and present an algorithm to aid in deciding whether the patient should keep her ovaries—and when oophorectomy might be a better option ( FIGURE ).

Among the hazards associated with bilateral oophorectomy are:

• an increased risk of death from coronary artery disease (CAD), lung cancer, all cancers (except ovarian), and all causes^3,4
• an increased risk of osteoporosis and hip fracture⁵
• when performed before the onset of menopause, an increased risk of parkinsonism, cognitive impairment, dementia, anxiety, and depression.^6-8

Benefits include a reduced risk of ovarian cancer, particularly among women who have a BRCA gene mutation or strong family history of ovarian or breast cancer.

Although ovarian cancer causes 15,000 deaths each year in the United States, that figure pales when compared with heart disease, which accounts for 350,000 deaths. In addition, hip fracture may cause approximately 66,000 deaths each year, and dementia attributable to bilateral oophorectomy may affect 100,000 to 200,000 women.⁹ Reoperation for adnexal pathology or pain after hysterectomy is rare, occurring in only 2.8% of women. Therefore, the benefits of oophorectomy are often outweighed by the risks of CAD, hip fracture, and neurologic conditions.

FIGURE Conservation vs oophorectomy: A guide to decision-making

* Estrogen replacement is recommended for women younger than 45 years who opt for oophorectomy

Ovarian cancer is a real, but relatively low, risk

In 2008, an estimated 21,650 new cases of ovarian cancer were diagnosed (age at diagnosis: mean, 63 years), and 15,520 women died from the disease.¹⁰ Because we lack a reliable screening test to detect early-stage ovarian cancer in the general population, most women are given a diagnosis when disease is advanced and the 5-year survival rate is 15% to 25%.

There is agreement that women who are known to have a BRCA mutation, which increases the risk of ovarian and breast cancer, should strongly consider oophorectomy once childbearing is complete.¹¹ In the general population, however, the outlook is different.

In the United States, the lifetime risk of ovarian cancer is 1.4% overall. Among white women who have had three or more term pregnancies and who have used an oral contraceptive for at least 4 years, the lifetime risk of ovarian cancer drops to 0.3%.¹²

Need for reoperation is very low

The percentage of women who require reoperation after ovarian conservation—2.8%—may surprise you.¹³ That figure is lower than once thought because many studies were performed before asymptomatic, benign ovarian cysts were determined to be a fairly common phenomenon in postmenopausal women (prevalence, 6.6%). These cysts do not undergo transformation to cancer and, therefore, do not need to be removed.¹⁴

In addition, studies indicate that only 0.1% to 0.75% of women who retain their ovaries at the time of hysterectomy develop ovarian cancer.^15,16 Therefore, the rationale of performing oophorectomy to avoid future surgery appears to be unfounded.

CAD risk rises sharply after oophorectomy

A recent systematic review found mixed evidence concerning the risk of CAD following bilateral salpingo-oophorectomy.¹⁷ In observational studies, however, earlier age of surgical or natural menopause has been associated with a higher risk of cardiovascular mortality.^18-20 Early reports from the Nurses’ Health Study found that the risk of myocardial infarction doubled among women who underwent oophorectomy and never used estrogen, compared with age-matched premenopausal women (relative risk [RR], 2.2; 95% confidence interval [CI], 1.2, 4.2).³ Even after age 50, the risk of a first myocardial infarction is increased among oophorectomized women, compared with women who retain their ovaries (RR, 1.4; 95% CI, 1.0–2.0).²¹

A study by researchers from the Mayo Clinic, who examined all causes listed on the death certificate, found a significant association between bilateral oophorectomy before the age of 45 years and cardiovascular mortality (hazard ratio [HR], 1.44; 95% CI, 1.01–2.05).²² This risk was significantly increased among women who were not treated with estrogen through at least age 45, compared with estrogen-treated women.

Oophorectomy may impair bone health

After menopause, ovaries continue to produce significant amounts of the androgens testosterone and androstenedione, which are converted to estrone peripherally by skin, muscle, and fat cells.^23,24 The levels of these hormones remain consistent and have been documented to age 80.²⁵

Both estrogens and androgens inhibit bone resorption, and androgens also stimulate bone formation.²⁶ Low levels of androgens and estrogens are linked to lower bone density and a higher risk of hip and vertebral fracture in postmenopausal women.^27-29

Postmenopausal women who have been oophorectomized may have an even greater risk of osteoporosis. Over 16 years of follow-up, 340 women who had undergone oophorectomy at a median age of 62 years had 54% more osteoporotic fractures than women who had intact ovaries.⁵ Two other studies found no association between oophorectomy and bone loss or fracture risk, however.^30,31

Hip fracture is a well-documented cause of increased morbidity and mortality in older women. One study found that, before hip fracture, 28% of patients were housebound; 1 year after hip fracture, the percentage was 46%.³² Women older than 60 who underwent oophorectomy had a doubled risk of mortality after low-trauma hip fracture, compared with women who had intact ovaries (odds ratio [OR], 2.18; 95% CI, 2.03–2.32).⁵

Loss of ovaries may affect mental health and sexuality

In a premenopausal woman, oophorectomy causes a sudden loss of estrogen and often triggers hot flashes, mood changes, sleep disturbances, headaches, and a decline in feelings of well-being.^33,34 Over time, vaginal dryness, painful intercourse, loss of libido, bladder dysfunction, and depression may occur.^35,36

Evidence suggests that, in women, sexual desire, sexual sensation, and orgasmic response are influenced by androgens. After elective oophorectomy, declines in sexual desire have been reported.^37-39

Mental health and sexuality may rebound over time, however. One study found less improvement in mental health measures and body image 6 months after hysterectomy among women who were oophorectomized, compared with those who retained their ovaries. After 2 years, improvement levels were similar between groups.⁴⁰

Cognitive function may suffer

Analysis of data from the Mayo Clinic Cohort Study of Oophorectomy and Aging found that bilateral oophorectomy before the onset of menopause increased the risk of parkinsonism, cognitive impairment or dementia, and anxiety or depression, particularly if estrogen was not replaced.^6-8 These risks increased with younger age at oophorectomy.

The Women’s Health Initiative found an increased risk of dementia or mild cognitive impairment in women who were treated by estrogen alone or estrogen plus progestin after age 65.^41-44

These disparate conclusions suggest that estrogen may have a protective effect on the brain if it is given right after natural menopause or premenopausal oophorectomy, but deleterious effects if it is started years later.⁴⁵

Other studies of endogenous estrogen and cognitive function are few and yield inconsistent results.

Ovarian conservation boosts long-term survival

When there is no family history of ovarian cancer, ovarian conservation appears to maximize survival among healthy women 40 to 65 years old who undergo hysterectomy for benign disease.⁴⁶ Among healthy women hysterectomized before the age of 55, calculations suggest that 8.6% more would be alive at age 80 if their ovaries were conserved than if they were removed.⁴⁶

A study from the Mayo Clinic found that all-cause mortality was significantly higher among women who underwent prophylactic bilateral oophorectomy before the age of 45 than it was among women in the control group (HR, 1.67; 95% CI, 1.16–2.40); it was particularly high in women who did not receive estrogen treatment before age 45 (HR, 1.93; 95% CI, 1.25–2.96).²²

In a recent study, investigators used the Nurses’ Health Study database to explore the long-term health outcomes of 29,380 women who underwent hysterectomy.⁴ Of these women, 13,035 (44.4%) had their ovaries conserved, and 16,345 (55.6%) underwent bilateral oophorectomy. Follow-up was 24 years. Oophorectomy was associated with an increased risk of nonfatal CAD among all women (HR, 1.17; 95% CI, 1.02, 1.35), especially those who underwent the procedure before age 45 (HR, 1.26; 95% CI, 1.04, 1.54). Oophorectomy was associated with a markedly reduced risk of ovarian cancer but an increased risk of lung cancer (HR, 1.26; 95% CI, 1.02–1.56).

In regard to fatal events, oophorectomy increased the risk of death from all causes (HR, 1.12; 95% CI, 1.03, 1.21). Specifically, there was an increased risk of death from CAD (HR, 1.28; 95% CI, 1.00, 1.64), lung cancer (HR, 1.31; 95% CI, 1.02, 1.68), and all cancers (HR, 1.17; 95% CI, 1.04, 1.32). There was no overall difference in the risk of death from stroke, breast cancer, and colorectal cancer between women who underwent oophorectomy and those who retained their ovaries.

During the 24 years of follow-up, 37 women died from ovarian cancer, accounting for 1.2% of all deaths. At no age did oophorectomy show a survival benefit.

How this evidence should inform your practice

It is unfortunate that the entire body of evidence on the risks and benefits of bilateral salpingo-oophorectomy consists of observational studies, which have significant inherent limitations. Although the Nurses’ Health Study was the largest prospective study to examine the effect of oophorectomy on women’s health, and involved the longest follow-up, the study was observational, and oophorectomy and ovarian conservation were self-selected. Nevertheless, recent data suggest that a more detailed informed-consent process is warranted than the process in place. Informed consent should cover the risks and benefits of both oophorectomy and ovarian conservation.

Prophylactic oophorectomy is recommended only if a preponderance of the evidence establishes that it clearly benefits the patient. The studies described in this article suggest that bilateral oophorectomy does harm more often than it does good. Therefore, a cautious approach to oophorectomy at the time of hysterectomy is advised.

CASE RESOLVED

After you describe the risks and benefits of oophorectomy, and address the patient’s concerns about her family history of heart disease, she decides to keep her ovaries.

CASE: Hysterectomy candidate asks about her ovaries

A 51-year-old premenopausal woman complains of severe menorrhagia that often causes her to miss work. Although she is taking an iron supplement, her hemoglobin level often drops below 10 g/dL. She has already been identified as having fibroids, with a uterine size of 14 weeks. You order ultra-sonography, which reveals an enlarged uterus with multiple fibroids and normal endometrial thickness, but no intracavitary lesions.

After you describe the treatment options, including uterine artery embolization, the patient requests a hysterectomy as a reasonably low-risk means of cure. During informed consent, she asks whether she should have her ovaries removed during the surgery. Further discussion reveals that her father died of a myocardial infarction when he was 64 years old, but there is no family or personal history of ovarian or breast cancer.

How do you advise this patient, based on her history and recent findings from medical research?

Many gynecologists have been trained to recommend bilateral oophorectomy for women older than 45 or 50 years who request a hysterectomy for benign disease. In these women, oophorectomy is recommended to prevent ovarian cancer and avert the potential for other ovarian pathology that might require later surgery.

In the United States, 78% of women 45 to 64 years old and 55% of women overall undergo bilateral oophorectomy at the time of hysterectomy.¹ These percentages mean that almost 300,000 women undergo bilateral oophorectomy each year.¹

Hysterectomy alone can sometimes lead to early ovarian failure, but this phenomenon is infrequent. A prospective study of premenopausal women found that, after 5 years of follow-up, 20% of women who underwent simple hysterectomy reached menopause, compared with 7% of matched women who did not undergo hysterectomy.²

In this article, I explore the risks and benefits associated with bilateral oophorectomy and present an algorithm to aid in deciding whether the patient should keep her ovaries—and when oophorectomy might be a better option ( FIGURE ).

Among the hazards associated with bilateral oophorectomy are:

• an increased risk of death from coronary artery disease (CAD), lung cancer, all cancers (except ovarian), and all causes^3,4
• an increased risk of osteoporosis and hip fracture⁵
• when performed before the onset of menopause, an increased risk of parkinsonism, cognitive impairment, dementia, anxiety, and depression.^6-8

Benefits include a reduced risk of ovarian cancer, particularly among women who have a BRCA gene mutation or strong family history of ovarian or breast cancer.

Although ovarian cancer causes 15,000 deaths each year in the United States, that figure pales when compared with heart disease, which accounts for 350,000 deaths. In addition, hip fracture may cause approximately 66,000 deaths each year, and dementia attributable to bilateral oophorectomy may affect 100,000 to 200,000 women.⁹ Reoperation for adnexal pathology or pain after hysterectomy is rare, occurring in only 2.8% of women. Therefore, the benefits of oophorectomy are often outweighed by the risks of CAD, hip fracture, and neurologic conditions.

FIGURE Conservation vs oophorectomy: A guide to decision-making

* Estrogen replacement is recommended for women younger than 45 years who opt for oophorectomy

Ovarian cancer is a real, but relatively low, risk

In 2008, an estimated 21,650 new cases of ovarian cancer were diagnosed (age at diagnosis: mean, 63 years), and 15,520 women died from the disease.¹⁰ Because we lack a reliable screening test to detect early-stage ovarian cancer in the general population, most women are given a diagnosis when disease is advanced and the 5-year survival rate is 15% to 25%.

There is agreement that women who are known to have a BRCA mutation, which increases the risk of ovarian and breast cancer, should strongly consider oophorectomy once childbearing is complete.¹¹ In the general population, however, the outlook is different.

In the United States, the lifetime risk of ovarian cancer is 1.4% overall. Among white women who have had three or more term pregnancies and who have used an oral contraceptive for at least 4 years, the lifetime risk of ovarian cancer drops to 0.3%.¹²

Need for reoperation is very low

The percentage of women who require reoperation after ovarian conservation—2.8%—may surprise you.¹³ That figure is lower than once thought because many studies were performed before asymptomatic, benign ovarian cysts were determined to be a fairly common phenomenon in postmenopausal women (prevalence, 6.6%). These cysts do not undergo transformation to cancer and, therefore, do not need to be removed.¹⁴

In addition, studies indicate that only 0.1% to 0.75% of women who retain their ovaries at the time of hysterectomy develop ovarian cancer.^15,16 Therefore, the rationale of performing oophorectomy to avoid future surgery appears to be unfounded.

CAD risk rises sharply after oophorectomy

A recent systematic review found mixed evidence concerning the risk of CAD following bilateral salpingo-oophorectomy.¹⁷ In observational studies, however, earlier age of surgical or natural menopause has been associated with a higher risk of cardiovascular mortality.^18-20 Early reports from the Nurses’ Health Study found that the risk of myocardial infarction doubled among women who underwent oophorectomy and never used estrogen, compared with age-matched premenopausal women (relative risk [RR], 2.2; 95% confidence interval [CI], 1.2, 4.2).³ Even after age 50, the risk of a first myocardial infarction is increased among oophorectomized women, compared with women who retain their ovaries (RR, 1.4; 95% CI, 1.0–2.0).²¹

A study by researchers from the Mayo Clinic, who examined all causes listed on the death certificate, found a significant association between bilateral oophorectomy before the age of 45 years and cardiovascular mortality (hazard ratio [HR], 1.44; 95% CI, 1.01–2.05).²² This risk was significantly increased among women who were not treated with estrogen through at least age 45, compared with estrogen-treated women.

Oophorectomy may impair bone health

After menopause, ovaries continue to produce significant amounts of the androgens testosterone and androstenedione, which are converted to estrone peripherally by skin, muscle, and fat cells.^23,24 The levels of these hormones remain consistent and have been documented to age 80.²⁵

Both estrogens and androgens inhibit bone resorption, and androgens also stimulate bone formation.²⁶ Low levels of androgens and estrogens are linked to lower bone density and a higher risk of hip and vertebral fracture in postmenopausal women.^27-29

Postmenopausal women who have been oophorectomized may have an even greater risk of osteoporosis. Over 16 years of follow-up, 340 women who had undergone oophorectomy at a median age of 62 years had 54% more osteoporotic fractures than women who had intact ovaries.⁵ Two other studies found no association between oophorectomy and bone loss or fracture risk, however.^30,31

Hip fracture is a well-documented cause of increased morbidity and mortality in older women. One study found that, before hip fracture, 28% of patients were housebound; 1 year after hip fracture, the percentage was 46%.³² Women older than 60 who underwent oophorectomy had a doubled risk of mortality after low-trauma hip fracture, compared with women who had intact ovaries (odds ratio [OR], 2.18; 95% CI, 2.03–2.32).⁵

Loss of ovaries may affect mental health and sexuality

In a premenopausal woman, oophorectomy causes a sudden loss of estrogen and often triggers hot flashes, mood changes, sleep disturbances, headaches, and a decline in feelings of well-being.^33,34 Over time, vaginal dryness, painful intercourse, loss of libido, bladder dysfunction, and depression may occur.^35,36

Evidence suggests that, in women, sexual desire, sexual sensation, and orgasmic response are influenced by androgens. After elective oophorectomy, declines in sexual desire have been reported.^37-39

Mental health and sexuality may rebound over time, however. One study found less improvement in mental health measures and body image 6 months after hysterectomy among women who were oophorectomized, compared with those who retained their ovaries. After 2 years, improvement levels were similar between groups.⁴⁰

Cognitive function may suffer

Analysis of data from the Mayo Clinic Cohort Study of Oophorectomy and Aging found that bilateral oophorectomy before the onset of menopause increased the risk of parkinsonism, cognitive impairment or dementia, and anxiety or depression, particularly if estrogen was not replaced.^6-8 These risks increased with younger age at oophorectomy.

The Women’s Health Initiative found an increased risk of dementia or mild cognitive impairment in women who were treated by estrogen alone or estrogen plus progestin after age 65.^41-44

These disparate conclusions suggest that estrogen may have a protective effect on the brain if it is given right after natural menopause or premenopausal oophorectomy, but deleterious effects if it is started years later.⁴⁵

Other studies of endogenous estrogen and cognitive function are few and yield inconsistent results.

Ovarian conservation boosts long-term survival

When there is no family history of ovarian cancer, ovarian conservation appears to maximize survival among healthy women 40 to 65 years old who undergo hysterectomy for benign disease.⁴⁶ Among healthy women hysterectomized before the age of 55, calculations suggest that 8.6% more would be alive at age 80 if their ovaries were conserved than if they were removed.⁴⁶

A study from the Mayo Clinic found that all-cause mortality was significantly higher among women who underwent prophylactic bilateral oophorectomy before the age of 45 than it was among women in the control group (HR, 1.67; 95% CI, 1.16–2.40); it was particularly high in women who did not receive estrogen treatment before age 45 (HR, 1.93; 95% CI, 1.25–2.96).²²

In a recent study, investigators used the Nurses’ Health Study database to explore the long-term health outcomes of 29,380 women who underwent hysterectomy.⁴ Of these women, 13,035 (44.4%) had their ovaries conserved, and 16,345 (55.6%) underwent bilateral oophorectomy. Follow-up was 24 years. Oophorectomy was associated with an increased risk of nonfatal CAD among all women (HR, 1.17; 95% CI, 1.02, 1.35), especially those who underwent the procedure before age 45 (HR, 1.26; 95% CI, 1.04, 1.54). Oophorectomy was associated with a markedly reduced risk of ovarian cancer but an increased risk of lung cancer (HR, 1.26; 95% CI, 1.02–1.56).

In regard to fatal events, oophorectomy increased the risk of death from all causes (HR, 1.12; 95% CI, 1.03, 1.21). Specifically, there was an increased risk of death from CAD (HR, 1.28; 95% CI, 1.00, 1.64), lung cancer (HR, 1.31; 95% CI, 1.02, 1.68), and all cancers (HR, 1.17; 95% CI, 1.04, 1.32). There was no overall difference in the risk of death from stroke, breast cancer, and colorectal cancer between women who underwent oophorectomy and those who retained their ovaries.

During the 24 years of follow-up, 37 women died from ovarian cancer, accounting for 1.2% of all deaths. At no age did oophorectomy show a survival benefit.

How this evidence should inform your practice

It is unfortunate that the entire body of evidence on the risks and benefits of bilateral salpingo-oophorectomy consists of observational studies, which have significant inherent limitations. Although the Nurses’ Health Study was the largest prospective study to examine the effect of oophorectomy on women’s health, and involved the longest follow-up, the study was observational, and oophorectomy and ovarian conservation were self-selected. Nevertheless, recent data suggest that a more detailed informed-consent process is warranted than the process in place. Informed consent should cover the risks and benefits of both oophorectomy and ovarian conservation.

Prophylactic oophorectomy is recommended only if a preponderance of the evidence establishes that it clearly benefits the patient. The studies described in this article suggest that bilateral oophorectomy does harm more often than it does good. Therefore, a cautious approach to oophorectomy at the time of hysterectomy is advised.

CASE RESOLVED

After you describe the risks and benefits of oophorectomy, and address the patient’s concerns about her family history of heart disease, she decides to keep her ovaries.

These important findings from SWAN confirm the memory problems reported by many women during the menopausal transition. They also build on the findings of clinical trials of HT in younger menopausal women, which explored the effect of HT on cardiovascular health, to underscore the critical role that timing of such therapy can play.^1,2

Other cohort studies of middle-aged women in the United States have found the menopausal transition to be associated with undesirable changes in mood^3,4; some experts have described the endocrine shifts that accompany menopause as “hormonal chaos.”⁵

Details of the study

Participants were 42 to 52 years old and had an intact uterus and at least one ovary at entry. They were followed for 4 years, with delineation of the menopausal stage (i.e., premenopause, early and late perimenopause, and menopause) and assessment of hormone use prior to the final menstrual period and after menopause. The outcome was longitudinal performance in three cognitive domains:

• processing speed—assessed using the Symbol Digit Modalities Test. Premenopausal, early perimenopausal, and postmenopausal women improved with repeated administration of this test, but late perimenopausal women did not. Prior use of HT improved the score, whereas late use of HT reduced it.
• verbal memory—evaluated via the East Boston Memory Test. Test scores increased during premenopause and postmenopause but not during early or late perimenopause. Prior use of HT improved the test score, but late use reduced the score.
• working memory—assessed using the Digit Span Backward test. This domain did not vary by stage of menopause.

Participants who initiated menopausal HT or oral contraceptives prior to the last menstrual period were excluded from the analysis during use of HT. They were allowed to reenter the study, however, once HT or oral contraceptives were discontinued.

As the cognitive component of SWAN began, the mean age of participants was 50 years, and 8% were premenopausal, 49% were early perimenopausal, 12% were late perimenopausal, and 27% were postmenopausal. In addition, 4% were both postmenopausal and current users of HT.

These important findings from SWAN confirm the memory problems reported by many women during the menopausal transition. They also build on the findings of clinical trials of HT in younger menopausal women, which explored the effect of HT on cardiovascular health, to underscore the critical role that timing of such therapy can play.^1,2

Other cohort studies of middle-aged women in the United States have found the menopausal transition to be associated with undesirable changes in mood^3,4; some experts have described the endocrine shifts that accompany menopause as “hormonal chaos.”⁵

Details of the study

Participants were 42 to 52 years old and had an intact uterus and at least one ovary at entry. They were followed for 4 years, with delineation of the menopausal stage (i.e., premenopause, early and late perimenopause, and menopause) and assessment of hormone use prior to the final menstrual period and after menopause. The outcome was longitudinal performance in three cognitive domains:

• processing speed—assessed using the Symbol Digit Modalities Test. Premenopausal, early perimenopausal, and postmenopausal women improved with repeated administration of this test, but late perimenopausal women did not. Prior use of HT improved the score, whereas late use of HT reduced it.
• verbal memory—evaluated via the East Boston Memory Test. Test scores increased during premenopause and postmenopause but not during early or late perimenopause. Prior use of HT improved the test score, but late use reduced the score.
• working memory—assessed using the Digit Span Backward test. This domain did not vary by stage of menopause.

Participants who initiated menopausal HT or oral contraceptives prior to the last menstrual period were excluded from the analysis during use of HT. They were allowed to reenter the study, however, once HT or oral contraceptives were discontinued.

As the cognitive component of SWAN began, the mean age of participants was 50 years, and 8% were premenopausal, 49% were early perimenopausal, 12% were late perimenopausal, and 27% were postmenopausal. In addition, 4% were both postmenopausal and current users of HT.

These important findings from SWAN confirm the memory problems reported by many women during the menopausal transition. They also build on the findings of clinical trials of HT in younger menopausal women, which explored the effect of HT on cardiovascular health, to underscore the critical role that timing of such therapy can play.^1,2

Other cohort studies of middle-aged women in the United States have found the menopausal transition to be associated with undesirable changes in mood^3,4; some experts have described the endocrine shifts that accompany menopause as “hormonal chaos.”⁵

Details of the study

Participants were 42 to 52 years old and had an intact uterus and at least one ovary at entry. They were followed for 4 years, with delineation of the menopausal stage (i.e., premenopause, early and late perimenopause, and menopause) and assessment of hormone use prior to the final menstrual period and after menopause. The outcome was longitudinal performance in three cognitive domains:

• processing speed—assessed using the Symbol Digit Modalities Test. Premenopausal, early perimenopausal, and postmenopausal women improved with repeated administration of this test, but late perimenopausal women did not. Prior use of HT improved the score, whereas late use of HT reduced it.
• verbal memory—evaluated via the East Boston Memory Test. Test scores increased during premenopause and postmenopause but not during early or late perimenopause. Prior use of HT improved the test score, but late use reduced the score.
• working memory—assessed using the Digit Span Backward test. This domain did not vary by stage of menopause.

Participants who initiated menopausal HT or oral contraceptives prior to the last menstrual period were excluded from the analysis during use of HT. They were allowed to reenter the study, however, once HT or oral contraceptives were discontinued.

As the cognitive component of SWAN began, the mean age of participants was 50 years, and 8% were premenopausal, 49% were early perimenopausal, 12% were late perimenopausal, and 27% were postmenopausal. In addition, 4% were both postmenopausal and current users of HT.

The author reports that he is a consultant to Eli Lilly, Pfizer, and Wyeth, and a speaker for Eli Lilly and Wyeth.

CASE 1: Premenopausal woman
at high risk of breast cancer

R. J. is a 43-year-old, nulliparous woman who reached menarche at age 11. She has undergone two breast biopsies, the most recent of which revealed ductal hyperplasia with marked atypia.

R. J.’s sister had breast cancer at 49 years of age; her mother had breast cancer at 66 years. Because of R. J.’s family history, she underwent testing for a BRCA mutation. The result was negative.

R. J. has come to your office today to find out if she can do anything to reduce her risk of breast cancer. What options can you offer?

The most common method of “prevention” of breast cancer involves early detection and assessment of abnormalities through frequent surveillance with mammography. Some women who have dense breasts, a history of breast biopsy, or other risk factors for breast cancer may benefit from intensive surveillance with both mammography and ultrasonography—and, in some cases, magnetic resonance imaging.

More aggressive options include:

• the use of a chemopreventive agent such as tamoxifen or raloxifene
• in rare cases—usually when a BRCA mutation is present—prophylactic mastectomy.

Before it is possible to determine the optimal approach for a particular woman, it is necessary to conduct an individualized assessment of her risk—that is, to estimate the probability that she will develop breast cancer over a defined period of time. Such an estimate is also useful for designing prevention trials in high-risk subsets of the population. (Prevention trials differ from therapeutic clinical trials in that asymptomatic healthy women are exposed to potentially toxic interventions for prolonged periods to reduce their risk of breast cancer.)

This article describes chemopreventive options for women at high risk, based on individualized risk assessment using the Gail model.

(Editor’s note: For additional discussion of the important role ObGyns play in the fight against breast cancer, see Editor in Chief Dr. Robert L. Barbieri’s Editorial.)

What constitutes high risk?

You can estimate the likelihood that a woman like your patient may develop breast cancer using various individual risk factors ( TABLE 1 ), but estimates for combinations of risk factors are preferable. The Gail model takes into account some nongenetic factors, such as parity and age at menarche, but also genetic factors, such as family history. The model calculates a woman’s individualized breast cancer probability and yields a numerical risk (a percentage) that she will develop invasive breast cancer over the next 5 years; it also yields an estimate of her risk of developing the malignancy over the remainder of her life.^1,2

A Gail-model 5-year estimate of 1.66% or higher denotes a high risk of developing breast cancer. That benchmark was the one employed in the Breast Cancer Prevention Trial (BCPT), conducted as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP).³

TABLE 1

What are the risk factors for breast cancer?
And what degree of relative risk do they confer?

Weaknesses of the Gail model

The Gail model’s approach to estimating risk has some limitations. The model uses the number of prior breast biopsies in its assessment—but the relative risk associated with prior biopsy is smaller for women older than 50 years than it is for younger women.

Furthermore, data on which Gail bases its estimates were collected in the late 1970s and early 1980s. Since then, the increasing ease of breast histopathologic assessment—through fine-needle aspiration and outpatient core-needle biopsy—has confused the issue of just what constitutes a breast “biopsy.” (Most patients surveyed consider it to be any histologic sampling of the breast.)

As a result, the 1.66% cutoff becomes somewhat difficult to interpret in light of current practice.

Consider the following example. A 50-year-old nulliparous Caucasian woman reached menarche when she was 11 years old, has never had a biopsy, and has no first-degree relatives with breast cancer. According to the Gail model, her risk of developing breast cancer is 1.2% over the next 5 years and 10.8% in her lifetime. Therefore, she is not considered at high risk. If she were to give a history of three previous breast biopsies, however, none of them showing hyperplasia, her 5-year risk would rise to 1.8% and push her over the line into the high-risk category.

Compare her situation to that of R. J., the nulliparous woman described in Case 1. R. J. also reached menarche at 11 years, but she has had two breast biopsies (one of which showed atypical hyperplasia) and has two first-degree relatives who have had breast cancer. Her Gail score shows a 5-year risk of breast cancer of 13.5% (the norm for a 43-year-old woman is 0.8%), and a lifetime risk of 69.2%. Clearly, she has a high risk of breast cancer.

How do we improve an imperfect science?

We need to identify objective findings that are patient-specific but highly correlative with the development of breast cancer. Patient-specific biomarkers have been proposed, such as ultrasensitive measurement of the serum estradiol level in postmenopausal women. In the Multiple Outcomes of Raloxifene Evaluation, also known as the MORE trial, women who experienced the greatest reduction in the rate of breast cancer during treatment with raloxifene were a subgroup who had the highest baseline level of serum estradiol—although, overall, all patients had an estradiol level well within the postmenopausal range (≤20 pmol/L).^4,5

How tamoxifen became a chemopreventive agent

Tamoxifen inhibits mammary tumors in mice and rats and suppresses hormone-dependent breast cancer cell lines in vitro.⁶ Clinical data from the Early Breast Cancer Trialists’ Collaborative Group yielded additional motivation for prevention trials with tamoxifen: Besides reducing the rate of recurrent breast cancer, tamoxifen reduced the risk of contralateral new-onset breast cancer by 47% after 5 years of adjuvant treatment.⁷ Preclinical findings in vitro and in animal models, coupled with clinical data and evidence of tamoxifen’s favorable effects on skeleton remodeling and lipid levels, led to a series of chemoprevention trials in the United States and Europe using tamoxifen.

In the aforementioned BCPT, launched in 1992, 13,388 women 35 years and older who were deemed to be at high risk of developing breast cancer were enrolled at numerous sites throughout the United States and Canada.³ The Gail model was used to select women for the trial—only those who had a 5-year risk of 1.66% or higher were included. Participants were randomly assigned to receive tamoxifen 20 mg or placebo daily for 5 years. The trial was terminated early because of the dramatic reduction in new-onset breast cancer with tamoxifen, compared with placebo.

The overall incidence of breast cancer in the tamoxifen group was 3.4 cases for every 1,000 women, compared with 6.8 cases for every 1,000 women receiving placebo.³ Overall, the reduction in invasive breast cancer with tamoxifen was 49% (P<.00001). When broken down by age group, the reduction was:

• 44% in women 35 to 49 years old
• 51% in women 50 to 59 years old
• 55% in women 60 years and older.

Even noninvasive breast cancer was reduced with tamoxifen

Tamoxifen decreased the incidence of noninvasive breast cancer (ductal carcinoma in situ [DCIS]) by 50%. Expanded use of mammography has increased the detection of DCIS. Most DCIS lesions appear to be estrogen-receptor positive.⁸

In addition, tamoxifen reduced breast cancer risk in women who had a history of lobular carcinoma in situ (LCIS), a precancer, by 56%, and it reduced the risk of breast cancer in women who had a history of atypical hyperplasia by 86%. Overall, tamoxifen reduced the occurrence of estrogen-positive tumors by 69%, but had no impact on the incidence of estrogen-receptor–negative tumors.

The BCPT was stopped 14 months before planned because the Data and Safety Monitoring Board felt it was unethical to continue to allow one half of such high-risk participants to take placebo in light of the dramatic reduction in both invasive and noninvasive breast cancer among women who took tamoxifen.

In postmenopausal women, tamoxifen increases some risks

Two secondary endpoints of the BCPT are worthy of consideration:

• The overall relative risk (RR) of endometrial cancer associated with tamoxifen therapy in healthy women was 2.53 (95% confidence interval [CI], 1.35, 4.97). However, further analysis by age yielded a RR of 4.01 in women who were older than 50 years (95% CI, 1.70, 10.90), compared with a RR of 1.21 in women 49 years and younger (95% CI, 0.41, 3.60).
• The same age distinction held true for deep venous thrombosis (DVT) and pulmonary embolus, with no statistically significant increases in either in women 49 years and younger, but a RR of 1.71 and 3.19, respectively, in women 50 years and older. It is unclear whether the trial was sufficiently powered for this particular secondary endpoint.

These findings suggest that serious adverse events do not occur at the same magnitude in women younger than 50 years that they do in women 50 and older. The difference in the risk–benefit profile between younger and older women has significant clinical implications for the care of perimenopausal patients.

Risk of other malignancies was not affected by tamoxifen

Overall, invasive cancers other than those of the breast and uterus occurred at the same rate in the tamoxifen and placebo groups of the BCPT. The RR of death from any cause was 0.81 (95% CI, 0.56–1.16). There was a slight increase in the risk of myocardial infarction (RR, 1.11; 95% CI, 0.65–1.92) and a slight decrease in the risk of severe angina (RR, 0.93; 95% CI, 0.40–2.14) in tamoxifen users, although neither of these risks was statistically significant.

The overall RR of fracture of the hip, spine, or radius was 0.81 (95% CI, 0.63–1.05). There was a statistically significant increase in the number of women who had cataracts who then underwent cataract surgery in the tamoxifen group (RR, 1.57; 95% CI, 1.16–2.14).

Tamoxifen is approved as a preventive for high-risk women only

Based on the results of the BCPT, the US Food and Drug Administration (FDA) approved tamoxifen in October 1998 for the primary prevention of breast cancer in women who are at high risk of the disease. The FDA recommends that use of tamoxifen be limited to women at high risk because of the potentially serious side effects seen in clinical trials, including the BCPT.

The FDA did not define “high risk,” but it did recommend that the decision to use tamoxifen as chemopreventive therapy be based on thorough evaluation of the patient’s personal, family, and medical histories; her age; and her understanding of the risks and benefits of treatment.

The FDA also required the following language in the package insert:

• You should not take tamoxifen to reduce the risk of breast cancer unless you are at high risk of breast cancer. Certain conditions put women at high risk, and it is possible to calculate this risk for any woman. Breast cancer risk-assessment tools to help calculate your risk of breast cancer have been developed and are available to your health-care professional. You should discuss your risk with your healthcare professional.

CASE 1 RESOLVED

You determine that R. J. is an excellent candidate for tamoxifen by virtue of her significant risk of breast cancer. You are able to reassure her that, as the BCPT demonstrated, tamoxifen should not increase the risk of uterine cancer, DVT, or pulmonary embolism in a woman her age.

Raloxifene

CASE 2: Patient worries about breasts and bones

S. T. is a 58-year-old Caucasian mother of two whose own mother had breast cancer when she was 74 years old, and whose older sister was given a diagnosis of the malignancy 4 years ago.

S. T. had her first period when she was 11 years old, delivered her first child when she was 31, and entered menopause when she was 52. She is 5 ft 5 in tall and weighs 144 lb.

Her main reason for visiting you today is a breast Mammotome biopsy that showed ductal hyperplasia with atypia. She has been tested for a BRCA mutation, but the result was negative. Her Gail-model score is a 9.7% risk of developing breast cancer over the next 5 years, and a lifetime risk of 44.2%.

She also asks about osteoporosis prevention, given that a dual-energy x-ray absorptiometry (DXA) scan 1 year ago yielded a T-score of –1.3 for her hip and –1.1 for her spine. Her World Health Organization FRAX 10-year risk of hip fracture is 0.7%, and her risk of major osteoporotic fracture is 8.6%.

How do you respond to her concerns?

This patient has a high risk of invasive breast cancer but does not meet criteria for pharmacotherapy for osteoporosis prevention. A good option for her would be raloxifene, a selective estrogen-receptor modulator (SERM) that has been shown to reduce the risk of breast cancer as well as osteoporosis. S. T. would benefit from it on the basis of its breast benefit alone.

The genesis of a drug with multiple benefits

Raloxifene is a benzothiophene derivative, unlike the triphenylethylene family from which tamoxifen is derived. Like tamoxifen, raloxifene was originally investigated as a treatment for advanced breast cancer.

Preclinical studies indicated that raloxifene had an antiproliferative effect on both estrogen-receptor–positive mammary tumors and estrogen-receptor–positive human breast cancer cell lines.⁹ In the 1980s, however, a small, phase-II trial revealed that raloxifene had no further antitumor effects in postmenopausal women with advanced breast cancer in whom tamoxifen had failed.¹⁰ After information surfaced about the neoplastic effect of tamoxifen on the uteri of postmenopausal women, interest in raloxifene revived.¹¹

Raloxifene has estrogen-agonistic activity on bone remodeling and lipid metabolism and was approved by the FDA for prevention of osteoporosis in postmenopausal women in December 1997. Its indication was extended to treatment of osteoporosis 2 years later.

Raloxifene appears to have no effect on the endometrium of postmenopausal women, compared with placebo. In a 12-month comparative trial, there was no difference in endometrial thickness, endoluminal masses, proliferation, or hyperplasia between the raloxifene and placebo groups.¹² This finding corroborates earlier evidence that raloxifene does not cause endometrial hyperplasia or cancer and is not associated with vaginal bleeding or increased endometrial thickness, as measured by transvaginal ultrasonography.

A big difference between raloxifene and tamoxifen, therefore, is their varying effect on the uterus of postmenopausal women.

Additional clinical trials confirm anticancer action of raloxifene

Preclinical data in animal models suggested that, like tamoxifen, raloxifene has potent antiestrogenic effects on breast tissue.⁹ The MORE trial involved 7,705 postmenopausal women up to 80 years old who had established osteoporosis.¹³ In that trial, participants were randomized to raloxifene or placebo. Bone mineral density (BMD) and fracture incidence were the primary endpoints; breast cancer was a secondary endpoint.

Over the 4 years of the trial, raloxifene significantly reduced the incidence of all invasive breast cancers by 72%, compared with placebo (RR, 0.28; 95% CI, 0.17–0.46). Raloxifene also significantly reduced the incidence of invasive estrogen-receptor–positive tumors by 84%, compared with placebo (RR, 0.16; 95% CI, 0.09–0.30), but had no effect on estrogen-receptor–negative tumors. The incidence of vaginal bleeding, breast pain, and endometrial cancer in the raloxifene group did not differ significantly from that of the placebo group.

Like tamoxifen, raloxifene appeared to be associated with an increased risk of thromboembolic disease, including DVT and pulmonary embolism, which developed in 1.1% of women taking raloxifene, compared with 0.5% of women in the placebo group (P=.003).

In a 4-year continuation of the MORE trial, known as the Continuing Outcomes Relevant to Evista, or CORE, trial, 5,231 women were randomized to continue raloxifene or placebo.¹⁴ Over the 8 years of the combined trials, the incidence of invasive breast cancer was reduced by 66% in the raloxifene group (RR, 0.34; 95% CI, 0.22–0.50). The 8-year data are extremely clinically relevant, in that raloxifene has no time limit, whereas tamoxifen is usually prescribed for no longer than 5 years.

Raloxifene is not approved for use in premenopausal women. SERM compounds, which are structurally similar to clomiphene citrate, seem to have different effects in premenopausal and postmenopausal women, as evidenced by tamoxifen’s differing effects by age in the BCPT.

Other investigations of raloxifene confirm its value in high-risk women

To compare the clinical safety and efficacy of tamoxifen and raloxifene in reducing the risk of breast cancer among healthy women, the Study of Tamoxifen and Raloxifene (STAR) was initiated in 1999.¹⁵ In that trial, 19,747 postmenopausal women older than 35 years were blindly assigned to raloxifene 60 mg or tamoxifen 20 mg daily.

Baseline characteristics of subjects in STAR are summarized in TABLE 2 . Mean age was 58.5 years. All women had a 5-year risk of developing breast cancer that exceeded 1.66%, according to the Gail model. The average Gail score was 4.03% (standard deviation, ±2.17%). Because it would have been unethical to subject high-risk women to a placebo group in light of the findings of the BCPT, there was no placebo control.

TABLE 2

Baseline characteristics of women
in the Study of Tamoxifen and Raloxifene (STAR) trial

Here are noteworthy findings of the STAR trial:

• 163 cases of invasive breast cancer occurred in the tamoxifen group, compared with 168 among women taking raloxifene (RR, 1.02; 95% CI, 0.82–1.28).
• 36 cases of uterine cancer occurred in the tamoxifen group, compared with 23 among women taking raloxifene (RR, 0.62; 95% CI, 0.35–1.08). Earlier studies had shown a marked difference in the rate of uterine cancer between these agents. Although the difference here is not statistically significant, uterine cancer was not an endpoint of the study; nor was the study powered to explore this difference.
• The number of hysterectomies among women who were diagnosed with endometrial hyperplasia with or without atypia was, proportionally, significantly higher among women taking tamoxifen ( TABLE 3 ).
• No difference between groups was found for other invasive cancers, ischemic heart events, or stroke.
• Thromboembolic events occurred less frequently in the raloxifene group (RR, 0.70; 95% CI, 0.54–0.91). However, both raloxifene and tamoxifen have consistently been associated with a twofold to threefold increase in the risk of thromboembolic events, compared with placebo.
• Vasomotor symptoms and leg cramps increased in frequency and severity among women in both groups of the trial. These symptoms appear to be less common and less severe among women who are older and more remote from the onset of menopause.

TABLE 3

Relative risk of hysterectomy and uterine hyperplasia during STAR

What is raloxifene’s effect on the heart?

The Raloxifene Use for The Heart (RUTH) trial explored the primary endpoints of coronary artery disease (CAD) and breast cancer in more than 10,000 women who had CAD or multiple risk factors for it.¹⁶ This study began prior to the Women’s Health Initiative, at a time when hormone replacement therapy was widely believed to reduce CAD.

In the double-blinded, randomized, placebo-controlled RUTH trial, raloxifene had no significant effect on primary coronary events (533 vs 553; hazard ratio [HR], 0.95; 95% CI, 0.84–1.07). Even in this population, however, there was a 44% reduction in invasive breast cancer (40 vs 70 events; HR, 0.56; 95% CI, 0.38–0.83).

Based on these results, the FDA approved raloxifene for the “reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer,” as well as for the “reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” ( FIGURE ).

FIGURE How raloxifene reduced invasive breast cancer in three trials

Raloxifene significantly reduced the risk of cancer, compared with placebo, in the Raloxifene Use for The Heart (RUTH), Multiple Outcomes of Raloxifene Evaluation (MORE), and Continuing Outcomes Relevant to Evista (CORE) trials.

CASE 2 RESOLVED

S. T. begins taking raloxifene 60 mg daily to lower her risk of invasive breast cancer. Although she temporarily experienced hot flashes after initiating the drug, they are only mildly bothersome, and she continues raloxifene therapy. She says she is grateful that there is an agent that can help her reduce the likelihood that she will develop breast cancer, and protection of her BMD is an added benefit.

CASE 3: At risk for both breast cancer and bone fracture

A. N., 63, is a nulliparous Caucasian woman who weighs 134 lb and stands 5 ft 4 in tall. She reached menarche when she was 12 years old and entered menopause at 49.

Although A. N. has never had a breast abnormality, her 59-year-old sister was just given a diagnosis of breast cancer. Her Gail score reveals that she has a 3.1% risk of developing breast cancer over the next 5 years.

In addition to her concerns about breast cancer, A. N. is worried about hip fracture—because her mother suffered one after menopause and because her T-score is –1.9 at the hip and –2.1 at the spine. A. N. has used steroids off and on for much of her life for asthma. Her FRAX score indicates that she has a 2.8% risk of hip fracture and a 25% risk of major osteoporotic fracture over the next 10 years.

What do you offer her?

Because of new FRAX criteria, this osteopenic woman is now a candidate for medication to reduce her risk of major osteoporotic fracture, and raloxifene is a good option. Her Gail score of 3.1% also makes her a good candidate for breast cancer risk reduction with raloxifene.

CASE 3 RESOLVED

Because A. N. needs an agent that benefits both breast and bone, you prescribe raloxifene. The drug should significantly reduce her risk of both invasive breast cancer and bone fracture, without increasing her risk of endometrial hyperplasia and cancer, both of which are associated with tamoxifen in her age group.

Aromatase inhibitors

A fairly new class of drugs being explored for their ability to reduce the risk of breast cancer is aromatase inhibitors. Substantial evidence suggests that estrogens facilitate the development of breast cancer in animals and in women, although the precise mechanism remains unknown.¹⁷ The most commonly held theory is that estrogen stimulates proliferation of breast cells and thereby increases the risk of genetic mutation that could lead to cancer.

Aromatase inhibitors block peripheral conversion of androstenedione to estrogens. In premenopausal women, the primary site of this action is in the ovary. In postmenopausal women, this conversion occurs primarily in extraovarian sites, including the adrenal glands, adipose tissue, liver, muscle, and skin.

Aromatase inhibitors may be more effective than SERMs in preventing breast cancer because of their dual role: blocking both the initiation and promotion of breast cancer.¹⁸ These agents reduce levels of the genotoxic metabolites of estradiol by lowering estradiol concentration in tissue. At the same time, aromatase inhibitors also block tumor promotion by lowering tissue levels of estrogen and preventing cell proliferation.

The main drawback of these agents—besides the fact that they are not FDA-approved for reducing risk—is their antiestrogenic effect on bone and lipid metabolism. They also induce vasomotor symptoms.

Studies of third-generation aromatase inhibitors in the prevention of breast cancer are under way in high-risk women. These agents include anastrozole, exemestane, and letrozole.

The author reports that he is a consultant to Eli Lilly, Pfizer, and Wyeth, and a speaker for Eli Lilly and Wyeth.

CASE 1: Premenopausal woman
at high risk of breast cancer

R. J. is a 43-year-old, nulliparous woman who reached menarche at age 11. She has undergone two breast biopsies, the most recent of which revealed ductal hyperplasia with marked atypia.

R. J.’s sister had breast cancer at 49 years of age; her mother had breast cancer at 66 years. Because of R. J.’s family history, she underwent testing for a BRCA mutation. The result was negative.

R. J. has come to your office today to find out if she can do anything to reduce her risk of breast cancer. What options can you offer?

The most common method of “prevention” of breast cancer involves early detection and assessment of abnormalities through frequent surveillance with mammography. Some women who have dense breasts, a history of breast biopsy, or other risk factors for breast cancer may benefit from intensive surveillance with both mammography and ultrasonography—and, in some cases, magnetic resonance imaging.

More aggressive options include:

• the use of a chemopreventive agent such as tamoxifen or raloxifene
• in rare cases—usually when a BRCA mutation is present—prophylactic mastectomy.

Before it is possible to determine the optimal approach for a particular woman, it is necessary to conduct an individualized assessment of her risk—that is, to estimate the probability that she will develop breast cancer over a defined period of time. Such an estimate is also useful for designing prevention trials in high-risk subsets of the population. (Prevention trials differ from therapeutic clinical trials in that asymptomatic healthy women are exposed to potentially toxic interventions for prolonged periods to reduce their risk of breast cancer.)

This article describes chemopreventive options for women at high risk, based on individualized risk assessment using the Gail model.

(Editor’s note: For additional discussion of the important role ObGyns play in the fight against breast cancer, see Editor in Chief Dr. Robert L. Barbieri’s Editorial.)

What constitutes high risk?

You can estimate the likelihood that a woman like your patient may develop breast cancer using various individual risk factors ( TABLE 1 ), but estimates for combinations of risk factors are preferable. The Gail model takes into account some nongenetic factors, such as parity and age at menarche, but also genetic factors, such as family history. The model calculates a woman’s individualized breast cancer probability and yields a numerical risk (a percentage) that she will develop invasive breast cancer over the next 5 years; it also yields an estimate of her risk of developing the malignancy over the remainder of her life.^1,2

A Gail-model 5-year estimate of 1.66% or higher denotes a high risk of developing breast cancer. That benchmark was the one employed in the Breast Cancer Prevention Trial (BCPT), conducted as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP).³

TABLE 1

What are the risk factors for breast cancer?
And what degree of relative risk do they confer?

Weaknesses of the Gail model

The Gail model’s approach to estimating risk has some limitations. The model uses the number of prior breast biopsies in its assessment—but the relative risk associated with prior biopsy is smaller for women older than 50 years than it is for younger women.

Furthermore, data on which Gail bases its estimates were collected in the late 1970s and early 1980s. Since then, the increasing ease of breast histopathologic assessment—through fine-needle aspiration and outpatient core-needle biopsy—has confused the issue of just what constitutes a breast “biopsy.” (Most patients surveyed consider it to be any histologic sampling of the breast.)

As a result, the 1.66% cutoff becomes somewhat difficult to interpret in light of current practice.

Consider the following example. A 50-year-old nulliparous Caucasian woman reached menarche when she was 11 years old, has never had a biopsy, and has no first-degree relatives with breast cancer. According to the Gail model, her risk of developing breast cancer is 1.2% over the next 5 years and 10.8% in her lifetime. Therefore, she is not considered at high risk. If she were to give a history of three previous breast biopsies, however, none of them showing hyperplasia, her 5-year risk would rise to 1.8% and push her over the line into the high-risk category.

Compare her situation to that of R. J., the nulliparous woman described in Case 1. R. J. also reached menarche at 11 years, but she has had two breast biopsies (one of which showed atypical hyperplasia) and has two first-degree relatives who have had breast cancer. Her Gail score shows a 5-year risk of breast cancer of 13.5% (the norm for a 43-year-old woman is 0.8%), and a lifetime risk of 69.2%. Clearly, she has a high risk of breast cancer.

How do we improve an imperfect science?

We need to identify objective findings that are patient-specific but highly correlative with the development of breast cancer. Patient-specific biomarkers have been proposed, such as ultrasensitive measurement of the serum estradiol level in postmenopausal women. In the Multiple Outcomes of Raloxifene Evaluation, also known as the MORE trial, women who experienced the greatest reduction in the rate of breast cancer during treatment with raloxifene were a subgroup who had the highest baseline level of serum estradiol—although, overall, all patients had an estradiol level well within the postmenopausal range (≤20 pmol/L).^4,5

How tamoxifen became a chemopreventive agent

Tamoxifen inhibits mammary tumors in mice and rats and suppresses hormone-dependent breast cancer cell lines in vitro.⁶ Clinical data from the Early Breast Cancer Trialists’ Collaborative Group yielded additional motivation for prevention trials with tamoxifen: Besides reducing the rate of recurrent breast cancer, tamoxifen reduced the risk of contralateral new-onset breast cancer by 47% after 5 years of adjuvant treatment.⁷ Preclinical findings in vitro and in animal models, coupled with clinical data and evidence of tamoxifen’s favorable effects on skeleton remodeling and lipid levels, led to a series of chemoprevention trials in the United States and Europe using tamoxifen.

In the aforementioned BCPT, launched in 1992, 13,388 women 35 years and older who were deemed to be at high risk of developing breast cancer were enrolled at numerous sites throughout the United States and Canada.³ The Gail model was used to select women for the trial—only those who had a 5-year risk of 1.66% or higher were included. Participants were randomly assigned to receive tamoxifen 20 mg or placebo daily for 5 years. The trial was terminated early because of the dramatic reduction in new-onset breast cancer with tamoxifen, compared with placebo.

The overall incidence of breast cancer in the tamoxifen group was 3.4 cases for every 1,000 women, compared with 6.8 cases for every 1,000 women receiving placebo.³ Overall, the reduction in invasive breast cancer with tamoxifen was 49% (P<.00001). When broken down by age group, the reduction was:

• 44% in women 35 to 49 years old
• 51% in women 50 to 59 years old
• 55% in women 60 years and older.

Even noninvasive breast cancer was reduced with tamoxifen

Tamoxifen decreased the incidence of noninvasive breast cancer (ductal carcinoma in situ [DCIS]) by 50%. Expanded use of mammography has increased the detection of DCIS. Most DCIS lesions appear to be estrogen-receptor positive.⁸

In addition, tamoxifen reduced breast cancer risk in women who had a history of lobular carcinoma in situ (LCIS), a precancer, by 56%, and it reduced the risk of breast cancer in women who had a history of atypical hyperplasia by 86%. Overall, tamoxifen reduced the occurrence of estrogen-positive tumors by 69%, but had no impact on the incidence of estrogen-receptor–negative tumors.

The BCPT was stopped 14 months before planned because the Data and Safety Monitoring Board felt it was unethical to continue to allow one half of such high-risk participants to take placebo in light of the dramatic reduction in both invasive and noninvasive breast cancer among women who took tamoxifen.

In postmenopausal women, tamoxifen increases some risks

Two secondary endpoints of the BCPT are worthy of consideration:

• The overall relative risk (RR) of endometrial cancer associated with tamoxifen therapy in healthy women was 2.53 (95% confidence interval [CI], 1.35, 4.97). However, further analysis by age yielded a RR of 4.01 in women who were older than 50 years (95% CI, 1.70, 10.90), compared with a RR of 1.21 in women 49 years and younger (95% CI, 0.41, 3.60).
• The same age distinction held true for deep venous thrombosis (DVT) and pulmonary embolus, with no statistically significant increases in either in women 49 years and younger, but a RR of 1.71 and 3.19, respectively, in women 50 years and older. It is unclear whether the trial was sufficiently powered for this particular secondary endpoint.

These findings suggest that serious adverse events do not occur at the same magnitude in women younger than 50 years that they do in women 50 and older. The difference in the risk–benefit profile between younger and older women has significant clinical implications for the care of perimenopausal patients.

Risk of other malignancies was not affected by tamoxifen

Overall, invasive cancers other than those of the breast and uterus occurred at the same rate in the tamoxifen and placebo groups of the BCPT. The RR of death from any cause was 0.81 (95% CI, 0.56–1.16). There was a slight increase in the risk of myocardial infarction (RR, 1.11; 95% CI, 0.65–1.92) and a slight decrease in the risk of severe angina (RR, 0.93; 95% CI, 0.40–2.14) in tamoxifen users, although neither of these risks was statistically significant.

The overall RR of fracture of the hip, spine, or radius was 0.81 (95% CI, 0.63–1.05). There was a statistically significant increase in the number of women who had cataracts who then underwent cataract surgery in the tamoxifen group (RR, 1.57; 95% CI, 1.16–2.14).

Tamoxifen is approved as a preventive for high-risk women only

Based on the results of the BCPT, the US Food and Drug Administration (FDA) approved tamoxifen in October 1998 for the primary prevention of breast cancer in women who are at high risk of the disease. The FDA recommends that use of tamoxifen be limited to women at high risk because of the potentially serious side effects seen in clinical trials, including the BCPT.

The FDA did not define “high risk,” but it did recommend that the decision to use tamoxifen as chemopreventive therapy be based on thorough evaluation of the patient’s personal, family, and medical histories; her age; and her understanding of the risks and benefits of treatment.

The FDA also required the following language in the package insert:

• You should not take tamoxifen to reduce the risk of breast cancer unless you are at high risk of breast cancer. Certain conditions put women at high risk, and it is possible to calculate this risk for any woman. Breast cancer risk-assessment tools to help calculate your risk of breast cancer have been developed and are available to your health-care professional. You should discuss your risk with your healthcare professional.

CASE 1 RESOLVED

You determine that R. J. is an excellent candidate for tamoxifen by virtue of her significant risk of breast cancer. You are able to reassure her that, as the BCPT demonstrated, tamoxifen should not increase the risk of uterine cancer, DVT, or pulmonary embolism in a woman her age.

Raloxifene

CASE 2: Patient worries about breasts and bones

S. T. is a 58-year-old Caucasian mother of two whose own mother had breast cancer when she was 74 years old, and whose older sister was given a diagnosis of the malignancy 4 years ago.

S. T. had her first period when she was 11 years old, delivered her first child when she was 31, and entered menopause when she was 52. She is 5 ft 5 in tall and weighs 144 lb.

Her main reason for visiting you today is a breast Mammotome biopsy that showed ductal hyperplasia with atypia. She has been tested for a BRCA mutation, but the result was negative. Her Gail-model score is a 9.7% risk of developing breast cancer over the next 5 years, and a lifetime risk of 44.2%.

She also asks about osteoporosis prevention, given that a dual-energy x-ray absorptiometry (DXA) scan 1 year ago yielded a T-score of –1.3 for her hip and –1.1 for her spine. Her World Health Organization FRAX 10-year risk of hip fracture is 0.7%, and her risk of major osteoporotic fracture is 8.6%.

How do you respond to her concerns?

This patient has a high risk of invasive breast cancer but does not meet criteria for pharmacotherapy for osteoporosis prevention. A good option for her would be raloxifene, a selective estrogen-receptor modulator (SERM) that has been shown to reduce the risk of breast cancer as well as osteoporosis. S. T. would benefit from it on the basis of its breast benefit alone.

The genesis of a drug with multiple benefits

Raloxifene is a benzothiophene derivative, unlike the triphenylethylene family from which tamoxifen is derived. Like tamoxifen, raloxifene was originally investigated as a treatment for advanced breast cancer.

Preclinical studies indicated that raloxifene had an antiproliferative effect on both estrogen-receptor–positive mammary tumors and estrogen-receptor–positive human breast cancer cell lines.⁹ In the 1980s, however, a small, phase-II trial revealed that raloxifene had no further antitumor effects in postmenopausal women with advanced breast cancer in whom tamoxifen had failed.¹⁰ After information surfaced about the neoplastic effect of tamoxifen on the uteri of postmenopausal women, interest in raloxifene revived.¹¹

Raloxifene has estrogen-agonistic activity on bone remodeling and lipid metabolism and was approved by the FDA for prevention of osteoporosis in postmenopausal women in December 1997. Its indication was extended to treatment of osteoporosis 2 years later.

Raloxifene appears to have no effect on the endometrium of postmenopausal women, compared with placebo. In a 12-month comparative trial, there was no difference in endometrial thickness, endoluminal masses, proliferation, or hyperplasia between the raloxifene and placebo groups.¹² This finding corroborates earlier evidence that raloxifene does not cause endometrial hyperplasia or cancer and is not associated with vaginal bleeding or increased endometrial thickness, as measured by transvaginal ultrasonography.

A big difference between raloxifene and tamoxifen, therefore, is their varying effect on the uterus of postmenopausal women.

Additional clinical trials confirm anticancer action of raloxifene

Preclinical data in animal models suggested that, like tamoxifen, raloxifene has potent antiestrogenic effects on breast tissue.⁹ The MORE trial involved 7,705 postmenopausal women up to 80 years old who had established osteoporosis.¹³ In that trial, participants were randomized to raloxifene or placebo. Bone mineral density (BMD) and fracture incidence were the primary endpoints; breast cancer was a secondary endpoint.

Over the 4 years of the trial, raloxifene significantly reduced the incidence of all invasive breast cancers by 72%, compared with placebo (RR, 0.28; 95% CI, 0.17–0.46). Raloxifene also significantly reduced the incidence of invasive estrogen-receptor–positive tumors by 84%, compared with placebo (RR, 0.16; 95% CI, 0.09–0.30), but had no effect on estrogen-receptor–negative tumors. The incidence of vaginal bleeding, breast pain, and endometrial cancer in the raloxifene group did not differ significantly from that of the placebo group.

Like tamoxifen, raloxifene appeared to be associated with an increased risk of thromboembolic disease, including DVT and pulmonary embolism, which developed in 1.1% of women taking raloxifene, compared with 0.5% of women in the placebo group (P=.003).

In a 4-year continuation of the MORE trial, known as the Continuing Outcomes Relevant to Evista, or CORE, trial, 5,231 women were randomized to continue raloxifene or placebo.¹⁴ Over the 8 years of the combined trials, the incidence of invasive breast cancer was reduced by 66% in the raloxifene group (RR, 0.34; 95% CI, 0.22–0.50). The 8-year data are extremely clinically relevant, in that raloxifene has no time limit, whereas tamoxifen is usually prescribed for no longer than 5 years.

Raloxifene is not approved for use in premenopausal women. SERM compounds, which are structurally similar to clomiphene citrate, seem to have different effects in premenopausal and postmenopausal women, as evidenced by tamoxifen’s differing effects by age in the BCPT.

Other investigations of raloxifene confirm its value in high-risk women

To compare the clinical safety and efficacy of tamoxifen and raloxifene in reducing the risk of breast cancer among healthy women, the Study of Tamoxifen and Raloxifene (STAR) was initiated in 1999.¹⁵ In that trial, 19,747 postmenopausal women older than 35 years were blindly assigned to raloxifene 60 mg or tamoxifen 20 mg daily.

Baseline characteristics of subjects in STAR are summarized in TABLE 2 . Mean age was 58.5 years. All women had a 5-year risk of developing breast cancer that exceeded 1.66%, according to the Gail model. The average Gail score was 4.03% (standard deviation, ±2.17%). Because it would have been unethical to subject high-risk women to a placebo group in light of the findings of the BCPT, there was no placebo control.

TABLE 2

Baseline characteristics of women
in the Study of Tamoxifen and Raloxifene (STAR) trial

Here are noteworthy findings of the STAR trial:

• 163 cases of invasive breast cancer occurred in the tamoxifen group, compared with 168 among women taking raloxifene (RR, 1.02; 95% CI, 0.82–1.28).
• 36 cases of uterine cancer occurred in the tamoxifen group, compared with 23 among women taking raloxifene (RR, 0.62; 95% CI, 0.35–1.08). Earlier studies had shown a marked difference in the rate of uterine cancer between these agents. Although the difference here is not statistically significant, uterine cancer was not an endpoint of the study; nor was the study powered to explore this difference.
• The number of hysterectomies among women who were diagnosed with endometrial hyperplasia with or without atypia was, proportionally, significantly higher among women taking tamoxifen ( TABLE 3 ).
• No difference between groups was found for other invasive cancers, ischemic heart events, or stroke.
• Thromboembolic events occurred less frequently in the raloxifene group (RR, 0.70; 95% CI, 0.54–0.91). However, both raloxifene and tamoxifen have consistently been associated with a twofold to threefold increase in the risk of thromboembolic events, compared with placebo.
• Vasomotor symptoms and leg cramps increased in frequency and severity among women in both groups of the trial. These symptoms appear to be less common and less severe among women who are older and more remote from the onset of menopause.

TABLE 3

Relative risk of hysterectomy and uterine hyperplasia during STAR

What is raloxifene’s effect on the heart?

The Raloxifene Use for The Heart (RUTH) trial explored the primary endpoints of coronary artery disease (CAD) and breast cancer in more than 10,000 women who had CAD or multiple risk factors for it.¹⁶ This study began prior to the Women’s Health Initiative, at a time when hormone replacement therapy was widely believed to reduce CAD.

In the double-blinded, randomized, placebo-controlled RUTH trial, raloxifene had no significant effect on primary coronary events (533 vs 553; hazard ratio [HR], 0.95; 95% CI, 0.84–1.07). Even in this population, however, there was a 44% reduction in invasive breast cancer (40 vs 70 events; HR, 0.56; 95% CI, 0.38–0.83).

Based on these results, the FDA approved raloxifene for the “reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer,” as well as for the “reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” ( FIGURE ).

FIGURE How raloxifene reduced invasive breast cancer in three trials

Raloxifene significantly reduced the risk of cancer, compared with placebo, in the Raloxifene Use for The Heart (RUTH), Multiple Outcomes of Raloxifene Evaluation (MORE), and Continuing Outcomes Relevant to Evista (CORE) trials.

CASE 2 RESOLVED

S. T. begins taking raloxifene 60 mg daily to lower her risk of invasive breast cancer. Although she temporarily experienced hot flashes after initiating the drug, they are only mildly bothersome, and she continues raloxifene therapy. She says she is grateful that there is an agent that can help her reduce the likelihood that she will develop breast cancer, and protection of her BMD is an added benefit.

CASE 3: At risk for both breast cancer and bone fracture

A. N., 63, is a nulliparous Caucasian woman who weighs 134 lb and stands 5 ft 4 in tall. She reached menarche when she was 12 years old and entered menopause at 49.

Although A. N. has never had a breast abnormality, her 59-year-old sister was just given a diagnosis of breast cancer. Her Gail score reveals that she has a 3.1% risk of developing breast cancer over the next 5 years.

In addition to her concerns about breast cancer, A. N. is worried about hip fracture—because her mother suffered one after menopause and because her T-score is –1.9 at the hip and –2.1 at the spine. A. N. has used steroids off and on for much of her life for asthma. Her FRAX score indicates that she has a 2.8% risk of hip fracture and a 25% risk of major osteoporotic fracture over the next 10 years.

What do you offer her?

Because of new FRAX criteria, this osteopenic woman is now a candidate for medication to reduce her risk of major osteoporotic fracture, and raloxifene is a good option. Her Gail score of 3.1% also makes her a good candidate for breast cancer risk reduction with raloxifene.

CASE 3 RESOLVED

Because A. N. needs an agent that benefits both breast and bone, you prescribe raloxifene. The drug should significantly reduce her risk of both invasive breast cancer and bone fracture, without increasing her risk of endometrial hyperplasia and cancer, both of which are associated with tamoxifen in her age group.

Aromatase inhibitors

A fairly new class of drugs being explored for their ability to reduce the risk of breast cancer is aromatase inhibitors. Substantial evidence suggests that estrogens facilitate the development of breast cancer in animals and in women, although the precise mechanism remains unknown.¹⁷ The most commonly held theory is that estrogen stimulates proliferation of breast cells and thereby increases the risk of genetic mutation that could lead to cancer.

Aromatase inhibitors block peripheral conversion of androstenedione to estrogens. In premenopausal women, the primary site of this action is in the ovary. In postmenopausal women, this conversion occurs primarily in extraovarian sites, including the adrenal glands, adipose tissue, liver, muscle, and skin.

Aromatase inhibitors may be more effective than SERMs in preventing breast cancer because of their dual role: blocking both the initiation and promotion of breast cancer.¹⁸ These agents reduce levels of the genotoxic metabolites of estradiol by lowering estradiol concentration in tissue. At the same time, aromatase inhibitors also block tumor promotion by lowering tissue levels of estrogen and preventing cell proliferation.

The main drawback of these agents—besides the fact that they are not FDA-approved for reducing risk—is their antiestrogenic effect on bone and lipid metabolism. They also induce vasomotor symptoms.

Studies of third-generation aromatase inhibitors in the prevention of breast cancer are under way in high-risk women. These agents include anastrozole, exemestane, and letrozole.

The author reports that he is a consultant to Eli Lilly, Pfizer, and Wyeth, and a speaker for Eli Lilly and Wyeth.

CASE 1: Premenopausal woman
at high risk of breast cancer

R. J. is a 43-year-old, nulliparous woman who reached menarche at age 11. She has undergone two breast biopsies, the most recent of which revealed ductal hyperplasia with marked atypia.

R. J.’s sister had breast cancer at 49 years of age; her mother had breast cancer at 66 years. Because of R. J.’s family history, she underwent testing for a BRCA mutation. The result was negative.

R. J. has come to your office today to find out if she can do anything to reduce her risk of breast cancer. What options can you offer?

The most common method of “prevention” of breast cancer involves early detection and assessment of abnormalities through frequent surveillance with mammography. Some women who have dense breasts, a history of breast biopsy, or other risk factors for breast cancer may benefit from intensive surveillance with both mammography and ultrasonography—and, in some cases, magnetic resonance imaging.

More aggressive options include:

• the use of a chemopreventive agent such as tamoxifen or raloxifene
• in rare cases—usually when a BRCA mutation is present—prophylactic mastectomy.

Before it is possible to determine the optimal approach for a particular woman, it is necessary to conduct an individualized assessment of her risk—that is, to estimate the probability that she will develop breast cancer over a defined period of time. Such an estimate is also useful for designing prevention trials in high-risk subsets of the population. (Prevention trials differ from therapeutic clinical trials in that asymptomatic healthy women are exposed to potentially toxic interventions for prolonged periods to reduce their risk of breast cancer.)

This article describes chemopreventive options for women at high risk, based on individualized risk assessment using the Gail model.

(Editor’s note: For additional discussion of the important role ObGyns play in the fight against breast cancer, see Editor in Chief Dr. Robert L. Barbieri’s Editorial.)

What constitutes high risk?

You can estimate the likelihood that a woman like your patient may develop breast cancer using various individual risk factors ( TABLE 1 ), but estimates for combinations of risk factors are preferable. The Gail model takes into account some nongenetic factors, such as parity and age at menarche, but also genetic factors, such as family history. The model calculates a woman’s individualized breast cancer probability and yields a numerical risk (a percentage) that she will develop invasive breast cancer over the next 5 years; it also yields an estimate of her risk of developing the malignancy over the remainder of her life.^1,2

A Gail-model 5-year estimate of 1.66% or higher denotes a high risk of developing breast cancer. That benchmark was the one employed in the Breast Cancer Prevention Trial (BCPT), conducted as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP).³

TABLE 1

What are the risk factors for breast cancer?
And what degree of relative risk do they confer?

Weaknesses of the Gail model

The Gail model’s approach to estimating risk has some limitations. The model uses the number of prior breast biopsies in its assessment—but the relative risk associated with prior biopsy is smaller for women older than 50 years than it is for younger women.

Furthermore, data on which Gail bases its estimates were collected in the late 1970s and early 1980s. Since then, the increasing ease of breast histopathologic assessment—through fine-needle aspiration and outpatient core-needle biopsy—has confused the issue of just what constitutes a breast “biopsy.” (Most patients surveyed consider it to be any histologic sampling of the breast.)

As a result, the 1.66% cutoff becomes somewhat difficult to interpret in light of current practice.

Consider the following example. A 50-year-old nulliparous Caucasian woman reached menarche when she was 11 years old, has never had a biopsy, and has no first-degree relatives with breast cancer. According to the Gail model, her risk of developing breast cancer is 1.2% over the next 5 years and 10.8% in her lifetime. Therefore, she is not considered at high risk. If she were to give a history of three previous breast biopsies, however, none of them showing hyperplasia, her 5-year risk would rise to 1.8% and push her over the line into the high-risk category.

Compare her situation to that of R. J., the nulliparous woman described in Case 1. R. J. also reached menarche at 11 years, but she has had two breast biopsies (one of which showed atypical hyperplasia) and has two first-degree relatives who have had breast cancer. Her Gail score shows a 5-year risk of breast cancer of 13.5% (the norm for a 43-year-old woman is 0.8%), and a lifetime risk of 69.2%. Clearly, she has a high risk of breast cancer.

How do we improve an imperfect science?

We need to identify objective findings that are patient-specific but highly correlative with the development of breast cancer. Patient-specific biomarkers have been proposed, such as ultrasensitive measurement of the serum estradiol level in postmenopausal women. In the Multiple Outcomes of Raloxifene Evaluation, also known as the MORE trial, women who experienced the greatest reduction in the rate of breast cancer during treatment with raloxifene were a subgroup who had the highest baseline level of serum estradiol—although, overall, all patients had an estradiol level well within the postmenopausal range (≤20 pmol/L).^4,5

How tamoxifen became a chemopreventive agent

Tamoxifen inhibits mammary tumors in mice and rats and suppresses hormone-dependent breast cancer cell lines in vitro.⁶ Clinical data from the Early Breast Cancer Trialists’ Collaborative Group yielded additional motivation for prevention trials with tamoxifen: Besides reducing the rate of recurrent breast cancer, tamoxifen reduced the risk of contralateral new-onset breast cancer by 47% after 5 years of adjuvant treatment.⁷ Preclinical findings in vitro and in animal models, coupled with clinical data and evidence of tamoxifen’s favorable effects on skeleton remodeling and lipid levels, led to a series of chemoprevention trials in the United States and Europe using tamoxifen.

In the aforementioned BCPT, launched in 1992, 13,388 women 35 years and older who were deemed to be at high risk of developing breast cancer were enrolled at numerous sites throughout the United States and Canada.³ The Gail model was used to select women for the trial—only those who had a 5-year risk of 1.66% or higher were included. Participants were randomly assigned to receive tamoxifen 20 mg or placebo daily for 5 years. The trial was terminated early because of the dramatic reduction in new-onset breast cancer with tamoxifen, compared with placebo.

The overall incidence of breast cancer in the tamoxifen group was 3.4 cases for every 1,000 women, compared with 6.8 cases for every 1,000 women receiving placebo.³ Overall, the reduction in invasive breast cancer with tamoxifen was 49% (P<.00001). When broken down by age group, the reduction was:

• 44% in women 35 to 49 years old
• 51% in women 50 to 59 years old
• 55% in women 60 years and older.

Even noninvasive breast cancer was reduced with tamoxifen

Tamoxifen decreased the incidence of noninvasive breast cancer (ductal carcinoma in situ [DCIS]) by 50%. Expanded use of mammography has increased the detection of DCIS. Most DCIS lesions appear to be estrogen-receptor positive.⁸

In addition, tamoxifen reduced breast cancer risk in women who had a history of lobular carcinoma in situ (LCIS), a precancer, by 56%, and it reduced the risk of breast cancer in women who had a history of atypical hyperplasia by 86%. Overall, tamoxifen reduced the occurrence of estrogen-positive tumors by 69%, but had no impact on the incidence of estrogen-receptor–negative tumors.

The BCPT was stopped 14 months before planned because the Data and Safety Monitoring Board felt it was unethical to continue to allow one half of such high-risk participants to take placebo in light of the dramatic reduction in both invasive and noninvasive breast cancer among women who took tamoxifen.

In postmenopausal women, tamoxifen increases some risks

Two secondary endpoints of the BCPT are worthy of consideration:

• The overall relative risk (RR) of endometrial cancer associated with tamoxifen therapy in healthy women was 2.53 (95% confidence interval [CI], 1.35, 4.97). However, further analysis by age yielded a RR of 4.01 in women who were older than 50 years (95% CI, 1.70, 10.90), compared with a RR of 1.21 in women 49 years and younger (95% CI, 0.41, 3.60).
• The same age distinction held true for deep venous thrombosis (DVT) and pulmonary embolus, with no statistically significant increases in either in women 49 years and younger, but a RR of 1.71 and 3.19, respectively, in women 50 years and older. It is unclear whether the trial was sufficiently powered for this particular secondary endpoint.

These findings suggest that serious adverse events do not occur at the same magnitude in women younger than 50 years that they do in women 50 and older. The difference in the risk–benefit profile between younger and older women has significant clinical implications for the care of perimenopausal patients.

Risk of other malignancies was not affected by tamoxifen

Overall, invasive cancers other than those of the breast and uterus occurred at the same rate in the tamoxifen and placebo groups of the BCPT. The RR of death from any cause was 0.81 (95% CI, 0.56–1.16). There was a slight increase in the risk of myocardial infarction (RR, 1.11; 95% CI, 0.65–1.92) and a slight decrease in the risk of severe angina (RR, 0.93; 95% CI, 0.40–2.14) in tamoxifen users, although neither of these risks was statistically significant.

The overall RR of fracture of the hip, spine, or radius was 0.81 (95% CI, 0.63–1.05). There was a statistically significant increase in the number of women who had cataracts who then underwent cataract surgery in the tamoxifen group (RR, 1.57; 95% CI, 1.16–2.14).

Tamoxifen is approved as a preventive for high-risk women only

Based on the results of the BCPT, the US Food and Drug Administration (FDA) approved tamoxifen in October 1998 for the primary prevention of breast cancer in women who are at high risk of the disease. The FDA recommends that use of tamoxifen be limited to women at high risk because of the potentially serious side effects seen in clinical trials, including the BCPT.

The FDA did not define “high risk,” but it did recommend that the decision to use tamoxifen as chemopreventive therapy be based on thorough evaluation of the patient’s personal, family, and medical histories; her age; and her understanding of the risks and benefits of treatment.

The FDA also required the following language in the package insert:

• You should not take tamoxifen to reduce the risk of breast cancer unless you are at high risk of breast cancer. Certain conditions put women at high risk, and it is possible to calculate this risk for any woman. Breast cancer risk-assessment tools to help calculate your risk of breast cancer have been developed and are available to your health-care professional. You should discuss your risk with your healthcare professional.

CASE 1 RESOLVED

You determine that R. J. is an excellent candidate for tamoxifen by virtue of her significant risk of breast cancer. You are able to reassure her that, as the BCPT demonstrated, tamoxifen should not increase the risk of uterine cancer, DVT, or pulmonary embolism in a woman her age.

Raloxifene

CASE 2: Patient worries about breasts and bones

S. T. is a 58-year-old Caucasian mother of two whose own mother had breast cancer when she was 74 years old, and whose older sister was given a diagnosis of the malignancy 4 years ago.

S. T. had her first period when she was 11 years old, delivered her first child when she was 31, and entered menopause when she was 52. She is 5 ft 5 in tall and weighs 144 lb.

Her main reason for visiting you today is a breast Mammotome biopsy that showed ductal hyperplasia with atypia. She has been tested for a BRCA mutation, but the result was negative. Her Gail-model score is a 9.7% risk of developing breast cancer over the next 5 years, and a lifetime risk of 44.2%.

She also asks about osteoporosis prevention, given that a dual-energy x-ray absorptiometry (DXA) scan 1 year ago yielded a T-score of –1.3 for her hip and –1.1 for her spine. Her World Health Organization FRAX 10-year risk of hip fracture is 0.7%, and her risk of major osteoporotic fracture is 8.6%.

How do you respond to her concerns?

This patient has a high risk of invasive breast cancer but does not meet criteria for pharmacotherapy for osteoporosis prevention. A good option for her would be raloxifene, a selective estrogen-receptor modulator (SERM) that has been shown to reduce the risk of breast cancer as well as osteoporosis. S. T. would benefit from it on the basis of its breast benefit alone.

The genesis of a drug with multiple benefits

Raloxifene is a benzothiophene derivative, unlike the triphenylethylene family from which tamoxifen is derived. Like tamoxifen, raloxifene was originally investigated as a treatment for advanced breast cancer.

Preclinical studies indicated that raloxifene had an antiproliferative effect on both estrogen-receptor–positive mammary tumors and estrogen-receptor–positive human breast cancer cell lines.⁹ In the 1980s, however, a small, phase-II trial revealed that raloxifene had no further antitumor effects in postmenopausal women with advanced breast cancer in whom tamoxifen had failed.¹⁰ After information surfaced about the neoplastic effect of tamoxifen on the uteri of postmenopausal women, interest in raloxifene revived.¹¹

Raloxifene has estrogen-agonistic activity on bone remodeling and lipid metabolism and was approved by the FDA for prevention of osteoporosis in postmenopausal women in December 1997. Its indication was extended to treatment of osteoporosis 2 years later.

Raloxifene appears to have no effect on the endometrium of postmenopausal women, compared with placebo. In a 12-month comparative trial, there was no difference in endometrial thickness, endoluminal masses, proliferation, or hyperplasia between the raloxifene and placebo groups.¹² This finding corroborates earlier evidence that raloxifene does not cause endometrial hyperplasia or cancer and is not associated with vaginal bleeding or increased endometrial thickness, as measured by transvaginal ultrasonography.

A big difference between raloxifene and tamoxifen, therefore, is their varying effect on the uterus of postmenopausal women.

Additional clinical trials confirm anticancer action of raloxifene

Preclinical data in animal models suggested that, like tamoxifen, raloxifene has potent antiestrogenic effects on breast tissue.⁹ The MORE trial involved 7,705 postmenopausal women up to 80 years old who had established osteoporosis.¹³ In that trial, participants were randomized to raloxifene or placebo. Bone mineral density (BMD) and fracture incidence were the primary endpoints; breast cancer was a secondary endpoint.

Over the 4 years of the trial, raloxifene significantly reduced the incidence of all invasive breast cancers by 72%, compared with placebo (RR, 0.28; 95% CI, 0.17–0.46). Raloxifene also significantly reduced the incidence of invasive estrogen-receptor–positive tumors by 84%, compared with placebo (RR, 0.16; 95% CI, 0.09–0.30), but had no effect on estrogen-receptor–negative tumors. The incidence of vaginal bleeding, breast pain, and endometrial cancer in the raloxifene group did not differ significantly from that of the placebo group.

Like tamoxifen, raloxifene appeared to be associated with an increased risk of thromboembolic disease, including DVT and pulmonary embolism, which developed in 1.1% of women taking raloxifene, compared with 0.5% of women in the placebo group (P=.003).

In a 4-year continuation of the MORE trial, known as the Continuing Outcomes Relevant to Evista, or CORE, trial, 5,231 women were randomized to continue raloxifene or placebo.¹⁴ Over the 8 years of the combined trials, the incidence of invasive breast cancer was reduced by 66% in the raloxifene group (RR, 0.34; 95% CI, 0.22–0.50). The 8-year data are extremely clinically relevant, in that raloxifene has no time limit, whereas tamoxifen is usually prescribed for no longer than 5 years.

Raloxifene is not approved for use in premenopausal women. SERM compounds, which are structurally similar to clomiphene citrate, seem to have different effects in premenopausal and postmenopausal women, as evidenced by tamoxifen’s differing effects by age in the BCPT.

Other investigations of raloxifene confirm its value in high-risk women

To compare the clinical safety and efficacy of tamoxifen and raloxifene in reducing the risk of breast cancer among healthy women, the Study of Tamoxifen and Raloxifene (STAR) was initiated in 1999.¹⁵ In that trial, 19,747 postmenopausal women older than 35 years were blindly assigned to raloxifene 60 mg or tamoxifen 20 mg daily.

Baseline characteristics of subjects in STAR are summarized in TABLE 2 . Mean age was 58.5 years. All women had a 5-year risk of developing breast cancer that exceeded 1.66%, according to the Gail model. The average Gail score was 4.03% (standard deviation, ±2.17%). Because it would have been unethical to subject high-risk women to a placebo group in light of the findings of the BCPT, there was no placebo control.

TABLE 2

Baseline characteristics of women
in the Study of Tamoxifen and Raloxifene (STAR) trial

Here are noteworthy findings of the STAR trial:

• 163 cases of invasive breast cancer occurred in the tamoxifen group, compared with 168 among women taking raloxifene (RR, 1.02; 95% CI, 0.82–1.28).
• 36 cases of uterine cancer occurred in the tamoxifen group, compared with 23 among women taking raloxifene (RR, 0.62; 95% CI, 0.35–1.08). Earlier studies had shown a marked difference in the rate of uterine cancer between these agents. Although the difference here is not statistically significant, uterine cancer was not an endpoint of the study; nor was the study powered to explore this difference.
• The number of hysterectomies among women who were diagnosed with endometrial hyperplasia with or without atypia was, proportionally, significantly higher among women taking tamoxifen ( TABLE 3 ).
• No difference between groups was found for other invasive cancers, ischemic heart events, or stroke.
• Thromboembolic events occurred less frequently in the raloxifene group (RR, 0.70; 95% CI, 0.54–0.91). However, both raloxifene and tamoxifen have consistently been associated with a twofold to threefold increase in the risk of thromboembolic events, compared with placebo.
• Vasomotor symptoms and leg cramps increased in frequency and severity among women in both groups of the trial. These symptoms appear to be less common and less severe among women who are older and more remote from the onset of menopause.

TABLE 3

Relative risk of hysterectomy and uterine hyperplasia during STAR

What is raloxifene’s effect on the heart?

The Raloxifene Use for The Heart (RUTH) trial explored the primary endpoints of coronary artery disease (CAD) and breast cancer in more than 10,000 women who had CAD or multiple risk factors for it.¹⁶ This study began prior to the Women’s Health Initiative, at a time when hormone replacement therapy was widely believed to reduce CAD.

In the double-blinded, randomized, placebo-controlled RUTH trial, raloxifene had no significant effect on primary coronary events (533 vs 553; hazard ratio [HR], 0.95; 95% CI, 0.84–1.07). Even in this population, however, there was a 44% reduction in invasive breast cancer (40 vs 70 events; HR, 0.56; 95% CI, 0.38–0.83).

Based on these results, the FDA approved raloxifene for the “reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer,” as well as for the “reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” ( FIGURE ).

FIGURE How raloxifene reduced invasive breast cancer in three trials

Raloxifene significantly reduced the risk of cancer, compared with placebo, in the Raloxifene Use for The Heart (RUTH), Multiple Outcomes of Raloxifene Evaluation (MORE), and Continuing Outcomes Relevant to Evista (CORE) trials.

CASE 2 RESOLVED

S. T. begins taking raloxifene 60 mg daily to lower her risk of invasive breast cancer. Although she temporarily experienced hot flashes after initiating the drug, they are only mildly bothersome, and she continues raloxifene therapy. She says she is grateful that there is an agent that can help her reduce the likelihood that she will develop breast cancer, and protection of her BMD is an added benefit.

CASE 3: At risk for both breast cancer and bone fracture

A. N., 63, is a nulliparous Caucasian woman who weighs 134 lb and stands 5 ft 4 in tall. She reached menarche when she was 12 years old and entered menopause at 49.

Although A. N. has never had a breast abnormality, her 59-year-old sister was just given a diagnosis of breast cancer. Her Gail score reveals that she has a 3.1% risk of developing breast cancer over the next 5 years.

In addition to her concerns about breast cancer, A. N. is worried about hip fracture—because her mother suffered one after menopause and because her T-score is –1.9 at the hip and –2.1 at the spine. A. N. has used steroids off and on for much of her life for asthma. Her FRAX score indicates that she has a 2.8% risk of hip fracture and a 25% risk of major osteoporotic fracture over the next 10 years.

What do you offer her?

Because of new FRAX criteria, this osteopenic woman is now a candidate for medication to reduce her risk of major osteoporotic fracture, and raloxifene is a good option. Her Gail score of 3.1% also makes her a good candidate for breast cancer risk reduction with raloxifene.

CASE 3 RESOLVED

Because A. N. needs an agent that benefits both breast and bone, you prescribe raloxifene. The drug should significantly reduce her risk of both invasive breast cancer and bone fracture, without increasing her risk of endometrial hyperplasia and cancer, both of which are associated with tamoxifen in her age group.

Aromatase inhibitors

A fairly new class of drugs being explored for their ability to reduce the risk of breast cancer is aromatase inhibitors. Substantial evidence suggests that estrogens facilitate the development of breast cancer in animals and in women, although the precise mechanism remains unknown.¹⁷ The most commonly held theory is that estrogen stimulates proliferation of breast cells and thereby increases the risk of genetic mutation that could lead to cancer.

Aromatase inhibitors block peripheral conversion of androstenedione to estrogens. In premenopausal women, the primary site of this action is in the ovary. In postmenopausal women, this conversion occurs primarily in extraovarian sites, including the adrenal glands, adipose tissue, liver, muscle, and skin.

Aromatase inhibitors may be more effective than SERMs in preventing breast cancer because of their dual role: blocking both the initiation and promotion of breast cancer.¹⁸ These agents reduce levels of the genotoxic metabolites of estradiol by lowering estradiol concentration in tissue. At the same time, aromatase inhibitors also block tumor promotion by lowering tissue levels of estrogen and preventing cell proliferation.

The main drawback of these agents—besides the fact that they are not FDA-approved for reducing risk—is their antiestrogenic effect on bone and lipid metabolism. They also induce vasomotor symptoms.

Studies of third-generation aromatase inhibitors in the prevention of breast cancer are under way in high-risk women. These agents include anastrozole, exemestane, and letrozole.

Ovarian cancer is relatively rare, but late diagnosis leads to a higher death rate than the death rate observed with other gynecologic malignancies. Detection at an early stage (I or II) is associated with higher survival than detection at a later stage (III or IV).

Earlier studies have suggested that ovarian cancer screening with the serum biomarker CA 125 and transvaginal ultrasonography (TVS) may help the clinician diagnose ovarian cancer at an earlier stage.

British study finds screening to be effective

In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, postmenopausal women 50 to 74 years old were randomized to one of the following:

• no screening (n=101,359)
• annual assessment of CA 125 using a proprietary risk-of-cancer algorithm, with TVS as a second-line test (multimodal screening, or MMS) (n=50,078)
• annual TVS in a 2:1:1 ratio (n=48,230). (A scan was considered abnormal when one or both ovaries had complex morphology or a simple cyst exceeded 60 cm³ in size.)

The mean age at screening was 60.6 years, and 96.5% of participants were white.

Women who underwent MMS were triaged according to their estimated risk of developing ovarian cancer, based on the CA 125 level and age-specific risk estimates. Women in the group with the lowest risk of ovarian cancer continued annual assessment of CA 125, whereas those at highest risk underwent repeat measurement of CA 125, followed by TVS if the repeat assay suggested elevated risk. If TVS findings were also abnormal, the patient underwent clinical evaluation.

In the MMS and TVS groups, 8.7% and 12.0% of subjects, respectively, underwent clinical assessment, and surgery was performed in 0.2% and 1.8%, respectively. A primary ovarian or tubal cancer was diagnosed in 42 and 45 women in the MMS and TVS groups, respectively. In addition, 8 (MMS) and 20 (TVS) borderline malignancies were identified.

Overall, 48.3% of invasive cancers were diagnosed during stage I or II, with no difference in the distribution of stages between MMS and TVS groups. The positive predictive value (PPV) of MMS and TVS for primary invasive epithelial and tubal cancers was 35.1% and 2.8%, respectively. The ratio of surgery to case of invasive ovarian cancer was 2.9:1 (MMS) and 35:1 (TVS).

In the US study, women underwent both CA 125 assessment and TVS

The US study involved four annual rounds of screening in women 55 to 74 years old, who underwent both CA 125 measurement and TVS imaging in each round. A CA 125 level of 35 U/mL or above, or ovarian volume greater than 10 cm³ (or detection of an ovarian cyst with complex morphology) was considered abnormal.

Of 34,621 women randomized to screening, 30,630 underwent at least one screen during the four rounds. Almost two thirds of participants were 55 to 64 years old, and almost 89% were non-Hispanic white.

The percentage of women who had at least one positive screen decreased over the four rounds of screening, from 5.8% in year 1 to 4.9%, 4.6%, and 4.5% in years 2 through 4, respectively. In each round of screening, TVS was more likely to be positive than was CA 125 measurement (e.g., 4.6% vs 1.4% in the first round).

Of the 28,746 women who underwent the initial (prevalence) screen, 1,675 (5.8%) had positive findings, 566 (1.97% of those who were screened) underwent surgery, and 27 neoplasms were detected (0.06% of those who were screened), including 18 ovarian or primary peritoneal invasive cancers. Nine borderline tumors were also identified.

The PPV of a positive screen in the first round was 1.1%. Of the 18 invasive cancers identified in this round, 16.7% were diagnosed during stage I or II, and 83.4% were identified during stage III or IV. The ratio of surgery to cases of invasive ovarian cancer was 31.4:1.

Why did the trials have different findings?

The findings of the UK study suggest that an MMS strategy of CA 125 assessment, followed selectively by TVS, can detect early-stage ovarian cancer with an acceptable PPV and ratio of surgery to case of invasive cancer.

In contrast, the US findings are discouraging because of the low PPV, the large percentage of malignancies detected at an advanced stage, and the high ratio of surgery to cases of invasive cancer.

Although the studies had different primary outcomes—ovarian and tubal cancers in the UK and ovarian and primary peritoneal cancers in the US—a majority of invasive malignancies detected in both studies were ovarian.

In the US study, the poor performance of screening may be due, in part, to universal rather than selective use of TVS; that modality generates substantially more false positives than does CA 125. The US study also defined an ovarian abnormality more broadly (volume greater than 10 cm³) than the British study did (volume greater than 60 cm³), which may have lowered the PPV in the US trial.

As investigators in the UK continue to follow participants and report their findings, we will learn more about the value of MMS, including its impact on cancer mortality, possibly as soon as 2014.

Ovarian cancer is relatively rare, but late diagnosis leads to a higher death rate than the death rate observed with other gynecologic malignancies. Detection at an early stage (I or II) is associated with higher survival than detection at a later stage (III or IV).

Earlier studies have suggested that ovarian cancer screening with the serum biomarker CA 125 and transvaginal ultrasonography (TVS) may help the clinician diagnose ovarian cancer at an earlier stage.

British study finds screening to be effective

In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, postmenopausal women 50 to 74 years old were randomized to one of the following:

• no screening (n=101,359)
• annual assessment of CA 125 using a proprietary risk-of-cancer algorithm, with TVS as a second-line test (multimodal screening, or MMS) (n=50,078)
• annual TVS in a 2:1:1 ratio (n=48,230). (A scan was considered abnormal when one or both ovaries had complex morphology or a simple cyst exceeded 60 cm³ in size.)

The mean age at screening was 60.6 years, and 96.5% of participants were white.

Women who underwent MMS were triaged according to their estimated risk of developing ovarian cancer, based on the CA 125 level and age-specific risk estimates. Women in the group with the lowest risk of ovarian cancer continued annual assessment of CA 125, whereas those at highest risk underwent repeat measurement of CA 125, followed by TVS if the repeat assay suggested elevated risk. If TVS findings were also abnormal, the patient underwent clinical evaluation.

In the MMS and TVS groups, 8.7% and 12.0% of subjects, respectively, underwent clinical assessment, and surgery was performed in 0.2% and 1.8%, respectively. A primary ovarian or tubal cancer was diagnosed in 42 and 45 women in the MMS and TVS groups, respectively. In addition, 8 (MMS) and 20 (TVS) borderline malignancies were identified.

Overall, 48.3% of invasive cancers were diagnosed during stage I or II, with no difference in the distribution of stages between MMS and TVS groups. The positive predictive value (PPV) of MMS and TVS for primary invasive epithelial and tubal cancers was 35.1% and 2.8%, respectively. The ratio of surgery to case of invasive ovarian cancer was 2.9:1 (MMS) and 35:1 (TVS).

In the US study, women underwent both CA 125 assessment and TVS

The US study involved four annual rounds of screening in women 55 to 74 years old, who underwent both CA 125 measurement and TVS imaging in each round. A CA 125 level of 35 U/mL or above, or ovarian volume greater than 10 cm³ (or detection of an ovarian cyst with complex morphology) was considered abnormal.

Of 34,621 women randomized to screening, 30,630 underwent at least one screen during the four rounds. Almost two thirds of participants were 55 to 64 years old, and almost 89% were non-Hispanic white.

The percentage of women who had at least one positive screen decreased over the four rounds of screening, from 5.8% in year 1 to 4.9%, 4.6%, and 4.5% in years 2 through 4, respectively. In each round of screening, TVS was more likely to be positive than was CA 125 measurement (e.g., 4.6% vs 1.4% in the first round).

Of the 28,746 women who underwent the initial (prevalence) screen, 1,675 (5.8%) had positive findings, 566 (1.97% of those who were screened) underwent surgery, and 27 neoplasms were detected (0.06% of those who were screened), including 18 ovarian or primary peritoneal invasive cancers. Nine borderline tumors were also identified.

The PPV of a positive screen in the first round was 1.1%. Of the 18 invasive cancers identified in this round, 16.7% were diagnosed during stage I or II, and 83.4% were identified during stage III or IV. The ratio of surgery to cases of invasive ovarian cancer was 31.4:1.

Why did the trials have different findings?

The findings of the UK study suggest that an MMS strategy of CA 125 assessment, followed selectively by TVS, can detect early-stage ovarian cancer with an acceptable PPV and ratio of surgery to case of invasive cancer.

In contrast, the US findings are discouraging because of the low PPV, the large percentage of malignancies detected at an advanced stage, and the high ratio of surgery to cases of invasive cancer.

Although the studies had different primary outcomes—ovarian and tubal cancers in the UK and ovarian and primary peritoneal cancers in the US—a majority of invasive malignancies detected in both studies were ovarian.

In the US study, the poor performance of screening may be due, in part, to universal rather than selective use of TVS; that modality generates substantially more false positives than does CA 125. The US study also defined an ovarian abnormality more broadly (volume greater than 10 cm³) than the British study did (volume greater than 60 cm³), which may have lowered the PPV in the US trial.

As investigators in the UK continue to follow participants and report their findings, we will learn more about the value of MMS, including its impact on cancer mortality, possibly as soon as 2014.

Ovarian cancer is relatively rare, but late diagnosis leads to a higher death rate than the death rate observed with other gynecologic malignancies. Detection at an early stage (I or II) is associated with higher survival than detection at a later stage (III or IV).

Earlier studies have suggested that ovarian cancer screening with the serum biomarker CA 125 and transvaginal ultrasonography (TVS) may help the clinician diagnose ovarian cancer at an earlier stage.

British study finds screening to be effective

In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, postmenopausal women 50 to 74 years old were randomized to one of the following:

• no screening (n=101,359)
• annual assessment of CA 125 using a proprietary risk-of-cancer algorithm, with TVS as a second-line test (multimodal screening, or MMS) (n=50,078)
• annual TVS in a 2:1:1 ratio (n=48,230). (A scan was considered abnormal when one or both ovaries had complex morphology or a simple cyst exceeded 60 cm³ in size.)

The mean age at screening was 60.6 years, and 96.5% of participants were white.

Women who underwent MMS were triaged according to their estimated risk of developing ovarian cancer, based on the CA 125 level and age-specific risk estimates. Women in the group with the lowest risk of ovarian cancer continued annual assessment of CA 125, whereas those at highest risk underwent repeat measurement of CA 125, followed by TVS if the repeat assay suggested elevated risk. If TVS findings were also abnormal, the patient underwent clinical evaluation.

In the MMS and TVS groups, 8.7% and 12.0% of subjects, respectively, underwent clinical assessment, and surgery was performed in 0.2% and 1.8%, respectively. A primary ovarian or tubal cancer was diagnosed in 42 and 45 women in the MMS and TVS groups, respectively. In addition, 8 (MMS) and 20 (TVS) borderline malignancies were identified.

Overall, 48.3% of invasive cancers were diagnosed during stage I or II, with no difference in the distribution of stages between MMS and TVS groups. The positive predictive value (PPV) of MMS and TVS for primary invasive epithelial and tubal cancers was 35.1% and 2.8%, respectively. The ratio of surgery to case of invasive ovarian cancer was 2.9:1 (MMS) and 35:1 (TVS).

In the US study, women underwent both CA 125 assessment and TVS

The US study involved four annual rounds of screening in women 55 to 74 years old, who underwent both CA 125 measurement and TVS imaging in each round. A CA 125 level of 35 U/mL or above, or ovarian volume greater than 10 cm³ (or detection of an ovarian cyst with complex morphology) was considered abnormal.

Of 34,621 women randomized to screening, 30,630 underwent at least one screen during the four rounds. Almost two thirds of participants were 55 to 64 years old, and almost 89% were non-Hispanic white.

The percentage of women who had at least one positive screen decreased over the four rounds of screening, from 5.8% in year 1 to 4.9%, 4.6%, and 4.5% in years 2 through 4, respectively. In each round of screening, TVS was more likely to be positive than was CA 125 measurement (e.g., 4.6% vs 1.4% in the first round).

Of the 28,746 women who underwent the initial (prevalence) screen, 1,675 (5.8%) had positive findings, 566 (1.97% of those who were screened) underwent surgery, and 27 neoplasms were detected (0.06% of those who were screened), including 18 ovarian or primary peritoneal invasive cancers. Nine borderline tumors were also identified.

The PPV of a positive screen in the first round was 1.1%. Of the 18 invasive cancers identified in this round, 16.7% were diagnosed during stage I or II, and 83.4% were identified during stage III or IV. The ratio of surgery to cases of invasive ovarian cancer was 31.4:1.

Why did the trials have different findings?

The findings of the UK study suggest that an MMS strategy of CA 125 assessment, followed selectively by TVS, can detect early-stage ovarian cancer with an acceptable PPV and ratio of surgery to case of invasive cancer.

In contrast, the US findings are discouraging because of the low PPV, the large percentage of malignancies detected at an advanced stage, and the high ratio of surgery to cases of invasive cancer.

Although the studies had different primary outcomes—ovarian and tubal cancers in the UK and ovarian and primary peritoneal cancers in the US—a majority of invasive malignancies detected in both studies were ovarian.

In the US study, the poor performance of screening may be due, in part, to universal rather than selective use of TVS; that modality generates substantially more false positives than does CA 125. The US study also defined an ovarian abnormality more broadly (volume greater than 10 cm³) than the British study did (volume greater than 60 cm³), which may have lowered the PPV in the US trial.

As investigators in the UK continue to follow participants and report their findings, we will learn more about the value of MMS, including its impact on cancer mortality, possibly as soon as 2014.

Baby Boomers have transformed attitudes toward many aspects of aging. Menopause is no exception. Once a taboo topic, menopause is now openly discussed among women who seek information about vasomotor symptoms, hormones and their alternatives, and ways to maintain health as they move past midlife. ObGyns are treating more and more of these women, and fielding their many questions.

In this Update, I examine recent data on three important aspects of menopause:

• how to reduce the risk of cardiovascular disease among women who enter menopause surgically, through oophorectomy
• what to offer women who ask for nonhormonal relief from vasomotor symptoms
• a new drug on the horizon to combat osteoporosis.

Bilateral oophorectomy raises young women’s risk of cardiovascular death

Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. 2009;16:15–23.

Parker WH, Manson JE. Oophorectomy and cardiovascular mortality: is there a link? Menopause. 2009;16:1–2.

Cardiovascular mortality does not increase among women who undergo unilateral oophorectomy, but it does rise among women who undergo bilateral oophorectomy before 45 years of age. However, among women who initiate estrogen therapy at the time of bilateral oophorectomy and continue that therapy through at least 45 years of age, no excess cardiovascular mortality occurs.

Those are the findings of a unique retrospective cohort study performed by investigators from the Mayo Clinic. In the study, investigators reviewed the death certificates of more than 2,300 women who underwent unilateral or bilateral oophorectomy for benign disease before menopause in Olmstead County, Minnesota, from 1950 to 1987. They also followed a similar number of age-matched women for several decades.

These results support the findings of other studies that have observed that menopausal hormone therapy is associated with a lower incidence of cardiovascular death in “young” menopausal women, including those in their 50s or within one decade of the onset of menopause.^1,2

More than 500,000 women undergo bilateral oophorectomy each year in the United States, usually in association with hysterectomy for benign disease.

Induced menopause merits special attention

Spontaneous menopause is physiologic. In contrast, induced menopause (whether associated with surgery, radiation therapy, or chemotherapy) and premature ovarian failure are pathologic conditions.³ Unless they are managed appropriately, induced menopause and premature ovarian failure raise the risk of cardiovascular disease.

Since the initial findings of the Women’s Health Initiative trial of estrogen–progestin therapy were published in 2002, many women and clinicians have become wary about the use of hormone therapy, even among young women who have no ovarian function and who lack a contraindication to hormone therapy.⁴ Unless hormonal management is contraindicated, it is recommended in this setting.

In addition, Parker and Manson recommend that gynecologic surgeons who routinely perform bilateral oophorectomy at the time of hysterectomy for benign disease in premenopausal women who do not have an elevated risk of ovarian cancer should consider updating their therapeutic recommendations and, whenever possible, preserving the ovaries.

Interest in nonhormonal therapies for hot flashes remains high

Bair YA, Gold EB, Zhang G, et al. Use of complementary and alternative medicine during the menopausal transition: longitudinal results from the Study of Women’s Health Across the Nation. Menopause. 2008;15:32–43.

Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized trial. Menopause. 2008;15:310–318.

More than three quarters of women use some type of complementary and alternative medicine (CAM) during the menopausal transition. So found a survey conducted as part of the Study of Women’s Health Across the Nation (SWAN), which involved more than 2,000 premenopausal and perimenopausal women.

More than one third of all US women use one or more forms of CAM, spending more than $600 million a year.

In the SWAN survey, Japanese and white women were significantly more likely to report use of CAM than were Chinese, African-American, and Hispanic women during menopause.

Some women use both CAM and hormones

A notable finding of this report from SWAN is that concomitant use of menopausal hormone therapy and CAM is common among symptomatic women, even though herbal therapies have not been proved to be more effective than placebo in the treatment of vasomotor symptoms.⁵

Given the high prevalence of use of CAM, ObGyns should recognize that symptomatic patients especially bothered by vasomotor symptoms may seek relief with both CAM and a prescription medication. For this reason, it is wise to ask perimenopausal and postmenopausal women to list all the remedies they use—both prescription and over the counter.

Gabapentin eases symptoms in some women

Along with the antidepressants paroxetine and venlafaxine, gabapentin is the most widely studied prescription agent used in the nonhormonal treatment of menopausal vasomotor symptoms.

Canadian investigators performed a double-blind, placebo-controlled trial involving 197 symptomatic, spontaneously menopausal women (age range: 45 to 65 years). Participants were randomized to gabapentin (300 mg) or placebo, given three times daily for 4 weeks.

Ten of the 99 women who were randomized to gabapentin and six of the 98 women who were randomized to placebo dropped out of the study because of adverse effects. Hot-flash scores decreased by 51% among women taking gabapentin and by 26% among women in the placebo arm (p<.001). Women who used gabapentin were significantly more likely to report dizziness, drowsiness, and unsteadiness than those who received placebo.

Despite its proven efficacy, gabapentin does not appear to equal estrogen in its ability to alleviate vasomotor symptoms. Further, gabapentin’s side-effect profile and the need for thrice-daily administration also limit its appeal. Nevertheless, symptomatic women who are interested in nonhormonal treatment may wish to consider this option.

Anti-osteoporosis arsenal may gain a new weapon

Cummings S, McClung M, Christiansen C, et al. A phase III study of the effects of denosumab on vertebral, nonvertebral, and hip fracture in women with osteoporosis: results from the FREEDOM Trial. Paper presented at: Annual Meeting of the American Society for Bone and Mineral Research; September 16, 2008; Montreal, Canada.

Miller PD, Bolognese MA, Lewiecki EM, et al; AMG Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized, blinded phase 2 clinical trial. Bone. 2008;43:222–229.

In a 3-year study in which more than 7,800 women 60 to 90 years old were randomized to denosumab (60 mg) or placebo, denosumab reduced the risk of vertebral fracture by 68% and the risk of hip fracture by 40%.

FIGURE A new agent to inhibit bone resorption

RankL is a protein that controls osteoclast maturation, activity, and survival. Denosumab mimics the endogenous decoy receptor OPG to inhibit RankL and reduce osteoclast proliferation, differentiation, and function. Denosumab is a monoclonal antibody to RankL, a mediator of osteoclast function ( FIGURE ). In contrast to alendronate, which enhances trabecular bone density (e.g., that found in the spine), denosumab increases cortical (as in long bones) as well as trabecular bone density.⁶ If the agent obtains approval by the US Food and Drug Administration, it will be an important new approach to the treatment of osteoporosis in menopausal women.⁷

The drug is administered every 6 months by subcutaneous injection.

Like estrogen, denosumab has rapidly reversible effects

The trial by Miller and associates found that the effects of denosumab are rapidly reversible after discontinuation of therapy, in contrast to alendronate. As Goldstein noted in “Update on Osteoporosis” in the November 2008 issue of OBG Management, clinicians are still exploring the relationships between alendronate and osteonecrosis of the jaw and proximal femoral-shaft fracture.⁷ Only further research and surveillance will clarify the clinical pros and cons of denosumab’s swift reversibility.

Baby Boomers have transformed attitudes toward many aspects of aging. Menopause is no exception. Once a taboo topic, menopause is now openly discussed among women who seek information about vasomotor symptoms, hormones and their alternatives, and ways to maintain health as they move past midlife. ObGyns are treating more and more of these women, and fielding their many questions.

In this Update, I examine recent data on three important aspects of menopause:

• how to reduce the risk of cardiovascular disease among women who enter menopause surgically, through oophorectomy
• what to offer women who ask for nonhormonal relief from vasomotor symptoms
• a new drug on the horizon to combat osteoporosis.

Bilateral oophorectomy raises young women’s risk of cardiovascular death

Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. 2009;16:15–23.

Parker WH, Manson JE. Oophorectomy and cardiovascular mortality: is there a link? Menopause. 2009;16:1–2.

Cardiovascular mortality does not increase among women who undergo unilateral oophorectomy, but it does rise among women who undergo bilateral oophorectomy before 45 years of age. However, among women who initiate estrogen therapy at the time of bilateral oophorectomy and continue that therapy through at least 45 years of age, no excess cardiovascular mortality occurs.

Those are the findings of a unique retrospective cohort study performed by investigators from the Mayo Clinic. In the study, investigators reviewed the death certificates of more than 2,300 women who underwent unilateral or bilateral oophorectomy for benign disease before menopause in Olmstead County, Minnesota, from 1950 to 1987. They also followed a similar number of age-matched women for several decades.

These results support the findings of other studies that have observed that menopausal hormone therapy is associated with a lower incidence of cardiovascular death in “young” menopausal women, including those in their 50s or within one decade of the onset of menopause.^1,2

More than 500,000 women undergo bilateral oophorectomy each year in the United States, usually in association with hysterectomy for benign disease.

Induced menopause merits special attention

Spontaneous menopause is physiologic. In contrast, induced menopause (whether associated with surgery, radiation therapy, or chemotherapy) and premature ovarian failure are pathologic conditions.³ Unless they are managed appropriately, induced menopause and premature ovarian failure raise the risk of cardiovascular disease.

Since the initial findings of the Women’s Health Initiative trial of estrogen–progestin therapy were published in 2002, many women and clinicians have become wary about the use of hormone therapy, even among young women who have no ovarian function and who lack a contraindication to hormone therapy.⁴ Unless hormonal management is contraindicated, it is recommended in this setting.

In addition, Parker and Manson recommend that gynecologic surgeons who routinely perform bilateral oophorectomy at the time of hysterectomy for benign disease in premenopausal women who do not have an elevated risk of ovarian cancer should consider updating their therapeutic recommendations and, whenever possible, preserving the ovaries.

Interest in nonhormonal therapies for hot flashes remains high

Bair YA, Gold EB, Zhang G, et al. Use of complementary and alternative medicine during the menopausal transition: longitudinal results from the Study of Women’s Health Across the Nation. Menopause. 2008;15:32–43.

Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized trial. Menopause. 2008;15:310–318.

More than three quarters of women use some type of complementary and alternative medicine (CAM) during the menopausal transition. So found a survey conducted as part of the Study of Women’s Health Across the Nation (SWAN), which involved more than 2,000 premenopausal and perimenopausal women.

More than one third of all US women use one or more forms of CAM, spending more than $600 million a year.

In the SWAN survey, Japanese and white women were significantly more likely to report use of CAM than were Chinese, African-American, and Hispanic women during menopause.

Some women use both CAM and hormones

A notable finding of this report from SWAN is that concomitant use of menopausal hormone therapy and CAM is common among symptomatic women, even though herbal therapies have not been proved to be more effective than placebo in the treatment of vasomotor symptoms.⁵

Given the high prevalence of use of CAM, ObGyns should recognize that symptomatic patients especially bothered by vasomotor symptoms may seek relief with both CAM and a prescription medication. For this reason, it is wise to ask perimenopausal and postmenopausal women to list all the remedies they use—both prescription and over the counter.

Gabapentin eases symptoms in some women

Along with the antidepressants paroxetine and venlafaxine, gabapentin is the most widely studied prescription agent used in the nonhormonal treatment of menopausal vasomotor symptoms.

Canadian investigators performed a double-blind, placebo-controlled trial involving 197 symptomatic, spontaneously menopausal women (age range: 45 to 65 years). Participants were randomized to gabapentin (300 mg) or placebo, given three times daily for 4 weeks.

Ten of the 99 women who were randomized to gabapentin and six of the 98 women who were randomized to placebo dropped out of the study because of adverse effects. Hot-flash scores decreased by 51% among women taking gabapentin and by 26% among women in the placebo arm (p<.001). Women who used gabapentin were significantly more likely to report dizziness, drowsiness, and unsteadiness than those who received placebo.

Despite its proven efficacy, gabapentin does not appear to equal estrogen in its ability to alleviate vasomotor symptoms. Further, gabapentin’s side-effect profile and the need for thrice-daily administration also limit its appeal. Nevertheless, symptomatic women who are interested in nonhormonal treatment may wish to consider this option.

Anti-osteoporosis arsenal may gain a new weapon

Cummings S, McClung M, Christiansen C, et al. A phase III study of the effects of denosumab on vertebral, nonvertebral, and hip fracture in women with osteoporosis: results from the FREEDOM Trial. Paper presented at: Annual Meeting of the American Society for Bone and Mineral Research; September 16, 2008; Montreal, Canada.

Miller PD, Bolognese MA, Lewiecki EM, et al; AMG Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized, blinded phase 2 clinical trial. Bone. 2008;43:222–229.

In a 3-year study in which more than 7,800 women 60 to 90 years old were randomized to denosumab (60 mg) or placebo, denosumab reduced the risk of vertebral fracture by 68% and the risk of hip fracture by 40%.

FIGURE A new agent to inhibit bone resorption

RankL is a protein that controls osteoclast maturation, activity, and survival. Denosumab mimics the endogenous decoy receptor OPG to inhibit RankL and reduce osteoclast proliferation, differentiation, and function. Denosumab is a monoclonal antibody to RankL, a mediator of osteoclast function ( FIGURE ). In contrast to alendronate, which enhances trabecular bone density (e.g., that found in the spine), denosumab increases cortical (as in long bones) as well as trabecular bone density.⁶ If the agent obtains approval by the US Food and Drug Administration, it will be an important new approach to the treatment of osteoporosis in menopausal women.⁷

The drug is administered every 6 months by subcutaneous injection.

Like estrogen, denosumab has rapidly reversible effects

The trial by Miller and associates found that the effects of denosumab are rapidly reversible after discontinuation of therapy, in contrast to alendronate. As Goldstein noted in “Update on Osteoporosis” in the November 2008 issue of OBG Management, clinicians are still exploring the relationships between alendronate and osteonecrosis of the jaw and proximal femoral-shaft fracture.⁷ Only further research and surveillance will clarify the clinical pros and cons of denosumab’s swift reversibility.

Baby Boomers have transformed attitudes toward many aspects of aging. Menopause is no exception. Once a taboo topic, menopause is now openly discussed among women who seek information about vasomotor symptoms, hormones and their alternatives, and ways to maintain health as they move past midlife. ObGyns are treating more and more of these women, and fielding their many questions.

In this Update, I examine recent data on three important aspects of menopause:

• how to reduce the risk of cardiovascular disease among women who enter menopause surgically, through oophorectomy
• what to offer women who ask for nonhormonal relief from vasomotor symptoms
• a new drug on the horizon to combat osteoporosis.

Bilateral oophorectomy raises young women’s risk of cardiovascular death

Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. 2009;16:15–23.

Parker WH, Manson JE. Oophorectomy and cardiovascular mortality: is there a link? Menopause. 2009;16:1–2.

Cardiovascular mortality does not increase among women who undergo unilateral oophorectomy, but it does rise among women who undergo bilateral oophorectomy before 45 years of age. However, among women who initiate estrogen therapy at the time of bilateral oophorectomy and continue that therapy through at least 45 years of age, no excess cardiovascular mortality occurs.

Those are the findings of a unique retrospective cohort study performed by investigators from the Mayo Clinic. In the study, investigators reviewed the death certificates of more than 2,300 women who underwent unilateral or bilateral oophorectomy for benign disease before menopause in Olmstead County, Minnesota, from 1950 to 1987. They also followed a similar number of age-matched women for several decades.

These results support the findings of other studies that have observed that menopausal hormone therapy is associated with a lower incidence of cardiovascular death in “young” menopausal women, including those in their 50s or within one decade of the onset of menopause.^1,2

More than 500,000 women undergo bilateral oophorectomy each year in the United States, usually in association with hysterectomy for benign disease.

Induced menopause merits special attention

Spontaneous menopause is physiologic. In contrast, induced menopause (whether associated with surgery, radiation therapy, or chemotherapy) and premature ovarian failure are pathologic conditions.³ Unless they are managed appropriately, induced menopause and premature ovarian failure raise the risk of cardiovascular disease.

Since the initial findings of the Women’s Health Initiative trial of estrogen–progestin therapy were published in 2002, many women and clinicians have become wary about the use of hormone therapy, even among young women who have no ovarian function and who lack a contraindication to hormone therapy.⁴ Unless hormonal management is contraindicated, it is recommended in this setting.

In addition, Parker and Manson recommend that gynecologic surgeons who routinely perform bilateral oophorectomy at the time of hysterectomy for benign disease in premenopausal women who do not have an elevated risk of ovarian cancer should consider updating their therapeutic recommendations and, whenever possible, preserving the ovaries.

Interest in nonhormonal therapies for hot flashes remains high

Bair YA, Gold EB, Zhang G, et al. Use of complementary and alternative medicine during the menopausal transition: longitudinal results from the Study of Women’s Health Across the Nation. Menopause. 2008;15:32–43.

Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized trial. Menopause. 2008;15:310–318.

More than three quarters of women use some type of complementary and alternative medicine (CAM) during the menopausal transition. So found a survey conducted as part of the Study of Women’s Health Across the Nation (SWAN), which involved more than 2,000 premenopausal and perimenopausal women.

More than one third of all US women use one or more forms of CAM, spending more than $600 million a year.

In the SWAN survey, Japanese and white women were significantly more likely to report use of CAM than were Chinese, African-American, and Hispanic women during menopause.

Some women use both CAM and hormones

A notable finding of this report from SWAN is that concomitant use of menopausal hormone therapy and CAM is common among symptomatic women, even though herbal therapies have not been proved to be more effective than placebo in the treatment of vasomotor symptoms.⁵

Given the high prevalence of use of CAM, ObGyns should recognize that symptomatic patients especially bothered by vasomotor symptoms may seek relief with both CAM and a prescription medication. For this reason, it is wise to ask perimenopausal and postmenopausal women to list all the remedies they use—both prescription and over the counter.

Gabapentin eases symptoms in some women

Along with the antidepressants paroxetine and venlafaxine, gabapentin is the most widely studied prescription agent used in the nonhormonal treatment of menopausal vasomotor symptoms.

Canadian investigators performed a double-blind, placebo-controlled trial involving 197 symptomatic, spontaneously menopausal women (age range: 45 to 65 years). Participants were randomized to gabapentin (300 mg) or placebo, given three times daily for 4 weeks.

Ten of the 99 women who were randomized to gabapentin and six of the 98 women who were randomized to placebo dropped out of the study because of adverse effects. Hot-flash scores decreased by 51% among women taking gabapentin and by 26% among women in the placebo arm (p<.001). Women who used gabapentin were significantly more likely to report dizziness, drowsiness, and unsteadiness than those who received placebo.

Despite its proven efficacy, gabapentin does not appear to equal estrogen in its ability to alleviate vasomotor symptoms. Further, gabapentin’s side-effect profile and the need for thrice-daily administration also limit its appeal. Nevertheless, symptomatic women who are interested in nonhormonal treatment may wish to consider this option.

Anti-osteoporosis arsenal may gain a new weapon

Cummings S, McClung M, Christiansen C, et al. A phase III study of the effects of denosumab on vertebral, nonvertebral, and hip fracture in women with osteoporosis: results from the FREEDOM Trial. Paper presented at: Annual Meeting of the American Society for Bone and Mineral Research; September 16, 2008; Montreal, Canada.

Miller PD, Bolognese MA, Lewiecki EM, et al; AMG Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized, blinded phase 2 clinical trial. Bone. 2008;43:222–229.

In a 3-year study in which more than 7,800 women 60 to 90 years old were randomized to denosumab (60 mg) or placebo, denosumab reduced the risk of vertebral fracture by 68% and the risk of hip fracture by 40%.

FIGURE A new agent to inhibit bone resorption

RankL is a protein that controls osteoclast maturation, activity, and survival. Denosumab mimics the endogenous decoy receptor OPG to inhibit RankL and reduce osteoclast proliferation, differentiation, and function. Denosumab is a monoclonal antibody to RankL, a mediator of osteoclast function ( FIGURE ). In contrast to alendronate, which enhances trabecular bone density (e.g., that found in the spine), denosumab increases cortical (as in long bones) as well as trabecular bone density.⁶ If the agent obtains approval by the US Food and Drug Administration, it will be an important new approach to the treatment of osteoporosis in menopausal women.⁷

The drug is administered every 6 months by subcutaneous injection.

Like estrogen, denosumab has rapidly reversible effects

The trial by Miller and associates found that the effects of denosumab are rapidly reversible after discontinuation of therapy, in contrast to alendronate. As Goldstein noted in “Update on Osteoporosis” in the November 2008 issue of OBG Management, clinicians are still exploring the relationships between alendronate and osteonecrosis of the jaw and proximal femoral-shaft fracture.⁷ Only further research and surveillance will clarify the clinical pros and cons of denosumab’s swift reversibility.

SAN DIEGO — Women who reach menopause before the age of 42 years are twice as likely to suffer a stroke in later life as women who reach menopause after age 42, according to a new analysis of data from the Framingham Heart Study presented at the International Stroke Conference.

The study involved prospectively collected data from 1,430 women who were followed for an average of 22 years, said Lynda Lisabeth, Ph.D., of the University of Michigan, Ann Arbor. All participants were stroke-free at 60 years of age, experienced natural menopause, and had never taken estrogen before menopause. The use of self-reported data on the age of menopause was a limitation of the study, Dr. Lisabeth acknowledged.

In all, the women had 234 ischemic strokes at an average age of 80 years. The unadjusted rate of strokes was 23% among women who reached menopause before the age of 42 years, 16% among women who reached menopause between the ages of 42 and 54 years, and 11% among women who reached menopause at age 55 years or older.

After adjustment for age, systolic blood pressure, atrial fibrillation, diabetes, current smoking, cardiovascular disease, and estrogen use after menopause, the investigators determined that the age of menopause was an independent predictor of ischemic stroke.

Compared with women who reached menopause before age 42 years, women who reached menopause between ages 42 and 54 years were half as likely to experience a stroke, and those who reached menopause at age 55 or older were 69% less likely to experience a stroke.

In other words, women who reached menopause before age 42 years were 2.03-fold more likely to have a stroke than the other women. This difference was statistically significant.

The study showed that 4%–5% of strokes in women can be attributed to menopause before age 42, Dr. Lisabeth said.

About 1%–2% of women reach menopause at or before age 40 years, which is referred to as “premature ovarian failure.” The etiology of this condition remains unknown, but investigators are certain that it's different than natural menopause. About 3%–10% of women experience “early” menopause, defined as natural menopause before age 45 years.

Several possible mechanisms could account for the increased rate of stroke, Dr. Lisabeth said. Estrogen may play a role, since estrogen deficiency is thought to promote cardiovascular disease through functional or structural changes in arteries. Androgens and sex hormone-binding globulin are also risk factors for cardiovascular disease.

Additional studies with measures of endogenous hormones would be needed to unravel the relationship between the hormonal changes of menopause and ischemic stroke, she said.

The study was supported by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke. Dr. Lisabeth said that she had no conflicts of interest.

SAN DIEGO — Women who reach menopause before the age of 42 years are twice as likely to suffer a stroke in later life as women who reach menopause after age 42, according to a new analysis of data from the Framingham Heart Study presented at the International Stroke Conference.

The study involved prospectively collected data from 1,430 women who were followed for an average of 22 years, said Lynda Lisabeth, Ph.D., of the University of Michigan, Ann Arbor. All participants were stroke-free at 60 years of age, experienced natural menopause, and had never taken estrogen before menopause. The use of self-reported data on the age of menopause was a limitation of the study, Dr. Lisabeth acknowledged.

In all, the women had 234 ischemic strokes at an average age of 80 years. The unadjusted rate of strokes was 23% among women who reached menopause before the age of 42 years, 16% among women who reached menopause between the ages of 42 and 54 years, and 11% among women who reached menopause at age 55 years or older.

After adjustment for age, systolic blood pressure, atrial fibrillation, diabetes, current smoking, cardiovascular disease, and estrogen use after menopause, the investigators determined that the age of menopause was an independent predictor of ischemic stroke.

Compared with women who reached menopause before age 42 years, women who reached menopause between ages 42 and 54 years were half as likely to experience a stroke, and those who reached menopause at age 55 or older were 69% less likely to experience a stroke.

In other words, women who reached menopause before age 42 years were 2.03-fold more likely to have a stroke than the other women. This difference was statistically significant.

The study showed that 4%–5% of strokes in women can be attributed to menopause before age 42, Dr. Lisabeth said.

About 1%–2% of women reach menopause at or before age 40 years, which is referred to as “premature ovarian failure.” The etiology of this condition remains unknown, but investigators are certain that it's different than natural menopause. About 3%–10% of women experience “early” menopause, defined as natural menopause before age 45 years.

Several possible mechanisms could account for the increased rate of stroke, Dr. Lisabeth said. Estrogen may play a role, since estrogen deficiency is thought to promote cardiovascular disease through functional or structural changes in arteries. Androgens and sex hormone-binding globulin are also risk factors for cardiovascular disease.

Additional studies with measures of endogenous hormones would be needed to unravel the relationship between the hormonal changes of menopause and ischemic stroke, she said.

The study was supported by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke. Dr. Lisabeth said that she had no conflicts of interest.

SAN DIEGO — Women who reach menopause before the age of 42 years are twice as likely to suffer a stroke in later life as women who reach menopause after age 42, according to a new analysis of data from the Framingham Heart Study presented at the International Stroke Conference.

The study involved prospectively collected data from 1,430 women who were followed for an average of 22 years, said Lynda Lisabeth, Ph.D., of the University of Michigan, Ann Arbor. All participants were stroke-free at 60 years of age, experienced natural menopause, and had never taken estrogen before menopause. The use of self-reported data on the age of menopause was a limitation of the study, Dr. Lisabeth acknowledged.

In all, the women had 234 ischemic strokes at an average age of 80 years. The unadjusted rate of strokes was 23% among women who reached menopause before the age of 42 years, 16% among women who reached menopause between the ages of 42 and 54 years, and 11% among women who reached menopause at age 55 years or older.

After adjustment for age, systolic blood pressure, atrial fibrillation, diabetes, current smoking, cardiovascular disease, and estrogen use after menopause, the investigators determined that the age of menopause was an independent predictor of ischemic stroke.

Compared with women who reached menopause before age 42 years, women who reached menopause between ages 42 and 54 years were half as likely to experience a stroke, and those who reached menopause at age 55 or older were 69% less likely to experience a stroke.

In other words, women who reached menopause before age 42 years were 2.03-fold more likely to have a stroke than the other women. This difference was statistically significant.

The study showed that 4%–5% of strokes in women can be attributed to menopause before age 42, Dr. Lisabeth said.

About 1%–2% of women reach menopause at or before age 40 years, which is referred to as “premature ovarian failure.” The etiology of this condition remains unknown, but investigators are certain that it's different than natural menopause. About 3%–10% of women experience “early” menopause, defined as natural menopause before age 45 years.

Several possible mechanisms could account for the increased rate of stroke, Dr. Lisabeth said. Estrogen may play a role, since estrogen deficiency is thought to promote cardiovascular disease through functional or structural changes in arteries. Androgens and sex hormone-binding globulin are also risk factors for cardiovascular disease.

Additional studies with measures of endogenous hormones would be needed to unravel the relationship between the hormonal changes of menopause and ischemic stroke, she said.

The study was supported by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke. Dr. Lisabeth said that she had no conflicts of interest.