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What nonhormonal therapies are effective for postmenopausal vasomotor symptoms?
Regular exercise may reduce vasomotor symptoms of menopause (strength of recommendation [SOR]: C—single observational study).1
Soy products/isoflavones, either through diet or supplementation, may reduce the incidence of hot flushes (SOR: D—inconsistent results of randomized trials).2
Clonidine, as an oral or transdermal preparation, reduces hot flushes (SOR: A—randomized clinical trials),3 as does gabapentin (SOR: A— single randomized clinical trial).4
In cancer patients who have had surgical menopause, selective serotonin reuptake inhibitors5 and megestrol6 (Megase) have been effective in reducing hot flushes (SOR: A; B for extrapolation to the general population).
Other therapies—including Bellergal (a combination of belladonna, ergotamine, and phenobarbital), methyldopa, evening primrose oil, mai quan, flaxseed, ginseng, and topical wild yam extract—have not been effective.7 Black cohosh may be effective, but the evidence for this is of poor quality (SOR: C). (See Table.)
TABLE
Nonhormonal therapies for postmenopausal vasomotor symptoms
| Agent | Effective | SOR † | Comments |
|---|---|---|---|
| Soy/isoflavones | Maybe | D | Multiple RCTs with conflicting results, no formal meta-analysis. Does have a positive effect on lipid profile |
| Clonidine (Catapres) | Yes | A | Multiple small RCTs |
| Venlafaxine* (Effexor) | Yes | B | Single RCT |
| Fluoxetine* (Prozac) | Yes | B | Single RCT |
| Gabapentin (Neurontin) | Yes | A | Single RCT |
| Megestrol* (Megace) | Yes | B | Single RCT |
| Exercise | Maybe | C | Single observational study |
| Black cohosh | Maybe | C | German E commission recommenda tion positive in 1989, but only 1 of 7 trials cited had placebo control. Recent RCT showed no benefit |
| Other: Bellergal, methyldopa, evening of effect | No | C | All have been advocated but no positive trials for any evidence primrose oil, ginseng, wild yam extract, mai quan, flaxseed |
| *Trials conducted only with patients with breast cancer and interventional menopause, most of whom were on anti-estrogen therapy. | |||
| †See page 290 for a description of strength of recommendation. | |||
| SOR, strength of recommendation; RCT, randomized controlled trial | |||
Evidence summary
Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.
A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.
Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.
Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.4
Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.
Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.
Recommendations from others
The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”8
The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.9 The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.10
Laura B. Hansen, PharmD, BCPS
University of Colorado Health Sciences Center, Denver
Behavioral modifications may be the first approach to reduce the incidence of vasomotor symptoms in menopausal women. Recommendations include wearing several layers of breathable clothing; keeping a glass of cold water, ice pack, or small fan by the bedside and nearby at work; performing deep breathing relaxation techniques; and exercising routinely.
Effective nonhormonal treatments include phytoestrogens (2 years), black cohosh (6 months), clonidine, selective serotonin reuptake inhibitors, and venlafaxine. Overall, there are few well-designed clinical trials regarding the safety and effectiveness of botanical agents used for vasomotor symptoms. Since the Food and Drug Administration does not regulate the marketing and standardization of these products, patients should be advised to purchase products from reputable companies with internal standardization processes.
Additionally, patients should talk with their health care provider prior to initiating any alternative medication to avoid drug-disease and drug-drug interactions.
1. Ivarsson T, Spetz AC, Hammar M. Physical exercise and vasomotor symptoms in postmenopausal women. Maturitas 1998;29:139-146.
2. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236-242.
3. Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132:788-793.
4. Guttuso T, Kurlan R, McDermott MP, et al. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003;101:337-345.
5. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347-352.
6. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578-1583.
7. Taylor M. Alternative medicine and the perimenopause: an evidence-based review. Obstet Gynecol Clin North Am 2002;29:555-573.
8. Use of botanicals for management of menopausal symptoms. ACOG Pract Bull No. 28. Washington, DC: American College of Obstetricians and Gynecologists, 2001.
9. Clinical challenges of perimenopause: consensus opinions of the North American Menopause Society. Menopause 2000;7:5-13.
10. Phytoestrogens. Med Lett Drugs Ther 2000;1072:17-18.
Regular exercise may reduce vasomotor symptoms of menopause (strength of recommendation [SOR]: C—single observational study).1
Soy products/isoflavones, either through diet or supplementation, may reduce the incidence of hot flushes (SOR: D—inconsistent results of randomized trials).2
Clonidine, as an oral or transdermal preparation, reduces hot flushes (SOR: A—randomized clinical trials),3 as does gabapentin (SOR: A— single randomized clinical trial).4
In cancer patients who have had surgical menopause, selective serotonin reuptake inhibitors5 and megestrol6 (Megase) have been effective in reducing hot flushes (SOR: A; B for extrapolation to the general population).
Other therapies—including Bellergal (a combination of belladonna, ergotamine, and phenobarbital), methyldopa, evening primrose oil, mai quan, flaxseed, ginseng, and topical wild yam extract—have not been effective.7 Black cohosh may be effective, but the evidence for this is of poor quality (SOR: C). (See Table.)
TABLE
Nonhormonal therapies for postmenopausal vasomotor symptoms
| Agent | Effective | SOR † | Comments |
|---|---|---|---|
| Soy/isoflavones | Maybe | D | Multiple RCTs with conflicting results, no formal meta-analysis. Does have a positive effect on lipid profile |
| Clonidine (Catapres) | Yes | A | Multiple small RCTs |
| Venlafaxine* (Effexor) | Yes | B | Single RCT |
| Fluoxetine* (Prozac) | Yes | B | Single RCT |
| Gabapentin (Neurontin) | Yes | A | Single RCT |
| Megestrol* (Megace) | Yes | B | Single RCT |
| Exercise | Maybe | C | Single observational study |
| Black cohosh | Maybe | C | German E commission recommenda tion positive in 1989, but only 1 of 7 trials cited had placebo control. Recent RCT showed no benefit |
| Other: Bellergal, methyldopa, evening of effect | No | C | All have been advocated but no positive trials for any evidence primrose oil, ginseng, wild yam extract, mai quan, flaxseed |
| *Trials conducted only with patients with breast cancer and interventional menopause, most of whom were on anti-estrogen therapy. | |||
| †See page 290 for a description of strength of recommendation. | |||
| SOR, strength of recommendation; RCT, randomized controlled trial | |||
Evidence summary
Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.
A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.
Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.
Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.4
Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.
Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.
Recommendations from others
The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”8
The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.9 The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.10
Laura B. Hansen, PharmD, BCPS
University of Colorado Health Sciences Center, Denver
Behavioral modifications may be the first approach to reduce the incidence of vasomotor symptoms in menopausal women. Recommendations include wearing several layers of breathable clothing; keeping a glass of cold water, ice pack, or small fan by the bedside and nearby at work; performing deep breathing relaxation techniques; and exercising routinely.
Effective nonhormonal treatments include phytoestrogens (2 years), black cohosh (6 months), clonidine, selective serotonin reuptake inhibitors, and venlafaxine. Overall, there are few well-designed clinical trials regarding the safety and effectiveness of botanical agents used for vasomotor symptoms. Since the Food and Drug Administration does not regulate the marketing and standardization of these products, patients should be advised to purchase products from reputable companies with internal standardization processes.
Additionally, patients should talk with their health care provider prior to initiating any alternative medication to avoid drug-disease and drug-drug interactions.
Regular exercise may reduce vasomotor symptoms of menopause (strength of recommendation [SOR]: C—single observational study).1
Soy products/isoflavones, either through diet or supplementation, may reduce the incidence of hot flushes (SOR: D—inconsistent results of randomized trials).2
Clonidine, as an oral or transdermal preparation, reduces hot flushes (SOR: A—randomized clinical trials),3 as does gabapentin (SOR: A— single randomized clinical trial).4
In cancer patients who have had surgical menopause, selective serotonin reuptake inhibitors5 and megestrol6 (Megase) have been effective in reducing hot flushes (SOR: A; B for extrapolation to the general population).
Other therapies—including Bellergal (a combination of belladonna, ergotamine, and phenobarbital), methyldopa, evening primrose oil, mai quan, flaxseed, ginseng, and topical wild yam extract—have not been effective.7 Black cohosh may be effective, but the evidence for this is of poor quality (SOR: C). (See Table.)
TABLE
Nonhormonal therapies for postmenopausal vasomotor symptoms
| Agent | Effective | SOR † | Comments |
|---|---|---|---|
| Soy/isoflavones | Maybe | D | Multiple RCTs with conflicting results, no formal meta-analysis. Does have a positive effect on lipid profile |
| Clonidine (Catapres) | Yes | A | Multiple small RCTs |
| Venlafaxine* (Effexor) | Yes | B | Single RCT |
| Fluoxetine* (Prozac) | Yes | B | Single RCT |
| Gabapentin (Neurontin) | Yes | A | Single RCT |
| Megestrol* (Megace) | Yes | B | Single RCT |
| Exercise | Maybe | C | Single observational study |
| Black cohosh | Maybe | C | German E commission recommenda tion positive in 1989, but only 1 of 7 trials cited had placebo control. Recent RCT showed no benefit |
| Other: Bellergal, methyldopa, evening of effect | No | C | All have been advocated but no positive trials for any evidence primrose oil, ginseng, wild yam extract, mai quan, flaxseed |
| *Trials conducted only with patients with breast cancer and interventional menopause, most of whom were on anti-estrogen therapy. | |||
| †See page 290 for a description of strength of recommendation. | |||
| SOR, strength of recommendation; RCT, randomized controlled trial | |||
Evidence summary
Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.
A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.
Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.
Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.4
Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.
Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.
Recommendations from others
The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”8
The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.9 The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.10
Laura B. Hansen, PharmD, BCPS
University of Colorado Health Sciences Center, Denver
Behavioral modifications may be the first approach to reduce the incidence of vasomotor symptoms in menopausal women. Recommendations include wearing several layers of breathable clothing; keeping a glass of cold water, ice pack, or small fan by the bedside and nearby at work; performing deep breathing relaxation techniques; and exercising routinely.
Effective nonhormonal treatments include phytoestrogens (2 years), black cohosh (6 months), clonidine, selective serotonin reuptake inhibitors, and venlafaxine. Overall, there are few well-designed clinical trials regarding the safety and effectiveness of botanical agents used for vasomotor symptoms. Since the Food and Drug Administration does not regulate the marketing and standardization of these products, patients should be advised to purchase products from reputable companies with internal standardization processes.
Additionally, patients should talk with their health care provider prior to initiating any alternative medication to avoid drug-disease and drug-drug interactions.
1. Ivarsson T, Spetz AC, Hammar M. Physical exercise and vasomotor symptoms in postmenopausal women. Maturitas 1998;29:139-146.
2. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236-242.
3. Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132:788-793.
4. Guttuso T, Kurlan R, McDermott MP, et al. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003;101:337-345.
5. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347-352.
6. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578-1583.
7. Taylor M. Alternative medicine and the perimenopause: an evidence-based review. Obstet Gynecol Clin North Am 2002;29:555-573.
8. Use of botanicals for management of menopausal symptoms. ACOG Pract Bull No. 28. Washington, DC: American College of Obstetricians and Gynecologists, 2001.
9. Clinical challenges of perimenopause: consensus opinions of the North American Menopause Society. Menopause 2000;7:5-13.
10. Phytoestrogens. Med Lett Drugs Ther 2000;1072:17-18.
1. Ivarsson T, Spetz AC, Hammar M. Physical exercise and vasomotor symptoms in postmenopausal women. Maturitas 1998;29:139-146.
2. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236-242.
3. Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132:788-793.
4. Guttuso T, Kurlan R, McDermott MP, et al. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003;101:337-345.
5. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347-352.
6. Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578-1583.
7. Taylor M. Alternative medicine and the perimenopause: an evidence-based review. Obstet Gynecol Clin North Am 2002;29:555-573.
8. Use of botanicals for management of menopausal symptoms. ACOG Pract Bull No. 28. Washington, DC: American College of Obstetricians and Gynecologists, 2001.
9. Clinical challenges of perimenopause: consensus opinions of the North American Menopause Society. Menopause 2000;7:5-13.
10. Phytoestrogens. Med Lett Drugs Ther 2000;1072:17-18.
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