Menopause: The Journal of The North American Menopause Society Vol. 21, No. 6, pp. 551/552 DOI: 10.1097/gme.0000000000000250 * 2014 by The North American Menopause Society
EDITORIAL Hot flashes: is a hot flash just a hot flash?
W
hether called hot flushes, hot flashes, or vasomotor symptoms (VMS), they are often the first signVand considered a hallmarkVof menopause. Although they have been described since the 17th century, their pathophysiology is not really known. They most commonly occur on the face, neck, and upper body, and often end in drenching sweat. They vary in frequency from one per day to more than 30 per day, and their severity can vary from mild to severe. The early work of Kronenberg1 showed that, among untreated women, 80% of hot flashes will be over in 3 years and 90% of hot flashes will be over by 6 years, but that a few women can have them for 40 years or more. In more recent studies of women who have hot flashes, 25% reported that these symptoms remained for more than 5 years, and 10% reported that these symptoms remained for more than 10 years.2 Freedman3 contributed enormously to the understanding of hot flash mechanism by explaining that these hot flashes occur because of a decrease in the thermoneutral zone, leading to easy heating and quick cooling with minimal temperature changes. He postulated that the reduction in this zone occurs when a norepinephrine-like substanceVcalled brain norepinephrine for the time beingVis released from estrogen brain receptors not receiving estrogen. Therefore, the recently or suddenly postmenopausal womanVhaving up-regulated receptorsVwould have both more frequent and more severe hot flashes. The understanding of the causes of these symptoms has also led to better studies of what these symptoms cause. A recent study by Whiteley et al4 observed that a greater severity of VMS in postmenopausal women was significantly associated with lower levels of health status and work productivity and greater use of healthcare resources. In addition, the extensive Study of Women’s Health Across the Nation showed that hot flashes were associated with a higher incidence of insulin resistance and, to a lesser extent, higher glucose levels. These metabolic factors may be relevant to understanding the link between hot flashes and cardiovascular disease risk.5 In addition, in a subgroup analysis from the Women’s Health Initiative trials of hormone therapy, higher risks of cardiovascular disease were found in women with a higher burden of menopausal symptoms. Those experiencing symptomatic menopause had a significantly increased risk of coronary heart disease (hazards ratio, 5.08; 95% CI, 2.08-12.40) compared with their counterparts who had a lower burden of menopausal symptoms. Similarly, the risk of stroke was significantly elevated (hazards ratio, 3.94; 95% CI, 1.09-1.14). This analysis supported the hypothesis that menopausal symptoms convey cardiovascular risk.6 However, because the risks for hot
flashes and cardiovascular disease are similar, final judgment on causal relationship should be withheld. However, in the positron emission tomography scan studies by Greene,7 it was apparent that there is a significant decrease in cerebral blood flow during a hot flash. This explains a woman’s inability to continue her tasks during a severe hot flash. It is also one of the reasons that the American College of Obstetricians and Gynecologists8 published the first clinical guidelines on the management of menopausal symptoms. This directive encouraged physicians to treat VMS and to not use age as a guideline, stating that the decision to treat should be individualized and that there is no need to discontinue medication if a woman is still symptomatic after age 65 years. This is a welcome policy change. The bulletin also lists therapies for VMSVwith the reinstatement of estrogen therapy and hormone therapy, including the recently approved combination of conjugated equine estrogens with bazedoxifene for women with an intact uterusVdepending on individual risks and benefits. Bazedoxifene avoids the need for a progestin in these women. Also included is the first nonhormonal Food and Drug Administration (FDA)Yapproved medication for the treatment of VMS, paroxetine 7.5 mg, a selective serotonin reuptake inhibitor that has been shown to have fewer adverse effects than higher-dose selective serotonin reuptake inhibitors9 and to have reduced VMS significantly better than placebo. The publication also mentions that gabapentin has been reported to decrease hot flashes, though not significantly different from placebo; therefore, it has not been approved by the FDA. In this issue of Menopause, Pinkerton et al10 published a study using a new formulation of gabapentin with a different dose schedule. This gastroretentive preparation (G-GR) provides a steady and continuous delivery of the medication, requires only twice-a-day dosing (600 mg with breakfast/1,200 mg with dinner), and results in fewer adverse effects than immediate-release formulations. In this phase 3 study, G-GR produced statistically significant reductions in frequency and severity compared with placebo. However, largely because of the immense response of the placebo group, it did not meet FDA guidelines for efficacy. However, a new scale called the Sleep Interference Scale, reflecting the extent to which hot flashes interfered with sleep (certainly a serious quality-of-life issue), was used. Women rated sleep interference on a scale from 1 to 10, using their cellular phoneYbased electronic diary. For this endpoint, there was a definite statistically significant difference between women on treatment and women on placebo (P = 0.0001). Menopause, Vol. 21, No. 6, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
551
EDITORIAL
There may be a special role for G-GR in women with mainly night sweats or in women taking other medications that have abolished hot flashes in daytime but not night sweats and sleep disturbance. Perhaps there should be a study of the Sleep Interference Scale in symptomatic women using only the bedtime dose for this indication. Financial disclosure/conflicts of interest: L.N. has received payment for lectures (including service on the speakers’ bureaus) from Shionogi Inc, Noven, and Pfizer.
Lila Nachtigall, MD, NCMP Department of Obstetrics and Gynecology New York University Langone Medical Center New York, New York REFERENCES 1. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990;592:52-86, discussion 123-133.
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Menopause, Vol. 21, No. 6, 2014
2. Politi MC, Schleinitz MD, Col NF. Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. J Gen Intern Med 2008;23: 1507-1513. 3. Freedman RR. Physiology of hot flashes. Am J Hum Biol 2001;13:453-464. 4. Whiteley J, Wagner JS, Bushmakin A, Kopenhafer L, Dibonaventura M, Racketa J. Impact of the severity of vasomotor symptoms on health status, resource use, and productivity. Menopause 2013;20:518-524. 5. Thurston RC, El Khoudary SR, Sutton-Tyrrell K, et al. Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation. Menopause 2011;18:1044-1051. 6. Roussauw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-1477. 7. Greene RA. Cerebral blood flow. Fertil Steril 2000;73:143. 8. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol 2014;123:202-216. 9. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause 2013;20:1027-1035. 10. Pinkerton J, Kagan R, Portman D, et al. Phase 3 randomized, controlled study of gastroretentive gabapentin for treatment of moderate to severe hot flashes in menopause. Menopause 2014;21:XXX-XXX.
* 2014 The North American Menopause Society
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
EDITORIAL Hot flashes: is a hot flash just a hot flash?
W
hether called hot flushes, hot flashes, or vasomotor symptoms (VMS), they are often the first signVand considered a hallmarkVof menopause. Although they have been described since the 17th century, their pathophysiology is not really known. They most commonly occur on the face, neck, and upper body, and often end in drenching sweat. They vary in frequency from one per day to more than 30 per day, and their severity can vary from mild to severe. The early work of Kronenberg1 showed that, among untreated women, 80% of hot flashes will be over in 3 years and 90% of hot flashes will be over by 6 years, but that a few women can have them for 40 years or more. In more recent studies of women who have hot flashes, 25% reported that these symptoms remained for more than 5 years, and 10% reported that these symptoms remained for more than 10 years.2 Freedman3 contributed enormously to the understanding of hot flash mechanism by explaining that these hot flashes occur because of a decrease in the thermoneutral zone, leading to easy heating and quick cooling with minimal temperature changes. He postulated that the reduction in this zone occurs when a norepinephrine-like substanceVcalled brain norepinephrine for the time beingVis released from estrogen brain receptors not receiving estrogen. Therefore, the recently or suddenly postmenopausal womanVhaving up-regulated receptorsVwould have both more frequent and more severe hot flashes. The understanding of the causes of these symptoms has also led to better studies of what these symptoms cause. A recent study by Whiteley et al4 observed that a greater severity of VMS in postmenopausal women was significantly associated with lower levels of health status and work productivity and greater use of healthcare resources. In addition, the extensive Study of Women’s Health Across the Nation showed that hot flashes were associated with a higher incidence of insulin resistance and, to a lesser extent, higher glucose levels. These metabolic factors may be relevant to understanding the link between hot flashes and cardiovascular disease risk.5 In addition, in a subgroup analysis from the Women’s Health Initiative trials of hormone therapy, higher risks of cardiovascular disease were found in women with a higher burden of menopausal symptoms. Those experiencing symptomatic menopause had a significantly increased risk of coronary heart disease (hazards ratio, 5.08; 95% CI, 2.08-12.40) compared with their counterparts who had a lower burden of menopausal symptoms. Similarly, the risk of stroke was significantly elevated (hazards ratio, 3.94; 95% CI, 1.09-1.14). This analysis supported the hypothesis that menopausal symptoms convey cardiovascular risk.6 However, because the risks for hot
flashes and cardiovascular disease are similar, final judgment on causal relationship should be withheld. However, in the positron emission tomography scan studies by Greene,7 it was apparent that there is a significant decrease in cerebral blood flow during a hot flash. This explains a woman’s inability to continue her tasks during a severe hot flash. It is also one of the reasons that the American College of Obstetricians and Gynecologists8 published the first clinical guidelines on the management of menopausal symptoms. This directive encouraged physicians to treat VMS and to not use age as a guideline, stating that the decision to treat should be individualized and that there is no need to discontinue medication if a woman is still symptomatic after age 65 years. This is a welcome policy change. The bulletin also lists therapies for VMSVwith the reinstatement of estrogen therapy and hormone therapy, including the recently approved combination of conjugated equine estrogens with bazedoxifene for women with an intact uterusVdepending on individual risks and benefits. Bazedoxifene avoids the need for a progestin in these women. Also included is the first nonhormonal Food and Drug Administration (FDA)Yapproved medication for the treatment of VMS, paroxetine 7.5 mg, a selective serotonin reuptake inhibitor that has been shown to have fewer adverse effects than higher-dose selective serotonin reuptake inhibitors9 and to have reduced VMS significantly better than placebo. The publication also mentions that gabapentin has been reported to decrease hot flashes, though not significantly different from placebo; therefore, it has not been approved by the FDA. In this issue of Menopause, Pinkerton et al10 published a study using a new formulation of gabapentin with a different dose schedule. This gastroretentive preparation (G-GR) provides a steady and continuous delivery of the medication, requires only twice-a-day dosing (600 mg with breakfast/1,200 mg with dinner), and results in fewer adverse effects than immediate-release formulations. In this phase 3 study, G-GR produced statistically significant reductions in frequency and severity compared with placebo. However, largely because of the immense response of the placebo group, it did not meet FDA guidelines for efficacy. However, a new scale called the Sleep Interference Scale, reflecting the extent to which hot flashes interfered with sleep (certainly a serious quality-of-life issue), was used. Women rated sleep interference on a scale from 1 to 10, using their cellular phoneYbased electronic diary. For this endpoint, there was a definite statistically significant difference between women on treatment and women on placebo (P = 0.0001). Menopause, Vol. 21, No. 6, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
551
EDITORIAL
There may be a special role for G-GR in women with mainly night sweats or in women taking other medications that have abolished hot flashes in daytime but not night sweats and sleep disturbance. Perhaps there should be a study of the Sleep Interference Scale in symptomatic women using only the bedtime dose for this indication. Financial disclosure/conflicts of interest: L.N. has received payment for lectures (including service on the speakers’ bureaus) from Shionogi Inc, Noven, and Pfizer.
Lila Nachtigall, MD, NCMP Department of Obstetrics and Gynecology New York University Langone Medical Center New York, New York REFERENCES 1. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990;592:52-86, discussion 123-133.
552
Menopause, Vol. 21, No. 6, 2014
2. Politi MC, Schleinitz MD, Col NF. Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. J Gen Intern Med 2008;23: 1507-1513. 3. Freedman RR. Physiology of hot flashes. Am J Hum Biol 2001;13:453-464. 4. Whiteley J, Wagner JS, Bushmakin A, Kopenhafer L, Dibonaventura M, Racketa J. Impact of the severity of vasomotor symptoms on health status, resource use, and productivity. Menopause 2013;20:518-524. 5. Thurston RC, El Khoudary SR, Sutton-Tyrrell K, et al. Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation. Menopause 2011;18:1044-1051. 6. Roussauw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-1477. 7. Greene RA. Cerebral blood flow. Fertil Steril 2000;73:143. 8. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol 2014;123:202-216. 9. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause 2013;20:1027-1035. 10. Pinkerton J, Kagan R, Portman D, et al. Phase 3 randomized, controlled study of gastroretentive gabapentin for treatment of moderate to severe hot flashes in menopause. Menopause 2014;21:XXX-XXX.
* 2014 The North American Menopause Society
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
