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© 2002 American Society for Clinical Oncology
Cooling Off Hot FlashesUniversity of Michigan Comprehensive Cancer Center, Ann Arbor, MI VASOMOTOR SYMPTOMS (or hot flashes) represent the most common complaint among perimenopausal women. It is estimated that up to 60% of postmenopausal women experience these symptoms, up to 20% of women find them intolerable, and a similar proportion of women will suffer symptoms up to 15 years after menopause.1 In the year 2001, up to 4 million women may complain of severe symptoms and many more will seek intervention. Women who suffer hot flashes may also complain of associated symptoms such as depression, anxiety, and difficulties with sleep and sexual function. Women who undergo premature menopause (such as chemotherapy-induced menopause) often suffer severe symptoms that are of longer duration.2 The use of antiestrogens may also worsen or contribute to the symptoms. Hot flashes are also experienced by 70% to 80% of men with prostate cancer on androgen ablation.3 Although hot flashes are common, the pathophysiology of the phenomenon is not well understood. Estrogen action in the CNS is complex. Estrogen exerts its function not only through an interaction with its receptors but also through an interaction with other receptors important in regulation of sleep, mood, and cognition.4 During menopause, there is a decline in hormone levels and, as a result, there is an alteration in the CNS thermoregulatory set point. Then, after a trigger, immediate changes in hormones or neurotransmitters lead to the hot flash sensation. Several changes in hormone and neurotransmitter levels may proceed or coincide with the hot flash. However, a biochemical trigger for hot flashes has not been found. Estrogen is highly effective for the treatment of vasomotor symptoms and is generally the drug of choice in perimenopausal women. However, the safety of estrogen has been debated for women after a breast cancer diagnosis or at high risk of developing the disease. This debate has resulted in reluctance among many physicians and women to accept this treatment. Progestin compounds such as megestrol acetate, medroxyprogesterone acetate, and depomedroxyprogesterone acetate are also very effective, reducing hot flashes by 85% or more.5-8 However, as is the case with estrogen, there is reluctance among women and physicians to accept this alternative hormonal therapy. Several nonpharmacologic approaches have been explored for the alleviation of hot flashes. These include strategies such as tolerance, fans or air conditioners, diet, exercise, and behavioral modifications. Unfortunately, only a few patients benefit from these approaches. A major contribution to research in the field has been the introduction of randomized placebo-controlled clinical trials, which have consistently demonstrated reduction of 20% to 30% in hot flash frequency and severity as a result of placebo alone.9 Approximately 25% of women who receive placebo may note 50% reduction in hot flash activity. The magnitude of the placebo effect stresses the need for such prospective randomized placebo-controlled studies to assess the efficacy of specific agents or compounds. In this regard, complementary and alternative medicines have been very attractive to men and women who suffer hot flashes, and anecdotal reports are often promising. However, scientifically designed clinical trials have demonstrated that complementary and alternative medicines such as Chinese medicinal herbs, black cohosh, and vitamin E are not more beneficial than placebo in reducing hot flashes.10-14 Soy compounds have been promoted as a nonpharmacologic agent to treat vasomotor symptoms. In this issue of the Journal of Clinical Oncology, Van Patten et al15 report results of a prospectively designed clinical trial in which 123 patients were randomized to receive soy beverage versus placebo rice beverage. Soy was associated with a 30% reduction in hot flash score, whereas placebo was associated with a 40% reduction. Overall, almost 1,000 women have been enrolled onto prospective randomized clinical trials comparing soy compounds with placebo for treatment of menopausal symptoms. Unfortunately, the studies have shown that soy is only marginally or no more effective than placebo.15-22 Adverse effects to soy products include mild gastrointestinal symptoms or vaginal spotting. More importantly, soy contains phytoestrogens, which exhibit a weak estrogenic effect. In vitro and in vivo studies suggest that phytoestrogens may stimulate breast cancer growth and antagonize the antitumor effect of tamoxifen. However, these data are conflicting,23 and safety of long-term use of soy compounds in women with a prior breast cancer is not known. Because of the lack of efficacy, mild toxicity, and potential estrogenic-like effects, it is difficult to recommend the use of soy as first-line therapy for hot flashes. Several nonhormonal pharmacologic agents have been investigated for the treatment of hot flashes, including neuroendocrine agents such as antidopaminergic compounds. These agents seem to be 1.5 to 2 times more effective than placebo in reducing hot flashes. However, they are associated with frequent side effects. Clonidine, orally or trans-dermally, is better tolerated than other neuroendocrine agents and is modestly active in reducing hot flashes.24-27 Clonidine is associated with dry mouth, constipation, and drowsiness, and its use may be limited by orthostatic hypotension. Recently, anecdotal reports suggested that selective serotonin reuptake inhibitors (SSRIs) may be effective in alleviating hot flashes. These reports led to several pilot trials with promising results. In this issue of the Journal of Clinical Oncology, Loprinzi et al28 report results of a double blind, randomized, cross-over clinical trial of fluoxetine (20 mg daily) versus placebo. Eighty-one women with or without a prior breast cancer were included in the study. Hot flash scores decreased by 50% and 36% in the fluoxetine and placebo groups, respectively.28 Adverse effects were mostly gastrointestinal or CNS and were not different than those commonly described with this group of drugs. Importantly, women reported improved sleep and libido. The same authors have also reported results of a randomized placebo-controlled study of venlafaxine versus placebo. In this study, the authors reported up to 61% reduction in hot flash score in venlafaxine-treated women. Of interest, a preliminarily report has suggested that sertraline is not more effective than placebo in reducing hot flashes.29 Paroxetine reduced hot flashes in a phase II study, and a phase III study is ongoing.30 Taken together, the results of the studies of SSRIs for the treatment of hot flashes suggest that this class of drugs represents a viable nonhormonal option for women who do not wish to take hormones and for whom natural therapies have not been successful. These studies also suggest that not all SSRIs are the same. The results of these studies and others may provide insight into pathophysiology of the phenomenon. The role of serotonin in thermoregulation has been long recognized.31 The two principal receptors for serotonin, the presynaptic 5-HT1A and postsynaptic 5-HT2, may exert different effects on body thermoregulation. In the rat, administration of serotonin agonist into the anterior hypothalamus produces an increase in body temperature.32 In contrast, administration of a 5-HT1A receptor agonist causes marked hypothermia.33 Perfusion of the hypothalamus with the selective serotonin reuptake inhibitor fluoxetine increases temperature significantly.34 These data suggest that stimulation of the presynaptic 5-HT1A receptors in the hypothalamus may reduce endogenous serotonin release and cause hypothermia. In contrast, stimulation of the 5-HT2 receptors results in hyperthermia. Anecdotal reports suggest that 5-HT2 antagonist may also be effective for the treatment of hot flashes.35 These studies could lead to the development of even more potent and less toxic therapies for hot flashes. Menopausal symptoms impair daily lives of many women and some men. Patients who suffer hot flashes have more choices then ever. It is reasonable to try nonpharmacologic interventions because they may be effective in up to 30% of patients, although perhaps through a placebo effect. To date, the most effective therapies have been hormonal and may be prescribed to a select group of women with a prior breast cancer. However, patients with hot flashes now have a nonhormonal option that is beneficial in reducing hot flashes and may also improve other symptoms such as insomnia or sexual dysfunction. After careful discussion of the risks and benefits, it is reasonable to offer women an SSRI as the first agent if nonpharmacologic methods have failed. Where should we go from here? The evidence correlating hormones with serotonin and other neurotransmitters should lead to more mechanistic investigations. Neuroimaging and evaluation of biochemical changes may assist in this task. Better understanding of the mechanism of action of hot flashes can lead to more targeted treatments or approaches with fewer adverse effects. Other important questions that need to be addressed include assessment of drug efficacy in subgroups of women, for example, in women who experience natural versus chemotherapy-induced menopause or women whose symptoms may be induced or worsened by endocrine manipulations. To assess these questions and others, larger prospective evaluations may be required. ACKNOWLEDGMENTS Supported in part by grant no. CI-3 of the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation and by a grant From the Fashion Footwear Foundation/QVC Presents Shoes on Sale. The authors have received support for clinical research regarding this topic From GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC. REFERENCES 1. Kronenberg F: Hot flashes: Phenomenology, quality of life, and search for treatment options. Exp Gerontol 29: 319-336, 1994[CrossRef][Medline] 2. Schwingl PJ, Hulka BS, Harlow SD: Risk factors for menopausal hot flashes. Obstet Gynecol 84: 29-34, 1994[Medline] 3. Lanfrey P, Mottet N, Dagues F, et al: Hot flashes and hormonal treatment of prostate cancer. Prog Urol 6: 17-22, 1996[Medline] 4. Stahl SM: Effects of estrogen on the central nervous system. J Clin Psychiatry 62: 317-318, 2001[Medline]
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Sloan JA, Loprinzi CL, Novotny PJ, et al: Methodologic lessons learned from hot flash studies. J Clin Oncol 19: 4280-4290, 2001 10. Israel D, Youngkin EQ: Herbal therapies for perimenopausal and menopausal complaints. Pharmacotherapy 17: 970-984, 1997[Medline] 11. Barton DL, Loprinzi CL, Quella SK, et al: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 16: 495-500, 1998[Abstract] 12. Liske E: Therapeutic efficacy and safety of Cimicifuga racemosa for gynecologic disorders. Adv Ther 15: 45-53, 1998[Medline]
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Jacobson JS, Troxel AB, Evans J, et al: Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 19: 2739-2745, 2001 14. Davis SR, Briganti EM, Chen RQ, et al: The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women: A randomised controlled trial. Med J Aust 174: 68-71, 2001[Medline] 15. Van Patten CL, Olivotto IA, Chambers GK, et al: The effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: A randomized, controlled clinical trial. J Clin Oncol 19: 1449-1455, 2001 16. St Germain A, Peterson CT, Robinson JG, Alekel DL: Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 8: 17-26, 2001[CrossRef][Medline] 17. Upmalis DH, Lobo R, Bradley L, et al: Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: A multicenter, double-blind, randomized, placebo-controlled study. Menopause 7: 236-242, 2000[Medline] 18. Scambia G, Mango D, Signorile PG, et al: Clinical effects of a standardized soy extract in postmenopausal women: A pilot study. Menopause 7: 105-111, 2000[Medline]
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Quella SK, Loprinzi CL, Barton DL, et al: Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 18: 1068-1074, 2000 20. Albertazzi P, Pansini F, Bonaccorsi G, et al: The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 91: 6-11, 1998[CrossRef][Medline] 21. Murkies AL, Lombard C, Strauss BJ, et al: Dietary flour supplementation decreases post-menopausal hot flushes: Effect of soy and wheat. Maturitas 21: 189-195, 1995[CrossRef][Medline] 22. Washburn S, Burke GL, Morgan T, et al: Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 6: 7-13, 1999[Medline] 23. Messina MJ, Loprinzi CL: Soy for breast cancer survivors: A critical review of the literature. J Nutr 131: 3095, 2001 (suppl 108S) 24. Goldberg RM, Loprinzi CL, O’Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes [published erratum appears in J Clin Oncol 14: 2411, 1996]. J Clin Oncol 12: 155-158, 1994[Abstract]
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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 132: 788-793, 2000 26. Loprinzi CL, Goldberg RM, O’Fallon JR, et al: Transdermal clonidine for ameliorating post-orchiectomy hot flashes. J Urol 151: 634-636, 1994[Medline] 27. Bressler LR, Murphy CM, Shevrin DH, et al: Use of clonidine to treat hot flashes secondary to leuprolide or goserelin. Ann Pharmacother 27: 182-185, 1993[Abstract]
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Loprinzi CL, Sloan JA, Perez EA, et al: Phase III evaluation of fluexetine (Prozac) for treatment of hot flashes. J Clin Oncol 20: 1578-1583, 2002 29. Kimmick GG, Lovato J, McQuellon R, et al: Randomized, placebo-controlled study of sertraline (Zoloft TM) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Proc Am Soc Clin Oncol 20: 397a, 2001 (abstr 1585)
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Stearns V, Isaacs C, Rowland J, et al: A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer patients. Ann Oncol 11: 17-22, 2000 31. Sheard MH, Aghajanian GK: Neural release of brain serotonin and body temperature. Nature 216: 495-496, 1967[CrossRef][Medline] 32. Myers RD: Serotonin and thermoregulation: Old and new views. J Physiol (Paris) 77: 505-513, 1981[Medline] 33. Gudelsky GA, Koenig JI, Meltzer HY: Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat: Evidence for opposing roles of 5-HT2 and 5-HT1A receptors. Neuropharmacology 25: 1307-1313, 1986[CrossRef][Medline]
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Lin MT, Tsay HJ, Su WH, et al: Changes in extracellular serotonin in rat hypothalamus affect thermoregulatory function. Am J Physiol 274: R1260-1267, 1998 35. Waldinger MD, Berendsen HH, Schweitzer DH: Treatment of hot flushes with mirtazapine: Four case reports. Maturitas 36: 165-168, 2000[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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