Alternatives to HRT for the Treatment of Hot Flashes

MARCH 01, 2008
Jeannette Y. Wick, RPh, MBA, FASCP

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The views expressed are those of the author and not those of any government agency.

During perimenopause, most women experience hot flashes of varying frequency and intensity. When they occur more than a few times daily, or even hourly, these episodes can be quite disruptive and are often accompanied by vaginal dryness, decreased libido, forgetfulness, difficulty concentrating, and night sweats that disturb sleep.

Although estrogen and progesterone are used to treat hot flashes, the Women's Health Initiative (WHI) study found that routine use of these therapies increases some specific risks.1-3 Many women who had used estrogen for hot flashes panicked and stopped their medications abruptly, and now those who might benefit from hormone replacement therapy (HRT) are searching for alternatives. For this reason, pharmacists need to be fully aware of self-care and medical treatment options that can help women manage menopausal symptoms.

Hot flashes usually subside over a year or 2 after menopause, but in the interim, these sudden sensations of intense heat, frequently accompanied by profuse sweating and facial or body flushing, are intrusive and embarrassing. The chill that follows can be terribly uncomfortable. Stress, heavy alcohol use, and cigarette smoking seem to exacerbate hot flash frequency and intensity. Sufferers may report anxiety, irritability, or mild to severe heart palpitations. Hot flashes can be especially difficult for women who cease menstruating abruptly from chemotherapy, antiestrogen treatment for breast cancer, or surgical removal of the ovaries.4

When to Treat

If hot flashes are mild or infrequent, treatment is usually unnecessary. Women who suffer moderate to severe or frequent hot flashes often look for relief, and some lifestyle choices may help. Breathing exercises, for example, have been shown to reduce hot flashes and emotional symptoms significantly5,6(Table).

If hot flashes are severe and disruptive, the patient may ask for medication. Short-term HRT—at the lowest dose needed for the shortest possible time—remains the most effective treatment. The WHI study linked HRT to an increased risk of breast cancer, cardiovascular disease, stroke, venous thromboembolism, and dementia. It also confirmed estrogen's protective role in bone health.1-3

Pharmacists need to know that treatment of menopausal symptoms such as hot flashes was not a WHI end point; WHI was designed to determine if HRT prevents chronic diseases like heart disease and osteoporosis. The average age of WHI participants was 63, or about 12 years postmenopausal. Since the study was published, it has become more evident that depending on the patient's age, hormone therapy has different benefits and risks.7-11

Before menopause, estrogen?progestin birth control pills can ameliorate hot flashes and other perimenopausal symptoms by preventing fluctuating hormones. Perimenopausal women who smoke, have diabetes, or have a personal or family history of cardiovascular disease or breast cancer should avoid using estrogen for hot flash relief.12-14

Women who have an intact uterus should not take unopposed estrogen; they must also take progesterone. Unopposed estrogen increases risk of endometrial malignancy.

Nonhormonal Alternatives

Interest in nonhormonal therapies is high at this time. Selective serotonin reuptake inhibitor (SSRI) antidepressant medications can reduce the number and severity of hot flashes; researchers believe their ability to inhibit serotonin reuptake may significantly reduce vasomotor symptoms of menopause. SSRIs are more likely to work if the patient's main complaints are hot flashes, irritability, or mood swings. Pharmacists need to provide the standard guidance about side effects, counsel patients to take these medications early in the day, especially if insomnia is a problem, and advise against abrupt discontinuation.15-20

Numerous studies have been conducted using clonidine, which may reduce peripheral vascular reactivity; however, many of them are older, small, or of poor design.21-25 To date, the strongest evidence of clonidine's utility is in women with tamoxifen-induced hot flashes.21,25 Because hot flashes in women with breast cancer are common and pose a management problem (estrogen therapy is contraindicated, and tamoxifen interacts with many drugs), this is an important option.

Black cohosh may reduce or prevent hot flashes, depression, and anxiety,26,27 but a large, randomized, controlled, placebo-blinded study (N = 351) could not confirm its efficacy in either premenopausal or postmenopausal women.28 (This same study found no benefit in soy supplements.) Although most of this herb's side effects are mild and transient (gastrointestinal upset or rash), numerous studies and case reports have documented black cohosh's rare but potential hepatotoxicity, which can cause death.29-33

Researchers recently have had encouraging preliminary results with 49 g of crushed flaxseed daily in a small study (N = 30) of perimenopausal women, noting reductions of >50% in hot flash severity and frequency. Mild or moderate abdominal distention was common, as was mild diarrhea. This dietary therapy needs more study to determine if it is more effective than placebo.34


Although the number of alternative treatments for hot flashes is increasing, hormonal therapies are still the most effective. Pharmacists need to be familiar with the risks and benefits of hormonal and nonhormonal therapies and aware of the OTC products women may use to find relief.

Clear communication about treatment risks and benefits, individualization of treatment to meet patient needs and beliefs, and careful follow-up can help women find potentially effective therapy. The good news: Since the WHI results were published, researchers have documented a significant decrease in prescriptions for HRT, but a significantly higher percentage of prescription filling. This seems to mean that women who choose HRT do so with greater certainty in their choice.35


  1. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA. 2003;290:1739-1748.
  2. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
  3. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
  4. Obermeyer CM, Reher D, Saliba M. Symptoms, menopause status, and country differences: a comparative analysis from DAMES. Menopause. 2007;14:788-797.
  5. Irvin JH, Domar AD, Clark C, Zuttermeister PC, Friedman R. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynaecol. 1996;17:202-207.
  6. Freedman RR, Woodward S, Brown B, Javaid JI, Pandey GN. Biochemical and thermoregulatory effects of behavioral treatment for menopausal hot flashes. Menopause. 1995;2:211-218
  7. Prentice RL, Langer RD, Stefanick ML, et al. Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. Am J Epidemiol. 2006;163:589-599.
  8. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: The role of time since menopause and age at hormone initiation. J Womens Health. 2006;15:35-44.
  9. Manson JE, Allison MA, Rossouw JE, et al; WHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591-2602.
  10. Anderson GL, Limacher M, Assaf AR, et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
  11. Shumaker SA, Legault C, Kuller L, et al; Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291:2947-2958.
  12. Panay N, Ylikorkala O, Archer DF, Gut R, Lang E. Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric. 2007;10:120-131.
  13. Prior JC, Nielsen JD, Hitchcock CL, Williams LA, Vigna YM, Dean CB. Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year randomized double-blind trial following premenopausal ovariectomy. Clin Sci (Lond). 2007;112:517-525.
  14. Kaunitz AM. Oral contraceptive use in perimenopause. Am J Obstet Gynecol. 2001;185(2 Suppl):S32-S37.
  15. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289:2827-2834.
  16. Gordon PR, Kerwin JP, Boesen KG, Senf J. Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause. 2006;13:568-575.
  17. Kerwin JP, Gordon PR, Senf JH. The variable response of women with menopausal hot flashes when treated with sertraline. Menopause. 2007;14:841-845.
  18. 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.
  19. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000;356:2059-2063.
  20. 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 survivors. Ann Oncol. 2000;11:17-22.
  21. 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.
  22. Edington RF, Chagnon JP, Steinberg WM. Clonidine (Dixarit) for menopausal flushing. Can Med Assoc J. 1980;123:23-26.
  23. Nagamani M, Kelver ME, Smith ER. Treatment of menopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gynecol. 1987;156:561-565.
  24. Nappi C, Petraglia F, de Chiara BM, et al. The effect of various drugs with neuroendocrine activity and transdermal estradiol on plasma gonadotropin concentrations after ovariectomy in reproductive-aged women. Acta Obstet Gynecol Scand. 1991;70:435-439.
  25. Goldberg RM, Loprinzi CL, O'Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol. 1994;12:155-158. [Erratum appears in J Clin Oncol. 1996;14:2411]
  26. Oktem M, Eroglu D, Karahan HB, Taskintuna N, Kuscu E, Zeyneloglu HB. Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized trial. Adv Ther. 2007;24:448-461.
  27. McKenna DJ, Jones K, Humphrey S, Hughes K. Black cohosh: Efficacy, safety, and use in clinical and preclinical applications. Alter Ther Health Med. 2001;7:93-100.
  28. Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006;145:869-879.
  29. Levitsky J, Alli TA, Wisecarver J, Sorrell MF. Fulminant liver failure associated with the use of black cohosh. Dig Dis Sci. 2005;50:538-539.
  30. Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl. 2006;12:989-992.
  31. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Austr. 2002; 177:440-443.
  32. Verma S, Thuluvath PJ. Complementary and alternative medicine in hepatology: review of the evidence of efficacy. Clin Gastroenterol Hepatol. 2007;5:408-416.
  33. Dunbar K, Solga SF. Black cohosh, safety, and public awareness. Liver Int. 2007;27:1017-1018.
  34. Pruthi S, Thompson SL, Novotny PJ, et al. Pilot evaluation of flaxseed for the management of hot flashes. J Soc Integr Oncol. 2007;5:106-112.
  35. Parente L, Uyehara C, Larsen W, Whitcomb B, Farley J. Long-term impact of the women's health initiative on HRT. Arch Gynecol Obstet. 2007;[Epub ahead of print].