US Pharm. 2010;35(3):20-24.
As many as 85% of perimenopausal women experience hot flashes (flushes), night sweats, and/or sleep disturbances secondary to vasomotor instability.1 Hot flashes are the most frequent symptoms of perimenopause and menopause, and almost all women report hot flashes with induced menopause (e.g., surgery, chemotherapy) or premature menopause (i.e., before age 40 years).2,3 Hot flashes also occur after the discontinuation of exogenous estrogen (e.g., hormone-replacement therapy).4
The mean age for onset of menopause in the United States is 51 years (range 40-58 years).5 Hot flashes are typically more severe at the onset of menopause (i.e., within the first 2 years) and become less intense and less frequent with age.4,5 In perimenopause, hot flashes occur when endogenous estrogen levels decrease, and then resolve as estrogen levels increase; considerable daily fluctuations occur approximately 1 year prior to menopause.6 At menopause, vasomotor symptoms are associated with a decline in ovarian function.7 Of the 80% of perimenopausal women reporting hot flashes, 85% remain symptomatic for more than 1 year, and 25% to 50% remain symptomatic for up to 5 years.4 According to a 25-year longitudinal study, prevalence of hot flashes decreases progressively with age.8 The maximal prevalence of hot flashes was between 52 and 54 years of age in the study, with prevalence reaching 9% by age 72.8 Vasomotor symptoms have the potential to interfere with daily functioning and alter quality of life. While vasomotor symptoms are not considered harmful, they do indicate an estrogen deficiency.9
Sleep disturbances are often a complication of hot flashes. Nocturnal hot flashes, or night sweats, disrupt sleep and, if recurrent, may contribute to insomnia.10 These sleep disturbances can eventually lead to fatigue, irritability, poor concentration, memory problems, anxiety, and depression; a decreased quality of life may be secondary to these symptoms.10 If hot flashes become especially disruptive to daily routines, pharmacists can recommend that patients discuss appropriate treatment options with their health care provider.10
PATHOPHYSIOLOGY OF HOT FLASHES
The exact mechanism of hot flashes is not completely understood.5 It is known, however, that the neuroendocrine system has an impact on the thermoregulatory nucleus in the hypothalamus, such that during menopause small temperature changes (as little as 0.01°F) can trigger hot flashes.11 Perspiration and vasodilation (i.e., the symptoms of hot flashes) occur when the body attempts to preserve heat loss and maintain the core body temperature.5,11 Changes in the neuroendocrine system that are associated with hot flashes commence with declines in estrogen and progesterone levels.5 Further, changes in the levels of endorphins, norepinephrine, and serotonin take place systemically.11-14 Estrogen-alone therapy or estrogen-progestin combination therapy can help balance the neuroendocrine system and readjust the trigger point in the hypothalamus.5 Antidepressants that inhibit norepinephrine or serotonin reuptake, or both, may also help to balance the alterations in the hypothalamus and potentially relieve hot flashes.5
CLINICAL PRESENTATION: SIGNS AND SYMPTOMS
TABLE 1 outlines the symptoms of hot flashes—a subjective sensation of intense warmth in the upper body typically lasting 30 seconds to 5 minutes; when these flashes manifest during the night, they are referred to as night sweats.6 Hot flashes vary in frequency (i.e., several in 1 day or a few each week).10 Persistent sweating may be experienced throughout the day and night, or patients may just feel occasional warmth.10 Hot flashes may alternate with other vasomotor symptoms such as chilly sensations and, less commonly, paresthesias.7
Avoiding triggers of hot flashes (TABLE 2) may help in decreasing their frequency and intensity.10 If treatment becomes necessary to ameliorate symptoms that interfere with everyday functioning, periodic reevaluation for continued need for treatment is recommended. Response to treatment is determined by improvement in subjective symptoms.9
Hormone therapy is recommended for moderate-to-severe hot flashes. Estrogen is the most effective treatment for hot flashes, although progestins are used as an alternative in some instances.
Estrogen: Pharmacotherapy with estrogen is specific and is the most effective treatment for vasomotor symptoms.7,10 Benefits include a reduction of hot flashes and night sweats (and associated sleep disturbance).6 Women with an intact uterus receive a progestin in combination with estrogen to protect against endometrial cancer.10 For women who have had a hysterectomy, an estrogen-only regimen is prescribed. For either regimen, the lowest effective dose for the shortest period of time required to relieve symptoms is recommended.10
Risks associated with combination therapy include an increased incidence of breast cancer, pulmonary embolism (PE), dementia, and coronary artery disease (CAD).6 The increased risk of CAD, which doubles during the first year of therapy and is particularly high in women with elevated LDL cholesterol prior to treatment, is not prevented with aspirin and statins.6 Estrogen-only therapy increases the incidence of ischemic stroke while having no effect on the incidence of CAD; effects of this therapy decrease the incidence of hip fractures and are less clear with regard to breast cancer and PE.6 Estrogen is contraindicated in patients with a history of venous thromboembolism or breast cancer.10 If estrogen is contraindicated in a patient, or deemed undesirable by the patient, other options may be considered.7
Progestins: Progestin-only therapy (e.g., megestrol acetate, medroxyprogesterone acetate) can be used as an alternative to estrogen and may relieve hot flashes, although no long-term safety data exist.2,6,10 Use of micronized progesterone appears to be associated with fewer adverse effects.6 Adverse effects of progestins include abdominal bloating, breast tenderness, increased breast density, headache, increased LDL cholesterol, and decreased HDL cholesterol.6
Nonhormonal medications are available and may provide comparable reduction in the frequency and severity of hot flashes.5 While their use may be off-label (i.e., not FDA approved for hot flashes), these agents are approved for other conditions and have been studied in patients with hot flashes.5,10 Available literature reviews (see below) provide assistance with choosing an appropriate nonhormonal regimen.
Antidepressants: Specific antidepressants have been found to relieve hot flashes, although not as effectively as hormone therapy for severe hot flashes.2,10 The American College of Obstetricians and Gynecologists acknowledges that antidepressants are useful in the treatment of hot flashes in patients with a history of breast cancer or in healthy menopausal women who do not wish to take hormonal therapy.15 Carroll and Kelley evaluated the published literature on the use of antidepressants for the management of hot flash symptoms via a literature search using PubMed, International Pharmaceutical Abstracts, and MEDLINE databases from inception through May 2009.5 Pharmacists can refer to Reference 5 for this evaluation of hot flashes in clinical trials of antidepressants, which includes specific dosages and adverse reactions reported.
Low doses of selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, sertraline, citalopram, escitalopram, fluvoxamine, fluoxetine) and serotonin and norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine, desvenlafaxine, duloxetine) may decrease hot flashes through their ability to inhibit the reuptake of neurotransmitters.5 Adverse effects (e.g., nausea, dizziness, weight gain, sexual dysfunction) should be considered when weighing benefits versus risks for an individual patient.10
Carroll and Kelley note that data indicate paroxetine and venlafaxine appear to be the most effective of the agents studied in reducing the frequency and severity of hot flashes; paroxetine remains the most studied of the SSRIs.5 These researchers indicate that when patients are unable to tolerate paroxetine or venlafaxine or fail a trial of therapy with these agents, desvenlafaxine, sertraline, fluoxetine, and citalopram should be considered as second- or third-line options.5 Based on their findings, Carroll and Kelley advise that until more rigorous studies (randomized, controlled trials with diverse menopausal patient populations at least 12 weeks in duration or longer) are conducted to assess their use in the management of hot flashes, duloxetine, escitalopram, fluvoxamine, and mirtazapine (see below) should be reserved as last-line therapy.5
Mirtazapine possesses potent inhibitory effects on serotonin, histamine, and alpha2-receptors, and is believed to be beneficial in the relief of hot flashes due to its inhibitory effects on serotonin and alpha2-receptors.5,11 Data indicate lack of efficacy, and the drug’s utility may be limited secondary to associated adverse effects of somnolence, appetite stimulation, and weight gain, occurring more frequently and severely than with the SSRIs and SNRIs.5
Gabapentin: The anticonvulsant agent gabapentin, also approved for postherpetic neuralgia, may be moderately effective in reducing hot flashes, especially in those with nocturnal symptoms.10 Adverse effects include drowsiness, dizziness, and headaches.10
Clonidine: The alpha2 adrenergic agonist clonidine relieves vasomotor symptoms in some patients; this is accomplished by the agent’s ability to diminish central adrenergic outflow that regulates blood flow to cutaneous vessels.7,16 Clonidine may be administered orally or transdermally. Due to common adverse effects including dizziness, sedation, dry mouth/nasal mucosa, and constipation, its usefulness in the treatment of hot flashes may be limited.10,16 Further, clonidine causes sodium and water retention, which may require coadministration with a diuretic.16
Patients should be advised about the risks of abrupt clonidine withdrawal; a rapid increase in blood pressure and symptoms of sympathetic overactivity can be avoided using a slow taper (e.g., over 1 week for oral dosage) when this agent is discontinued.16,17 If clonidine needs to be discontinued in a patient receiving both a beta-blocker and clonidine, the beta-blocker is withdrawn first, several days before clonidine; then clonidine is slowly decreased to discontinuation.17
While alternative therapies have shown promise for relieving symptoms such as hot flashes in menopause, more data are required to establish the risks (e.g., adverse effects, interactions with medications) and benefits of these nontraditional remedies.2 Of further importance is the non–FDA-regulated status of these formulations.2 Patients should be reminded to inform their health care providers about any alternative therapies they are taking.
Black Cohosh: Black cohosh, which has a good safety record, is popular in the U.S. and is widely used in Europe for the relief of hot flashes.10 While there is little evidence regarding its effectiveness for menopausal symptom relief, some studies suggest black cohosh may be useful for very short-term (6 months or less) relief of hot flashes and night sweats.2,10 Gastrointestinal upset is an associated side effect.2
Soy and Red Clover: Isoflavones are estrogen-like compounds in soy, red clover, and numerous other plants and are thought to have weak estrogen-like effects that may reduce hot flashes.2,10 Studies involving soy and women with hot flashes have generally found no benefit, although selected isoflavones have mixed results for menopausal symptom relief.10
Evening Primrose Oil: Although there is no scientific evidence to support its use, this botanical is often used to treat hot flashes.2 Patients taking anticoagulants should not use this product; side effects include nausea and diarrhea.2
Flaxseed: Flaxseed is available as a whole seed and seed oil and may also be referred to as linseed.2 There is no evidence supporting its use to decrease the symptoms of menopause, particularly hot flashes.2
Patients should be instructed to avoid triggers of hot flashes (TABLE 2). Keeping the body cool (e.g., use of fans during the day, bedroom cool at night, light layers of clothing with natural fibers such as cotton) and practicing deep breathing (e.g., 15 minutes in the morning, 15 minutes in the evening, and at the onset of hot flashes) have been recommended to reduce the likelihood and/or intensity of vasomotor symtoms.2,10 Suggested measures for daily exercise include walking, swimming, dancing, and bicycling.2
Vasomotor symptoms have the potential to interfere with daily functioning and alter quality of life. Hot flashes are the most frequent symptoms of perimenopause and menopause, and pharmacologic and lifestyle measures are available options used in their treatment. The choice between hormone therapy and nonhormonal therapy, such as an antidepressant for relief of vasomotor symptoms, requires consideration of the current scientific evidence and the patient’s comorbidities and related medication therapy.
1. Santoro N, Brown JR, Adel T, et al. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996;81:1495-1501.
2. Menopause and hot flashes. WebMD. www.webmd.com/menopause/guide/hot-flashes. Accessed February 15, 2010.
3. Dorland’s Pocket Medical Dictionary. 28th ed. Philadelphia, PA: Elsevier Saunders: 2009.
4. Beers MH, Berkow R, eds. The Merck Manual of Geriatrics. 3rd ed. Whitehouse Station, NJ: Merck & Co; 2000:1208-1209,1211,1216.
5. Carroll DG, Kelley KW. Use of antidepressants for management of hot flashes. Medscape. www.medscape.com/viewarticle/711910. Accessed February 15, 2010.
6. Beers MH, Porter RS, Jones TV, et al. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:2081-2082.
7. Loose DS, Stancel GM. Estrogens and progestins. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill Companies; 2006:1541-1571.
8. Rodstrom K, Bengtsson C, Lissner L, et al. A longitudinal study of the treatment of hot flushes: the population study of women in Gothenburg during a quarter of a century. Menopause. 2002;9:156-161.
9. Ruggiero RJ. Gynecologic disorders. In: Herfindeal ET, Gourley DR, eds. Textbook of Therapeutics: Drug and Disease Management. 7th ed. Lippincott Williams & Wilkins: Philadelphia, PA; 2000:2008-2009.
10. Hot flashes. Mayo Clinic Web site. www.mayoclinic.com/health/hot-flashes/ds01143. Updated June 12, 2009. Accessed February 15, 2010.
11. Perez D, Loprinzi CL, Barton DL, et al. Pilot evaluation of mirtazapine for the treatment of hot flashes. J Support Oncol. 2004;2:50-56.
12. Berendsen HH. The role of serotonin in hot flushes. Maturitas. 2000;36:155-164.
13. Casper RF, Yen SS. Neuroendocrinology of menopausal flushes: a hypothesis of flush mechanism. Clin Endocrin. 1985;22:296-312.
14. Rosenberg J, Larsen SH. Hypothesis: pathogenesis of postmenopausal hot flush. Med Hypotheses.
15. American College of Obstetricians and Gynecologists. Vasomotor symptoms. Obstet Gynecol.
16. Howland RD, Mycek MJ. Pharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:77,223-224.
17. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 14th ed. Hudson, OH: Lexi-Comp, Inc; 2009. 1991;35:349-350. 2004;4(suppl):S106-S107.
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