Treatment of Hot Flashes
A number of disorders and conditions have been associated with recurrent hot flashes including alcohol ingestion, food (eg, red peppers), carcinoid syndrome, mastocytosis, menopause, nicotinic acid intake, pheochromocytoma, rosacea, and stress. Hot flashes are the most common symptom of menopause and are attributed to hormonal, metabolic, and psychogenic factors, resulting from gradual declines in estrogen and androgen levels. Hot flashes actually begin during perimenopause, several years before menopause. The underlying mechanism of flushing is unknown; however, hot flashes, associated with decreased estrogen levels, may result from a decline in estrogen-enhanced a2-adrenergic activity. In 65% to 70% of women, the age at which menopause occurs is between 45 and 55 years. There appears to be cultural variability in the reported incidence of postmenopausal vasomotor symptoms. The reported occurrence of menopausal vasomotor symptoms and hot flashes in North American women is between 60% to 85%. Vasodilation and increases in skin temperature cause decreased skin resistance, sweating, and improved skin conductance. Vasomotor symptoms are more severe in women who have had their ovaries removed than in women with intact ovaries. In general, hot flashes occur from 0.5 to 5 years after natural menopause and may last as long as 15 years in 10% of women. Hot flashes range in duration from » 30 seconds to 5 minutes, typically lasting » 4 minutes and occasionally up to 1 hour. They may be infrequent (eg, monthly) or occur as often as 20 times a day. Flashes may be preceded by palpitations or headache, and are often accompanied by anxiety, faintness, nausea, weakness, or vertigo, and end with sweating and a cold sensation. Sleep disturbances are a common problem associated with hot flashes and may lead to fatigue, poor concentration, and avoidance of activities that may trigger hot flashes. The frequency of occurrence of hot flashes tends to decrease as the time from the onset of menopause increases. Men may also experience hot flashes, resulting from testosterone withdrawal (eg, orchiectomy for prostate cancer). The reported frequency of hot flashes in men following orchiectomy is 73%.
Drug Treatment
Androgens: While testosterone (eg, Delatestryl) alone is not effective in treating menopausal hot flashes, it does not interfere with the beneficial effects of estrogen when used concurrently. However, in a randomized, double-blind study, danazol (Danocrine) decreased the frequency and severity of hot flashes in 3 of 6 postmenopausal women 88% and 53%, respectively. In a study of 66 surgically menopausal women, treatment with oral estrogen alone or an estrogen-androgen combination reduced menopausal symptoms of somatic origin (eg, hot flashes). Menopausal women whose vasomotor symptoms are not adequately controlled by estrogen alone, may benefit from the same dose of estrogen in combination with an androgen (eg, methyltestosterone [eg, Metandren]). Hot flashes in men caused by testosterone withdrawal may also be relieved by methyltestosterone, another androgen, or estrogen therapy. Hot flashes may recur following discontinuation of treatment.
Clonidine (eg, Catapres): The antihypertensive agent clonidine has been reported to be effective in the treatment of flushing caused by carcinoid syndrome, menopause, nicotinic acid ingestion, and tamoxifen (eg, Nolvadex). Hot flashes are a common side effect of tamoxifen. In a randomized, double-blind, placebo-controlled study, the effect of clonidine (0.1 mg/day for 8 weeks) on hot flashes was evaluated in 194 postmenopausal women with breast cancer receiving tamoxifen therapy. Clonidine decreased hot flashes after 4 weeks of treatment by 37% compared with 20% for placebo, and after 8 weeks by 38% compared with 24%, respectively. Patients receiving clonidine reported greater difficulty sleeping. A 29-year-old woman with carcinoid syndrome experienced hot flashes provoked by red wine or milk chocolate. During treatment with clonidine, flushing did not occur following ingestion of red wine or milk chocolate. In 22 patients with hot flashes induced by a nicotinic acid derivative, 0.075 mg/day of clonidine suppressed flushing. For hot flashes associated with menopause, clonidine in doses of 0.05 to 0.2 mg twice daily reduced the frequency of hot flashes 12% to 40%. However, the higher doses were often associated with dizziness. In a double-blind, placebo-controlled, crossover study involving 6 patients who had menopausal flushing for < 1 year, 0.05 mg of clonidine twice daily decreased the frequency, severity, and duration of flushing attacks 78%, 89%, and 88%, respectively. The frequency of hot flashes associated with perimenopause and menopause is reduced » 20% with oral or transdermal clonidine administration. Although clonidine may be helpful in reducing hot flashes, it does not appear to be effective in the treatment of other postmenopausal symptoms. Other a-adrenergic agonists that influence vasomotor responses would be expected to be useful in the management of hot flashes.
Estrogens: Estrogens are indicated for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. Estrogen treatment has been found to be effective in decreasing the frequency and severity of hot flashes and associated sleep disturbances, and other conditions occurring with menopause (eg, osteoporosis). Controlled studies have found short-term estrogen therapy to be effective in reducing hot flashes whether given orally, transdermally, or by implant. The effect of estrogens on hot flashes is dose related. In naturally menopausal women, estrogen therapy reduced hot flashes 50% compared with a 70% decrease in surgically menopausal women. Improvement in symptoms usually occurs in 2 to 4 weeks. In a study of 66 surgically menopausal women, treatment with either oral estrogen alone or an estrogen-androgen combination reduced menopausal symptoms of somatic origin (eg, hot flashes). Menopausal women whose vasomotor symptoms are not adequately controlled by estrogen alone, may benefit from the same dose of estrogen in combination with an androgen (eg, methyltestosterone). Hot flashes in men caused by testosterone withdrawal may also be relieved by methyltestosterone, another androgen, or estrogen therapy. The effect of estrogen patches on hot flashes was investigated in 12 men receiving hormonal therapy with leuprolide (Lupron) for advanced prostate cancer. Transdermal estrogen reduced the overall severity and daily frequency of hot flashes. Hot flashes may recur following withdrawal of treatment. Hormonal replacement therapy is contraindicated in patients with breast or endometrial cancer, undiagnosed vaginal bleeding, and active deep vein thrombosis.
Gabapentin (Neurontin): A reduction in the frequency of hot flashes was reported in 6 patients during administration of gabapentin. One patient, a 52-year-old woman experiencing hot flashes caused by total abdominal hysterectomy and bilateral salpingo-oophorectomy, experienced complete resolution of her hot flashes 2 days after starting gabapentin. A second patient, a 58-year-old man with prostate cancer, experienced 15 hot flashes each day (10 of which occurred during the evening) while being treated with leuprolide. Within 1 day of starting gabapentin, there was complete resolution of nocturnal hot flashes; however, the daytime hot flashes persisted. When the patient neglected to take gabapentin at night, he experienced nocturnal hot flashes. Controlled clinical trials are needed to further assess the efficacy of gabapentin in the treatment of hot flashes.
Methyldopa (Aldomet): Methyldopa, 250 mg 2 to 3 times daily, has been reported to be beneficial in the treatment of hot flashes. In a randomized, double-blind, placebo-controlled, crossover study, the effects of methyldopa 250 mg twice daily on vasomotor flushes were evaluated in 10 menopausal women. Compared with placebo, methyldopa 250 mg twice daily reduced hot flashes; however, use may be limited by the occurrence of side effects.
Naloxone (eg, Narcan): Study results are conflicting. A decrease in subjective flushes has been reported during treatment with naloxone (2 mg infused over 90 minutes), while others have found no effect on subjective flushes when administered during menopause.
Paroxetine (Paxil): In 30 women who were breast cancer survivors, 20 mg/day of paroxetine reduced the frequency and severity of hot flashes 67% and 75%, respectively. At the conclusion of the study, 25 of the participants chose to continue paroxetine therapy. The most common side effect was somnolence. Similar results may be expected with other selective serotonin reuptake inhibitors (eg, fluoxetine [eg, Prozac]).
Venlafaxine (Effexor): The frequency and severity of hot flashes in breast cancer survivors were reduced 61% in patients receiving venlafaxine 75 mg daily compared with a 27% reduction with placebo. A minority of patients experienced decreased appetite, nausea, and dry mouth. With a dose of venlafaxine 150 mg/day, there was no increase in efficacy against hot flashes; however, there were more side effects. In a non placebo-controlled study, treatment with venlafaxine was evaluated in 16 men with prostate cancer who were experiencing hot flashes while undergoing androgen deprivation therapy. Administration of 25 mg/day of venlafaxine decreased hot flash scores 54% from baseline during 4 weeks of therapy. The average incidence of very severe and severe hot flashes decreased from a baseline frequency of 2.3 to 0.6 daily by the end of the study. Role of Serotonin Article
Progestins: Combined use of progestins and estrogens is indicated for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. Progestational agents may be the treatment of choice for hot flashes when estrogens are contraindicated (eg, women treated for breast cancer) or not well tolerated. In controlled trials, medroxyprogesterone (eg, Provera) and megestrol acetate (Megace) have been demonstrated to reduce hot flashes. In a double-blind crossover study involving menopausal women, medroxyprogesterone reduced the number of vasomotor flushes noted at the second week of treatment and produced a 73.9% decrease in the number of flushes observed at the ninth to twelfth week of treatment. When these women were subsequently given placebo, their symptoms immediately worsened. Vasomotor flushes were reduced 70% after administering medroxyprogesterone 20 mg/day for 4 weeks, compared with a 15% reduction with placebo. As with estrogen therapy, improvement in frequency and severity of hot flashes may not be seen until after 2 to 4 weeks of therapy. Side effects occurring with progestins include abdominal bloating, breast tenderness, irregular vaginal bleeding, and altered mood.
Vitamin E: Study results performed 50 to 60 years ago indicate that vitamin E has some benefit in the treatment of menopausal symptoms. However, these investigations were not double-blind or placebo-controlled. In a survey of 501 women, 251 of 438 women taking vitamin E for hot flashes, stated that the vitamin helped their hot flashes. Other studies have reported that vitamin E offered little benefit in decreasing the frequency and intensity of hot flashes in breast cancer survivors who kept a daily diary and were asked to complete an open-ended questionnaire after 9 weeks of taking vitamin E. Controlled clinical trials are needed to determine the efficacy of vitamin E for the treatment of hot flashes.
Herbal Treatment
Ginseng: In anecdotal reports, women have indicated experiencing a decrease in severity and frequency of hot flashes while taking ginseng. However, controlled studies have not been performed to verify these claims.
Phytoestrogens: Certain plants (eg, soybeans, alfalfa sprouts, legumes) are dietary sources of plant estrogens (ie, phytoestrogens). These phytoestrogens are weakly estrogenic. Eating foods high in phytoestrogen content may modulate short-term menopausal complaints. In a randomized, double-blind study of 58 postmenopausal women with ³ 14 hot flashes/week, hot flashes decreased 40% in women receiving 45 g of soy flour daily and 25% in women consuming 45 g of wheat flour daily. The decrease occurred over a shorter period of time in women receiving soy flour. Controlled clinical studies are needed to assess the effect of phytoestrogens on hot flashes.
Summary: Estrogens alone and in combination with progestins are indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause. During menopause, estrogen therapy is often effective in treating hot flashes. Responses usually occur in 2 to 4 weeks. If adequate relief does not occur with estrogen alone, combined use of an estrogen and androgen may prove to be beneficial. Estrogens are the most effective treatment of menopausal hot flashes. However, if they are contraindicated, a number of hormonal and non hormonal alternatives are available. Androgens, in combination with an estrogen, may be beneficial in the management of menopausal hot flashes and for the treatment of hot flashes in men caused by testosterone withdrawal. Clonidine decreased tamoxifen-induced hot flashes in postmenopausal women with breast cancer and decreased the frequency of hot flashes occurring during perimenopause and menopause » 20%. A similar effect would be expected with other a-adrenergic agonists. Gabapentin has been reported to decrease hot flashes associated with abdominal hysterectomy or prostate cancer. Methyldopa may reduce hot flashes; however, use is limited because of side effects. The effects of naloxone on hot flashes are equivocal with reports of a decrease or no effect on subjective flushes during menopause. Paroxetine and venlafaxine reduced the frequency and severity of hot flashes in breast cancer survivors. Similar effects may be expected with other serotonin reuptake inhibitors. While some subjective benefit in the treatment of hot flashes has been reported with vitamin E and certain natural products (eg, ginseng, plants containing phytoestrogens) controlled clinical studies are needed to determine the efficacy of these products for the treatment of hot flashes.
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