Hot Flashes

Kunal C. Kadakia

Charles L. Loprinzi

Menopause can be associated with multiple adverse symptoms, including vasomotor instability, urinary incontinence, sexual dysfunction, depression, and insomnia. Vasomotor instability is a constellation of symptoms commonly referred to as hot flashes. Although variable, hot flashes are often characterized as a sudden and disturbing sensation of intense warmth perceived mainly in the upper part of the chest. Red blotches can appear on the skin and the increase in skin temperature can lead to profuse diaphoresis. This feeling of intense warmth can be accompanied by palpitations, irritability, and anxiety. Hot flashes usually last a few minutes but can occur for a few seconds or for 10 minutes or longer. The frequency of hot flashes can also be quite variable, ranging from every 20 minutes to once a month. Nearly one-third of women during perimenopause and three-quarters of women during menopause experience hot flashes (1). However, the prevalence of (or reporting of) hot flashes has been noted to be variable among differing cultures and ethnic groups. African American women, cigarette smoking, low socioeconomic status, and obesity are associated with a higher prevalence of hot flashes (2). The majority of women experience hot flashes for 6 months to 2 years, although some women have them for 10 years or longer.

Hot flashes can be more substantial in patients with cancer. In many premenopausal women with breast cancer and other gynecologic malignancies, the precipitation of menopause by oophorectomy, chemotherapy, radiotherapy, or hormonal manipulation can lead to the rapid onset of hot flash symptoms that are more frequent and severe than those associated with natural menopause (3). Other reasons for the high frequency of menopausal symptoms in breast cancer survivors include age at diagnosis (frequently older than 50 years) and the abrupt withdrawal of hormonal therapy.

Hot flashes also affect men undergoing androgen deprivation therapy for prostate cancer. Hot flashes have been reported to occur in up to 70% of men after orchiectomy, 80% of men receiving neoadjuvant hormonal therapy before radical prostatectomy, and 70% to 80% of men receiving long-term androgen deprivation therapy (4,5,6). Hot flash symptoms can have serious detrimental effects on a patient’s work, recreation, sleep, and general perception of quality of life (7).

PATHOPHYSIOLOGY OF HOT FLASHES

The pathophysiology of hot flashes is not entirely understood. The thermoregulatory nucleus in the medial preoptic area of the hypothalamus is felt to regulate the mechanism leading to heat loss during hot flashes. The thermoregulatory nucleus activates perspiration and vasodilatation to keep core body temperature within a tightly regulated range, known as the thermoregulatory zone. In menopausal women with hot flashes, the thermoregulatory zone is shifted downward and is narrower than it is in menopausal women who do not have hot flashes (8). Therefore, in women with hot flashes, small changes in body temperature (as low as 0.01°C) may trigger the mechanisms of heat loss and lead to vasomotor symptoms (9).

The dramatic decreases in sexual hormone levels that occur in menopausal women and in men receiving androgen deprivation therapy are thought to be responsible for lowering and narrowing the thermoregulatory zone. However, sexual hormones have profound effects on multiple neuroendocrine pathways, and the exact mechanisms by which they affect the thermoregulatory zone continue to be elucidated. Since estrogen withdrawal results in decreased central serotonergic activity and since some of the newer antidepressants have been shown to relieve hot flashes in placebocontrolled, randomized clinical trials (vide infra), serotonin (5-HT) is thought to play an important role in mediating the thermoregulatory effects of estrogen. In particular, the 5-HT_2A receptor has been closely associated with thermoregulation in mammals. Multiple animal and human studies have shown that central expression of the 5-HT_2A receptor decreases after estrogen withdrawal and that estrogen treatment reverses this change in estrogen-deficient animals and women (10,11). In addition, tamoxifen has been shown to block the positive effects of estrogen on central 5-HT_2A receptor expression in ovariectomized rats (12). Since estrogen withdrawal and tamoxifen treatment result in decreased central expression of 5-HT_2A receptors, it is possible that the efficacy of the newer antidepressants against hot flashes is due, at least in part, to their ability to cause a “compensatory” increase in central 5-HT_2A signaling (13). Similarly, norepinephrine has also been implicated in the pathophysiology of hot flashes. Estrogen withdrawal leads to increased norepinephrine levels in the hypothalamus, which are thought to contribute to the lowering and narrowing of the thermoregulatory zone as well (8).

Another possible mechanism for hot flashes is endogenous opioid peptide withdrawal. In morphine-dependent rats, abrupt opioid withdrawal was associated with rapid temperature changes, which were eliminated with estrogen administration (14). This theory suggests that estrogen increases central opioid peptide activity, and therefore,
estrogen deficiency may be associated with decreased endogenous central opioid activity and subsequent thermoregulatory dysfunction.

The neuroendocrine pathways that govern thermoregulation in mammals are extraordinarily complex and, as yet, incompletely understood. There is a clear need for further research to clarify the pathophysiology of hot flashes and guide the development of more targeted nonhormonal therapeutic options.

TREATMENT OF HOT FLASHES

It is recommended that hot flashes are routinely assessed during clinical encounters in both cancer and noncancer patients as a component of systematic symptom surveys. Assessment of frequency, intensity, duration, and potential triggers of hot flashes may be helpful. Self-directed diaries to record these variables can be used to formulate treatment recommendations. The Hot Flash Related Daily Interference Scale (HFRDIS) is a validated tool utilized in the research setting to monitor hot flash symptomology prior to and following treatment (15). Studies are ongoing regarding devices that measure skin conductance as an objective marker for hot flashes; however, these have not been well validated (16). At this time, patient reports of hot flash experiences are the most reasonable measure.

PHARMACOLOGIC INTERVENTIONS

Hormonal Therapy

Estrogen

Estrogen therapy is the most established effective treatment option for hot flashes and can reduce symptoms by 80% to 90% (17). However, the use of estrogen has become controversial in the last decade, due to evidence of associated long-term health risks including coronary heart disease, cerebrovascular disease, venous thromboembolism, and breast cancer (18,19). The controversy surrounding its effect on breast cancer has been especially influential on clinical practice. The Woman’s Health Initiate trial demonstrated a 26% increased risk of breast cancer in females receiving combination hormonal therapy (estrogen plus progestin) (19). The HABITS (hormonal replacement therapy after breast cancer—is it safe?) trial was stopped prematurely after an interim analysis found an increased risk of new breast cancers in breast cancer survivors (HR = 2.4) with the use of combination hormonal therapy after 2 years (20). However, the Stockholm trial found no such risk at a median follow-up of 4 years (21). The maj or difference in the Stockholm trial was the use of a lower dose of progestin. Several other prospective and retrospective studies suggest that at least some breast cancer survivors (small tumors, negative lymph node status, long disease-free survival, or estrogen receptor-negative tumors) could be safely treated with estrogen replacement (22). Despite these data, the use of estrogen in women with a history of, or at high risk for, breast cancer remains controversial and is not recommended.

Commonly utilized estrogen formulations include daily oral micronized 17-β-estradiol (1 mg), conjugated equine estrogens (0.625 mg), piperazine estrone sulfate (1.25 mg), and transdermal 17-β-estradiol (50 µg/d). Although the preceding doses are effective, lower doses have also been shown to be efficacious and should be used for the shortest period of time possible. Contraindications to estrogen use include known coronary heart disease, previous venous thromboembolic disease or stroke, active liver disease, history of estrogen-dependent cancer, or those at high risk for these pathologies.

Progesterone Analogs

Progesterone therapy alone is another effective hormonal agent for the treatment of hot flashes. A placebo-controlled, randomized clinical trial of megestrol 40 mg daily in 97 women with a history of breast cancer and 66 men receiving androgen deprivation therapy showed a marked reduction in hot flashes, of 75% to 80%, in the treatment group compared with 20% to 25% in the placebo group (23). Three years after the completion of the trial, one-third of the women who were still taking megestrol reported having less hot flashes than women who had discontinued therapy (24). Similar results were found in another trial utilizing depot intramuscular medroxyprogesterone acetate (DMPA), a progestational agent (25). Most recently, the use of a single intramuscular dose of MPA was better tolerated and more efficacious than venlafaxine at a target dose of 75 mg daily over a 6-week period (26).

Despite the efficacy of progestational agents for the treatment of hot flashes, many physicians are hesitant in using hormonally active agents in patients with a history of breast or prostate cancer. Though there is some evidence that progestational agents are active against breast cancer (27), in vitro data suggest that they can increase epithelial cell proliferation, a potentially undesirable effect in patients with a history of breast cancer (28). In addition, megestrol was reported to increase the prostate-specific antigen level in a patient with prostate cancer (29).

Despite its efficacy, patients need to be counseled before starting a progestational agent if they have a history of breast or prostate cancer. Commonly prescribed regimens include oral megestrol acetate 20 to 40 mg daily, intramuscular DMPA 400 to 500 mg once, or intramuscular DMPA 400 to 500 mg every 2 weeks for three doses. Adverse effects of progestational agents include vaginal bleeding upon discontinuation of the medication, weight gain, bloating, and thromboembolic phenomena.

Nonhormonal Therapy

The reluctance to use hormonal agents in patients with a history of breast cancer provided an impetus for finding nonhormonal agents that could help alleviate hot flashes. The following is a summary of their clinical development and therapeutic yield (Table 9.1).

TABLE 9.1 Evidence and adverse effects of beneficial nonestrogenic therapeutics

	Treatment	Evidence^a	Adverse Events
Women	Citalopram	Two large RCTs	Constipation, dry mouth, nausea
	Desvenlafaxine	Two large RCTs	Dizziness, nausea, vomiting
	DMPA	One large RCT Three moderate RCTs One small RCT	Bloating, weight gain, thrombogenic
	Escitalopram	One large RCT	Fatigue, headaches, insomnia, nausea
	Gabapentin	Two large RCT Two moderate RCTs	Dizziness, fatigue, somnolence
	Megestrol acetate	Two moderate RCTs	Bloating, weight gain, thrombogenic
	Paroxetine	Two large RCTs	Insomnia, nausea, sexual dysfunction
	Pregabalin	One moderate RCT	Cognitive difficulty, sleepiness, weight gain
	Venlafaxine	Three large RCTs One moderate RCT	Anorexia, dry mouth, insomnia, nausea
Men on ADT	DMPA	One large RCT One small RCT	Bloating, weight gain, thrombogenic
	Gabapentin	One large RCT	Dizziness, fatigue, somnolence
	Megestrol acetate	One moderate RCT	Bloating, weight gain, thrombogenic
	Paroxetine	One pilot study	Insomnia, nausea, sexual dysfunction
	Venlafaxine	One pilot study One large RCT (not placebo-controlled)	Anorexia, dry mouth, insomnia, nausea
Note: See sections on each therapeutic for further details.
^aNumber of participants in study: large: >100; moderate: 50 to 99; and small: <50.
DMPA, depomedroxyprogesterone acetate; RCT, randomized controlled trial; ADT, androgen deprivation therapy.

Newer Antidepressants

In the 1990s, several authors reported reductions in hot flash frequency and severity in postmenopausal women who were taking four of the newer antidepressants for other reasons. Since then, the results of multiple prospective studies of antidepressants for the treatment of hot flashes have been reported. These studies have been reviewed and systematically analyzed in detail elsewhere (30,31). Given the reluctance to use hormonal agents in women with a history of breast cancer, many of these studies were done in this patient population, but some studies have been done in noncancer patients as well as in men with a history of prostate cancer. Self-completed daily hot flash diaries were used to document the frequency and severity of hot flashes in the majority of these studies. Data on toxicity, quality of life, and mood status were commonly obtained. The main efficacy measures used in most studies were the change from baseline in the weekly average number of daily hot flashes and average hot flash score (defined as the number of mild hot flashes plus twice the number of moderate hot flashes plus three times the number of severe hot flashes plus four times the number of very severe hot flashes during that week).

Venlafaxine. Venlafaxine selectively inhibits serotonin, norepinephrine, and dopamine reuptake, in order of decreasing potency and is referred to as a serotonin norepinephrine reuptake inhibitor (SNRI). In 1998, the efficacy of venlafaxine for the treatment of hot flashes was first supported (32). This pilot study included 23 women with a history of breast
cancer and 5 men receiving androgen deprivation therapy for prostate cancer. Patients treated with venlafaxine 12.5 mg twice daily had a greater than 50% reduction in median hot flash scores at 4 weeks. Patients also reported significant improvement in fatigue, sweating, and difficulty sleeping, and, at the completion of the study, 64% of the patients chose to continue venlafaxine.

Subsequently, a placebo-controlled, double-blind, randomized clinical trial was conducted to assess the efficacy and toxicity of venlafaxine in women with hot flashes (33). One-hundred and ninety one women were randomized to placebo or one of three target doses of venlafaxine extended release (ER): 37.5 mg daily, 75 mg daily, or 150 mg daily for 4 weeks. After 4 weeks of treatment, the median frequency of hot flashes decreased by 19%, 30%, 46%, and 58% in women in the four study groups, respectively. Despite improvement in Beck Depression Inventory scores, patients with normal baseline depression scores had a similar reduction in hot flashes to those with higher scores. Dry mouth, nausea, constipation, and decreased appetite were dose-dependent toxicities associated with venlafaxine. Sixty-nine percent of the women were taking tamoxifen and efficacy was similar whether tamoxifen was being used or not.

In another placebo-controlled, double-blind, randomized clinical trial, venlafaxine ER at a target dose of 75 mg daily was found to significantly decrease patient-perceived hot flash scores. This trial included 80 postmenopausal women who were treated for a total of 12 weeks. Despite the improvement in subjective hot flash scores, there were no statistically significant differences between the two groups in hot flash frequency or severity. This is likely because the authors of this study did not collect pretreatment baseline measures for hot flash frequencies or severity (34). Dry mouth, insomnia, and decreased appetite were significantly more common in the venlafaxine group. Mental health and vitality were significantly improved in the venlafaxine group and 93% of women in this group chose to continue venlafaxine at the conclusion of the trial.

Venlafaxine has also been compared with gabapentin and DMPA in two separate clinical trials. To compare venlafaxine and gabapentin, a group-sequential, open-label, randomized, crossover clinical trial of 4 weeks on each therapy was constructed (35). When compared with gabapentin at a target dose of 300 mg three times daily, venlafaxine ER 75 mg daily was found to be as effective in reducing hot flash scores (66% reduction in each group). However, women preferred venlafaxine to gabapentin at the end of the trial period (68% vs. 32%). Clinically, since there were approximately one-third of women in this trial who felt that gabapentin worked better for their hot flashes, this can be tried in those where venlafaxine is not helpful.

When compared with a single intramuscular dose of DMPA 400 mg, venlafaxine ER 75 mg daily was found to be less effective and less well tolerated (26). However, there were significant reductions in hot flash scores in both groups over the 6-week period (79% vs. 55%), respectively.

The efficacy of venlafaxine for the alleviation of hot flashes in men undergoing androgen deprivation therapy was evaluated in two published trials to date. In the first pilot study, 23 men were treated with venlafaxine 12.5 mg twice daily for 4 weeks; however, only 16 completed the study (36). Of these, 10 patients had a greater than 50% reduction in their hot flash scores at the end of the study. Treatment was well tolerated and median weekly hot flash scores decreased by 54%. The average incidence of severe and very severe hot flashes decreased from 2.3 per day at baseline to 0.6 per day at the end of the study. In the second trial, 919 men undergoing androgen deprivation therapy were randomly assigned to either venlafaxine 75 mg daily, oral MPA 20 mg daily, or cyproterone acetate 100 mg daily over a 1-month period (37). In this double-blind trial, the change in median daily hot flash scores between randomization and 1 month was -47%, -84%, and -95%, respectively.

Given available data, venlafaxine is a viable first-line option for the treatment of hot flashes in women and men. Therapy should be initiated with venlafaxine ER 37.5 mg daily and increased to 75 mg daily after 1 week, if tolerated. Common adverse effects include loss of appetite, dry mouth, insomnia, and nausea.

Desvenlafaxine. Desvenlafaxine is a newer SNRI and is the succinate salt form of the major active metabolite of venlafaxine. Desvenlafaxine has been studied in two large, randomized, placebo-controlled, clinical trials involving women without a history of breast cancer (38,39). In both trials, desvenlafaxine was associated with a 60% to 70% reduction in severity and frequency of hot flashes compared with placebo (˜50% reduction). Therapy should be initiated at 50 mg daily and increased to 100 mg daily after 3 days if tolerated. The major adverse effect is dose-dependent nausea, vomiting, and dizziness.

Paroxetine. Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with minimal effects on the reuptake of norepinephrine. The efficacy of paroxetine against hot flashes was initially supported in a pilot study in 2000 (40). In this study, women were treated with paroxetine 10 mg daily for 1 week, followed by 20 mg daily for 4 weeks. After 5 weeks of treatment, the mean hot flash frequency decreased by 67%, while the mean hot flash severity score decreased by 75%. There was also a statistically significant, change from baseline, improvement in depression, sleep, anxiety, and quality of life scores.

Given the positive findings, the authors conducted a placebo-controlled, double-blind, randomized clinical trial evaluating paroxetine controlled release (CR) in women suffering from hot flashes (41). One hundred and sixty-five women were randomized to either placebo, paroxetine CR 12.5 mg daily, or paroxetine CR 25 mg daily for 6 weeks. Among the 139 women who completed the trial, the hot flash score had decreased by 62% and 65% in the lower and higher dose paroxetine groups, respectively, compared with a 38% reduction in the placebo group. The mean daily hot flash frequency decreased from 7.1 to 3.8, 6.4 to 3.2, and 6.6 to 4.8 in the three groups, respectively. The improvement in hot flash symptoms was independent of tamoxifen use. Adverse
events were reported by 54% of women taking placebo and by 58% of women taking paroxetine. Subsequent to this trial, a placebo-controlled, double-blind, randomized, crossover clinical trial evaluating paroxetine 10 and 20 mg daily was completed (42). In this trial, 151 women were assigned to receive 4 weeks of paroxetine 10 or 20 mg daily followed by placebo or vice versa. Paroxetine 10 mg daily was found to reduce hot flash frequency by 41% compared with 14% with placebo. Paroxetine 20 mg reduced the frequency of hot flashes by 52% compared with 27% with placebo. While doses had relatively similar efficacy, patients taking the 10 mg dose were less likely to discontinue treatment.

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