Hormone Replacement Therapy
Estrogen replacement effectively controls hot flashes associated with biologic or treatment-associated postmenopausal states in women. The proposed mechanism of action of estrogen replacement therapy is that it ameliorates hot flashes by raising the core body temperature sweating threshold;[Level of evidence: I] however, many women have relative or absolute contraindications to estrogen replacement. Physicians and breast cancer survivors often think there is an increased risk of breast cancer recurrence or de novo breast malignancy with hormone replacement therapies and defer hormonal management of postmenopausal symptoms. Methodologically strong data evaluating the risk of breast cancer associated with hormone replacement therapy in healthy women have been minimal, despite strong basic science considerations suggesting the possibility of such a risk.
In May 2002, the Women's Health Initiative (WHI), a large, randomized, placebo-controlled trial of the risks and benefits of estrogen plus progestin in healthy postmenopausal women, was stopped prematurely at a mean follow-up of 5.2 years (±1.3) because of the detection of a 1.26-fold increased breast cancer risk (95% confidence interval [CI], 1.00–1.59) in women receiving hormone replacement therapy. Tumors among women in the hormone replacement therapy group were slightly larger and more advanced than in the placebo group, with a substantial and statistically significant rise in the percentage of abnormal mammograms at first annual screening; such a rise might hinder breast cancer diagnosis and account for the later stage at diagnosis.[3,4][Level of evidence: I] These results are supported by a population-based case-control study suggesting a 1.7-fold (95% CI, 1.3–2.2) increased risk of breast cancer in women using combined hormone replacement therapy. The risk of invasive lobular carcinoma was increased 2.7-fold (95% CI, 1.7–4.3), the risk of invasive ductal carcinoma was increased 1.5-fold (95% CI, 1.1–2.0), and the risk of estrogen receptor–positive/progesterone receptor–positive breast cancer was increased 2.0-fold (95% CI, 1.5–2.7). Increased risk was highest for invasive lobular tumors and in women who used hormone replacement therapy for longer periods of time. Risk was not increased with unopposed estrogen therapy.
The very limited data available do not indicate an increased risk of breast cancer recurrence with single-agent estrogen use in patients with a history of breast cancer.[6,7] A series of double-blind placebo-controlled trials suggests that low-dose megestrol acetate (i.e., 20 mg by mouth twice a day) and selective serotonin reuptake inhibitors (SSRIs) are among the more promising agents for hot flash management in this population. Limited data suggest that brief cycles of intramuscular depot medroxyprogesterone acetate also play a role in the management of hot flashes.[Level of evidence: I] Risk associated with progestin use is unknown.Other Pharmacologic Interventions
Numerous nonestrogenic, pharmacologic treatment interventions for hot flash management in women with a history of breast cancer and in some men who have undergone androgen deprivation therapy have been evaluated. Options with reported efficacy include androgens, progestational agents, gabapentin, SSRIs, selective serotonin norepinephrine inhibitors, alpha adrenergic agonists (e.g., methyldopa, clonidine), beta-blockers, and veralipride (an antidopaminergic agent). Inferior efficacy, lack of large definitive studies, and potential side effects limit the use of many of these agents.[9-11][Level of evidence: I]
Agents that have been found to be helpful in large, randomized, placebo-controlled clinical trials include venlafaxine, paroxetine, citalopram, fluoxetine, gabapentin, pregabalin, and clonidine.[9-11] These agents demonstrate a 40% to 60% reduction in hot flash frequency and score (a measure combining severity and frequency). Agents conferring a 55% to 60% reduction in hot flashes are venlafaxine extended release, 75 mg daily; paroxetine, 12.5 mg controlled release  or 10 mg daily; gabapentin, 300 mg tid;[16,17][Level of evidence: I];[Level of evidence: II] and pregabalin, 75 mg bid.[Level of evidence: I] Other effective agents resulting in about a 50% reduction in hot flashes include citalopram, 10 to 20 mg per day, which was studied in clinical trial NCCTG-N05C9;[Level of evidence: I] and fluoxetine, 20 mg per day. Clonidine, 0.1 mg transdermal  or oral daily,[Level of evidence: I] can reduce hot flashes by about 40%.
One study compared the efficacy and patient preference of venlafaxine, 75 mg, once daily to gabapentin, 300 mg, 3 times per day for the reduction of hot flashes. Sixty-six women with histories of breast cancer were randomly assigned in an open-label fashion to receive venlafaxine or gabapentin for 4 weeks; after a 2-week washout period, they received the opposite treatment for an additional 4 weeks. Both treatments reduced hot flash scores (severity multiplied by frequency) by about 66%. However, significantly more women preferred venlafaxine over gabapentin (68% vs. 32%, respectively).
A study using citalopram to evaluate hot flashes examined how much of a reduction in hot flashes was needed to have a positive impact on activities of daily living and general health-related quality of life. The authors reported that hot flashes had to be reduced at least 46% for women to report significant improvements in the degree of bother they experienced in daily activities.
Agents that have been evaluated in phase II trials but have not shown efficacy include bupropion, aprepitant, and desipramine.[Level of evidence: II] Interestingly, these agents do not primarily modulate serotonin. In addition, randomized clinical trials with sertraline have not provided convincing evidence of its efficacy in hot flash management.[28-30][Level of evidence: I]
If nighttime hot flashes or night sweats are a particular problem without causing much bother during daytime, strategies to simultaneously improve sleep and hot flashes are in order. Limited data exist related to effective treatments that can target both symptoms. One pilot trial evaluated mirtazapine (a tetracyclic antidepressant that mainly affects serotonin) for hot flashes because it is often prescribed for sleep difficulties. Twenty-two women were titrated up to 30 mg per day of mirtazapine at bedtime over a 3-week period; then they could choose 15 mg or 30 mg at bedtime daily for the fourth week. Hot flashes were reduced about 53% in this nonrandomized trial, and women were statistically significantly satisfied with their hot flash control. However, only 16 of the 22 women stayed on the agent for the entire study period because of excessive grogginess. Therefore, although this agent could be further studied in a larger randomized trial, it would be particularly important to evaluate the risk/benefit ratio.
Trazodone is another possible agent to use for nighttime hot flashes, based on clinical experience. Trazodone, an atypical antidepressant that is often used as a sleeping aid, has anecdotally been shown to be particularly helpful in patients with nocturnal hot flashes. Doses range from 50 mg to 300 mg. Clinical experience suggests that trazodone can help patients fall asleep and can control hot flashes during the night, helping them to stay asleep. Trazodone is a tricyclic antidepressant and, as such, would not be expected to have a great impact on hot flashes: one open-label pilot trial conducted with a tricyclic antidepressant, desipramine, as a proof-of-principle study did not show a benefit. However, this study has not been replicated. The effect of trazodone on sleep may be so profound that hot flashes are not bothersome; this hypothesis needs further study.
Side effects for antidepressant agents in the doses used to treat hot flashes are minimal in the short term and primarily include nausea, sedation, dry mouth, and appetite suppression or stimulation. In the long term, the prevalence of decreased sexual function with the use of SSRIs at doses for treating hot flashes is not known. The anticonvulsants gabapentin and pregabalin can cause sedation, dizziness, and difficulty concentrating, while clonidine can cause dry mouth, sedation, constipation, and insomnia.[16,17,19][Level of evidence: I] Patients respond as individuals to both the efficacy and the toxicity of various medications. Therefore, careful assessment and tailored treatment chosen collaboratively by provider and health care consumer are needed.
Data indicate that if one medication is not helpful for an individual, switching to another medication—whether a different antidepressant or gabapentin—may be worthwhile. In a randomized phase III trial (NCCTG-N03C5) of gabapentin alone versus gabapentin in conjunction with an antidepressant in women who had inadequate control of their hot flashes with an antidepressant alone,[Level of evidence: I] gabapentin use resulted in an approximately 50% median reduction in hot flash frequency and score, regardless of whether the antidepressant was continued. In other words, for women who were using antidepressants exclusively for the management of hot flashes that were inadequately controlled, initiation of gabapentin with discontinuation of the antidepressant produced results equal to those obtained with combined therapy, resulting in the need for fewer medications. Similarly, in a pilot study of women receiving inadequate benefit from venlafaxine for hot flash reduction, switching to open-label citalopram, 20 mg per day, resulted in a 50% reduction in hot flash frequency and score.Drug Interactions
Many of the SSRIs can inhibit the cytochrome P450 enzymes involved in the metabolism of tamoxifen, which is commonly used in the treatment of breast cancer. When SSRIs are being used, drug-drug interactions are noted. Tamoxifen, used in the management of breast cancer, is metabolized by the cytochrome P450 enzyme system, specifically CYP2D6. Wild-type CYP2D6 metabolizes tamoxifen to an active metabolite, 4-hydroxy-N-desmethyl-tamoxifen, also known as endoxifen. A prospective trial evaluating the effects of the coadministration of tamoxifen and paroxetine, a CYP2D6 inhibitor, on tamoxifen metabolism, found that paroxetine coadministration resulted in decreased concentrations of endoxifen. The magnitude of decrease was greater in women with the wild-type CYP2D6 genotype than in those with a variant genotype (P = .03).[Level of evidence: II]
In a prospective observational study of 80 women initiating adjuvant tamoxifen therapy for newly diagnosed breast cancer, variant CYP2D6 genotypes and concomitant use of SSRI CYP2D6 inhibitors resulted in reduced endoxifen levels. Variant CYP2D6 genotypes do not produce functional CYP2D6 enzymes.[Level of evidence: II] Since this study was published, several researchers have been evaluating the clinical implications of this finding.;[37-39][Level of evidence: II] One study followed more than 1,300 women for a median of 6.3 years and concluded that women who were poor metabolizers or heterozygous extensive/intermediate metabolizers (hence, less CYP2D6 activity) had higher rates of recurrence, worse event-free survival, and worse disease-free survival than did women who were extensive metabolizers. Similarly, a retrospective cohort study of more than 2,400 women in Ontario who were being treated with tamoxifen and had overlapping treatment with an SSRI has been completed. Authors concluded that women who concomitantly used paroxetine and tamoxifen had an increased risk of death that was proportionate to the amount of time they used these agents together.[Level of evidence: II]
The clinical implications of these changes and of other CYP2D6 genotypes  have not yet been elucidated, but the pharmacokinetic interaction between tamoxifen and the newer antidepressants used to treat hot flashes merits further study. Likewise, the risk of soy phytoestrogen use on breast cancer recurrence and/or progression has not yet been clarified. Soy phytoestrogens are weak estrogens found in plant foods. In vitro models suggest that these compounds have a biphasic effect on mammary cell proliferation that is dependent on intracellular concentrations of phytoestrogen and estradiol.Information Specific to Men
Data regarding the pathophysiology and management of hot flashes in men with prostate cancer are scant. The limited data that exist suggest that hot flashes in men are related to changes in sex hormone levels that cause instability in the hypothalamic thermoregulatory center analogous to the proposed mechanism of hot flashes that occur in women. As in women with breast cancer, hot flashes impair the quality of life for men with prostate cancer who are receiving androgen deprivation therapy. The vasodilatory neuropeptide, calcitonin gene–related peptide, may be instrumental in the genesis of hot flashes. With the exception of clonidine, the agents mentioned previously (refer to the Other Pharmacologic Interventions section of this summary) that have been found effective for hot flashes have shown similar rates of efficacy when studied in men. Treatment modalities include estrogens, progesterone, SSRIs, gabapentin 300 mg 3 times per day as an option for men, and cyproterone acetate, an antiandrogen. Cyproterone acetate is not available in the United States.
One large, multisite study from France  randomly assigned men who were taking leuprorelin for prostate cancer to receive venlafaxine, 75 mg; cyproterone acetate (an antiandrogen), 100 mg; or medroxyprogesterone acetate, 20 mg, when they reported at least 14 hot flashes per week. All three treatments significantly reduced hot flashes, with cyproterone resulting in a 100% median reduction, medroxyprogesterone resulting in a 97% reduction, and venlafaxine resulting in a 57% reduction at 8 weeks. More adverse events were reported with cyproterone acetate, including one serious adverse event (dyspnea) attributable to the drug. Venlafaxine was not associated with any serious adverse events and overall had a 20% adverse event rate attributable to the drug. Medroxyprogesterone was the most well-tolerated drug, with an adverse event rate of 12%, but with one serious event, urticaria. The most frequent side effects for all agents were related to gastrointestinal issues: nausea, constipation, diarrhea, and abdominal pain.
Pilot studies of the efficacy of the SSRIs paroxetine and fluvoxamine suggest that these drugs decrease the frequency and severity of hot flashes in men with prostate cancer.[45,46] As in women with hormonally sensitive tumors, there are concerns about the effects of hormone use on the outcome of prostate cancer, in addition to other well-described side effects.Cognitive and Behavioral Methods
Comprehensive nonpharmacologic interventions have been developed and evaluated for their ability to reduce hot flashes, night sweats, and the perception of burden or problems related to hot flashes and night sweats. These interventions have typically included the following:[48-51]
- Psychoeducation about managing general symptoms, including stress, anxiety, and sexual and other menopausal concerns.
- Relaxation exercises, including slow, deep breathing, called paced breathing.
- Cognitive restructuring that addresses catastrophizing, negative beliefs, and avoidance behaviors.
Behavioral interventions as a primary or adjunctive modality may also play a role in hot flash management. Core body temperature has been shown to increase before a hot flash; therefore, interventions that control body temperature could improve hot flash management. Some methods of controlling body temperature include the use of loose-fitting cotton clothing and the use of fans and open windows to keep air circulating. On the basis of the theory that serotonin may be involved as a central hot flash trigger, behavioral interventions such as stress management may modulate serotonin, causing a decrease in hot flashes.
Relaxation training and slow, deep breathing (paced breathing) were initially found to decrease hot flash intensity by as much as 40% to 50% in controlled pilot trials;[53,54] however, randomized trials with control arms using a different pace of breathing have not demonstrated significant benefit for paced-breathing interventions.[55,56]
Three large studies [49-51] with similar interventions have been completed using no treatment, usual care, or wait-list control comparison groups. While all of the studies demonstrated significant reductions in problem ratings or bother ratings related to hot flashes and night sweats, none showed actual reductions in hot flash frequency. Only one of the three studies demonstrated some significant improvements in night sweats at some data points. Cognitive behavioral interventions may be an important addition to pharmacological treatment to improve a patient’s overall experience with symptoms related to hot flashes. However, data have not supported the sole use of cognitive behavior therapy for reducing hot flashes.
Medical hypnosis is a newer intervention for hot flashes that has been shown to be helpful. In medical hypnosis, the provider facilitates a deep relaxation and trance state and, with the patient in that state, gives suggestions to the subconscious that would mitigate the symptom or problem being addressed. For hot flashes, medical hypnosis uses cooling suggestions and stress reduction to prevent rises in core body temperature and to decrease sympathetic activation. On the basis of strong pilot data, a randomized controlled trial with 187 postmenopausal women used an attention-control comparison and demonstrated significantly greater reductions in hot flashes in the hypnosis group than in the control group. The hypnosis intervention was 5 weeks long. At week 6, hot flash frequency was reduced in the hypnosis group 64%, compared with a 9% reduction in the control group. At week 12, the reduction in the hypnosis group was 75%, compared with a 17% reduction in the control group. Cancer survivors were not included in this study, but previous research has not demonstrated that interventions have a differential effect on hot flashes based on breast cancer history.
Future research on hot flash management may be aided by the development of psychometrically sound assessment tools such as the Hot Flash Related Daily Interference Scale, which evaluates the impact of hot flashes on a wide variety of daily activities.Integrative Approaches
Numerous herbs and dietary supplements are popularly used for hot flash reduction. Several of these substances have not been well studied in rigorous clinical trials. Furthermore, the biologic activity of various over-the-counter supplements has yet to be determined and is far from standardized. Some of the more well-studied agents include soy phytoestrogen, black cohosh, and vitamin E.
Vitamin E, 400 IU twice a day, appears to confer a modest reduction in hot flashes that is only slightly better than that seen with placebo. The reduction in hot flashes is roughly 35% to 40%.[59,60][Level of evidence: I]
Soy has been a dietary supplement of interest for decreasing menopausal symptoms and breast cancer for some time. The interest comes primarily from association studies of a high-soy diet and decreased breast cancer/menopausal symptoms in Asia. Soy is an isoflavone, which is part of a much larger class of plant compounds called flavonoids. Three types of isoflavones are found in soy products:
Isoflavones are often referred to as phytoestrogens or plant-based estrogens because they have been shown, in cell line and animal studies, to have the ability to bind with the estrogen receptor.
There is confusion about the safety of these plant-based estrogens because these agents can have properties that can cause estrogen-like effects in some cells, causing them to proliferate (divide and grow); while in other cells, isoflavones can stop or block estrogen effects, causing unwanted cells to not grow or even die. There is continuing debate about the following questions:
- What doses and types of soy inhibit estrogen as a growth factor?
- Under what circumstances does soy inhibit estrogen as a growth factor?
- In what doses or circumstances does soy promote estrogen-related growth?
Definitive answers to these questions are not known, but phytoestrogens continue to be investigated for chemopreventive properties. On the other hand, soy has been well studied in numerous randomized, placebo-controlled trials for its effects on reducing hot flashes.[63-67][Level of evidence: I] Most of those trials show that soy is no better than a placebo in reducing hot flashes.[Level of evidence: I]; Currently, there are no compelling data that would inspire the use of soy for hot flash management.
Similarly, trials of black cohosh that have been well designed with a randomized, placebo-controlled arm have also found that black cohosh is no better than a placebo in reducing hot flashes.[67,70,71][Level of evidence: I] Black cohosh used to be thought of as having estrogenic properties, but it is now known that it acts on serotonin receptors, as discussed at the Workshop on the Safety of Black Cohosh in Clinical Studies. One study evaluated black cohosh, red clover, estrogen and progesterone, and placebo in a randomized, double-blind trial.[Level of evidence: I] Each treatment arm was small (n = 22); however, over 12 months, hot flashes were reduced 34% by black cohosh, 57% by red clover, 63% by placebo, and 94% by hormone therapy. Of note, adherence rates were reported to be about 89% over the four groups during this long-term study. At 12 months, physiologic markers such as endometrial thickness, estradiol, estrone, follicle-stimulating hormone, sex hormone–binding globulin, and liver function tests were not statistically different for those on either red clover or black cohosh, compared with those on placebo. However, because these groups were small, the power for this secondary analysis was not reported, and it was likely underpowered to detect important differences.
Flaxseed is a plant that is part of the genus Linum, native to the area around the eastern Mediterranean and India. Flaxseed is a rich source of lignans and omega 3 fatty acids. Lignans found in flaxseed are called secoisolariciresinol diglucoside (SDG) and alpha-linolenic acid (ALA). Flaxseed is also a source of fiber. Lignans are a type of phytoestrogen (plant estrogen) that, like soy, is thought to have estrogen agonist-antagonist effects as well as antioxidant properties. Lignans are converted by colonic bacteria to enterodiol and enterolactone, which are metabolites believed to have important physiological properties such as decreasing cell proliferation and inhibiting aromatase, 5-alpha reductase, and 17-beta hydroxysteroid activity. Cell line studies have shown properties of aromatase inhibition with enterolactone but less so with enterodiol. It is thought that these properties can reduce the risk of hormone-sensitive cancers.[74-76] In addition, studies have shown that flaxseed can reduce estrogen levels through excretion in the urine.[77,78]
On the basis of preliminary data testing flaxseed for its effect on hot flashes and related endpoints,[79,80][Level of evidence: I] an open-label pilot study was conducted to evaluate 40 g of flaxseed in decreasing hot flashes. This study of 30 women showed a 57% reduction in hot flash scores and a 50% reduction in hot flash frequency over a 6-week period. However, a follow-up phase III, randomized, controlled trial conducted by the North Central Cancer Treatment Group with 188 women failed to show any benefit of 410 mg of lignans in a flaxseed bar over placebo.[Level of evidence: I]
Many plants and natural products are touted as wonderful remedies for hot flashes. Some of these products are plant phytoestrogens, and some have unknown properties. The agents include dong quai, milk thistle, red clover, licorice, and chaste tree berry. There is incomplete understanding of the biology of these agents and whether taking them would impact breast cancer risk or recurrence in a negative or positive way. Data suggest that these plants have different effects, dependent not only on the dose used but also on a woman's hormone environment when she takes them. Little is known about these agents, and caution with respect to taking them—if a woman is to avoid estrogen supplementation—is needed. [83-86]Acupuncture
Pilot and randomized sham trials have evaluated the use of acupuncture to treat hot flashes.[87-91][Level of evidence: I] Research in acupuncture is difficult to conduct, owing to the lack of novel methodology—specifically, the conundrum of what serves as an adequate control arm. In addition, the philosophy surrounding acupuncture practice is quite individualized, in that two women experiencing hot flashes would not necessarily receive the same treatment. It would be important to study acupuncture utilizing relevant clinical procedures; so far, acceptable research methods to accomplish this are lacking. Therefore, the data with respect to the effect of acupuncture on hot flashes are quite mixed, with many studies suffering from ineffective control arms. Therefore, as concluded in at least one review, there is not a body of evidence to definitively delineate the role or practice of acupuncture for hot flashes. (Refer to the Vasomotor symptoms section in the PDQ summary on Acupuncture for more information.)References
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