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.
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.
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]
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.)
- Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 77 (3): 487-90, 2002. [PUBMED Abstract]
- Pritchard KI: Hormone replacement in women with a history of breast cancer. Oncologist 6 (4): 353-62, 2001. [PUBMED Abstract]
- Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002. [PUBMED Abstract]
- Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003. [PUBMED Abstract]
- Li CI, Malone KE, Porter PL, et al.: Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 289 (24): 3254-63, 2003. [PUBMED Abstract]
- Vassilopoulou-Sellin R, Asmar L, Hortobagyi GN, et al.: Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. J Clin Oncol 17 (5): 1482-7, 1999. [PUBMED Abstract]
- Decker DA, Pettinga JE, VanderVelde N, et al.: Estrogen replacement therapy in breast cancer survivors: a matched-controlled series. Menopause 10 (4): 277-85, 2003 Jul-Aug. [PUBMED Abstract]
- Bertelli G, Venturini M, Del Mastro L, et al.: Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Ann Oncol 13 (6): 883-8, 2002. [PUBMED Abstract]
- Barton D, Loprinzi CL: Making sense of the evidence regarding nonhormonal treatments for hot flashes. Clin J Oncol Nurs 8 (1): 39-42, 2004. [PUBMED Abstract]
- Loprinzi CL, Stearns V, Barton D: Centrally active nonhormonal hot flash therapies. Am J Med 118 (Suppl 12B): 118-23, 2005. [PUBMED Abstract]
- Loprinzi CL, Barton DL, Sloan JA, et al.: Mayo Clinic and North Central Cancer Treatment Group hot flash studies: a 20-year experience. Menopause 15 (4 Pt 1): 655-60, 2008 Jul-Aug. [PUBMED Abstract]
- Sloan JA, Loprinzi CL, Novotny PJ, et al.: Methodologic lessons learned from hot flash studies. J Clin Oncol 19 (23): 4280-90, 2001. [PUBMED Abstract]
- Loprinzi CL, Kugler JW, Sloan JA, et al.: Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 356 (9247): 2059-63, 2000. [PUBMED Abstract]
- Stearns V, Beebe KL, Iyengar M, et al.: Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 289 (21): 2827-34, 2003. [PUBMED Abstract]
- Stearns V, Slack R, Greep N, et al.: Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 23 (28): 6919-30, 2005. [PUBMED Abstract]
- Guttuso T Jr, Kurlan R, McDermott MP, et al.: Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 101 (2): 337-45, 2003. [PUBMED Abstract]
- Pandya KJ, Morrow GR, Roscoe JA, et al.: Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 366 (9488): 818-24, 2005 Sep 3-9. [PUBMED Abstract]
- Biglia N, Sgandurra P, Peano E, et al.: Non-hormonal treatment of hot flushes in breast cancer survivors: gabapentin vs. vitamin E. Climacteric 12 (4): 310-8, 2009. [PUBMED Abstract]
- Loprinzi CL, Qin R, Baclueva EP, et al.: Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1. J Clin Oncol 28 (4): 641-7, 2010. [PUBMED Abstract]
- Barton DL, LaVasseur BI, Sloan JA, et al.: Phase III, placebo-controlled trial of three doses of citalopram for the treatment of hot flashes: NCCTG trial N05C9. J Clin Oncol 28 (20): 3278-83, 2010. [PUBMED Abstract]
- Goldberg RM, Loprinzi CL, O'Fallon JR, et al.: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12 (1): 155-8, 1994. [PUBMED Abstract]
- 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 132 (10): 788-93, 2000. [PUBMED Abstract]
- Bordeleau L, Pritchard KI, Loprinzi CL, et al.: Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol 28 (35): 5147-52, 2010. [PUBMED Abstract]
- Barton D, Loprinzi C, Diekmann B, et al.: Citalopram for hot flashes: “the rest of the story”. [Abstract] Support Care Cancer 16 (6): A-20-201, 730, 2008.
- Pérez DG, Loprinzi CL, Sloan J, et al.: Pilot evaluation of bupropion for the treatment of hot flashes. J Palliat Med 9 (3): 631-7, 2006. [PUBMED Abstract]
- Bardia A, Thompson S, Atherton PJ, et al.: Pilot evaluation of aprepitant for the treatment of hot flashes. Support Cancer Ther 3 (4): 240-6, 2006. [PUBMED Abstract]
- Barton DL, Loprinzi CL, Atherton P, et al.: Phase II Evaluation of Desipramine for the Treatment of Hot Flashes. Support Cancer Ther 4 (4): 219-24, 2007. [PUBMED Abstract]
- Kimmick GG, Lovato J, McQuellon R, et al.: Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J 12 (2): 114-22, 2006 Mar-Apr. [PUBMED Abstract]
- Gordon PR, Kerwin JP, Boesen KG, et al.: Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause 13 (4): 568-75, 2006 Jul-Aug. [PUBMED Abstract]
- Wu MF, Hilsenbeck SG, Tham YL, et al.: The efficacy of sertraline for controlling hot flashes in women with or at high risk of developing breast cancer. Breast Cancer Res Treat 118 (2): 369-75, 2009. [PUBMED Abstract]
- Perez DG, Loprinzi CL, Barton DL, et al.: Pilot evaluation of mirtazapine for the treatment of hot flashes. J Support Oncol 2 (1): 50-6, 2004 Jan-Feb. [PUBMED Abstract]
- Loprinzi CL, Kugler JW, Barton DL, et al.: Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. J Clin Oncol 25 (3): 308-12, 2007. [PUBMED Abstract]
- Loprinzi CL, Flynn PJ, Carpenter LA, et al.: Pilot evaluation of citalopram for the treatment of hot flashes in women with inadequate benefit from venlafaxine. J Palliat Med 8 (5): 924-30, 2005. [PUBMED Abstract]
- Stearns V, Johnson MD, Rae JM, et al.: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95 (23): 1758-64, 2003. [PUBMED Abstract]
- Jin Y, Desta Z, Stearns V, et al.: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97 (1): 30-9, 2005. [PUBMED Abstract]
- Desmarais JE, Looper KJ: Interactions between tamoxifen and antidepressants via cytochrome P450 2D6. J Clin Psychiatry 70 (12): 1688-97, 2009. [PUBMED Abstract]
- Bijl MJ, van Schaik RH, Lammers LA, et al.: The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat 118 (1): 125-30, 2009. [PUBMED Abstract]
- Schroth W, Goetz MP, Hamann U, et al.: Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 302 (13): 1429-36, 2009. [PUBMED Abstract]
- Kelly CM, Juurlink DN, Gomes T, et al.: Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 340: c693, 2010. [PUBMED Abstract]
- Bonanni B, Macis D, Maisonneuve P, et al.: Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol 24 (22): 3708-9; author reply 3709, 2006. [PUBMED Abstract]
- Goetz MP, Loprinzi CL: A hot flash on tamoxifen metabolism. J Natl Cancer Inst 95 (23): 1734-5, 2003. [PUBMED Abstract]
- This P, De La Rochefordière A, Clough K, et al.: Phytoestrogens after breast cancer. Endocr Relat Cancer 8 (2): 129-34, 2001. [PUBMED Abstract]
- Loprinzi CL, Dueck AC, Khoyratty BS, et al.: A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB). Ann Oncol 20 (3): 542-9, 2009. [PUBMED Abstract]
- Irani J, Salomon L, Oba R, et al.: Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncol 11 (2): 147-54, 2010. [PUBMED Abstract]
- Loprinzi CL, Barton DL, Carpenter LA, et al.: Pilot evaluation of paroxetine for treating hot flashes in men. Mayo Clin Proc 79 (10): 1247-51, 2004. [PUBMED Abstract]
- Nishiyama T, Kanazawa S, Watanabe R, et al.: Influence of hot flashes on quality of life in patients with prostate cancer treated with androgen deprivation therapy. Int J Urol 11 (9): 735-41, 2004. [PUBMED Abstract]
- Spetz AC, Zetterlund EL, Varenhorst E, et al.: Incidence and management of hot flashes in prostate cancer. J Support Oncol 1 (4): 263-6, 269-70, 272-3; discussion 267-8, 271-2, 2003 Nov-Dec. [PUBMED Abstract]
- Tremblay A, Sheeran L, Aranda SK: Psychoeducational interventions to alleviate hot flashes: a systematic review. Menopause 15 (1): 193-202, 2008 Jan-Feb. [PUBMED Abstract]
- Mann E, Smith MJ, Hellier J, et al.: Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial. Lancet Oncol 13 (3): 309-18, 2012. [PUBMED Abstract]
- Ayers B, Smith M, Hellier J, et al.: Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial. Menopause 19 (7): 749-59, 2012. [PUBMED Abstract]
- Duijts SF, van Beurden M, Oldenburg HS, et al.: Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial. J Clin Oncol 30 (33): 4124-33, 2012. [PUBMED Abstract]
- Freedman RR, Woodward S: Core body temperature during menopausal hot flushes. Fertil Steril 65 (6): 1141-44, 1996. [PUBMED Abstract]
- Freedman RR: Hot flashes: behavioral treatments, mechanisms, and relation to sleep. Am J Med 118 (Suppl 12B): 124-30, 2005. [PUBMED Abstract]
- Wijma K, Melin A, Nedstrand E, et al.: Treatment of menopausal symptoms with applied relaxation: a pilot study. J Behav Ther Exp Psychiatry 28 (4): 251-61, 1997. [PUBMED Abstract]
- Carpenter JS, Burns DS, Wu J, et al.: Paced respiration for vasomotor and other menopausal symptoms: a randomized, controlled trial. J Gen Intern Med 28 (2): 193-200, 2013. [PUBMED Abstract]
- Sood R, Sood A, Wolf SL, et al.: Paced breathing compared with usual breathing for hot flashes. Menopause 20 (2): 179-84, 2013. [PUBMED Abstract]
- Elkins GR, Fisher WI, Johnson AK, et al.: Clinical hypnosis in the treatment of postmenopausal hot flashes: a randomized controlled trial. Menopause 20 (3): 291-8, 2013. [PUBMED Abstract]
- Carpenter JS: The Hot Flash Related Daily Interference Scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage 22 (6): 979-89, 2001. [PUBMED Abstract]
- Barton DL, Loprinzi CL, Quella SK, et al.: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 16 (2): 495-500, 1998. [PUBMED Abstract]
- Ziaei S, Kazemnejad A, Zareai M: The effect of vitamin E on hot flashes in menopausal women. Gynecol Obstet Invest 64 (4): 204-7, 2007. [PUBMED Abstract]
- Enderlin CA, Coleman EA, Stewart CB, et al.: Dietary soy intake and breast cancer risk. Oncol Nurs Forum 36 (5): 531-9, 2009. [PUBMED Abstract]
- Anastasius N, Boston S, Lacey M, et al.: Evidence that low-dose, long-term genistein treatment inhibits oestradiol-stimulated growth in MCF-7 cells by down-regulation of the PI3-kinase/Akt signalling pathway. J Steroid Biochem Mol Biol 116 (1-2): 50-5, 2009. [PUBMED Abstract]
- Quella SK, Loprinzi CL, Barton DL, et al.: Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 18 (5): 1068-74, 2000. [PUBMED Abstract]
- Van Patten CL, Olivotto IA, Chambers GK, et al.: Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol 20 (6): 1449-55, 2002. [PUBMED Abstract]
- St Germain A, Peterson CT, Robinson JG, et al.: Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 8 (1): 17-26, 2001 Jan-Feb. [PUBMED Abstract]
- Nikander E, Kilkkinen A, Metsä-Heikkilä M, et al.: A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol 101 (6): 1213-20, 2003. [PUBMED Abstract]
- Newton KM, Reed SD, LaCroix AZ, et al.: Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 145 (12): 869-79, 2006. [PUBMED Abstract]
- Reed SD, Newton KM, LaCroix AZ, et al.: Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study. Menopause 15 (1): 51-8, 2008 Jan-Feb. [PUBMED Abstract]
- Lethaby AE, Brown J, Marjoribanks J, et al.: Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev (4): CD001395, 2007. [PUBMED Abstract]
- Osmers R, Friede M, Liske E, et al.: Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol 105 (5 Pt 1): 1074-83, 2005. [PUBMED Abstract]
- Pockaj BA, Gallagher JG, Loprinzi CL, et al.: Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol 24 (18): 2836-41, 2006. [PUBMED Abstract]
- Geller SE, Shulman LP, van Breemen RB, et al.: Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause 16 (6): 1156-66, 2009 Nov-Dec. [PUBMED Abstract]
- Wang C, Mäkelä T, Hase T, et al.: Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. J Steroid Biochem Mol Biol 50 (3-4): 205-12, 1994. [PUBMED Abstract]
- Thompson LU, Chen JM, Li T, et al.: Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res 11 (10): 3828-35, 2005. [PUBMED Abstract]
- Thompson LU, Seidl MM, Rickard SE, et al.: Antitumorigenic effect of a mammalian lignan precursor from flaxseed. Nutr Cancer 26 (2): 159-65, 1996. [PUBMED Abstract]
- Touillaud MS, Thiébaut AC, Fournier A, et al.: Dietary lignan intake and postmenopausal breast cancer risk by estrogen and progesterone receptor status. J Natl Cancer Inst 99 (6): 475-86, 2007. [PUBMED Abstract]
- Haggans CJ, Hutchins AM, Olson BA, et al.: Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women. Nutr Cancer 33 (2): 188-95, 1999. [PUBMED Abstract]
- Haggans CJ, Travelli EJ, Thomas W, et al.: The effect of flaxseed and wheat bran consumption on urinary estrogen metabolites in premenopausal women. Cancer Epidemiol Biomarkers Prev 9 (7): 719-25, 2000. [PUBMED Abstract]
- Lemay A, Dodin S, Kadri N, et al.: Flaxseed dietary supplement versus hormone replacement therapy in hypercholesterolemic menopausal women. Obstet Gynecol 100 (3): 495-504, 2002. [PUBMED Abstract]
- Lewis JE, Nickell LA, Thompson LU, et al.: A randomized controlled trial of the effect of dietary soy and flaxseed muffins on quality of life and hot flashes during menopause. Menopause 13 (4): 631-42, 2006 Jul-Aug. [PUBMED Abstract]
- Pruthi S, Thompson SL, Novotny PJ, et al.: Pilot evaluation of flaxseed for the management of hot flashes. J Soc Integr Oncol 5 (3): 106-12, 2007. [PUBMED Abstract]
- Pruthi S, Qin R, Terstreip SA, et al.: A phase III, randomized, placebo-controlled, double-blind trial of flaxseed for the treatment of hot flashes: North Central Cancer Treatment Group N08C7. Menopause 19 (1): 48-53, 2012. [PUBMED Abstract]
- Liu J, Burdette JE, Xu H, et al.: Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 49 (5): 2472-9, 2001. [PUBMED Abstract]
- Tamir S, Eizenberg M, Somjen D, et al.: Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells. Cancer Res 60 (20): 5704-9, 2000. [PUBMED Abstract]
- Lau CB, Ho TC, Chan TW, et al.: Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in women with breast cancer: is it appropriate? Menopause 12 (6): 734-40, 2005 Nov-Dec. [PUBMED Abstract]
- Rotem C, Kaplan B: Phyto-Female Complex for the relief of hot flushes, night sweats and quality of sleep: randomized, controlled, double-blind pilot study. Gynecol Endocrinol 23 (2): 117-22, 2007. [PUBMED Abstract]
- Borud EK, Alraek T, White A, et al.: The Acupuncture on Hot Flushes Among Menopausal Women (ACUFLASH) study, a randomized controlled trial. Menopause 16 (3): 484-93, 2009 May-Jun. [PUBMED Abstract]
- Hervik J, Mjåland O: Acupuncture for the treatment of hot flashes in breast cancer patients, a randomized, controlled trial. Breast Cancer Res Treat 116 (2): 311-6, 2009. [PUBMED Abstract]
- Vincent A, Barton DL, Mandrekar JN, et al.: Acupuncture for hot flashes: a randomized, sham-controlled clinical study. Menopause 14 (1): 45-52, 2007 Jan-Feb. [PUBMED Abstract]
- Borud EK, Alraek T, White A, et al.: The effect of TCM acupuncture on hot flushes among menopausal women (ACUFLASH) study: a study protocol of an ongoing multi-centre randomised controlled clinical trial. BMC Complement Altern Med 7: 6, 2007. [PUBMED Abstract]
- Liljegren A, Gunnarsson P, Landgren BM, et al.: Reducing vasomotor symptoms with acupuncture in breast cancer patients treated with adjuvant tamoxifen: a randomized controlled trial. Breast Cancer Res Treat 135 (3): 791-8, 2012. [PUBMED Abstract]
- Cho SH, Whang WW: Acupuncture for vasomotor menopausal symptoms: a systematic review. Menopause 16 (5): 1065-73, 2009 Sep-Oct. [PUBMED Abstract]