Menopausal hot flashes

INTRODUCTION — Hot flashes occur in approximately 75 to 80 percent of menopausal women in the United States. The flashes most often begin in the perimenopausal period, although, in some women, they do not begin until after menopause. Hot flashes are almost always due to menopause. Other causes, including carcinoid syndrome, are uncommon (table 1).

The prevalence, pathophysiology, and treatment of hot flashes will be reviewed here. Other menopausal symptoms and the risks, benefits, and practical aspects of menopausal hormone therapy (MHT) are reviewed separately. (See "Clinical manifestations and diagnosis of menopause" and "Menopausal hormone therapy: Benefits and risks" and "Treatment of menopausal symptoms with hormone therapy" and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment".)

EPIDEMIOLOGY — Symptoms become far more common during the menopausal transition, with a frequency of approximately 40 percent in the early transition and increasing to 60 to 80 percent in the late menopausal transition and early postmenopausal stage (figure 1) [1-5].

Prevalence and natural history — Vasomotor symptoms (VMS) or "hot flashes" are the most common complaint during the menopausal transition, occurring in up to 80 percent of women [2,6-8], although the frequency appears to vary by culture and ethnicity [9,10] (see 'Risk factors' below). Many to most women describe their symptoms as severe, but only approximately 20 to 30 percent of women seek medical attention for treatment [1,11,12]. Some women first develop hot flashes that cluster around menses during their late reproductive years, but symptoms are typically mild and do not require treatment.

Symptoms become far more common during the menopausal transition, with a frequency of approximately 40 percent in the early transition and increasing to 60 to 80 percent in the late menopausal transition and early postmenopausal stage (figure 1) [1-5].

Four different trajectories of menopausal symptoms occur with nearly equal frequency: early onset 18.4 percent; onset near final menstrual period with later decline 29.0 percent; early onset with persistently high frequency 25.6 percent; and persistently low frequency 27.0 percent (figure 2) [13].

Risk factors

●Obesity – Obese postmenopausal women have higher serum estrone concentrations than lean women due to increased peripheral conversion of androstenedione in adipose tissue [14,15], but paradoxically, these women are more likely to have hot flashes [16,17]. Weight loss may help reduce their hot flashes [18]. (See 'Role of complementary and alternative therapies' below.)

●Smoking [16,17].

●Reduced physical activity.

●Socioeconomic factors – Obtaining less than a high school education and having difficulty paying for basics are associated with a higher frequency of hot flashes [16].

●Hormonal concentrations – Annual serum follicle-stimulating hormone (FSH) levels, but not other hormones (estradiol, testosterone, dehydroepiandrosterone sulfate [DHEAS]), when collectively modeled longitudinally, are associated with both the prevalence and frequency of VMS [1].

●Ethnic factors – African American women report more frequent hot flashes than Caucasian women, and Japanese and Chinese women report less [8,16].

●Genetic variants – Women who have variations in the gene that codes for tachykinin receptor 3 (TACR3) are more likely to experience hot flashes than women without those variations [19]. Baseline genotype samples were obtained from over 17,000 women enrolled in the Women's Health Initiative Observational Study and more than 11 million single-nucleotide polymorphisms (SNPs) were evaluated for the presence or absence of vasomotor symptoms. A number of SNPs on chromosome 4 were found to be associated with vasomotor symptoms; all were on TACR3, which is implicated in the secretion of gonadotropin-releasing hormone (GnRH). Neurokinin B (NKB) (a hypothalamic neuropeptide) and its receptor (NK3R) are also thought to be associated with vasomotor symptoms as TACR3 is the gene that encodes NK3R, and peripheral infusion of NKB induces hot flashes in postmenopausal women [20]. (See 'Anti-epileptics/other' below.)

Duration — It had been thought that VMS diminish and stop within a few years of onset in most women [12]. However, accumulating data suggest that symptoms typically last far longer [21-24]:

●In the Penn Ovarian Aging Study, the mean duration of moderate/severe hot flashes was 4.9 years, but one-third of women continued to experience moderate/severe hot flashes for 10 years after the final menstrual period (FMP) [23].

●Nine percent of women were still experiencing hot flashes at age 72 years in one study [22]. In a second study, 8 percent of women continued to have hot flashes into their late menopausal years (≥20 years beyond menopause) [21].

●The best estimate of total VMS duration comes from the Study of Women across the Nation (SWAN) [24]. Among 1449 women with VMS, the median total VMS duration was 7.4 years, with symptoms persisting for a median of 4.5 years after the FMP. Women who were premenopausal or early perimenopausal when they first experienced VMS had the longest total duration (>11.8 years, post-FMP median duration 9.4 years). When compared with other racial/ethnic groups, African American women had the longest total VMS duration (10.1 years), while Chinese and Hispanic women had the shortest (approximately five years). The different trajectories of menopausal symptoms are described above (figure 2). (See 'Prevalence and natural history' above.)

The long duration of hot flashes raises treatment challenges for many women (typically no more than four to five years to avoid excess breast cancer risk). Therefore, many women will continue to be symptomatic after their MHT is discontinued. (See 'Duration of therapy' below.)

PATHOPHYSIOLOGY — Hot flashes are mediated by thermoregulatory dysfunction at the level of the hypothalamus and are induced by estrogen withdrawal [25]. The thermoneutral zone is narrowed in women with hot flashes [26]. While premenopausal women initiate mechanisms to dissipate heat when the core body temperature increases by 0.4°C, this happens with much lower increases in temperature in menopausal women [27].

The feeling of warmth results from inappropriate peripheral vasodilatation with increased digital and cutaneous blood flow. Perspiration results in rapid heat loss and a decrease in core body temperature below normal. Shivering may then occur as a normal mechanism to restore the core temperature to normal [25]. Estrogen administration restores the "thermoneutral zone" to normal and largely abolishes hot flashes.

The observation that prepubertal girls, whose endogenous estrogen levels are very low, do not experience hot flashes provides evidence that hypoestrogenemia alone is not adequate for hot flashes to occur. Data from patients with Turner syndrome and functional hypothalamic amenorrhea suggest that exposure to adult levels of estrogen followed by withdrawal are necessary for hot flashes to occur. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations", section on 'Clinical manifestations'.)

Evidence for central mediation of the changes in temperature comes from studies demonstrating that hot flashes occur simultaneously with, but are not caused by, pulses of luteinizing hormone (LH) [28,29]. The close proximity of the medial preoptic area (the major thermoregulatory area in mammals) and a high density of gonadotropin-releasing hormone (GnRH)-containing neurons suggest the possibility of simultaneous activation of a burst of GnRH release and thermoregulatory changes.

One hypothesis, now supported by increasing evidence, suggests that KNDy (kisspeptin, neurokinin B, and dynorphin) neurons mediate the LH and thermoregulatory changes [30]. (See 'Neurokinin 3 receptor antagonist' below.)

CLINICAL MANIFESTATIONS

Typical symptoms — Hot flashes typically begin as the sudden sensation of heat centered on the upper chest and face that rapidly becomes generalized. The sensation of heat often lasts from two to four minutes, is often associated with profuse perspiration and occasionally palpitations, and is sometimes followed by chills, shivering, and a feeling of anxiety. Hot flashes may range from an average of less than one each day to as many as one per hour during the day and night.

Hot flashes have a negative impact on quality of life as well as an association with adverse health indicators (increased cardiovascular risk and greater bone loss/increased bone turnover) [31,32].

Although several grading scales have been reported, a practical classification of hot flashes and nights sweats utilizes a four-point scale [33]:

●(1) Not present

●(2) Mild – Do not interfere with usual activities

●(3) Moderate – Interfere somewhat with usual activities

●(4) Severe – So bothersome that usual activities cannot be performed

Other causes of sweating — Other causes of sweating may mimic hot flashes or night sweats, including the carcinoid syndrome, medications, hyperthyroidism, infection, and malignancy, all of which are reviewed in detail separately (table 2 and table 3). (See "Evaluation of the patient with night sweats or generalized hyperhidrosis", section on 'Medications'.)

Effect on sleep — When hot flashes occur at night, women typically describe them as "night sweats." Vasomotor symptoms (VMS) at night can cause significant sleep disturbances in many women [34-36]. In one study of 34 symptomatic perimenopausal women undergoing one to five overnight polysomnographic (PSG) recordings, 69 percent of hot flashes were associated with awakening [37]. Hot flashes, although not the only cause of sleep disturbance, accounted for 27 percent of wakefulness during the night in these women. The estimated prevalence of difficulty sleeping based upon two longitudinal cohort studies was 32 to 40 percent in the early menopausal transition, increasing to 38 to 46 percent in the late transition [7,38].

PSG studies suggest that nocturnal hot flashes are more common during the first four hours of sleep, whereas rapid eye movement (REM) sleep in the subsequent four hours suppresses hot flashes, arousals, and awakenings [34].

Other sleep problems — VMS can disrupt sleep in peri- and postmenopausal women, but there are many other issues that disturb sleep in this population including primary sleep disorders, anxiety, and depression. Menopausal sleep disturbances are discussed separately. (See "Clinical manifestations and diagnosis of menopause", section on 'Sleep disturbance'.)

MANAGEMENT

General principles — The approach to management of hot flashes is based upon a number of factors, including:

●Symptom intensity and frequency.

●Medical history – Is the patient a candidate for menopausal hormone therapy (MHT)? (See "Treatment of menopausal symptoms with hormone therapy", section on 'Is my patient a candidate for MHT?'.)

●Personal choice – Is the patient interested in MHT?

●Coexistence of other menopausal symptoms, such as depression, as these women often require treatment with both MHT and antidepressants (usually selective serotonin reuptake inhibitors [SSRIs]). (See "Treatment of menopausal symptoms with hormone therapy", section on 'Perimenopausal mood disorders'.)

Women with mild hot flashes

Simple behavioral measures — Women with mild flashes (hot flashes that do not interfere with usual activities) usually do not need pharmacotherapy (see 'Typical symptoms' above). Instead, simple behavioral measures, such as lowering room temperature, using fans, dressing in layers of clothing that can be easily shed, and avoiding triggers (such as spicy foods and stressful situations), can help reduce the number of hot flashes. The concept of the narrowing of the thermoregulatory zone, described above, explains why reducing the layers of clothing may reduce the severity of hot flashes [27]. (See 'Pathophysiology' above.)

Other — Most women do well with the simple measures described. Others may try complementary and alternative therapies, which are described below. Most of these have limited evidence of efficacy, but benefits from the placebo effects of these therapies can be substantial. (See 'Role of complementary and alternative therapies' below.)

Other potential options may include weight loss, cognitive behavioral therapy (CBT), vitamin E, and hypnosis. Several other approaches are either ineffective, not widely available, or more appropriate as a back-up option for women with severe symptoms (eg, stellate ganglion block) [39,40].

Some clinicians recommend vitamin E to women with mild hot flashes because, at low doses, it is well tolerated and not associated with toxicity [40]. In one report, vitamin E and placebo were associated with reductions in hot flash frequencies of 32 and 29 percent, respectively, a marginal difference that is not clinically important [39].

Women with moderate to severe hot flashes — Hormonal or other pharmacotherapy is usually needed for women with more bothersome hot flashes.

Hormonal options

Menopausal hormone therapy — For most women with moderate to very severe hot flashes and no contraindications, we suggest MHT. Women with an intact uterus need both estrogen and a progestin, while those who have undergone hysterectomy can receive estrogen only. The management of menopausal women who choose to take hormone therapy and the available estrogen and progestin preparations are discussed in detail separately. (See "Treatment of menopausal symptoms with hormone therapy" and "Preparations for menopausal hormone therapy".)

For women interested in MHT, the first step is to determine the potential risks for the specific individual. The majority of perimenopausal and recently menopausal women are good candidates for short-term hormone therapy for symptom relief. However, for women with a history of breast cancer, coronary heart disease (CHD), a previous venous thromboembolic event (VTE) or stroke, or those at moderate or high risk for these complications, alternatives to hormone therapy should be suggested [41]. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Is my patient a candidate for MHT?'.)

For women who are candidates for and choose to take estrogen, further discussion about the type, dose, and route of estrogen; addition of a progestin (required for nearly all women with a uterus, unless the selective estrogen receptor modulator [SERM] bazedoxifene is added to an estrogen); the most appropriate progestin regimen; and the duration of therapy are reviewed in detail separately. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Our preferred regimens'.)

Bazedoxifene/conjugated estrogen — An emerging class of drugs called tissue selective estrogen complexes (TSECs) involves the combination of a SERM and an estrogen [42]. Bazedoxifene, a SERM, combined with conjugated estrogens is available in the United States and the European Union for the treatment of postmenopausal vasomotor symptoms (VMS) and osteoporosis prevention [43].

Bazedoxifene/conjugated estrogen has estrogen agonist effects on bone, antagonist effects on the endometrium, and apparently neutral effects on breast. A theoretical advantage of this combination would be to relieve estrogen deficiency symptoms while avoiding progestin-associated side effects, breast tenderness, and the increased risks of endometrial and breast cancer.

Therefore, potential indications for bazedoxifene/conjugated estrogen include for women with moderate to severe hot flashes who have breast tenderness with estrogen-progestin therapy, or for women who cannot tolerate oral progestin therapy. Its potential role for bone loss is reviewed separately. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Bazedoxifene-conjugated estrogen'.)

The combination of conjugated estrogen 0.45 mg/bazedoxifene 20 mg in women with moderate to severe hot flashes decreases hot flash frequency by approximately 75 percent (versus 50 percent for placebo) [43,44]. The combination also provides endometrial protection (without addition of a progestin) and results in similar rates of amenorrhea as placebo and higher cumulative rates of amenorrhea than estrogen-progestin therapy (87 percent for conjugated estrogen 0.45 mg/bazedoxifene 20 mg, 54 percent for conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg) [45,46]. Conjugated estrogen/bazedoxifene has also been associated with a lower incidence of breast pain and tenderness (5 to 8 percent) than combined conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg (20 to 24 percent); in addition, breast density does not appear to increase with conjugated estrogen/bazedoxifene [42,47].

Like other SERMs, the risk of VTE is increased with bazedoxifene [48]. To date, no additive effect on VTE has been observed with the combination conjugated estrogen/bazedoxifene, but longer studies are needed to fully address this risk. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Bazedoxifene'.)

Combination of estrogen plus intrauterine levonorgestrel — This approach has been suggested as a means of giving estrogen without the systemic effects of a progestogen while preventing uterine stimulation [49]. However, intrauterine levonorgestrel was associated with increased breast cancer in premenopausal women in one study [50], and systemic absorption of levonorgestrel occurs. Long-term safety in postmenopausal women has not been demonstrated. For these reasons, we are cautious about recommending this approach [51]. If this option is chosen, the lack of long-term safety data should be discussed with the patient.

Other treatment options for women who cannot tolerate oral progestin therapy are reviewed separately. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Progestins'.)

Not recommended: Bioidentical hormone therapy — The term "bioidentical hormone" technically refers to an exogenous hormone with the same molecular structure as a hormone that is endogenously produced. However, in popular culture, the term refers to the use of custom-compounded, multihormone regimens with dose adjustments based upon serial hormone monitoring. Some postmenopausal women have turned to this approach based upon claims of better safety and efficacy. However, there is no evidence to support this, and we suggest against this approach [52]. (See "Preparations for menopausal hormone therapy", section on 'Compounded bioidentical hormone therapy'.)

Nonhormonal pharmacotherapy — For women with moderate to severe hot flashes who are not candidates for hormone therapy based upon their breast cancer, CHD, or VTE risk and for those who choose not to take MHT, we suggest nonhormonal agents [41,53]. The best studied agents with positive results include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), anti-epileptics, clonidine and oxybutynin, and centrally acting drugs.

These drugs are also often tried in women who experience recurrent hot flashes after stopping MHT. Our choice of drug depends upon whether the patient is taking tamoxifen, the pattern of hot flashes, and the presence of a mood disorder or sleep problem.

Importance of placebo effect — Interpretation of the efficacy of various agents studied in clinical trials is confounded by the placebo effect, which can reduce hot flashes by approximately 20 to 50 percent [54-56]. Women with higher anxiety scores may be more likely to respond to placebo [57]. These observations suggest that even statistically significantly effective agents may act at least partially through a placebo-mediated mechanism. The high placebo rate highlights the importance of testing every hot flash therapy against placebo in randomized, controlled trials.

SSRIs/SNRIs — The most effective pharmacologic alternatives to estrogen include some of the antidepressants in the SSRI and SNRI classes [54,55,58,59]. Their efficacy has been demonstrated in individual placebo-controlled trials [60-69], a pooled analysis of seven trials of SSRIs/SNRIs (and three trials of gabapentin) [54], and a meta-analysis of 43 trials of nonestrogen therapies [55]. Key points about the use of these drugs for VMS in postmenopausal women include the following:

●The clinical response is more rapid (days) than the typical response to SSRIs for depression (weeks) [67].

●These drugs appear to be equally effective in women with breast cancer (with or without tamoxifen) and in women with surgical or natural menopause [70].

●Although no head-to-head trials have been performed, indirect comparisons suggest that venlafaxine, desvenlafaxine, paroxetine, citalopram, and escitalopram have a similar modest benefit for hot flashes. Results from some of the individual trials of nonestrogenic treatment options are shown in the figure (figure 3) [65].

●One author of this topic suggests low-dose paroxetine (7.5 mg/day) [71] as the first choice of SSRIs/SNRIs, since this is the only agent that has received approval by the US Food and Drug Administration (FDA) for the treatment of hot flashes. Paroxetine preparations shown to be modestly effective for hot flashes include paroxetine mesylate (7.5 mg/day) and paroxetine hydrochloride (10 and 20 mg/day, and 12.5 mg and 25 mg/day [controlled release]) [61,64,71].

However, paroxetine should be avoided in women taking tamoxifen (see 'Women with breast cancer' below). In addition, the new low-dose preparation is more expensive and is not covered by many insurers.

●A second author of this topic suggests citalopram as the first choice of SSRI/SNRIs. The optimal dose of this agent appears to be 20 mg, and side effects are minimal and similar to those of the other SSRI/SNRIs [66,67,72-74].

●We suggest against the use of sertraline and fluoxetine, because neither has a clinically important effect on hot flashes. In three trials, sertraline was no more effective than placebo [62,72,75,76]. In addition, neither of these agents should be used in women on tamoxifen [62,72,75,76].

●While venlafaxine is well studied, it has more acute toxicity (nausea and vomiting) and can have significant withdrawal symptoms in occasional patients [60,63,77,78]. If it is used, we suggest the sustained-release preparation starting with 37.5 mg/day for one week, increasing to 75 mg/day after the first week, to reduce the incidence of initial nausea [63]. When patients stop therapy, they should be instructed to decrease to 37.5 mg for one week before stopping altogether. One trial reported that venlafaxine (75 mg/day) had similar efficacy for hot flash relief as a low dose of oral estradiol (0.5 mg) [77]. However, in a clinical setting, increasing the dose of venlafaxine would be unlikely to result in a further reduction in hot flashes, while increasing the dose of estrogen could potentially eliminate hot flashes altogether.

●Desvenlafaxine, the main active metabolite of venlafaxine, has similar benefits for hot flashes and a similar side effect profile as venlafaxine [79]. While not commonly used, an advantage of this agent is that dose escalation is not usually necessary, as the variability in conversion of precursor to active drug is not a factor.

●While SSRIs or SNRIs are preferred as first-line therapy for most women, gabapentin may be a better option in some, for example, women whose hot flashes are primarily at night (see 'Anti-epileptics/other' below). In a trial comparing venlafaxine and gabapentin, hot flash reduction was similar with both drugs, but patients preferred venlafaxine by a 2:1 ratio [78]. For those preferring venlafaxine, their average hot flash score improved by 41 percent more on venlafaxine than on gabapentin. In those preferring gabapentin, their average hot flash score improved by 47 percent more than with venlafaxine, illustrating that gabapentin may work better in some patients. (See 'Anti-epileptics/other' below.)

●As paroxetine blocks the conversion of tamoxifen to active metabolites through CYP2D6, it should not be used in women on tamoxifen. Venlafaxine minimally blocks this enzyme and is preferred in women taking this antiestrogen. It should be noted that the effect of CYP2D6 on tamoxifen efficacy is a subject of substantial controversy with no consensus at present [80]. (See 'Women with breast cancer' below.)

●Since hot flashes gradually subside without therapy in most, but not all, postmenopausal women, any drug can be gradually tapered after a reasonable period of time; in the authors' experience, one to two years would be an appropriate time. Women should be instructed to taper SSRIs and SNRIs to avoid drug withdrawal symptoms.

●For women taking nonhormonal pharmacotherapies, we suggest trying another pharmacologic agent if one therapy is ineffective or not tolerated. If one SSRI/SNRI is tried but does not work, a second one could be tried before moving to another class of drug. If the SSRI/SNRI class of drugs is ineffective, a trial of gabapentin would be reasonable. Other options would include pregabalin or clonidine. (See 'Anti-epileptics/other' below.)

●If these pharmacologic options or MHT are ineffective or not tolerated, systemic progestin therapy or less well-established therapies (see 'Role of complementary and alternative therapies' below) can be tried. In addition, other causes of flushes or night sweats should be considered in women who do not respond to multiple therapies (table 2 and table 3).

Anti-epileptics/other

●Gabapentin – Gabapentin is an anti-epileptic drug that it is commonly used for other indications, including post-herpetic neuralgia and painful diabetic neuropathy. However, it is also effective for hot flashes in some women. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects" and "Overview of the management of epilepsy in adults".)

Gabapentin 900 mg/day (typically administered as 300 mg three times per day) has been shown to be more effective than placebo in a number of trials (figure 3) [54,68,69,81,82].

Nocturnal hot flashes appear to occur primarily in the first four hours of sleep, whereas rapid eye movement (REM) sleep in the subsequent four hours suppresses hot flashes [34]. In women whose hot flashes occur primarily at night, the authors have found that a single dose of gabapentin given at bedtime often relieves the hot flashes that awaken patients from sleep. If night sweats do occur, many women find that they fall back asleep more easily than they did pretreatment. The sedating effect of gabapentin and its effects to reduce vasomotor instability work together. This regimen also minimizes the side effects of gabapentin encountered during the daytime.

Individualized dosing is needed because of variable patient sensitivity to this agent. We suggest starting with 100 mg one hour before bedtime and increasing by 100 mg every three nights until relief of hot flashes, side effects, or a maximum of 900 mg.

At much higher doses, gabapentin may be as effective as estrogen but it is limited by its side effects. In a one trial (20 patients per arm) of women receiving gabapentin (dose titrated up to 2400 mg over 12 days), conjugated estrogen (0.625 mg), or placebo, both gabapentin and estrogen reduced hot flash severity score to a similar degree when compared with placebo (72, 71, and 54 percent, respectively) [83]. However, at this dose, gabapentin caused significant side effects including headache, dizziness, and disorientation.

Combined therapy with gabapentin and an antidepressant (SSRI or venlafaxine) does not appear to be more effective for hot flashes than gabapentin alone in patients with inadequate control of their hot flashes with an antidepressant alone [84]. Nonetheless, when switching from an antidepressant to gabapentin, it might be best to continue the antidepressant for the first two weeks and then titrate down. The reason for this is that there were more side effects noted in the patients who stopped the antidepressant than in those who took both. This is likely from the withdrawal symptoms from discontinuing the antidepressant, which the patient might inappropriately attribute to the newly initiated gabapentin.

●Pregabalin – Pregabalin, like gabapentin, is used for a number of indications, including seizures, neuropathic pain, and postherpetic neuralgia and is effective in relieving hot flashes. The drug at the recommended dose of 300 mg is reasonably well tolerated. We currently suggest gabapentin over pregabalin as it has been better studied for hot flashes and is less expensive [85].

●Clonidine – Clonidine, a centrally active alpha-2 adrenergic agonist, was modestly more effective than placebo in a meta-analysis of 10 trials [55]. Clonidine is now used infrequently, given its side-effect profile (dry mouth, dizziness, constipation, and sedation) and the availability of other effective nonhormonal medications for hot flashes. If used (ie, if all other options are ineffective or not tolerated), the transdermal preparations might be superior to oral tablets because of stable blood levels. We suggest starting with the TTS-1 (transdermal therapeutic system 1) patch, which delivers 0.1 mg per day, and increasing to TTS-2 (0.2 mg/day) and TTS-3 (0.3 mg/day) based on efficacy and side effects. Oral clonidine, at a dose of 0.1 to 1 mg/day in divided doses, may also be used (and may be substantially less expensive).

●Oxybutynin – Oxybutynin, an oral anticholinergic agent used primarily for overactive bladder, was more effective than placebo for relief of hot flashes in an observational study, a randomized clinical trial, and a preliminary report from a second clinical trial [86]. The optimal daily dose appears to be 5 to 10 mg [86]. Dry mouth, the most common side effect of oxybutynin, occurred in 20 to 30 percent of subjects in one trial [86] and 50 percent in another [87]. Further studies are required to determine its relative efficacy compared to other agents.

Observational studies suggest that oxybutynin and other anticholinergic drugs may be associated with an increased risk of dementia in older adults. (See "Risk factors for cognitive decline and dementia", section on 'Medications'.)

Neurokinin 3 receptor antagonist — The thermoregulatory center in the hypothalamus is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons that are stimulated by neurokinin B (NKB) and inhibited by estrogen. After menopause, estrogen declines and NKB signaling is increased. It has been proposed that this results in unregulated KNDy neuron activation and vasomotor symptoms [19,20,88]. Antagonism of NKB signaling at its receptor (neurokinin 3 receptor [NK3R]) has been studied as an alternative to MHT for management of hot flashes, an approach that appears to be promising. (See 'Risk factors' above.)

In a randomized, crossover trial of an oral NK3R antagonist (MLE4901) or placebo, administered for four weeks each in 28 symptomatic postmenopausal women, MLE4901 reduced both the frequency and severity of hot flashes more than placebo. However, three women experienced asymptomatic increases in transaminase (alanine aminotransferase [ALT] > aspartate aminotransferase [AST]) with MLE4901 that returned to baseline after stopping treatment. Because of the potential hepatotoxicity, this drug was not developed further [89].

In a second trial of NK3R antagonists, 80 postmenopausal women with moderate to severe hot flashes were randomly assigned to receive fezolinetant (90 mg orally twice daily) or placebo for 12 weeks [90]. Results included the following:

●In the fezolinetant group, the mean frequency of moderate/severe vasomotor symptoms (VMS) declined from 80.7 episodes per week (95% CI 70.6-90.8) at baseline to 5.7 episodes per week at 12 weeks (95% CI 2.4-9.1). This represented a reduction of 93 percent compared with baseline.

●In the placebo group, the mean frequency of moderate/severe VMS declined from 72.0 episodes per week (95% CI 63.9-80.1) at baseline to 39.0 episodes per week (95% CI 26.6-51.5). This represented a reduction of 46 percent compared with baseline.

●An increase in AST was seen more frequently with placebo (4 subjects, 9.1 percent) than with fezolinetant (2 subjects, 4.8 percent); increased values for ALT were more frequent with fezolinetant (5 subjects, 11.9 percent) than placebo (1 subject, 2.3 percent). The increases in ALT and AST were mild, transient, and did not exceed three times the upper limit of normal. None of the ALT and/or AST abnormalities was considered clinically significant except for one occurrence in the placebo group. Additional hepatic safety data will be needed on this agent.

NK3R antagonists may represent a new nonhormonal approach to the management of hot flushes. However, additional trials are needed before recommending this approach.

Options if nonhormonal therapies ineffective or not tolerated — The approaches listed above are commonly used and well accepted. For women with moderate to severe hot flashes not responding to these therapies, or for women not wishing to use estrogens or SSRI/SNRIs, high-dose progestogens are effective and can be used under these limited circumstances. The paragraphs below describe the various agents studied.

●Depot medroxyprogesterone acetate without concomitant estrogen – Only one author of this topic uses the approach described in this section:

Depot medroxyprogesterone acetate without estrogen reduces both hot flash frequency and severity/frequency scores with efficacy similar to estrogen therapy. As this agent has also been used to treat breast cancer, the concern about causing breast cancer is thought to be minimal, although no long-range studies have been conducted to prove this.

The mechanism of action of high-dose progestin to reduce hot flashes is speculative but may result from inhibition of gonadotropin secretion and increases in endogenous hypothalamic opioid peptide activity [91]. Limited data suggest that high doses of progestins may be as effective as MHT for hot flashes [92].

If progestin therapy is to be used, the best option may be to use a single 500 mg intramuscular dose of depot medroxyprogesterone acetate. This can effectively relieve hot flashes for months in many patients. Depot medroxyprogesterone acetate therapy appears to be as or more effective than the SNRI venlafaxine [93]. In a trial comparing intramuscular medroxyprogesterone acetate in a single-dose regimen of 400 mg to venlafaxine 37.5 mg daily for seven days followed by 75 mg daily, the single-dose medroxyprogesterone acetate regimen and venlafaxine reduced hot flash scores by 80 and 55 percent, respectively (figure 3). This is the first direct comparison between the SSRI or SNRI class of agents and a progestin; additional data are needed before concluding that progestin therapy is more effective.

●Norethindrone acetate at an oral dose of 10 mg daily also appears to be effective for vasomotor flushes [93].

●Tibolone – Widely used in Europe and other countries for nearly 20 years, tibolone is a synthetic steroid whose metabolites have estrogenic, androgenic, and progestogenic properties. It reduces VMS when compared with placebo, has a beneficial effect on bone mineral density [94-97], and may be more effective than estrogen/progestin therapy for treatment of sexual dysfunction in postmenopausal women.

However, tibolone has been associated with an increased risk of stroke and possibly breast cancer, and we do not recommend its routine use for hot flash management. Additional information on tibolone is found elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Therapies not recommended' and "Overview of sexual dysfunction in females: Management", section on 'Tibolone'.)

Special considerations

Women with breast cancer — Women with breast cancer have more problems with hot flashes than other women for a number of reasons. One is that premenopausal women may become estrogen deficient relatively abruptly, due to chemotherapy that results in early ovarian failure or due to bilateral oophorectomy. In addition, many postmenopausal women with breast cancer receive tamoxifen, an adjuvant therapy associated with hot flashes in up to 80 percent of women, 30 percent of whom rate them as severe. Women who take tamoxifen for chemoprevention may also experience severe hot flashes. Inheritance of specific estrogen receptor genotypes may also influence the risk and severity of tamoxifen-induced hot flashes [98].

Aromatase inhibitors may also cause hot flashes, but they tend to be less frequent and less severe [99]. Lastly, in women with a history of breast cancer, systemic estrogen therapies are considered relatively contraindicated.

The principles and approach to treating women with breast cancer and hot flashes include [100]:

●The efficacy of the nonhormonal therapies described above for hot flashes (including SSRIs/SNRIs) appear to be similar in women taking tamoxifen compared with those who are not taking tamoxifen [70].

●While SSRIs help reduce hot flashes in women on tamoxifen, coadministration of some of these drugs also inhibits the activity of CYP2D6, the enzyme that converts tamoxifen to its most active metabolite, endoxifen. Among SSRIs and SNRIs used to treat hot flashes, there is a gradient of potency for inhibition of CYP2D6; for example, paroxetine is a strong CYP2D6 inhibitor, while venlafaxine, citalopram, and duloxetine are less so [101]. While there is no evidence for an increased risk of breast cancer recurrence in women taking strong inhibitors of CYP2D6 (paroxetine) with tamoxifen, we suggest other agents such as citalopram or venlafaxine in this setting. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators", section on 'Patients taking SSRIs'.)

●SSRIs do not interfere with the metabolism of aromatase inhibitors and can therefore be used safely in women receiving adjuvant aromatase inhibitor therapy.

●We suggest using an SSRI or an SNRI for women on tamoxifen who are experiencing moderate to severe hot flashes throughout the day and night (with the exception of the potent CYP2D6 inhibitors paroxetine and fluoxetine). The largest experience is with venlafaxine, but citalopram, desvenlafaxine, and escitalopram are also reasonable choices. We typically use citalopram as it is better tolerated than venlafaxine.

●In women whose hot flashes are particularly symptomatic at night, graded doses of gabapentin can be administered at bedtime only. (See 'Anti-epileptics/other' above.)

Perimenopausal women — Women often seek intervention for hot flashes while they are still having menstrual cycles, ie, during the late menopausal transition. Management of these patients with MHT can be more challenging; a low-dose oral contraceptive is often used to control bleeding and provide contraception. This issue is reviewed in more detail separately. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Use of oral contraceptives during the menopausal transition'.)

Coexisting depression — Women with significant hot flashes and coexisting depression often require treatment with both MHT and antidepressants (usually selective SSRIs). (See "Treatment of menopausal symptoms with hormone therapy", section on 'Perimenopausal mood disorders'.)

Role of complementary and alternative therapies — It is estimated that between 50 to 75 percent of postmenopausal women use complementary and alternative therapies for management of menopausal symptoms [102,103], and the prevalence may be even higher in breast cancer patients [102]. For most of these therapies, safety and efficacy are not well established, but selected individual studies report benefit. Interpretation of the available data has been difficult given the small size and short duration of many studies. As placebos reduce hot flashes in up to 50 percent of patients, carefully controlled, randomized trials are necessary to demonstrate efficacy of specific agents.

As evidence for the efficacy of these is variable, we will arbitrarily categorize these as (1) promising therapies: need further study, (2) inconsistent evidence of efficacy, (3) evidence of no efficacy.

Promising therapies: Need further study

●Cognitive behavioral therapy (CBT) – CBT appears to be a modestly effective intervention for menopause-associated insomnia [104] but less so for hot flashes [53]. A major limitation of CBT is the need for frequent in-person visits.

Two randomized trials of intensive group or self-help CBT in breast cancer survivors [105] and peri- and postmenopausal women without breast cancer [106] demonstrated a significant reduction of bother related to hot flashes compared with those receiving no treatment. However, there was no reduction in hot flash frequency.

New-onset sleep disturbances are common during perimenopause and early menopause, typically in women with hot flashes, but also in women without hot flashes (see 'Effect on sleep' above). Women with combined VMS and insomnia have lower physical and mental quality of life than women without insomnia, and their insomnia symptoms improve with MHT [107,108]. Many women are treated with prescription sleeping pills, but a nonpharmacologic alternative (in-person CBT for insomnia [CBT-I]) is also effective (albeit with the practical limitation of frequent in-person visits).

In a trial of telephone-based therapies, 106 peri- and postmenopausal women with insomnia and hot flashes were randomly assigned to an eight-week intervention with CBT-I versus standard menopause education control (MEC) [104]. Insomnia severity was assessed with the Insomnia Severity Index (ISI), a seven-item questionnaire. After eight weeks, CBT-I, but not MEC, resulted in a clinically meaningful insomnia score reduction. The percentage of women who achieved ISI scores in the "no insomnia" range was 70 and 24 percent for CBT-I and MEC, respectively. CBT-I reduced hot flash "bother" but not frequency.

●Hypnosis – Hypnosis may be beneficial for hot flashes, but data are limited [109,110]. In a trial comparing hypnosis to a "structured attention intervention," hypnosis was more effective. At 12 weeks of follow-up, the mean reduction in physiologically monitored hot flashes per day was six (57 percent) in the hypnosis group versus one (10 percent) in the control group. While these results appear promising, the response rate in the control group is unusually low; a placebo effect of 20 to 50 percent is typically seen in hot flash trials. Before hypnosis can be recommended, procedures need to be standardized and educational tools developed to facilitate development of competency with this method. (See 'Nonhormonal pharmacotherapy' above.)

●Mind-body-based therapies – Small numbers of studies of mind-body-based therapies (stress management, relaxation, deep breathing techniques, and guided imagery) had mixed results in two meta-analyses [58,111]. A 2014 systematic review of relaxation studies reported no differences between relaxation techniques, paced respiration, placebo, and no treatment [112].

•Mindfulness training – A randomized trial of mindfulness-based stress reduction (MBSR) reported a decrease in bother from menopausal hot flashes but no effect on hot flash intensity scores (based upon frequency and severity) when compared with no treatment [113]. As MBSR requires intensive training like CBT, further evidence of benefit is needed before routinely recommending this approach [53].

●Stellate ganglion block – Pilot trials suggested that a stellate ganglion block can alleviate hot flashes. In a trial of 40 women with moderate to severe hot flashes undergoing stellate ganglion block or sham injection, the overall frequency of hot flashes in the subsequent six months was not different between groups, but the frequency of moderate to very severe symptoms was reduced more in the active group compared with the sham treatment group (event rate ratio 0.50, 95% CI 0.35-0.71) [114]. In a second trial of 40 patients randomized to three months of stellate ganglion blocks or pregabalin therapy, both therapies were effective, but the reduction in hot flashes was greater with stellate ganglion blocks [115].

Inconsistent evidence of efficacy — Plant-based therapies (phytoestrogens and herbal remedies) are commonly used by postmenopausal women, but their efficacy has not been well established. Other complementary therapies that have been studied with inconsistent results include acupuncture, mind-body-based therapies, paced respiration, weight loss, and exercise.

●Plant-based therapies – There are a variety of plant-based therapies used for hot flashes including isoflavones (dietary or supplements) and herbal therapies.

Isoflavones and phytoestrogens (nonsteroidal compounds that occur naturally in many plants, fruits, and vegetables) have not been consistently found to be more efficacious than placebo for hot flashes. Phytoestrogens have both estrogenic and antiestrogenic properties and are categorized as isoflavones, coumestans, or lignans.

Two types of isoflavones, genistein and daidzein, are found in soybeans, chickpeas, and lentils and are thought to be the most potent estrogens of the phytoestrogens (although they are much weaker than human estrogens). Lignans (eg, enterolactone and enterodiol) are found in flaxseed, lentils, grains, fruits, and vegetables. Most trials have not shown benefit for hot flashes when compared with placebo [116-122]. In a review of 11 randomized clinical trials of soy or isoflavone supplementation, only three of eight trials with at least six weeks of follow-up demonstrated a beneficial effect [116].

In contrast, a meta-analysis of 21 trials in menopausal women with hot flashes receiving phytoestrogens (dietary soy isoflavones, supplements of soy isoflavones, or red clover) reported a decrease in the number of daily hot flashes (-1.31, 95% CI -2.02 to -0.61) but no change in night sweat frequency [123]. Although this was statistically significant, it may not be clinically significant for women with severe, frequent hot flashes [124]. When different isoflavones were analyzed separately, red clover was ineffective for hot flashes, similar to results from previous studies [55,111,125].

A 2013 systematic review of 43 clinical trials found no beneficial effect of phytoestrogens of any type on hot flashes, with the exception of genistein [126]. Results of four genistein trials (not pooled for meta-analysis, because of high risk of bias) suggested that doses >30 mg/day might reduce hot flash frequency compared with placebo.

An issue of potential concern is that phytoestrogens are SERMs and therefore have both estrogen agonist and antagonist effects. However, the impact of increasing dietary soy or taking concentrated isoflavone supplements on breast cancer risk or recurrence in women with estrogen receptor-positive (ER+) breast cancer is unknown. Many experts suggest that dietary soy is reasonable in women with ER+ breast cancer but that dietary supplements should be avoided until their safety has been established.

●Herbal therapies

•Black cohosh – Among the alternative therapies available for management of hot flashes, black cohosh (Actaea racemosa or Cimicifuga racemosa) is one of the most widely used [102,103]. Although individual small, short-term trials suggested benefits from black cohosh [127,128], most have not [111,129-131]. In addition, systematic reviews and meta-analyses suggest that black cohosh is no more effective than placebo for treatment of hot flashes [123,132].

A potential safety concern about black cohosh is its possible estrogenic effect on the breast, but there is no evidence to date that use of black cohosh is associated with increased risk of recurrence in women with ER+ breast cancer [133,134]. However, some groups suggest that women with breast cancer wait until more safety data are available before using it [135].

There have also been concerns about possible hepatotoxicity (abnormal liver function tests) with black cohosh [136], but a meta-analysis of five black cohosh trials involving a total of 1117 women found no evidence of an adverse effect on liver function [137].

•Chinese herbs – Data from two meta-analyses suggest that Chinese herbal therapy is ineffective for the treatment of menopausal hot flashes [123,138].

●Paced respiration – A relaxation-based method known as paced respiration appears to be relatively easy to learn, but its impact on hot flash symptoms is not yet established [139,140].

●Weight loss – As noted above, obesity is a risk factor for hot flashes (see 'Risk factors' above). Weight loss may help reduce hot flashes, as illustrated by a six-month trial in overweight and obese pre- and postmenopausal women randomized to an intensive behavioral weight loss intervention or a structured health education program [18]. Among women with bothersome hot flashes at baseline, the intensive intervention resulted in a qualitative improvement in hot flashes when compared with the control intervention.

Ineffective therapies — Some complementary therapies have been shown to be ineffective for hot flashes in randomized clinical trials. These include:

●Acupuncture – Acupuncture is among the most frequently used complementary therapies for hot flashes, but results thus far are conflicting [141-145]. In a systematic review and meta-analysis, acupuncture was less effective than MHT (three trials), no different from sham acupuncture (eight studies), but statistically more effective than no therapy (four trials) [146].

Results from individual sham acupuncture (eg, placebo-controlled) trials have been variable; most are limited by small sample size and methodologic flaws. The best evidence to date that acupuncture is no more effective than placebo (sham acupuncture) comes from a randomized, sham-controlled trial in 327 peri- or postmenopausal women with moderate to severe hot flashes who were randomly assigned to 10 traditional Chinese acupuncture or non-insertive sham acupuncture treatments over eight weeks [147]. Hot flash scores, a calculated score based upon hot flash frequency and severity, were no different between the groups at the end of treatment (both showed approximately 40 percent improvement). Thus, like other nonhormonal and complementary therapies for hot flashes, acupuncture has an important placebo effect, but it has no additional benefit over sham acupuncture. (See 'Importance of placebo effect' above.)

Similar results were seen in another trial [148]. Although electroacupuncture appeared to be as effective as gabapentin for reducing hot flashes, it was no better than sham acupuncture. (See 'Importance of placebo effect' above.)

●Evening primrose oil – Evening primrose oil is a rich source of gamma-linolenic acid and is widely used by postmenopausal women to treat hot flashes. However, available data suggest that it is no more effective than placebo. In the only randomized trial to address this issue, 56 symptomatic postmenopausal women were randomly assigned to evening primrose oil (4 g/day plus 80 mg vitamin E) versus placebo for six months [149]. Among the 35 women who completed the trial, all showed improvement in their symptoms but no significant differences were found between the two groups.

●Flaxseed – Flaxseed has not been shown to be more effective than placebo for hot flashes [150,151].

●Exercise – Clinical trials, systematic reviews, and a meta-analysis have not found a significant beneficial effect of exercise on hot flashes [111,152,153]. Hormone therapy was more effective than exercise in one trial [154]. One possible explanation for lack of benefit is that exercise raises core body temperature, thereby triggering hot flashes.

●Other – A number of other herbal and complementary therapies have been studied with largely negative results. In a systematic review of 10 clinical trials noted above [116], no reduction in frequency of flushes was seen with ginseng or dong quai. Wild yam and progesterone creams also appear to be ineffective [111,116]. Traditional medicinal Chinese herbs, reflexology, and magnetic devices have all been studied and appear to have no beneficial effect [111].

Duration of therapy — For women who choose estrogen or combined estrogen-progestin therapies, short-term use has been suggested (generally for not more than five years) based on the original interpretation of the Women's Health Initiative (WHI) data (see "Menopausal hormone therapy: Benefits and risks"). However, several expert societies, including the Endocrine Society, the American College of Obstetrics and Gynecology, the North American Menopause Society, and the International Menopause Society no longer recommend a specific duration of treatment in symptomatic women, based upon revised safety data and the observation that hot flashes persist well beyond five years in many women (figure 2). (See 'Duration' above and "Menopausal hormone therapy: Benefits and risks", section on 'Estimates of risk in women 50 to 59 years' and "Treatment of menopausal symptoms with hormone therapy", section on 'Extended use of MHT'.)

For select women who experience recurrent, bothersome hot flashes (unresponsive to nonhormonal therapies) after stopping estrogen, extended use of estrogen therapy can be considered for quality of life. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Extended use of MHT'.)

Some experts now suggest that menopausal hormone therapy can be considered for primary prevention of disease (cardiovascular disease, osteoporosis, dementia) in asymptomatic, young, menopausal women [155]. However, this view is not shared by other experts [41].

For women who use nonhormonal pharmacotherapy as their initial therapy for hot flashes, we typically taper and stop the drug after about two years to see if hot flashes have resolved. If hot flashes have not resolved and they are moderate to severe, the same therapy can be resumed, and another taper can be tried one to two years later. Women should be instructed that tapering SSRIs and SNRIs is important to avoid drug withdrawal symptoms.

Suggested approach — The approach to management of hot flashes is based upon a number of factors, including (see 'General principles' above):

●Symptom intensity and frequency.

●Medical history – Is the patient a candidate for MHT? (See "Treatment of menopausal symptoms with hormone therapy", section on 'Is my patient a candidate for MHT?'.)

●Personal choice – Is the patient interested in MHT?

●Coexistence of other menopausal symptoms, such as depression, as these women often require treatment with both MHT and antidepressants (SSRIs or SNRIs). (See "Treatment of menopausal symptoms with hormone therapy", section on 'Perimenopausal mood disorders'.)

Women with mild hot flashes (symptoms that do not interfere with usual daily activities) typically do not require pharmacotherapy (see 'Women with mild hot flashes' above). Instead, simple behavioral measures, such as lowering room temperature, using fans, dressing in layers of clothing that can be easily shed, and avoiding triggers, can help reduce the number of hot flashes. Others may try complementary and alternative therapies which are described below (see 'Role of complementary and alternative therapies' above). After a full discussion of risks and benefits, some women with mild hot flashes may choose MHT.

For most women with moderate to severe hot flashes, we suggest MHT as first-line therapy if there are no contraindications (see 'Women with moderate to severe hot flashes' above). Women with an intact uterus need both estrogen and a progestin, while those who have undergone hysterectomy can receive estrogen only. Details of MHT use are reviewed separately. (See "Treatment of menopausal symptoms with hormone therapy".)

For women who are candidates for and choose to take estrogen, further discussion about the type, dose, and route of estrogen; addition of a progestin (required for all women with a uterus); the most appropriate progestin regimen; and the duration of therapy are reviewed in detail separately. (See "Treatment of menopausal symptoms with hormone therapy".)

For women who choose not to take MHT, we suggest SSRIs or SNRIs. One author of this topic prefers low-dose paroxetine (although this should not be used in women taking tamoxifen), while another prefers citalopram. Gabapentin is a good option for women whose symptoms occur primarily at night. (See 'Nonhormonal pharmacotherapy' above.)

The suggested duration of therapy is reviewed above. (See 'Duration of therapy' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Menopause".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Menopause (The Basics)")

●Beyond the Basics topics (see "Patient education: Menopause (Beyond the Basics)" and "Patient education: Menopausal hormone therapy (Beyond the Basics)" and "Patient education: Non-estrogen treatments for menopausal symptoms (Beyond the Basics)" and "Patient education: Vaginal dryness (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Vasomotor symptoms (VMS) or "hot flashes" are the most common complaint during the menopausal transition, occurring in up to 80 percent of women during the late transition (figure 1). However, only approximately 20 to 30 percent of women seek medical attention for treatment. (See 'Prevalence and natural history' above.)

●Typical symptoms – Hot flashes typically begin as the sudden sensation of heat centered on the upper chest and face that rapidly becomes generalized. The sensation of heat lasts from two to four minutes and is often associated with profuse perspiration and occasionally palpitations (see 'Typical symptoms' above). VMS at night can cause significant sleep disturbances in many women. (See 'Effect on sleep' above.)

Four different trajectories of menopausal symptoms occur with nearly equal frequency: early onset 18.4 percent, onset near final menstrual period with later decline 29.0 percent, early onset with persistently high frequency 25.6 percent, and persistently low frequency 27.0 percent (figure 2).

●Management

•Mild symptoms – Individuals with mild hot flashes usually do not seek or require pharmacologic intervention. Simple lifestyle changes such as keeping the core body temperature cool are often adequate to manage symptoms. (See 'Women with mild hot flashes' above.)

•Moderate to severe symptoms

-Hormone therapy – For postmenopausal women with moderate to severe VMS (and no history of breast cancer or cardiovascular disease nor moderate to high risk of these diseases), we use low-dose estrogen plus progestin therapy (or estrogen alone if no uterus). Additional information on menopausal hormonal therapy (MHT), including its risks and benefits, potential candidates for therapy, as well as information on dose, regimens, and duration of therapy are discussed in detail separately. (See 'Hormonal options' above and "Treatment of menopausal symptoms with hormone therapy", section on 'Our preferred regimens'.)

-Nonhormonal options – For women with moderate to severe hot flashes occurring both in the daytime and at night, in whom estrogen is contraindicated, not well tolerated, or for women who have stopped estrogen and are experiencing recurrent symptoms but wish to avoid resuming estrogen, we suggest nonhormonal therapies such as selective serotonin reuptake inhibitors (SSRIs), or gabapentin (Grade 2C). (See 'Nonhormonal pharmacotherapy' above.)