The physiopathological mechanisms that underlie VMS are not entirely known. Although altered estrogen levels due to decreased ovarian function are known to contribute significantly to the development of VMS, they are not the sole cause of these phenomena [5, 6, 12, 13]. Studies have found that the combination of high FSH and low E2 concentrations may be associated with a higher probability of VMS, especially in perimenopausal women with non-ovulating cycles; however, not all women who exhibit these alterations report VMS [2, 13, 14].

Body temperature is maintained through a dynamic equilibrium between internal and external factors. Symptomatic postmenopausal women have been found to display a narrowing of the thermoneutral zone or the range of temperatures in which the body can be maintained without triggering thermoregulatory homeostatic mechanisms such as sweating or shivering [13].

The thermoregulatory system monitors and maintains body temperature through the interaction of three main elements: the brain, the internal abdominal cavity, and the peripheral vascular system. When body temperature drops below the optimum level for normal physiological functioning, peripheral vasoconstriction and shivering may occur so as to conserve heat and increase body temperature. Conversely, when body temperature rises above the optimum level, peripheral vasodilation and sweating may take place, so as to facilitate heat loss through the skin [5]. These phenomena are controlled by a hypothalamic nucleus (anterior hypothalamus/preoptic area) which is responsible for maintaining body temperature within the thermoneutral zone, an optimal temperature range whose limits vary slightly over the circadian cycle [7, 12–14]. The hypothalamic thermoregulatory center is also sensitive to variations in monoamine neurotransmitters, such as serotonin and noradrenaline; to changes in gonadal steroids, such as progesterone and the luteinizing hormone; and to some medications and medical conditions [4, 5, 15, 16].

Information about changes in body temperature reaches the brain through heat- and cold-sensitive fibers in the central nervous system, in deep tissues, and in the skin. The temperature sensors involved in the activation of thermoregulatory responses are located deep within the body (in the gastrointestinal tract and other internal organs, in intra-abdominal veins, and in the spinal medulla) as well as in peripheral organs (skin) [5]. The preoptic area sends fibers to effector structures in the brain stem and the medulla through the medial forebrain bundle. These projections control heat loss effectors in the lateral hypothalamus, the periaqueductal gray, and the reticular formation, which are responsible for peripheral vasodilation and sweating. Body temperature is essentially maintained by changes in cutaneous and subcutaneous blood flow and sweating. If body temperature rises above the normal level, peripheral vasodilation is triggered, leading to an increase in blood flow (sympathetic nervous system). When temperature drops below the thermoregulatory limit, there is a reduction in blood flow to peripheral tissues, so as to maintain body heat [13, 14, 17].

The exact physiopathological mechanisms behind VMS have not been completely elucidated. Of the three most prominent hypotheses for the origin of VMS, the one proposed by Tataryn et al. [18] appears to be the most accepted. According to this theory, stimulation by beta-2-adrenergic receptors may lead to increased sympathetic activity during the menopausal transition, which could lead to a reduction in the thermoneutral zone. VMS could therefore consist of large responses to small variations in body temperature [13]. Significant decreases in cardiac vagal control have been found to occur during hot flashes, which may help elucidate the physiology of hot flashes [19]. These responses could involve intense sensations of heat, skin flushing, and increased blood flow leading to changes in heart rate and blood pressure, all of which are commonly associated with hot flashes. Conversely, reductions in body temperature may induce an exaggerated vasodilation, leading to chills and sweating [5].

Another hypothesis suggests that a decrease in the responsiveness of peripheral vascular systems (skin) to temperature variations could interfere with the speed and efficiency of vessel responses, leading to exaggerated reactions to stimuli and, consequently, VMS. Perimenopausal fluctuations and a postmenopausal decrease in estradiol levels could contribute to this disequilibrium, reducing blood vessel elasticity and leading to inadequate responses to variations in body temperature [5].

A third hypothesis associates the occurrence of VMS with neurochemical alterations secondary to gonadal hormone variations. These hypotheses have served as the basis for the development of medications that aim to control VMS by normalizing norepinephrine and/or 5-HT levels [5].

VMS appear to vary according to race and ethnicity, with African-American women being more likely to report such symptoms and Chinese and Japanese women being less likely to do so [4, 6]. In the Ovarian Aging Study cohort, both obese and nonobese African-American women as well as obese white women were found to be significantly more prone to hot flashes than nonobese white women (interaction, p = 0.01) [11]. The reasons for these differences are not entirely clear, although E2 levels, body mass index (BMI), hormone use, and socioeconomic status are thought to be risk factors for VMS. The possible role of a soy-rich diet, such as that seen in Asian cultures, is still a controversial topic [4]. Gene variants in estrogen α-receptors and in enzymes involved in the synthesis of and conversion between more and less potent estrogens have been associated with varying probabilities of VMS in different ethnic and racial groups due to their impact on steroid hormone activity. A number of studies have investigated the contribution of polymorphisms in estrogen receptors and in nucleotides involved in the synthesis and metabolism of different estrogens (E2, estrogen, estriol) to the development of VMS. Although the results of these studies are not definitive, they appear to suggest that associations between genetics and VMS may be observed both at a central (brain) and peripheral level (autonomic nervous system, vascular system, or other structures involved in VMS) [4].

The SWAN Genetics Study [20] identified important associations between genetic sex steroid hormone pathway variants and measures of health status. The study describes selected genetic characteristics of health-related attributes during the menopausal transition in African-American, Caucasian, Chinese, and Japanese women. The sample consisted of menstruating women aged 42–52 years, living in the community, who were not using exogenous hormones. The genotypes and haplotypes of six genes (27 single nucleotide polymorphisms [SNPs]) in the sex steroid hormone pathway were found to be associated with circulating hormone concentrations, menstrual cycle profiles, and health-related outcomes, including lipid levels, diabetes mellitus, depressive symptoms, measures of cognition, bone mineral density (BMD), and vasomotor symptoms. Allele frequencies and distances differed significantly between the four ethnic groups evaluated, which resulted in variable patterns of association between genetic variables and the health-related measures evaluated. Several SNPs were associated with health outcomes, and some associations were significantly more prominent in specific ethnicities. For instance, ESR1 rs3798577 was related to circulating estradiol concentrations, indicators of ovarian aging, high-density lipoprotein (HDL) cholesterol, apolipoprotein A-1, insulin sensitivity, and lumbar spine BMD. CYP1A1 rs2606345 was found to be associated with estrogen metabolite concentrations, vasomotor symptoms, and depressive symptoms. In Chinese women, statistically significant associations were found between ESR2 rs1256030 and HDL cholesterol, lumbar spine BMD, hip BMD, and metabolic syndrome [20].

Obesity has also been considered a risk factor for VMS [4, 6]. Although obesity used to be considered protective against VMS due to the aromatization of androgens to estrogens in adipose tissue, recent studies have found that obesity may actually be a risk factor for these symptoms during perimenopause and early menopause. This association is consistent with a thermoregulatory model of VMS, even though the mechanisms underlying this interaction remain unclear. The adipose tissue may act as an insulator and prevent the dissipation of the heat caused by VMS, increasing their frequency and severity and possibly having an impact on other neuroendocrine processes. Every 1-SD increase in total and subcutaneous abdominal adiposity was associated with a proportional increase in the odds of hot flashes in age- and site-adjusted models (odds ratio [OR] = 1.28; 95 % CI: 1.06–1.55 and OR = 1.30; 95 % CI: 1.07–1.58, respectively). Visceral adiposity was not associated with susceptibility to hot flashes [21]. This phenomenon may be more applicable to women in the beginning of the menopausal transition [4]. Body fat gains were associated with a higher frequency of hot flashes during the menopausal transition. However, the association between changes in body fat distribution and night sweats was not statistically significant [22]. Bioimpedance studies have found that, regardless of BMI, a higher percentage of fat mass was associated with a greater likelihood of VMS, even after controlling for other confounders. Lean mass was not found to be related to VMS. Studies using abdominal tomography have also shown that high abdominal adiposity, especially if subcutaneous, is associated with more complaints about hot flashes in women who report higher gains in body fat from 1 year to the next [2].

Lifestyle may also be related to the occurrence of VMS. Among the lifestyle factors studied in relation to these symptoms, smoking deserves special attention [4, 6, 23]. In fact, SWAN results show that both active smoking and passive exposure to smoke are associated with a greater likelihood of VMS. It has been hypothesized that the association between smoking and VMS may be attributable to the antiestrogenic effects of cigarette smoking. On the other hand, the study also found that variations in endogenous E2 levels did not account for the association between smoking and VMS [23].

Other lifestyle factors, such as diet and physical activity, have shown weaker associations with VMS. Dietary factors, such as total kilocalories, fats, fibers, caffeine, alcohol, vitamins, or isoflavones (genistein), consumed have shown no relationship with VMS in the SWAN study [24, 25]. The same has been found for physical activity [26]. However, it is possible that the latter may have a dual and opposing influence on VMS (positive effect on mood and body weight and negative effect on core body temperature, which could increase the occurrence of symptoms) [25].

Mood and negative emotions, especially anxiety, also appear to influence the intensity of VMS [4, 6, 11]. Although this interaction has not been extensively studied, it is thought that the influence of physiological and psychological factors may be both combined and bidirectional [4]. Studies suggest that VMS may precede, follow, or occur simultaneously with depression, which suggests a number of possible causal relationships. Other factors, including social variables such as childhood abuse or neglect, low socioeconomic status, low education, and income, may also have a negative influence on the intensity of VMS. To examine whether women were more likely to experience a major depressive episode during perimenopause or postmenopause compared to the premenopausal period, 221 premenopausal women were analyzed. The results showed that women were two to four times more likely to experience a major depressive episode when they were in perimenopausal (OR = 2.27) or postmenopausal (OR = 3.57), even after controlling for several factors associated with depression, such as history of major depression at baseline, annual psychotropic medication use, high BMI, upsetting life events, and frequent VMS [27]. On the other hand, a second study assessed a randomly identified, population-based cohort of midlife women, who were followed for 6 years to estimate the association between anxiety and menopausal hot flashes in the early transition to menopause. At the end of the study, 32 % of the women were in the early transition stage, and 20 % were in the late menopausal transition or postmenopausal. A total of 37 % of the premenopausal women, 48 % of those in the early transition, 63 % of women in the late transition, and 79 % of the postmenopausal women reported to experiencing hot flashes. Anxiety scores were significantly associated with the occurrence, severity, and frequency of hot flashes (each outcome at P < 0.001). The study also revealed that women with moderate and high anxiety were three and five times more likely, respectively, to report hot flashes than women in the normal anxiety range [28].

A multicenter study conducted on 896 Chilean, Ecuadorian, Panamanian, and Spanish women in the peri- and postmenopausal period aimed to assess the association between climate (altitude, temperature, humidity, and annual temperature range) and the occurrence of hot flashes and/or night sweats. A total of 58.5 % (524/896) of the sample reported regular symptoms, and higher symptom prevalence was found in women living in places with higher temperatures and lower altitudes [29].

Overall, studies show that, although quality of life may not be influenced by menopause itself, it may be significantly lower in women who report VMS [4]. This relationship may be due to the impact of such symptoms on life and general health, as VMS may influence sleep quality, mood, and cognition and interact with other medical conditions. There appears to be a strong association between VMS and the quality and continuity of sleep (difficulty falling or remaining asleep or trouble waking up) [4]. For instance, the sleep disturbances caused by VMS may be an important risk factor for depression. Conversely, the serotonergic and noradrenergic symptoms commonly associated with depression may also influence the development of VMS [4]. In the SWAN study, difficulty sleeping was reported by 37.7 % of 12,603 women (78.5 % of those participating in this cross-sectional survey), 40–55 years old. These prevalence rates increased between pre- and late perimenopause. Late perimenopausal and surgically menopausal women were the most likely to report difficulty sleeping. The study suggested that women who begin the menopausal transition at an earlier age may experience more frequent and/or severe sleep symptoms [30]. Additionally, an experimental model of leuprolide-induced hot flashes has demonstrated a causal relationship between hot flashes and poor sleep quality [31].

Cognitive performance may also be impaired during the perimenopausal period, and there have been reports of temporary reductions in learning ability which subsequently resolve in the postmenopausal period [4, 32, 33]. In the Rochester Investigation of Cognition Across Menopause [33], 117 middle-aged women were recruited and categorized into the following stages: late reproductive (n = 34), early menopausal transition (n = 28), late menopausal transition (n = 41), or early postmenopause (n = 14). Women in the first year postmenopause performed significantly worse than women in the late reproductive and late menopausal transition stages on measures of verbal learning, verbal memory, and motor function. They also performed significantly worse than women in the late menopausal transition stage on attention/working memory tasks. In a separate study, a cohort of 1,903 midlife US women were followed longitudinally for 6 years and asked whether the symptoms reported during the menopausal transition negatively affected cognitive performance. The study also investigated whether these symptoms were responsible for the negative effect of perimenopause on cognitive processing speed. After adjustment for demographic variables, the results showed that women with concurrent depressive symptoms scored 1 point lower on the Symbol Digit Modalities Test (SDMT) (p < 0.05) than those without such symptomatology. On the East Boston Memory Test, the rate of learning in women with anxiety symptoms was 0.09 lower at each assessment (p = 0.03) and was found to be equivalent to 53 % of the mean learning rate for the cohort as a whole. The SDMT learning rate was 1.00 point smaller in late perimenopause than during premenopause (p = 0.04); statistical adjustment for symptoms did not attenuate this negative effect. Depressive and anxiety symptoms had a small negative effect on processing speed. The authors concluded that depression, anxiety, sleep disturbance, and VMS did not account for the decrement in SDMT learning observed during late perimenopause [32]. Although these changes are not directly related to VMS, these findings suggest that physiological changes associated with these phenomena may have an impact on cognitive function [4].

The Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS) have also investigated the relationship between VMS and other medical conditions. These studies found that the presence of moderate and severe VMS may be associated with cardiovascular disease (CVD). Results also showed that CVD was more frequent among symptomatic women undergoing hormone therapy (HT) [34–36]. The SWAN Heart Study assessed 588 women and found that those with hot flashes displayed medial carotid thickening (a marker of atherosclerosis), a symptom which had been previously reported mostly in overweight and obese women. Women reporting hot flashes, and in the case of IMT more frequent hot flashes, had poorer endothelial function, greater aortic calcification, and greater IMT when compared to individuals without hot flashes, even after controlling for demographic confounds, other known cardiovascular risk factors, as well as E2 levels. These findings support the association between VMS and CVD [37, 38].

Women with VMS also appear to have lower mineral bone density (MBD) than asymptomatic women, with reductions in spine and hip density being more common in the postmenopausal period and lower femoral neck density being more frequent in premenopausal women [4].

Many treatments may help control VMS. However, it is important to weigh the risks and benefits of each treatment on a case-by-case basis and to discuss treatment preferences with the patient in order to select the most adequate option. Estrogen has been used as a hormone supplement, and many studies indicate that it is superior to placebo in alleviating VMS, reducing the frequency of hot flashes by 77 % or by approximately 2.5–3 hot flashes daily. However, recent studies have reported adverse effects of estrogen, raising important concerns about its use [39]. There has been an increasing amount of literature on nonhormonal agents for the treatment of hot flashes. Conventional nonhormonal treatments (CNHT) and complementary and alternative medicines (CAM) have both been studied for their ability to relieve VMS. CNHT are neuroactive agents considered to be safe in cases in which estrogens are contraindicated, such as psychotropic medications like selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and gabapentin. CAM are defined as a group of healthcare systems, practices and products which are not normally considered to be conventional medicine: herbal products, acupuncture, vitamins, exercise, yoga, and many others. Another promising nonpharmacological therapy which is currently under investigation involves stellate ganglion blocking [40].