Hot flush is a subjective feeling of warmth often associated with dilatation of cutaneous vessels and decrease of core temperature. It is often accompanied by sweating, tachycardia, anxiety, hypersensitivity or even panic. It typically lasts for several minutes although it ranges from seconds to over ten minutes and the frequency and intensity varies among individuals. Aura often appears before impending hot flush and is not identical to the hot flush itself. It is usually described as ‘sickness’, ‘agitation’, ‘numbness’, or ‘head tightness’. It lasts for about 5 to 60 seconds and tachycardia or increase of cutaneous vascular flow may temporarily appear.

Hot flush may appear even before the menopause. Korean women are reported to experience hot flush in 70% which is the most frequent symptom of menopause and 60% of those who had hot flush replied the symptom began before the menopause.1 Daily routine is compromised in 10% who undergo hot flush due to its intensity. Hot flush typically begins immediately after the last menstruation. It is frequent for the first 2 years in case of natural menopause and gradually subsides subsequently. Surgical castration triggers intense hot flush in a few weeks after the surgery. Those who receive tamoxifen as a treatment for breast cancer are reported to undergo severe and frequent hot flush for the first 2 to 3 months followed by gradual decrease and stabilization. Hot flush usually lasts for several months although it may persist for years.

Serum estradiol or estrone level is reported to be lower in women who have hot flush, however the symptom varies individually even among those who have similar level of estrogen. Underweight, poor exercise, or smoking are risk factors after menopause which are related to low level of serum estrogen. However, SWAN study reported that perimenopausal women of 40 to 55 years of age and those whose BMI is over 27 are predictive factors for hot flush which may be explained as the compromised role of estrogen by the insulation of increased body fat followed by increased core temperature.2 Hot flush also varies between ethnicity or culture. For instance, it is less frequent in asians and caucasian than in african Americans. Also, in a prospective study of women with natural menopause, hot flush was more frequent in women who had longer period of transition (51% vs. 39%).3 Further investigation is warranted regarding the relationship between hot flush and other factors such as genetic factors, diet, or exercise.

Recent studies report that the risk of cardiovascular disease was high in women with menopausal symptoms such as hot flush. Women with hot flush showed the change of lipid metabolism characterized by high BMI, hypertension, high frequency of atherosclerosis, and decreased endothelium-dependent vasodilation.4

Estrogen withdrawal rather than the low serum level of estrogen is regarded as the cornerstone of hot flush although the mechanism is not established. Oophorectomy before menopause is followed by sudden estrogen withdrawal and intense hot flush whereas gonadal dysgenesis such as Turner syndrome with intrinsically low estrogen level does not provoke hot flush. If a gonadal dysgenesis patient abruptly ceases estrogen replacement after months of hormone therapy, the hot flush may appear which shows the estrogen withdrawal is an important precipitating factor for hot flush.

Hot flush also accompanies other hormonal changes such as increase of LH, adrenocorticotropic hormone, and GH before the symptom, or increase of cortisone which may follow after hot flush appears. Other related hormonal changes are the decrease of average SHBG, increase of free androgen index, calcitonin gene-related peptide, and neuropeptide Y, though a direct evidence still lacks that these changes are related to hot flush.

Estrogen withdrawal is induced by the failure of central temperature control center while peripheral nerves, vessels or central nervous system were suspected to be involved. Hot flush is not known to be directly related to serum estrogen, FSH, or LH levels. Hot flush is related to the pulsatile change of LH although it does not always appear in every LH elevation. Moreover, hot flush is not decreased by LH depression with GnRH agonist and it is not triggered by LH stimulation with GnRH. These imply hot flush is not directly caused by LH pulse though these two might have certain relationship. Hypophysectomized women due to a tumor in hypophysis were reported to experience hot flush and this suggests that temperature center failure is related to the dysfunctional temperature control center of hypothalamus rather than the pituitary gland.5

Sweating and vasodilation is activated to promote heat discharge in hot flush. In human, it is medial preoptic area that temperature control center resides to undertake this function. Sweating and vasodilation is to maintain core temperature in the range so-called ‘thermoregulatory zone’. A recent study reported minute core temperature change 15 minutes before symptom in 60% of those who have hot flush.6 Also, the thermoregulatory zone moves downward in those with hot flush and the zone is narrower. Heat loss occurs only with 0.01 degree of increase in core temperature over thermoregulatory zone and menopausal women who have narrow homeostatic range of temperature easily loose heat only with minute change in core temperature before hot flush followed by series of symptoms. Dysfunctional regulation of core temperature is mediated by number of neurotransmitters such as norepinephrine, estrogen, testosterone, and endorphin.

Norepinephrine is the most important neurotransmitter in lowering critical temperature and promoting heat loss. Serum levels of norepinephrine metabolites surge immediately after hot flush and the core temperature rises followed by heat loss when norepinephrine is injected into hypothalamus.6 The production and secretion of norepinephrine is depressed by endorphins and catecholamine which is estrogen metabolite in temperature control nucleus. Estrogen and testosterone also stimulates endogenous endorphin production hence directly and indirectly control norepinephrine secretion.

Another neurotransmitter, serotonin (5-HT), is important in controlling temperature regulation and related to multiple steps, time- and dose-dependent. Temperature control response seems dependent to certain serotonin receptor in brain. Serotonin1a (5-HT1a) and 2a (5-HT2a) receptors are two out of several serotonin receptors known to be closely related to temperature control. Serotonin 2a receptor induces heat loss and activated by increased serotonin eventually producing hot flush. However, when combined with serotonin 2c receptor, a negative feedback to 2a receptor occurs. This implies that the role of serotonin in temperature regulation has multiple and complex steps.7 In an animal model, hyperthermia was prevented by 5-HT2a antagonist, whereas hyperthemia was induced by direct stimulation of 5-HT2a receptor in rodents. On the contrary, peripheral injection of 5-HT1a agonist lowered core temperature in rodents and human. These indicate that the balance between 5-HT1a and 5-HT2a receptor is crucial in adequate control of body temperature. Manifestation and activation of 5-HT receptor can be regulated by gonadal hormones and adrenal corticosteroid which suggests that serotonin is linked to other hormonal systems related to hot flush. Estrogen withdrawal leads to decrease in serum serotonin, increase in sensitivity of 5-HT2a in hypothalamus. And under this condition, certain intrinsic or extrinsic stimulus increases serum serotonin and induces 5-HT2a receptor, changes set-point of temperature control, and eventually hot flush appears.7 When hot flush appears, set-point is down-regulated and normal body temperature is identified as being higher than the new set-point, leading to the activation of temperature regulation mechanism to lose heat. When the core temperature decreases, it stimulates heat preservation mechanism leading to the series of symptoms related to hot flush.8

Generalized diseases that accompanied by hot flush are carcinoid syndrome, mastocytosis, medullary thyroid carcinoma, pancreatic carcinoma, pheochromocytoma, and renal carcinoma. Neurotic hot flush may occur with anxiety, brain tumor, migraine, Parkinson's disease, or spinal-cord lesion. Opiods also are capable of inducing hot flush such as which are luteinizing hormone-releasing hormone agonists or antagonists, anti-estrogens, SERMs, or aromatase inhibitors. Hot flush may be related to alcohol or drug reactions such as aromatase inhibitor, bromocriptin, calcium-channel blockers, cephalosporin, cholinergic drugs, chlorpropamide, ketonazole, metronidazole, and nicotinic acid. Hot flush also may be related to dietary habit and food additives in conditions such as auriculotemporal syndrome, dumping syndrome, taste problem, hot beverages, monosodium glutamate, sodium nitrite and sulphites.9

Tests for differential diagnosis to rule out these conditions may be performed. For thyroid diseases, thyroid-stimulating hormone test, complete blood count for subacute and chronic infection, and C-reactive protein. For psychiatric disease or stress, patient stress questionnaire, complete blood count to rule out leukemia.Urine vanillylmandelic acid (u-VMA) test to rule out pheochromocytoma or chromogranin a urine 5-hydroxy indole acetic acid (5-HIAA) test to rule out carcinoid may be needed. CT or MRI is warranted to rule out malignant tumors (Krause et al., 2015). If relationship with postmenopausal hormone deficiency is not certain, consultation to other department such as internal medicine or neurology should be considered.

The current available treatments for hot flush are not purposed to ‘cure’ but to decrease frequency and intensity hence to relieve symptoms and to reduce discomforts in daily life. No wonder, hot flush easily comes back when the treatment is discontinued. The exact mechanisms of the medications currently used for hot flush are not elucidated and placebo are effective in cases.

Treatment for hot flush is classified by pharmacologic and non-pharmacologic.

Pharmacologic treatments are either hormonal or non-hormonal medications. Hormonal therapy includes single estrogen, combined estrogen and progesterone, estrogen agonists and antagonists, testosterone, biologic hormones and single progesterone. Single estrogens are transdermal patches of ultra-low dose, low dose and standard dose. For combined estrogen and progesterone, oral medroxyprogesterone acetate (MPA) 5 mg per day as a standard dose and intrauterine levonorgestrel. For single progesterone, oral and depo injection form may be used. Non-hormonal medications include SSRI, SNRI, gabapentin, and clonidine. Paroxetine, fluxetine, citalopram and sertaline are SSRI; and venlafaxine and desvenlafaxine are SNRI. Non-pharmacologic treatments are acupuncture, exercise, rest, yoga, horse-riding, phyto-estrogens, vitamin E and omega-3 fatty acids.10