Cooling off hot flashes: uncoupling of the circadian pattern of core body temperature and hot flash frequency in breast cancer survivors.

H ot flashes are commonly defined as transient periods of intense heat or burning that typically start in the chest, rise to the neck and head, and are often followed by flushing of the skin. Many hot flashes are followed by chills and may be accompanied by profuse sweating, palpitations, red blotching of the skin, anxiety, irritability, and even panic. The exact mechanism of hot flashes is complex and not well understood. Perspiration and cutaneous vasodilation are classic mechanisms of heat loss that are activated during a hot flash. The thermoregulatory center in the hypothalamus activates these mechanisms to maintain core body temperature within a normal thermoregulatory zone. Results of recent studies suggest that hot flashes may be preceded by a rise in core body temperature. It has been theorized that women susceptible to hot flashes have both a dysfunction of the central thermoregulatory center and a temperature regulating zone that is shifted downward and is narrower compared with that in women who do not have hot flashes. Thus, a small rise in core body temperature in conjunction with a narrow thermoregulatory zone may trigger the heat-loss mechanisms that result in a hot flash. The trigger that induces a change in thermoregulation set-point activity in the hypothalamus during menopause is not known. In general, control of core body temperature has been localized to the rostral hypothalamus. The neurons in this region are temperature dependent and work to maintain a set core temperature. Changes in the external environment can affect the firing of neurons in this region and elicit a hot flash (sweating, vasodilation, changes in heart rate, and increased blood flow to the skin) in an attempt to adjust core body temperature. Although estrogen withdrawal is thought to be the central change that leads to hot flashes, accumulating evidence suggests that complex neuroendocrine pathways involving norepinephrine, estrogen, testosterone, serotonin, and endorphins all play a role in regulating the thermoregulatory center and are possible sites where dysfunction may occur. Blood levels of norepinephrine are increased both before and during hot flashes, and norepinephrine can increase core body temperature and induce a heat-loss response. Norepinephrine in the thermoregulatory center is inhibited by endorphins and catecholestrogen, a metabolic byproduct of estrogen metabolism. In addition, testosterone and androgens can inhibit norepinephrine by their ability to stimulate endorphin production. Recent evidence suggests that serotonin also may play a role in the pathogenesis of hot flashes. Estrogen withdrawal has been associated with decreased blood serotonin levels and an up-regulation of serotonin receptors in the hypothalamus. The role of serotonin is very complex, as the effect of serotonin varies depending on the type of receptor activated. Activation of the serotonin 5-HT2A receptor has been shown to precipitate heat loss, whereas activation of the 5-HT2C receptor can exert negative feedback on 5-HT2A. 7 After the hot flash, evaporative cooling occurs, followed by a drop in skin and internal temperature and relief from symptoms. Among affected individuals, components of the menopause syndrome—such as hot flashes, perspiration, muscle and joint pain, palpitations, fatigue, headache, and irritability—vary greatly both in intensity and frequency. Some women will have hot flashes several times a week, whereas others complain that symptoms occur every hour. Hot flashes resulting from a chemically-induced menopause can be of a more profound nature than hot flashes as a consequence of natural menopause. Women who undergo premature menopause (such as chemotherapy-induced menopause) often suffer severe symptoms that are of longer duration. Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by treatment with cytotoxic chemotherapy drugs or the antiestrogen, tamoxifen citrate, and/or the disMenopause: The Journal of The North American Menopause Society Vol. 11, No. 4, pp. 369–371 DOI: 10.1097/01.GME. 0000132624.84597. 9F © 2004 The North American Menopause Society Text printed on acid-free paper.