The Cardiovascular Impact of Hot Flushes

Cardiovascular disease (CVD) increases aggressively after menopause and is the leading cause of mortality in women in the US. Autonomic dysregulation and high blood pressure (BP), often demonstrated in postmenopausal women, are directly linked to CVD. Women who experience vasomotor symptoms (VMS) of menopause, such as night sweats or hot flushes, are at an increased CVD risk. For example, VMS were associated with endothelial dysfunction, elevated blood pressure (BP) and cholesterol, suggesting that VMS may be a marker of adverse vascular changes associated with CVD. Thus, the investigators have designed a pilot study to 1) replicate the hot flush induction protocol and 2) determine if the cardiovascular responses (increased blood pressure and heart rate) during hot flushes are altered. The investigators hypothesize that VMS, and in particular, hot flushes, will cause elevated BP and HR compared with asymptomatic women. These findings will provide important information to physiological responses of VMS in women, which will provide mechanistic insight to the greater cardiovascular risk observed in women who report these symptoms compared with asymptomatic women.

Hot flushes are the most common symptom of climacteric and are reported as feelings of intense warmth along with sweating, flushing and chills. Indeed, it is suggested that 50-80% of women post-menopause will experience hot flushes. Hot flushes usually last for one to five minutes but can last up to an hour. The median duration of symptoms is about four years, but some can last as long as 20 years. Although estrogen withdrawal is necessary to produce a hot flush, it is not sufficient to explain the occurrence of them as some women do not experience them, but all women experience a deficit in estradiol and progesterone during menopause. There are also no relationships between symptoms and plasma, urinary, or vaginal levels of estrogens, nor are there differences in plasma levels between women with and without hot flushes. The putative physiological trigger of hot flashes is core body temperature elevations acting within a reduced thermoneutral zone. This reduction appears to be closely related to increased central nervous levels of norepinephrine (NE), partly through alpha 2 -adrenergic receptors. The involvement of NE in central thermoregulation and the etiology of hot flushes are supported by results from experimental and animal studies that demonstrate increased central nervous system NE levels narrow the width of the thermoneutral zone. During hot flushes, skin temperature increases in digits, face, arms, chest, abdomen, back and legs; sweating often occurs; and heart rate increases. In previous research, measurable sweating occurred in 90% of hot flushes. Sweat rate corresponds closely to skin conductance, the electrical measure of sweating, during hot flushes. Indeed, sternal skin conductance and skin temperature are the gold standard objective measurement of a hot flush.

Body weight and adiposity are increased by estrogen deficiency, thus estradiol may have a protective role against increased body fat in aging women. In addition, fat mass increases as a consequence of aging and menopause in females. However, aromatase, the rate limiting enzyme of androgen to estradiol conversion, is mainly produce in adipocytes (fat cells), where it becomes an important source for estradiol in the postmenopausal period. Thus, the varying levels of estradiol could influence hot flushes in women. Thus, it is important to characterize fat mass in postmenopausal women to determine if body fat percentage influences the severity or frequency of VMS, either spontaneous or induced.

Hot flushes occur spontaneously, which can make it challenging to measure their etiology and physiological responses to them. Because these vasomotor symptoms are strongly connected with CVD, it is important to understand the mechanism by which these symptoms may lead to CVD. Thus, being able to reliably induce a hot flush is key to understanding these mechanisms. Previous research has demonstrated that hot flushes can be induced pharmacologically with yohimbine, an alpha 2 -adrenergic antagonist, and with controlled heating to the torso in symptomatic women, but not asymptomatic women. While measuring physiological responses to hot flushes, the investigators will be able to determine factors that contribute to the greater CVD risk in women who experience VMS.

Importantly, being able to compare the responses of hot flushes to the predictable and known responses to the cold pressor test. The investigators' central hypothesis is that hot flushes can be induced in symptomatic women with a temperature controlled, water heating pad and that BP and HR will be elevated in these women compared with asymptomatic women. If these findings prove to be true, it suggests that women who have vasomotor symptoms may also demonstrate exaggerated responses to stress and this may be occurring frequently in women who experience these debilitating menopausal symptoms.