Many women in the menopausal transition experience hot flashes: unpredictable, sometimes disruptive, periods of intense heat in the upper torso, neck and face. Although generations of physicians have prescribed hormones to reduce these symptoms, very little research has focused on the underlying causes of hot flashes.
Three new studies explore the role of genes, obesity and alcohol consumption in contributing to - or lessening - the intensity and frequency of hot flashes in midlife women. These studies are part of a five-year research effort led by University of Illinois veterinary biosciences professor Jodi Flaws and colleagues at the University of Maryland, Mercy Medical Center in Baltimore and the School of Medicine at Johns Hopkins University.
Physicians have long noted that some factors, such as smoking, increase the likelihood that a woman will experience more - or more intense - hot flashes than other women. Race also appears to play a role, with African American women at higher risk than others. But the mechanisms that cause some women to suffer from severe (frequent and intense) hot flashes have remained a mystery.
"Even though more than 40 million women experience hot flashes each year," the authors wrote in their paper published in Maturitas, "little is known about the factors that predispose women to hot flashes."
To examine whether genetics might play a role in hot flashes, Flaws and her colleagues conducted a cross-sectional study involving 639 women aged 45 to 54. The researchers looked at individual differences in the genes that code for various hormones. An earlier study by the same team had found that one of these genetic polymorphisms, in an estrogen metabolizing enzyme, cytochrome P450 1B1, was more common in women who reported higher-than-average frequency, intensity and duration of hot flashes.
The new study tied the same genetic polymorphism to lower levels of an androgen known as DHEA-S, and to lower progesterone levels.
These are the first studies to find evidence of a genetic basis for hot flashes, and the first to look at genetic polymorphisms associated with hormone levels in healthy women with and without hot flashes.
The progesterone finding is of particular interest, said Flaws, because the medical community has focused almost exclusively on the role of low estrogen levels in bringing on hot flashes. Hormone replacement therapy, which is sometimes offered to women to alleviate hot flashes or other symptoms of the menopausal transition, may include one or more estrogens alone or in combination with progesterone or an analogue, progestin.
"We think there should be more studies looking at the role of progesterone in causing hot flashes," Flaws said.
The research team identified a second polymorphism, in a gene encoding an enzyme, 3-beta-hydroxysteroid dehydrogenase, which also is associated with an increase in hot flashes.
"People typically didn't think of hot flashes as having a genetic component," Flaws said. "Now we have some evidence that there is at least in part some genetics behind it."
In another paper, published in the journal Climacteric, the researchers used the same data to analyze the link between obesity and hot flashes. They had shown in an earlier study that obesity is associated with more frequent and intense hot flashes in midlife women. They now wanted to see what might be causing this effect: Did the higher incidence of hot flashes in obese women correlate with varying levels of specific hormones or other factors?
When looking at blood levels of specific hormones and related enzymes, the researchers found a significant link between obesity and hormone levels. Higher body mass index (BMI) was significantly correlated with higher testosterone and lower total estradiol, estrone, progesterone and sex hormone binding globulin (SHBG) in midlife women.
The researchers were surprised by the findings related to estrogen, because adipose tissue produces and stores estradiol, the major estrogen in humans. Most people had assumed that obese women would have higher circulating estrogen levels because of this, Flaws said. That assumption turned out to be incorrect, at least for women in midlife.
"It could be that estrogen levels are higher in the fat, but not circulating in the blood," she said. "It's the blood that gets to the brain and to the thermoregulatory centers that govern hot flashes."
A third analysis, published in the journal Fertility and Sterility, examined the influence of alcohol consumption on hot flashes in midlife women.
This study attempted to explain an earlier finding that moderate alcohol consumption (up to three drinks per month) actually reduced the severity of hot flashes by 25 percent. This effect vanished in women who consumed more than three drinks per month.
Because alcohol consumption is known to affect metabolism in some animals, the team thought that light drinking might alter sex steroid hormone levels in midlife women. But their analysis failed to turn up any significant hormonal differences between the alcohol users and the women who never used alcohol.
"We don't know why (moderate alcohol consumption) is reducing the risk of hot flashes, other than it doesn't seem to be doing so by changing hormone levels," Flaws said.
Together, these studies point to some risk factors for hot flashes that women can change and others that cannot be changed, Flaws said.
"Body mass index, alcohol use and smoking are three things that can change," she said. "So probably if women quit smoking, and they lose weight, it will reduce their risk. If they (engage in) light drinking, that might also reduce the risk of hot flashes. And then there's the genetic piece, which we can't change."