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What Happens During a Hot Flash?

  • Published10 Feb 2021
  • Author Helen Santoro
  • Source BrainFacts/SfN
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At work eighteen years ago, Naomi Rance felt a sudden flush of heat in her arms, neck, chest, and face. She had her first hot flash. This sudden spike in the sensation of heat didn’t last long, but as the flashes continued over the next five years, she remembers waking up frequently at night. “For me, that was one of the worst things — you basically lose a lot of sleep,” says Rance, a pathology professor at the University of Arizona.

Hot flashes, or flushes, are the most common symptom of the menopausal transition and postmenopausal period, a time in a woman’s 40s or 50s when menstrual periods become irregular and eventually stop. More than 75% of women experience hot flashes and they last anywhere from 30 seconds to five minutes. They can disrupt people’s lives — some women get them several times an hour. They last for years, with a median duration of seven years. “Hot flushes are really one of the main reasons that women seek a physician for symptoms of menopause,” says Rance.

For decades, Rance has studied the hypothalamus, a small region near the base of the brain that plays a crucial role in regulating pituitary hormone secretion and body temperature. In her studies, she examined the hypothalamus of women before and after menopause. She used animal models to understand the findings. Through her research, she helped uncover how hot flashes work. Here, she discusses with what hot flashes are, the brain circuits involved, and new possibilities for treatments.

What is a hot flash?

If your body says, “I’m too hot,” it triggers the mechanisms to get rid of heat. These heat loss mechanisms are the components of a flush — blood rises to the surface of your skin, you get red, heat radiates from your skin to the external environment, and you start sweating, which gets rid of heat. This is a normal response to elevated body temperature. But in menopause, this heat loss response is stimulated inappropriately.

Flushing is caused by the decline in estrogen secretion as women go through menopause.   Estrogen is produced by the ovarian follicles, and these structures also contain immature eggs. Women are born with a limited number of follicles, which decline over a woman’s life. Estrogen also affects the health of the reproductive system, urinary tract, bones, and more. As the body loses follicles and therefore loses estrogen, it tries in vain to stimulate the production of more estrogen.

What brain circuits are involved in hot flashes?

In the hypothalamus, there is a set of neurons known as the KNDy neurons. These neurons get their name from the presence of three peptides — kisspeptin, neurokinin B, and dynorphin. In postmenopausal women these neurons in the hypothalamus get larger due to the loss of ovarian estrogen. These neurons synapse on the gonadotropin-releasing hormone neurons that control reproduction and stimulates the secretion of luteinizing hormone from the anterior pituitary gland. Releasing luteinizing hormones in young women increases estrogen. But, due to the loss of ovarian follicles, estrogen remains low in postmenopausal women. Thus, KNDy neurons are part of the brain circuity that is activated in response to losing estrogen.

KNDy neurons also synapse on neurons in the preoptic area, a region of the hypothalamus that controls body temperature. By releasing neurokinin B and stimulating the neurokinin B receptor (the neurokinin 3 receptor), these neurons stimulate the heat loss mechanisms that produce a flash. This hypothesis is supported by clinical studies. Infusing neurokinin B into the blood stream of young women triggers a hot flash. Conversely, treatment with a NK3 receptor antagonist reduces the severity and frequency of hot flashes.

I’ve heard men experience menopause as well. Do they also get hot flashes?

Men have changes in reproductive function as they age, but it’s not like the total loss of ovarian follicles in women. Testosterone decreases gradually, and it can decrease to a point where men do report hot flashes. Men with prostate cancer also experience this — one common treatment is to deplete the production of testosterone. This results in pretty severe hot flashes.

Are there any available treatments for hot flashes?

Estrogen is a very effective treatment. But, it’s not for everyone. Women who have had breast cancer can’t use estrogen replacement because it may spur the growth of their cancer. Some women are concerned about side effects. Some people won’t take it — it’s controversial. One study showed the risks of taking estrogen outweighed the benefits — it increased the risks of breast cancer, stroke, and coronary heart disease. There are many other treatments, including antidepressants but estrogen is probably the most efficacious treatment we have at this time.

However, other ways to treat hot flashes are in development. KNDy neurons possess neurokinin 3 receptors and stimulate the neurokinin 3 receptors in the preoptic area to produce a flash. This means you could conceivably treat hot flashes with drugs that block this receptor. In several clinical studies these blocking drugs, called neurokinin 3 receptor antagonists, effectively reduced hot flashes in women within three days and lasted as long as the women took the drugs. There’s hope this will provide a new targeted treatment of flashes that doesn’t involve taking estrogens. One drug is in Phase III clinical trials now.

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