Most menopausal women are familiar with hot flashes (the sudden onset of rapidly rising heat, often accompanied by sweating, rapid heartbeat, dizziness, fatigue and/or anxiety), which are far more debilitating than their name suggests.
Up to 80% of women experience these hot flashes during menopause, a time when fluctuating and eventually falling levels of the hormone estrogen lead to the permanent cessation of menstruation and natural fertility. According to Naomi Raines, a retired professor of neuropathology at the University of Arizona School of Medicine and a pioneer in hot flash research, hot flashes mimic the way the body cools itself when it gets hot, but they are an “insufficient activation.” Because the body temperature is maintained within the normal range.
Scientists have long been puzzled about this symptom of menopause (also called hot flashes and vasomotor symptoms) because they didn’t understand exactly what causes a woman to suddenly become hot. But recently researchers have identified a group of neurons in the brain’s hypothalamus that are responsible for triggering these hot flashes.
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Nanette Santoro, professor of obstetrics and gynecology at the University School of Medicine, says: “We’ve always said that hot flashes happen because the hypothalamus malfunctions, but we are now understanding the details of why this is so.” from Colorado, USA, and a longtime menopause researcher.
The US Food and Drug Administration is studying a drug that blocks the effects of these neurons and, if approved, could offer a non-hormonal treatment option as early as 2023. Currently, the main treatment is menopausal hormones to restore some estrogen, but not all women can safely take these drugs.
The new drug “will be the first new class of drugs specifically for hot flashes” since the advent of the estrogen-based treatment Premarin in 1941, says Stephanie Faubion, director of the Mayo Clinic Center for Women’s Health and medical director of the society. (NAMS).
more than a nuisance
Women with moderate to severe hot flashes experience them for an average of four years, and a third experience them for a decade. These figures are especially evident in the case of black populations and Native Americans. “Women of color have earlier onset, longer duration, and more frequent hot flashes, so the burden is much greater,” says Genevieve Neal-Perry, MD, professor of obstetrics and gynecology at the University of California School of Medicine. University of North Carolina (USA), which is investigating the new drug. Obese women of any ethnicity are also more prone.
Once the crisis passes (mostly lasting between 30 seconds and 5 minutes and occurring several times a day), the difficulties persist. “You may feel a little fatigued,” says Santoro. Hot flashes are especially troublesome at night because they interrupt sleep.
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Faubion says women often enter menopause in the prime of their careers, making this symptom a career drag. In a British survey, nearly two-thirds of working women aged 45 to 55 said menopause symptoms were making them less able to concentrate, and more than half said they lost patience with co-workers and customers. “These symptoms cause women to drop out, change jobs, and turn down opportunities for advancement.”
Persistent and frequent hot flashes can also be a harbinger of poor health, as some research suggests that these symptoms are associated with an increased risk of developing cardiovascular disease, such as heart attack, stroke or heart failure.
Raines’ quest to understand hot flashes began three decades ago, when he was examining microsections of the brains of premenopausal and postmenopausal women, looking for changes in the hypothalamus, which, along with the pituitary gland, controls ovulation. Promotes and releases the sex hormones that control sex. Reproduction. They observed a cluster of swollen neurons in postmenopausal women. “I didn’t know what they were or why they got that big,” he recalls.
They soon located estrogen receptors on neurons, leading them to hypothesize that the absence of the hormone may have played a role in the increase in size and change in activity level after menopause. Eventually, his lab identified three signal proteins produced by these neurons: two of them, kisspeptin and neurokinin B, play important roles in fertility; The third is dynorphin. All three were nicknamed KNDy neurons, pronounced “candy,” a pun on their initials and a nod to the experts at Penn State in Hershey, Pennsylvania, who first identified kisspeptin.
Raines’ animal research later revealed how these KNDy neurons regulate temperature. “Neurons send axons to areas that control body temperature in the hypothalamus,” he explains. Because they are “very sensitive to estrogen levels,” when the hormone decreases, the activity of KNDY neurons increases.
Other researchers working with rodents have also linked neurons to bothersome hot flashes. His first challenge, says Neal-Perry: understanding when a mouse is glowing hot, because you can’t exactly ask it.
To solve this problem, Neal-Perry’s lab developed a special surface called a thermocline that is cold at one end and hot at the other. Mice placed on the comfortable side that were injected with placebo saline remained there. Instead, those given capsaicin (a compound in chili peppers known to trigger hot flashes in humans and animals) moved to a cooler location for relief. Finally, a third group of mice was given a drug that activated neurokinin receptors on KNDy neurons. Like capsaicin, the drug caused the rats to run to the colder side, suggesting that it triggered hot flashes.
Later studies confirmed the importance of neurokinin in causing hot flashes in women. “In the last decade, we’ve finally been able to put the pieces of the puzzle together,” Neill-Perry says.
“We shouldn’t think of hot flashes as a puzzle,” says Rains, “as has long been done.” “We should be thinking about how estrogen affects brain circuits that affect thermoregulatory pathways.”
Block Peptide, Block Flash
In recent years, companies have begun testing drugs that block receptors on KNDy neurons to reduce hot flashes. “Unlike estrogen-based menopausal hormone therapy, the current standard,” says Santoro, “it’s a well-aimed bullet aimed at where the problem is.”
A small phase 2 clinical trial showed that for women experiencing seven or more hot flashes per day, taking an oral drug (Phazolinent, which blocks the neurokinin receptor) reduced weekly hot flashes by 45%. has decreased.
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In October, Neill-Perry presented preliminary results from a Phase 3 trial (not yet published in a medical journal) of her research with Phaseolinent involving more than 1,000 women at the North American Menopause Society. They reported that women taking the daily pill experienced two to four fewer hot flashes each day than those taking the placebo. The improvements started immediately and continued throughout the year of the study, Neal-Perry says. They say the drug was just as effective in African-American women, whose high burden of hot flashes often makes it difficult to treat.
Another drug that blocks KNDY activity, alginate, is also under investigation under phase 3 trials.
Clinical trials of a third drug candidate, pavinent, were halted after causing liver problems. None of the other drugs raised the same concerns, Neil-Perry says. In the fezolinetant research, the most common complaint was transient headache, according to results presented at NAMS.
FDA approval of the KNDY antagonist would be particularly beneficial for menopausal women who cannot safely take hormone therapy or feel uncomfortable doing so. Although the NAMS guideline stresses that oral or transdermal estrogen-based treatments are safe for most women under the age of 60 who had their last menstrual period in the past decade, this is not the case for older women or those who Those who have had breast cancer, heart disease. Personal or family risk of heart disease, stroke, or blood clotting disorder.
Neal-Perry says other future beneficiaries could be men taking drugs for prostate cancer and women taking tamoxifen, a cancer drug for which hot flashes are a common side effect. And since KNDY neurons are involved in the regulation of ovulation, they may eventually provide a new avenue for infertility treatment, Rains says. Preliminary animal research reveals a role for neurons in polycystic ovary syndrome, a hormonal medical disorder that can cause infertility.
Those who treat women with hot flashes are excited by the prospect of a new drug. “It’s always good to get more rotations in the chamber,” says Santoro.
Plus, women’s health experts are thrilled that the scientific confusion behind hot flashes has finally been resolved. Given that nearly all women who reach middle age experience them, Neil-Perry says, “The fact that we didn’t understand the biology of hot flashes until the last decade is pretty amazing. “