Most women who reach menopause know only too well what hot flashes are: sudden hot blows often accompanied by sweating, palpitations, dizziness, fatigue and/or anxious state, and which are much more debilitating than their name lets it think.
Up to 80 % of women declare themselves subject to this type of puff during menopause, a period during which fluctuation and then fall in the estrogen rate leads to the permanent cessation of menstrual cycles and put an end to natural fertility. According to Naomi Rance, professor of retired neuropathology from the Medicine School of the University of Arizona and pioneer in research on hot flashes, the latter imitate the way in which an overheating body cools, except that it is an “inappropriate activation”, because the body temperature is in the usual range.
These typical hot flashes of menopause, which are also called vasomotor symptoms, for a long time intrigue scientists, who do not understand what can cause this feeling of sudden warmth. However, recently, researchers have identified in the hypothalamus a group of neurons responsible for the triggering of these puffs.
“We have always argued that heat puffs occurred because of a dysfunction of the hypothalamus, which is true. But now, we understand the details that make it happen, ”explains Nanette Santoro, president of the Department of Obstetrics and Gynecology of the Medicine School of the University of Colorado and longtime researcher on menopause.
A drug blocking the effects of these neurons is currently being examined by the American Federal Food and Medicated Products (Food and Drug Administration, FDA) and, if it were to be approved, could offer a non -hormonal medical alternative in 2023. Currently, the main treatment available against menopause is hormonal therapy that partly restores estrogens, but which has dangers for certain women.
According to Stephanie Faubion, director of the Center for the Health of Women of Mayo Clinic and Medical Director of the North American Society of Menopause (NAMS), this new treatment “would be the first pharmacological class dedicated to heat puffs” since the premarin, a treatment based on estrogens in 1941.
Women who have low -heat puffs have seriously suffered them for four years on average, and a third of them suffer for ten years. These figures are particularly high in black and Amerindian people. “Racalized women tend to see the symptoms occur earlier, last longer and have more frequent hot flashes, so the burden is much more important,” explains Genevieve Neal-Perry, director of the Department of Obstetrics and Gynecology at the Medicine School of the University of North Carolina, which studies the new treatment. Obese women, whatever their ethnicity, are also more vulnerable.
After a hot flash (most last between 30 seconds to 5 minutes and occur several times a day), difficulties remain. “There can be a feeling of energy loss, you can feel somewhat diminished,” says Nanette Santoro. Night heat puffs are particularly problematic because they disrupt sleep.
According to Stephanie Faubion, women generally reach menopause during the best years of their career, and symptoms generally constitute a professional obstacle. As part of a British survey, almost two -thirds of active women aged 45 to 55 interviewed said that the symptoms of menopause had reduced their concentration capacity, and more than half of them reported to have lost patience with colleagues and customers. “Women miss work, women change jobs, and women refuse professional opportunities because of these symptoms,” deplores Stephanie Faubion.
These persistent and frequent hot flashes can also be a harmful sign of poor health. Indeed, according to some studies, these symptoms are linked to an increased risk of cardiovascular disease: infarction, stroke, heart failure, etc.
The quest for Naomi Rance to shed light on heat puffs started three decades ago. At that time, she was interested in brain microsections of pre-menopausal and menopausal women and watched variations in the hypothalamus which, with pituitary gland, promoted ovulation and release of sex hormones that govern reproduction. She noticed a group of swollen neurons in menopausal women. “I had no idea what it was, nor the reason they were growing,” she recalls.
It was not long in locating estrogen receptors on neurons, which led her to issue the hypothesis that the absence of this hormone made them grow and modify their activity after menopause. His laboratory ended up identifying three signaling proteins produced by these neurons: kisspeptine and neurokinin B, which play an important role in fertility, then dynorphine. We attributed to these neurons the nickname “KNDY” (pronounce “Candy”), word game with their initials and nod to the experts of Penn State, in Hershey, Pennsylvania, who identified for the first time the Kisspeptin.
Subsequently, naomi rancid research on animals revealed how KNDY neurons regulate temperature. “Neurons send axons to the hypothalamus regions that control body temperature,” she explains. As they are “very, very sensitive to estrogen levels”, when hormones decrease, the activity of KNDY neurons increases.
Other researchers working with rodents have also established a link between these neurons and hot flashes. Their first challenge: knowing how to determine when a mouse has a hot puff. Indeed, as Genevieve Neal-Perry reminds us, we don’t really ask them.
To overcome this problem, the Genevieve Neal-Perry laboratory has developed a special surface, a thermocline, cold on one side and hot on the other. The mice placed on the hot side to which a salin placebo had been injected there. But those to whom we administered capsaicin, a compound present in peppers and known to cause puffs of heat in humans and animals, rushed on the cold side to relieve themselves. Finally, a third group of mouse was administered a drug that activated Neurokinine receptors on Kndy neurons. Just as with capsaicin, with this medicine, the mouse rushed to the colder side, suggesting that it had triggered a puff of heat.
Studies carried out later have confirmed the importance of neurokinin in the appearance of hot flashes in women. “In the past ten years, we have finally been able to assemble the pieces of the puzzle,” rejoices Genevieve Neal-Perry.
“We should not see hot flashes as puzzles,” as has long been the case, according to Naomi Rance. “We should think about how estrogen affects the cerebral circuits that influence thermoregulatory paths. »»
In recent years, companies have started testing drugs that block KNDY neurons receptors to reduce hot flashes. Unlike the hormonal treatment of menopause (THM) which involves taking estrogen, and which is the current norm, “this is a very well -drawn ball in the problem”, explains Nanette Santoro who partially conducted this research.
A limited phase 2 clinical trial has shown that for women with seven hot flashes per day or more, the daily taking of an oral medication (Fezolinetant, which blocks the neurokinin receiver) reduced the number of weekly heat puffs by 45 %.
In October, at Nams, Genevieve Neal-Perry presented the preliminary results of phase 3 of the trial (which have not yet been published in a medical journal) and his research on the Fezolinetant in which more than 1,000 women participated. According to her, women who took their daily tablet had two to four less hot flashes per day than those who received a placebo. In addition, improvements have been seen immediately and were maintained throughout the year that the experience on these women lasted. According to her, the treatment has proven to be just as effective in racialized women, whose sibt heat puffs more virulent and therefore more difficult to treat.
Another drug blocking the activity of the Kndy, the Elinzaneant, is also being studied; Phase 3 clinical trials are underway.
A clinical trial for a third candidate, the pavinator, was interrupted after he caused liver problems. According to Genevieve Neal-Perry, neither of the other drugs sparked similar concerns. According to the results presented at the NAMS, as part of research on Fezolinetant, the most frequent complaint concerned transient headache.
The marketing authorization of a chemical opponent at the KNDY by the FDA would be particularly beneficial for women during menopause unable to be prescribed without danger a hormonal treatment, or which are not comfortable at the idea of following one. According to NAMS advice, oral or transdermal treatments based on estrogen are sure for most women under the age of 60 who have had their last menstruation in the past ten years. However, this is not worth older women or for those who have had breast cancer, heart disease, stroke or who have a personal or family risk of blood clots.
According to Genevieve Neal-Perry, among future beneficiaries of treatment could also appear men taking drugs against prostate cancer and women taking tamoxifen, a drug that is taken in cancer remission, and for whom heat puffs are a frequent side effect. In addition, according to Naomi Rance, as Kndy neurons play a role in the regulation of ovulation, they may open the way for new treatments against infertility. Avant-garde studies carried out on animals reveal the role of neurons in Stein-Leventhal syndrome, a hormonal disease that can lead to this condition.
People responsible for treating women for hot flashes do not hide their enthusiasm from the idea that a new treatment may be born. “It is always good to have several strings to your bow,” comments Nanette Santoro.
In addition, women’s health specialists are delighted that the scientific confusion surrounding hot flashes were finally dissipated. According to Genevieve Neal-Perry, given the fact that all women reaching forty or fifties suffer from hot flashes, “the fact that it was necessary to wait for the past decade to understand the biology of hot flashes is quite extraordinary”.