New treatments for hot flashes target neurons

“When estrogen falls, it causes this KNDy neuron complex to just basically go bonkers,” said Dr. Susan Reed.

As many as 75 percent of the women in North American experience hot flashes, and many of these women still look to hormone therapy to relieve the surge of hormones, otherwise known as vasomotor symptoms, or VMS.

But new research, shared recently at the Annual North American Menopause Society Conference, shows the direction of VMS therapy is turning toward new nonhormonal drug treatments targeting neurons in the brain.

Dr. Susan Reed, an ob-gyn with the University of Washington School of Medicine and research director for the UW Medicine Women’s Reproductive Health Research Center, was one of the keynote speakers at the conference. She shared the  most recent research into nonhormonal drug therapy for hot flashes on last month.

Specifically, Reed talked about research into drugs that act at the kisspeptin/neurokinin B/ dynorphin (KNDy) neuron complex in the hypothalamus which controls reproduction and hormonal control. During menopause, estrogen levels decrease, which causes these neurons to be hyperstimulated, thereby causing hot flashes.  

“When estrogen falls, it causes this KNDy neuron complex to just basically go bonkers,” she said. “It’s like turning on a gazillion fire hydrants, which spill over into the adjacent thermoregulatory center and cause thermoregulatory dysregulation, resulting in hot flashes. The thermoregulator center sends signals to the rest of the body to cool us when we are too hot (via hot flashes) and to warm us when we are too cool (shiver).” Dysregulation causes hot flashes at a normal core body temperature.

Currently, the FDA has not approved any of the drugs for menopause treatment –- which target the KNDy neuron complex, Reed noted. But some of her research with collaborators at UW (Dr.  Robert Steiner, of UW Medicine’s obstetrics and gyecology and Dr. Charles Chavkin of pharmacology and pain medicine) and Harvard (Dr. Victor Navarro) evaluating kappa agonists and research of others evaluating NKB antagonists has been promising.

“The KNDy neuron manipulation, is really exciting and holds great promise for rapid and efficacious treatment of menopausal symptoms,” said Reed. “We’re still looking at safety in the Phase 3 trials for the NKB antagonists (targeting the N in KNDy)  but this treatment is up to 80 percent effective in amelioration of hot flashes, with improvement of other menopausal symptoms such as sleep and well-being.” Some of the NKB antagonists have been shown to have minor adverse effects on liver function, so further studies are ongoing to confirm their safety.

Reed and her collaborators have evaluated drugs similar to Dynorphin (the Dy from KNDy).   These drugs  are kappa agonists and bind the kappa opiod receptor. Unlike the common opiods that are used for pain and bind the mu opioid receptor, this group of kappa agonists do not appear to cause the addictive behavior or the side effects well known to the class of opiods used for pain. The kappa agonists have an inhibitory effect on the KNDy neuron complex, blocking the overdrive effect that occurs with low estrogen.

Earlier this year, Reed was lead author in a paper looking at new treatments for menopause, including hot flashes. One of the treatments studied looked at using low doses of a class of drugs called selective serotonin uptake inhibitors (SSRIs) to treat hot flashes. SSRIs have traditionally been used to treat depression, but low doses effectively reduced hot flashes and night sweats, the researchers found.

 “The [National Institutes of Health] asked us to give options to women for treatment of menopausal symptoms,” said Reed. The paper summarizes 10 years of data from five randomized trials performed by the research group known as MsFLASH. She is PI for this grant along with her colleagues Dr. Katherine Guthrie (Fred Hutch) and Dr. Andrea LaCroix (UC San Diego).

Yoga, exercise, and omega 3 vitamins also were evaluated for relief of hot flashes, but none was supported by the study data.  Reed hastened to add, though, that yoga and exercise help overall quality of life and health and can be helpful for well-being in midlife.

Reed said future research will examine the vaginal microbiome of menopausal women as well as the brain area beside the hypothalamus, which regulates body temperature and cold stimuli.

“We know there is a lot of crosstalk between the hypothalamic neurons in the reproductive center and the thermoregulatory center, and that they chat back and forth,"  she said. "Unlocking the key to how this area of the brain is controlled will be critical to our understanding of the etiology of menopausal symptoms so that we can best target future safe effective nonhormonal therapies."

Barbara Clements - 253-740-5043,

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