When Naomi Rance, a neuropathologist at the University of Arizona in Tucson, began studying menopause and the brain, she was taken aback. In studies of postmortem brains, she had found neurons in a region called the hypothalamus that nearly doubled in size after menopause in women. It was the 90s and few other researchers were interested in her studies. Rance went it alone, meticulously unraveling what the neurons were doing and perfecting a way to study menopausal symptoms in rats by monitoring tiny temperature changes in their tails as a measure of hot flashes, a common menopausal symptom thought to is triggered in the hypothalamus. Thirty years later, a drug called Fezolinetant, based on Rance’s discoveries, is now under careful evaluation by the United States Food and Drug Administration, and its approval and subsequent commercialization is expected in the next few months. Fezolinetant could be a milestone: the first non-hormonal therapy to treat the source of hot flashes, a symptom that has become almost synonymous with menopause and affects about 80 percent of women.
For Rance and others in the field, the progress of the Fezolinetant up to this point are a sign that research into the causes and effects of menopausal symptoms is finally being taken seriously. In the coming years, the global number of postmenopausal women is projected to exceed one billion. But many women still struggle to access menopause-related care, and research into how best to manage those symptoms has lagged behind. This is slowly changing. Armed with improved animal models and a growing literature on the effects of existing treatments, other researchers are entering the field to fill this gap.
They increasingly recognize that menopause and the transition to it, a phase called perimenopause, could set the stage for brain health in later life, and there are even indications that it could correlate with the risk of neurodegenerative diseases, such as Alzheimer’s disease. . Fezolinetant and similar drugs in the pipeline also represent a shift in thinking: from menopause as a condition of the female reproductive organs, to research focusing on neurological causes and effects. “We think of menopause as driven by changes in the ovaries,” says Hadine Joffe, who studies mental health and aging in women at Harvard Medical School in Boston, Massachusetts. “The notion of the brain at the helm of menopause, that’s a different concept.”
Menopause is a gradual process
Menopause is defined as the cessation of menstruation for at least 12 consecutive months and typically occurs between the ages of 45 and 55, with irregular production of key sex hormones such as estrogen and progesterone. “It’s not something that happens overnight, it’s a long process,” says Ami Raval, who studies reproduction and neurology at the University of Miami in Florida. “The ovary is slowly sending the ‘shutdown’ signal.” “That can mean years of fluctuating hormones that no longer rise and fall in their once predictable patterns. During this period of perimenopause, circuits in the brain that previously relied on estrogen signaling can be left in a bind,” says Roberta Brinton, a neurobiologist at the University of Arizona in Tucson.
Estrogens do a lot for the brain: they stimulate glucose uptake and energy production. Once the transition to menopause is complete, neurons get used to its absence. But during perimenopause, hormone levels can plummet one week only to soar the next. “The result may be a period of neuronal discord in which brain cells are periodically deprived of estrogen, but not long enough to forge the pathways needed to adapt to life without it,” Brinton says.
Perimenopause is also when many of the characteristic symptoms of menopause occur. Hot flashes are the hallmark of perimenopause; other symptoms include irregular periods, anxiety, high blood pressure, and the dreaded “brain fog” that prevents concentration. “There’s this idea that women in their perimenopause shouldn’t be symptomatic, that they ‘shouldn’t be complaining yet,’” says Joffe. “But it’s actually the time when people are most symptomatic, in some ways.”
It could also be a key time to intervene with treatments that ease the transition to menopause and which could slow the pace of age-related diseases that seem to accelerate afterward. Raval and other researchers think this perimenopausal transition could lay the groundwork for postmenopausal increases in the risk of conditions like Alzheimer’s disease and stroke.
But perimenopause has no clear beginning and end, which makes it difficult to study. “Large clinical trials of treatments like HRT have often focused on postmenopausal women, sometimes years after their last period,” says Stacey Missmer, a researcher at Michigan State University in Grand Rapids. “Some women have a short duration of perimenopause symptoms and others continue to be symptomatic for years or decades,” she says. “And we don’t know if that has anything to do with their health for the rest of their lives.” Meanwhile, the scarcity of treatment options has led some women to seek unproven treatments, such as herbal supplements.
Increase attention
“The taboo around discussing menopause — which combines the two historically sidelined themes of aging and women’s reproductive health — is easing,” says Kathryn Schubert, president of the Society for Women’s Health Research in Washington DC. “As discussions of both topics have become more palatable, women are being more vocal about the symptoms they experience during perimenopause.” Pharmaceutical and consumer health companies are also working to increase awareness and the size of their market. Behavioral scientist Vasiliki Michopoulos of Emory University in Atlanta, Georgia, says she and her colleagues who study menopause in nonhuman primates were stunned to see an American advertisement about hot flashes during this year’s Super Bowl, on biggest game of the season in America. The announcement was sponsored by Astellas Pharma, the Tokyo-based pharmaceutical company developing Fezolinetant.
Source
Nature