The menopausal transition, or perimenopause, is a 2-to-10-year stretch of hormone irregularity leading up to menopause, when menstruation ceases permanently. It is a time that can come with a variety of challenging symptoms—including hot flashes, sleep disturbances and problems concentrating—as well as often underrecognized mental health challenges, such as heightened irritability, mood swings, increased anxiety and panic attacks. Importantly, a woman’s risk of depression grows two to five times higher than before or after the transition. Suicidal ideation and suicide rates in women are highest between the ages of 45 and 55.
What exactly is happening in the perimenopausal brain to trigger these increased risks? We know that perimenopause represents a major “neurological transition state”; the brain is exposed to drastically changing levels of ovarian hormones, similar to puberty but in reverse. As ovarian function declines, so do levels of the ovarian hormones estradiol and progesterone. The pituitary gland tries to compensate, resulting in erratic hormone fluctuations. These changes are sensed by the ovarian hormone receptors present throughout the brain, particularly in limbic areas important for emotion regulation and memory, such as the hypothalamus and the hippocampus. Neuroimaging studies in living humans have reported changes in estrogen receptor availability and brain metabolism across the menopausal transition.
We also know that estradiol acts as a potent neuromodulator in the brain, affecting multiple neurotransmitter systems, including the serotonergic, noradrenergic and dopaminergic systems, and neuropeptides, such as brain-derived neurotrophic factor—all of which are known to be linked to depression and anxiety disorders. Mouse studies have revealed that hormone shifts across the ovarian cycle induce changes in chromatin organization that underlie changes in hippocampal gene expression, synaptic plasticity and anxiety-related behavior.
It seems likely that the mental health changes observed during perimenopause are related to the shifts in hormones and their receptors in the brain. Few studies, however, have explored the biological mechanisms underlying the increased psychiatric risk. Understanding these changes is essential both for developing new treatments for women in perimenopause who are experiencing mood and memory issues, and for understanding how these changes affect long-term brain health; metabolic changes during perimenopause are thought to increase the risk for Alzheimer’s disease, for instance.
We know little about the mechanisms underlying well-known perimenopause symptoms in the brain. More research—in animals and humans—is essential.
