Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women.

Abstract

As longitudinal studies determined that anxiety is a strong risk factor for hot flashes, we hypothesized that an anxiogenic stimulus that signals air hunger (hypercapnic, normoxic gas) would trigger an exacerbated hot flash-associated increase in tail skin temperature (TST) in a rat ovariectomy (OVEX) model of surgical menopause and hot flashes in symptomatic postmenopausal women. We also assessed TST responses in OVEX serotonin transporter (SERT) rats that models a common polymorphism that is associated with increased climacteric symptoms in postmenopausal women and increases in anxiety traits. OVEX and sham-OVEX rats (initial experiment) and wildtype and SERT OVEX rats (subsequent experiment) were exposed to a 5-minute infusion of 20% carbon dioxide (CO2) normoxic gas while measuring TST. Postmenopausal women were given brief 20% and 35% CO2 challenges, and hot flashes were self-reported and objectively verified. Compared to controls, OVEX rats had exacerbated increases in TST, and SERT OVEX rats had prolonged TST increases following CO2. Most women reported mild/moderate hot flashes after CO2 challenges, and the hot flash severity to CO2 was positively correlated with daily hot flash frequency. The studies demonstrate that this anxiogenic stimulus is capable of inducing cutaneous vasomotor responses in OVEX rats, and eliciting hot flashes in postmenopausal women. In rats, the severity of the response was mediated by loss of ovarian function and increased anxiety traits (SERT), and, in women, by daily hot flash frequency. These findings may provide insights into anxiety-related triggers and genetic risk factors for hot flashes in thermoneutral environments.