Effects of endogenous and exogenous ovarian hormones on Electronic Nicotine Delivery Systems (ENDS) Use - ABSTRACT In 2018 the U.S. Surgeon General declared Electronic Nicotine Delivery Systems (ENDS) use a youth epidemic. ENDS use continues to soar, especially among young adults (ages 18-24) who use more than any other cohort. ENDS use is associated with negative cardiovascular, immunologic, and neurodevelopmental illness. Young women are disproportionately impacted by ENDS use, due to more nicotine withdrawal symptoms, greater cue induced cravings, and poorer treatment response. Yet, little is known about factors that can inform sex-specific ENDS treatments. Variation in exposure to ovarian hormones either endogenously via the menstrual cycle or exogenously via oral contraceptives may be critical sex-specific factors impacting ENDS use. There is a dearth of studies focused on ENDS; however, burgeoning animal and human research on combustible cigarettes suggests that there may be three pathways linking ovarian hormones to nicotine use. Endogenous estradiol and progesterone are ovarian hormones that fluctuate across the menstrual cycle. Based on the positive reinforcement pathway naturally occurring increases in estradiol paired with decreases in progesterone during the follicular phase enhance the rewarding effects of nicotine leading to use. Based on the negative reinforcement pathway we expect that individuals who experience affective reactivity in response to naturally occurring drops in estradiol and progesterone during the luteal phase use nicotine to cope with distress. Lastly, ethinyl estradiol (a synthetic form of estrogen common in oral contraceptives) increases nicotine metabolism (i.e., quicker elimination of nicotine) resulting in more use to “replenish” nicotine concentrations. Despite promising studies supporting these three pathways, meta-analytic findings show that several studies show no effects. This may be because most studies do not directly measure ovarian hormones or include biomarkers of nicotine metabolism, rely on cross-sectional between-subject designs, and infer a dichotomized menstrual cycle phase, rather than capture hormonal variation. This project will utilize a 35-day experience-sampling methods protocol that prospectively tracks menstrual cycle day, oral contraceptive use, ENDS use, perceived nicotine reward, and affect. Ovarian hormones and a ratio of trans 3'-Hydroxycotinine to cotinine (an established biomarker of nicotine metabolism) will be assessed from dried blood spots. We will recruit ENDS users with naturally occurring menstrual cycles (n=100) and those on combined-type oral contraceptives (n=100). This project expands research on biological sex-specific mechanisms and will generate data that can guide tailored interventions.
