ABSTRACT Attention-Deficit/Hyperactivity Disorder (ADHD) is increasingly recognized as a serious and debilitating problem in adolescent and adult females, with impairment and comorbidity in female patients with ADHD increasing dramatically around puberty. Given the deleterious consequences of ADHD and substantial comorbidities in this group, there is an urgent need to understand sex-specific factors contributing to symptom expression in this understudied population. One promising but understudied factor is ovarian hormones which become activated around puberty and fluctuate monthly in adulthood. To date, no study outside of our lab has examined the effects of estrogen and progesterone changes on ADHD symptoms in female patients, but basic science data from animal studies provide a strong scientific premise for this work. These studies date back 20 years and suggest that withdrawal from—and lower levels of—estradiol, the predominant estrogen, cause cognitive and attention problems, based on experimental work with ovariectomized rats. In fact, we have pilot data establishing the basic scientific premise and feasibility of this study design showing declines in estrogen predict worsening response inhibition and working memory and increases in ADHD symptoms in a clinical sample of female patients with ADHD. Yet, it remains unclear what accounts for these effects at the neurobiological level in humans, despite animal work showing estrogen effects on dopamine and human work in female heavy drinkers showing estrogen effects on insular brain activation patterns during response inhibition tasks. The current project aims to use an innovative, quasi-experimental, and intensive longitudinal menstrual cycle study design to elucidate the neurobiological mechanisms of estrogen effects on neural mechanisms of cognition and ADHD symptoms in a clinical sample of 120 young adult female patients ages 18 to 25 with ADHD. The project will evaluate whether menstrual cycle phase and hormonal effects on the neural circuitry involved in response inhibition and working memory predict short-term longitudinal change in ADHD symptoms and medication response in young adult females with ADHD. This work is a critical extension of our preliminary data, which found cycle phase and hormonal effects on ADHD and response inhibition and working memory but did not evaluate neural mechanisms or hormonal effects on treatment response. The long-term goal of this project is to test whether medication titration or hormone stabilization across menstrual cycle phase or reproductive phase improves ADHD symptoms and normalizes underlying neurocognitive and biological mechanisms in females. Such information is critical to advancing neurobiological theory of ADHD and suggesting new avenues for personalized, sex-specific assessment and psychopharmacological treatment of ADHD, which may need to be targeted to cycle or reproductive phase, hormonal profiles, and impacted neurofunctional regions in pha...