Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that exhibits striking developmental trajectories, as well as sex differences, in symptoms, prevalence, and correlates. Yet, sex differences in ADHD across development are perhaps the most understudied aspect of this common and costly disorder. ADHD has a global prevalence rate of roughly 5 % in children between the ages of 6 to 18 years (Polanczyk et al., 2015), and often persists into adolescence and adulthood (American Psychiatric Association, 2022; Faraone and Biederman, 2005). ADHD symptoms and impairment increase in girls starting during adolescence, which is also when comorbidity and suicide risk increase (Biederman et al., 2008; Chronis-Tuscano et al., 2010; Eng et al., 2023).

It is important to note that sex assigned at birth and gender are not necessarily synonymous for individuals. Within-person changes may be particularly relevant to individuals who were assigned female at birth (AFAB), as psychopathology does not just vary within-individuals between different stages of life but also within a single month. AFAB individuals experience cyclical changes in ovarian steroid hormones across the menstrual cycle (see Fig. 1), which can represent a significant biological source of symptom variability. Historically, researchers have not always distinguished between biological sex and gender identity, and have reported all participants as women, girls, or female, leaving it unclear how individual participants self-identify (Heidari et al., 2016). In this paper, we attempt to be more conscientious in our use of the terms ‘girls’ and ‘women’ when discussing public health implications, especially in younger groups, and use the word ‘female’ when focusing on biological influences. However, we want to be clear that often we are generally focused on AFAB because our main focus is on endogenous hormones and menstrual cycles (vs. how individuals identify their gender). Therefore, we may be both more and less inclusive than these limited terms can denote.

There is a significant gender-biased prevalence rate in ADHD of a ratio of at least 3:1 favoring boys in childhood (American Psychiatric Association, 2022; Skogli et al., 2013). However, these sex/gender differences in prevalence rates decrease during adolescence, and by adulthood, men and women experience ADHD at similar rates (Das et al., 2012).

Importantly, girls and women with ADHD become more impaired and exhibit higher rates of comorbidity than boys and men, beginning during adolescence and persisting into adulthood. Girls with ADHD are at increased risk of experiencing important health outcomes like increased suicide attempts, affective disorders, risky sexual behavior, substance use, and binge-drinking (Chronis-Tuscano et al., 2010; Flory et al., 2006; Molina et al., 2007; Molina and Pelham, 2003). Despite the prevalence of depressive symptoms in youth with ADHD, little work has examined why these symptoms increase as youth with ADHD age (Brunsvold et al., 2008). However, recent work suggests that these effects are exacerbated as youth advance through puberty, particularly in girls, suggesting possible hormonal influences (Eng et al., 2023).

Unlike in males, in which the prenatal period seems to be the most critical period for development of ADHD risk (Shao et al., 2020; Zhu et al., 2015), females seem to experience multiple critical developmental periods corresponding with reproductive life events, including adolescence/puberty, pregnancy, and menopause (Kinsley et al., 2006; Martel et al., 2009; Rehbein et al., 2021; Schulz et al., 2009). Each of these periods seems characterized by particular profiles of risk and have distinct hormonal patterns.

Adolescence is perhaps the most well-studied of these periods, particularly important because it is a time when individuals transition from childhood to adulthood, including both gendered social transitions and a physical sexual maturation process known as puberty. Beginning in early adolescence, females begin to exhibit low self-esteem, social pressures, sexuality, and increased expectations of maturity, including a focus on body image (Deković et al., 1997; Forney et al., 2019; Galambos and Tilton-Weaver, 2000; Helfert and Warschburger, 2013; Rosenthal et al., 1991). Adolescence is also the period when depression, anxiety, conduct problems, and substance use increase (Lee and Hinshaw, 2006; Whitesell et al., 2013). Puberty also seems to exacerbate these effects on depression and anxiety in females (Costello et al., 2011; Eng et al., 2023; McGuire et al., 2019; Reardon et al., 2009). Although both males and females with ADHD experience increases in impairment as they age, females consistently show higher levels of impairment than males (Eng et al., 2023). Further, females with ADHD are also twice as likely to have an unplanned pregnancy and more likely to become pregnant earlier than their neurotypical peers (Hua et al., 2021; Meinzer et al., 2020).

Adolescence and puberty may be particularly risky because that is when females experience dramatic rises in reproductive hormones, along with the onset of cyclical hormonal changes (and menstruation) that continue into adulthood. Estradiol (E2) and progesterone begin to fluctuate during late puberty as youth experience their first ovulation, leading to their first menstruation. Yet, only one prior study has directly examined pubertal effects on ADHD and associated problems. That study indicated that pubertal development is associated with increased impairment and depressive symptoms and decreased hyperactive symptoms in females (Eng et al., 2023). However, studies that rely on pubertal stage do not capture the day to day changes in hormones related to the menstrual cycle, and little is known about when hormonal effects on ADHD symptoms begin.

Even less is known about other important reproductive periods in females compared to adolescence and puberty. Although higher absolute progesterone and estrogen levels, such as during estrus and pregnancy, are associated with improved memory and cognition in animal models (Paris and Frye, 2008), the literature in humans is inconsistent, perhaps due to differential hormone sensitivity. Pregnancy is also a time of elevated risk for affective disorders and both subjective and objective cognitive dysfunction (Carter and Kostaras, 2005; Davies et al., 2018; Marcus, 2009; Uguz et al., 2019). Cognitively, some females report experiences of “pregnancy brain,” which refers to pregnancy-related deficits in cognitive functioning, memory, and executive functioning (Brown and Schaffir, 2019; Davies et al., 2018; Kumari, 2019). Neuroimaging research also shows reductions in gray matter that endure for years after pregnancy (Hoekzema et al., 2017). However, more research is needed to elucidate potential cognitive and emotional changes in patients with ADHD during pregnancy.

The last reproductive life event females experience is the menopause transition. During this transition, there is evidence for elevated incidence of affective disorders (Freeman et al., 2006). Some females may experience both subjective symptoms and declines in cognitive performance similar to ADHD, such as difficulties in learning, verbal memory, attention, and forgetfulness during menopause which are linked to declines in estrogen as well as changes in brain structure and function, sleep, and mood (Greendale et al., 2020; Maki and Jaff, 2022).

Despite significant risks of affective, cognitive, and functional changes evident at reproductive life events characterized by large hormonal shifts, the exact mechanisms of such changes—and individual differences in susceptibility to such changes—remain largely understudied. This lack of understanding of cognitive hormone effects is particularly concerning in the case of ADHD, where patients are already experiencing cognitive difficulties.

Most information about hormonal effects on cognition and mood across the lifespan, including the previously reviewed reproductive periods in girls and women, is based on research conducted in individuals without ADHD. Reproductive psychiatric disorders can be viewed as a continuum, where some individuals seem to be more or less sensitive to hormonal changes than others. However, in many cases, people with ADHD seem to be at elevated risk of these hormone-related symptoms. Yet, little work has evaluated the relevance of such effects to ADHD symptoms, or examined how such effects look in females with ADHD.

There is some important extant theory that could guide such study. Organizational and activational hormonal effects and theory on more general phenomena is well known and articulated. Organizational effects refer to the ability of steroids to dictate long-lasting structural and functional changes that persist past exposure to that steroid. The prenatal effects of testosterone on ADHD (Martel et al., 2008; Martel and Roberts, 2014), touted to be important for males, are organizational (Phoenix et al., 1959). Activational effects, in contrast, are more transient (e.g., during puberty), and serve to impact previously organized neural circuitry, behavior, and the body. The differential impact of hormones across multiple reproductive periods for females with ADHD suggest that activational effects may be particularly important for conceptualizing these developmental changes.

The menstrual cycle is a key activational hormonal event in females, beginning toward the end of puberty. Monthly ovulation and menses (i.e., the menstrual cycle) typically begin between the ages of twelve and thirteen, although this age has been trending downward (Martinez, 2020), and is associated with a number of factors including ethnicity, breast development, and body mass index (Biro et al., 2018; Cheng et al., 2022). The psychological effects of estrogen and progesterone on cognition and emotional functioning are complex, with mixed evidence that appears to point to prominent individual differences in neurobiological sensitivity to normal hormonal events (Garcia et al., 2018; Klump et al., 2013; Sandstrom and Williams, 2001; Schiller et al., 2016). Estradiol (E2) is the most common type of estrogen in females during their reproductive years and contributes to a range of functions including learning and memory, fine motor control, pain perception and mood (Boulware and Mermelstein, 2005; Luine, 2014). The effects of progesterone on cognition and mood remain unclear with some studies finding effects and others not finding an effect (Barros et al., 2015; Henderson, 2018; Sofuoglu et al., 2011; Standeven et al., 2020).

There has been more work on hormonal and menstrual cycle effects on other forms of psychopathology (i.e., not ADHD), with key examples being depression and eating disorders (Endicott, 1993; Klump et al., 2013; Martel et al., 2009). Extensive work on depression suggests a greater risk of depressive symptoms and suicide attempts in the late luteal and menstrual weeks (Baca-Garcia et al., 2010; Jang and Elfenbein, 2019). The hormonal causes of this late luteal or menstrual worsening of depression appear to be heterogeneous; they can be triggered in some cases by delayed deleterious effects of periovulatory hormone surges (Schmidt et al., 1991, Schmidt et al., 2017), and in other cases by the immediate deleterious effects of perimenstrual steroid withdrawal (Eisenlohr-Moul et al., 2022). There is also even more limited and conflictual information around increases in drinking and risk-taking mid-cycle with rises in estrogen (Barone et al., 2023; Martel et al., 2017), and rises in anxiety mid to late luteal phase (Golub, 1976; Reynolds et al., 2018).

Based on this extant literature, our group has developed a cutting-edge theory about hormonal effects on psychopathology beginning during puberty with the onset of the menstrual cycle (Peters et al., Under Review). In our innovative Multiple Hormone Sensitivity Theory, there are three proposed cyclical mechanisms that have the potential to trigger or exacerbate transdiagnostic psychiatric symptoms at different phases of the cycle due to neurobiological sensitivity to normal hormone changes. Currently, we postulate that these distinct sensitivities include: 1) luteally bound increases in hypersensitivity resulting in symptoms such as heightened irritability, interpersonal reactivity, higher-arousal negative affect (e.g., anger and anxiety), and sensory sensitivities (e.g., misophonia), driven primarily by fluctuations in P4 metabolites, 2) perimenstrual increases in cognitive functioning, depression, anhedonia, anxiety, or suicidality, driven by E2 withdrawal and/or depletion, and 3) periovulatory increases in reward-seeking behavior, such as maladaptive substance use and proactive aggression, driven by sudden increases in E2. In addition, these sensitivities can interact with each other, with baseline personality and physiology, and with environmental factors to produce specific symptom profiles.

Our Multiple Hormone Sensitivity Theory suggests estrogen withdrawal sensitivity leads to perimenstrual decreases in executive cognitive functioning, producing symptoms such as difficulties with attention and poorer emotion regulation behaviors. More specifically, this theory postulates facilitative effects of E2 on dopaminergic responses throughout the brain, and we propose two specific mechanisms through which perimenstrual E2 withdrawal effects on dopamine (DA) may contribute to the observed symptoms: 1) altered DA functioning in the prefrontal cortex resulting in temporary impairments in executive cognitive functions and downstream impairments in effective regulation of emotion and behavior, and 2) reduced DA functioning in mesolimbic regions, resulting in altered reward responsivity and related increases in anhedonia (Peters et al., Under Review).

In addition, such estrogen withdrawal can interact with the other psychological changes across the menstrual cycle, namely reward sensitivity at the end of the first half of the menstrual cycle and negative affect at the end of the cycle. Thus, rapidly changing and/or declining levels of estrogen may be expressed behaviorally as a function of the underlying approach or avoidance attitudes and also interact with individual differences in traits such as positive and negative affect or impulsivity.

Our preliminary pilot work suggests that there are likewise substantial activational hormonal effects on ADHD across the menstrual cycle. Specifically, in nonclinical, community-recruited young adult females ages 18 to 25, declines in E2 predicted clinically significant 2-fold increases in ADHD symptoms of inattention and hyperactivity-impulsivity (Roberts et al., 2018). These effects were particularly strong for the more impulsive females, and effects were moderated by positive and negative urgency (or urgency due to positive and negative affect, respectively; Chester et al., 2016; Cyders and Smith, 2008).

These effects were somewhat different for hyperactivity-impulsivity and inattention respectively. Namely, effects for hyperactivity-impulsivity appeared mainly driven by declines in estrogen regardless of levels of progesterone, consistent with more of an ovulatory effect. In contrast, inattentive effects were driven by declines in estrogen but were moderated by levels of progesterone. Specifically, the effect of declines in estrogen in the context of lower than usual progesterone was strongest for individuals who were higher in negative urgency. In the context of lower than usual progesterone, the effect of declines in estrogen was strongest for individuals higher in positive urgency.

Such results are consistent with the idea that rapid changes in estrogen, particularly declines, increase the risk for ADHD symptoms. Our preliminary pilot work and theory suggest that declines in estrogen are correlated with increased ADHD symptoms throughout the cycle, both post-ovulatory and at the end of the cycle. Although pronounced individual differences are observed, estrogen appears generally protective for cognition across the menstrual cycle and has also been implicated in emotion regulation (Rehbein et al., 2021). Therefore, mid-cycle declines in estrogen may interact with or exacerbate prior increases in approach and reward behaviors, leading differentially to hyperactivity and impulsivity mid-cycle, around ovulation. In contrast, at the end of the cycle, declines in estrogen may be interacting with or exacerbate tendencies toward social withdrawal and negative affect, leading to more inattentive symptoms.

Adolescents may be particularly vulnerable to these end of cycle and mid-cycle activational effects given adolescence is also a time of organizational effects (Sisk and Zehr, 2005). In particular, the prefrontal cortex is still underdeveloped during adolescence, so the ability to control emotional impulses is not as strong as it is in adults (Vink et al., 2014). Adolescents with ADHD in particular have highly active limbic systems and demonstrate an abnormally high preference for small, immediate rewards compared to larger delayed rewards (Demurie et al., 2012; Scheres and Solanto, 2021). These increases in the environmental stressors associated with this time period provide more opportunities for emotional dysregulation and engagement in risk-taking behaviors.

The timing of puberty appears to play a significant role in the impact of hormonal effects on psychopathology, as the brain may be more sensitive to gonadal hormones during adolescence. Animal models have been utilized to parse the entanglement of aging and pubertal effects via experimental manipulations that would otherwise be unable to be utilized in humans. For example, this process has been modeled in rodents with females experiencing greater neuron loss in the medial prefrontal cortex than males across adolescence and prepubertally ovariectomized females having more neurons and white matter than controls (Koss et al., 2015; Willing and Juraska, 2015). Similarly, female mice that undergo hormonal treatments to induce early puberty show increases in inhibitory neurotransmission in the frontal cortex, indicating organizational effects of ovarian hormones during puberty (Piekarski et al., 2017).

The brain gradually becomes less sensitive to the organizing effects of circulating hormones, therefore, earlier puberty may have greater effects on the brain than on-time or late puberty (Schulz et al., 2009). Puberty may close a sensitive period for enhanced plasticity in the associative cortex (Piekarski et al., 2017). We theorize that early puberty may predispose some individuals to be more impulsive or have more negative affect due to a premature decrease in plasticity and thus the early closure of sensitive periods for cognitive development.

Overall, females may be preferentially vulnerable to the organizational effects of early puberty because it closes off the sensitive period of neurodevelopment in such a way as to predispose them to impulsivity and depression. In addition to the compounding organizational effects of early puberty on the neurobiology implicated in impulsivity and depression, fluctuations in estrogen across the menstrual cycle appear to exacerbate risk. Estrogen surges and declines around ovulation appear to worsen impulsivity by interacting with dysregulated approach behaviors and reward sensitivity, in line with organizational effects on impulsivity at puberty. Further, activational declines in estrogen at the end of the menstrual cycle appear to worsen depression and inattention. This might allow known activational effects of hormones across the menstrual cycle to serve as a double whammy of risk.