Adolescent Hormonal Contraceptive Use in the Context of Brain Development and Depression Risk: A Review and Considerations for Future Research.

Preclinical work has demonstrated that endogenous E2 and P4 exert widespread effects on the brain, influencing neuroplasticity, neurogenesis, and neurotransmission ( 81 ). E2 and P4 receptors are expressed throughout the brain, including in the amygdala, hippocampus, and prefrontal cortex (PFC) ( 2 , 3 ). The brain is sensitive to E2 and P4 changes over months and years, such as those occurring during puberty ( 11 ), pregnancy, and menopause ( 82 ), as well as shorter-term fluctuations across the menstrual cycle ( 83 , 84 ). Cyclic fluctuations have been linked to small whole-brain functional ( 85 , 86 , 87 ) and, to a lesser extent, structural ( 88 ) changes. Once thought to be concentrated in the medial temporal lobe ( 89 , 90 , 91 ), these changes are now understood to be distributed across cortical and subcortical regions, reflecting the importance of network perspectives. Preclinical findings have also played a central role in elucidating potential mechanisms linking HCs to changes in the brain and subsequent behavior, in particular, through interactions with HPA axis functioning and stress responsivity ( 30 , 92 , 93 ). Converging with emerging evidence from humans, rodent models have shown that HCs appear to blunt cortisol/corticosterone responses to stress, which is consistent with a reduced release of glucocorticoids and altered downstream effects on stress signaling pathways ( 30 ). For example, HCs have been associated with increased circulating FK506 binding proteins (FKBP5). FKBP5 dampens glucocorticoid receptor sensitivity and modifies the negative feedback loop of the HPA axis, resulting in altered stress reactivity ( 94 ). Recent adolescent rodent models have further demonstrated HC-related changes in HPA axis function and alterations in the fold change expression of genes related to neuroimmune, hormone, GABAergic (gamma-aminobutyric acidergic), and monoamine signaling in the hypothalamus and the medial PFC (mPFC) [see ( 93 ) for details]. Although some of these HC-related changes may be specific to adolescence, such as gene expression alterations in the hypothalamus and mPFC, further research in adult rodents is required to replicate these findings. Importantly, the analogous brain regions in humans have a high density of E2 and P4 receptors and undergo substantial maturation during adolescence. Alterations in these stress- and emotion-related brain regions have also been linked to an elevated risk of depression ( 18 , 19 , 20 ). Together, these findings outline potential neuroendocrine mechanisms through which HCs may shape resilience and vulnerability to depression, although direct evidence in humans, especially adolescents, remains limited. Given the well-established influence of gonadal hormones on brain structure and function ( 11 , 95 ) and mechanistic evidence from rodent models ( 88 , 89 , 90 ), the relative scarcity of neuroimaging research on HCs in humans is striking. A 2020 systematic review ( 96 ) identified only 33 structural and functional imaging studies, with just 1 including participants under 18 years (55 users vs. 55 nonusers, age range: 13.5–15.5 years) ( 97 ). Existing evidence, drawn largely from small adult samples, provides tentative and mixed findings that HC use may relate to differences in brain structure and function, although interpretations remain unclear ( 43 , 96 ). Methodological variability, including menstrual cycle phase, HC formulation, duration of use, small sample sizes, and small effects, likely contribute to inconsistent results ( 37 , 43 ). Findings on cortical thickness have been relatively consistent, with most studies reporting a localized thinner cortex, particularly within frontolimbic regions, in HC users compared with nonusers ( 42 ). However, findings for other brain metrics have been variable. Some studies have reported lower global cortical ( 98 , 99 ) and intracranial volumes ( 100 ) or lower regional gray matter volumes in prefrontal [e.g., middle and superior frontal gyri ( 100 )], temporal [e.g., anterior cingulate and fusiform gyrus ( 101 )], and subcortical [e.g., the hippocampus ( 98 ), putamen ( 102 ), and amygdala ( 99 )] regions. However, other studies have reported volumetric increases in some of these regions ( 100 , 101 , 103 ). Functional imaging findings have also been mixed: Some studies have reported lower prefrontal activity in HC users during emotion-processing tasks ( 104 ), while others—including the only task-based adolescent study reported to date—found higher temporal lobe activity ( 97 ). Resting-state functional connectivity findings remain inconclusive, with studies reporting both higher and lower connectivity or no differences at all between HC users and nonusers ( 96 ). Neuroimaging research on adolescent HC use remains extremely limited. In adolescents, Marečková et al. ( 97 ) reported higher temporal lobe activity in COC users compared with nonusers, diverging from adult findings of reduced prefrontal activation during a similar emotion-processing task ( 104 ). More recently, Heller et al. conducted the first whole-brain analysis of cortical morphology in the ABCD (Adolescent Brain Cognitive Development) Study and found lower cortical thickness in the paracentral gyrus in adolescent HC users compared with nonusers after controlling for age, pubertal stage, and intracranial volume ( 105 ). Although this was the only finding surviving multiple comparison correction, the small number of HC users versus nonusers ( n = 65 vs. 1169; mean age 14 years) reduced statistical power and generalizability. Moreover, limited data in the ABCD Study on HC formulation, duration of use, and menstrual cycle or intake phase (active or placebo pill phase) at time of scanning also restrict interpretations. Importantly, the functional significance of HC-related brain differences remains unclear, including in adults. One study in adults found that prefrontal cortical thickness differences associated with COC use were not linked to depressive symptoms ( 106 ). Considering that adolescence is a period of heightened hormonal change, brain development, and increased depression risk, this represents a critical knowledge gap. To advance the field, a range of thoughtfully designed neuroimaging approaches is needed, collecting new data or leveraging existing datasets ( 18 ). Longitudinal and multimodal studies, whether large-scale or dense sampling, offer opportunities to examine developmental trajectories and within-person fluctuations. For example, the ABCD Study will be well positioned to examine how brain development and depression trajectories differ between HC users and a matched group of nonusers. However, it currently lacks detailed HC-related information from individuals, limiting making inferences beyond the group level. Moreover, a dense sampling study with an adult COC user demonstrated that brain structural dynamics across the menstrual cycle differed significantly from those observed in a naturally cycling individual. These differences were likely driven by the E2-dominant hormonal milieu associated with COC use ( 88 ). Extending such designs to adolescents would allow researchers to examine how endogenous and exogenous hormonal fluctuations relate to brain features and mood across the adolescent menstrual cycle and during HC use. It would also allow investigation of how these associations vary across HC types, formulations, and individuals. At the same time, well-powered cross-sectional studies can provide valuable mechanistic insights, such as by comparing adolescents using different HC formulations, delivery methods, or mechanisms of action. All new data collection should include careful characterization of HC formulation, duration and indication of use, endogenous and exogenous hormone levels, menstrual cycling, pubertal status, and psychosocial and clinical measures ( 37 , 107 ). Crucially, the associations between HCs, adolescent brain development, and depression must be examined within the broader developmental and social context of adolescence (see Consideration 3: Context of Use ) and, where possible, using designs that strengthen causal inference, including within-person or prospective approaches and detailed consideration of potential confounders. Existing evidence underscores that little is known about how HC use interacts with depression risk and brain development during adolescence. A lack of adolescent-specific data, methodological differences, and limited attention to the developmental and social context, all constrain interpretation of existing findings. Addressing these challenges requires a shift toward more developmentally and mechanistically grounded research frameworks. In the following section, we outline 3 key considerations to guide future research on HCs, the brain, and mental health in adolescence: 1) heterogeneity in HC formulations and mechanisms of action; 2) developmental features of adolescent menstrual cycles; and 3) the broad individual, interpersonal, and societal contexts in which adolescent HC use occurs. Together, these considerations are aimed at supporting a more nuanced understanding of how exogenous ovarian hormones may modulate adolescent brain development and depression risk and inform future study design while guiding interpretations.

This is a pivotal moment in women’s reproductive health research, especially for adolescents and young adults. Advances in developmental neuroscience, including large-scale longitudinal studies and investigator-led deep phenotyping studies, provide unprecedented opportunities to conduct rigorous, transparent, and developmentally sensitive research that can transform the understanding of how HCs interact with the adolescent brain and mental health. Such progress is urgently needed, not only to improve scientific understanding but also to stem the rising tide of misinformation and empower young people to make their own informed decisions about their reproductive and mental health.

Adolescent HC use does not occur in isolation. Inspired by Bronfenbrenners’s Ecological Systems Theory ( 127 ) and as illustrated in Figure 1 , we conceptualize HC use as embedded within interacting individual (micro), interpersonal (meso), and sociocultural (macro) systems that jointly shape who initiates HCs, which methods are chosen, and how use and side effects are experienced. We selectively highlight contextual factors most relevant to adolescent depression and brain development, noting that this is not a comprehensive review. Figure 1 The confluence of hormonal contraceptive use, brain development, and depression risk in adolescent females occurs within a developmental ecosystem of individual, interpersonal, and sociocultural factors. (Figure created in BioRender .) The confluence of hormonal contraceptive use, brain development, and depression risk in adolescent females occurs within a developmental ecosystem of individual, interpersonal, and sociocultural factors. (Figure created in BioRender .) Gynecological conditions are common in adolescence but are often underdiagnosed and underresearched, despite their substantial impact on emotional, social, and academic functioning ( 55 , 128 , 129 , 130 ). For example, primary dysmenorrhea, the leading cause of school absenteeism among adolescent females ( 55 , 128 , 131 , 132 ) and heavy menstrual bleeding, more frequent in adolescence than adulthood ( 133 ), are associated with reduced participation in social activities and sports and higher depressive symptoms ( 128 , 134 ). However, these symptoms are often normalized as part of growing up and managed without medical consultation ( 130 ). Given the significant physical and emotional changes associated with puberty, menstrual symptoms can amplify vulnerability to distress and negatively impact well-being ( 135 ). The scarcity of adolescent-specific reproductive health research limits our ability to characterize the full spectrum of menstrual cycle patterns in adolescence, including symptoms that affect functioning and well-being regardless of whether they signal underlying pathology ( 136 ). In turn, this constrains research on brain development and mental health, as unrecognized hormonal variability may obscure key associations ( 82 , 107 ) and may limit how well clinical guidance reflects adolescent-specific developmental physiology ( 123 ). At the same time, HCs are often prescribed to adolescents for noncontraceptive indications, such as managing heavy menstrual bleeding, dysmenorrhea, and endometriosis ( 1 , 137 ). These therapeutic uses play a central role in adolescent health care, improving quality of life and daily functioning. As such, it is important to recognize both the clinical advantages of HC use and the need to balance them with careful evaluation of potential neuroendocrine or mood-related effects. Understanding how endogenous hormonal changes, gynecological conditions, and the exogenous hormones introduced by HCs interact during this sensitive developmental period is therefore critical for interpreting the broader effects of HC use on adolescent brain and mental health. Beyond gynecological factors, individual differences in genetic propensity for mental health conditions, pubertal timing, menstrual cycle regularity, hormonal sensitivity, and neurodevelopmental conditions may influence, and be influenced by, initiation and experience of HC use. For example, individuals who initiated HCs before the age of 19 had a higher polygenic score for depression and attention-deficit/hyperactivity disorder (ADHD) on average ( 138 ). These findings suggest potential genetic confounding. However, the interplay of genetic factors with HC use, depression risk, and brain development remains largely unexplored and represents an important direction for future research. Moreover, oral contraceptive use among female adolescents with ADHD may compound an already heightened risk for depression in this group ( 139 ). Knowledge and beliefs about HCs can also affect uptake and adherence ( 57 ); concerns about mood-related side effects, potentially amplified by online misinformation ( 27 , 28 , 29 ), may shape expectations, bias self-reported outcomes in research studies, and confound findings. Future studies should also assess antidepressant and other psychotropic medication use, as antidepressant prescriptions are often used as a proxy for depression diagnosis in epidemiological studies. However, the pharmacological and behavioral interactions between HCs and antidepressants remain poorly understood and should be investigated as they could potentially aid the development of tailored treatments. Together, these individual-level influences are important to consider in studies linking HCs to neurobiological or mental health outcomes. Decisions around HC use are embedded within interpersonal environments, and shaped by partners, family, peers, and increasingly, online influencers. Partner influence is strong, reflecting entrenched gender norms that position contraception as women’s responsibility, subject to male approval ( 57 , 140 ). Family attitudes, particularly parental disapproval of adolescent sexual activity, can deter HC use or encourage secretive HC use ( 57 ). Many adolescents may also feel embarrassed or reluctant to discuss contraception with their parents and therefore rely on peers or online sources for information. While peers, family, and online spaces can promote autonomy and shared learning among adolescents, anecdotal experiences from these sources often carry more weight than medical advice ( 27 , 57 , 141 ). Social media, in particular, can empower youth with accessible reproductive health information, but it can also amplify misconceptions surrounding HCs, including overgeneralized and exaggerated claims about physical side effects, infertility, and cancer risks ( 27 , 28 , 29 , 142 , 143 ). Furthermore, social media has become a prominent space for self-diagnosis and discussion of mental health conditions ( 144 ), highlighting broader shifts in how young people think about and engage with their psychological well-being. These evolving narratives extend to how young people interpret and report their mental health experiences in relation to HC use, which should be considered by researchers ( 18 ). Together, interpersonal and online influences can both facilitate and constrain HC use, shaping the socioemotional environment in which HC initiation and (dis)continuation occur. Patterns of HC use vary widely across geographic regions, reflecting differences in reproductive health care access and cost, education, knowledge about reproductive rights, and sociocultural norms ( 57 ). HC use is highest among adolescents in high-income countries (HICs) and lowest in low- and middle-income countries (LMICs) ( 49 ). Furthermore, use of HC types also varies regionally: OCs remain the most used HC by adolescents in HICs, although the use of LARCs has increased recently ( 50 , 51 , 145 ). In LMICs, OCs, injectables, and implants are the most prevalent HCs used by adolescents ( 146 ). Importantly, adolescent-specific epidemiological data remain limited globally, constraining granular comparisons by formulation or sociodemographic factors. For example, reports from the United Nations Department of Economic and Social Affairs typically aggregate contraceptive use across broad age bands (e.g., 15–19 and 20–24 years) and method categories (e.g., modern vs. traditional), without age-specific breakdowns by contraceptive type ( 49 ). Nonetheless, this regional variability underscores the importance of considering the sociocultural context when studying HC use. For example, judgmental attitudes and lack of specialized knowledge on HCs from health care providers can deter use ( 147 ). Broader societal structures and norms regarding, for example, religion, premarital sex, and gender roles also shape whether and how adolescents initiate, continue, or discontinue HC use. Importantly, societal stigma and systemic barriers not only limit HC access but also contribute to unmet health needs for adolescents with gynecological conditions or menstrual problems for which HCs are commonly prescribed ( 1 , 148 ). These macrolevel influences intersect with individual and interpersonal contexts to shape who uses HCs, for what reasons, and how their effects—both physiological and psychological—are experienced and reported. Recognizing these broader determinants is critical for situating research on adolescent HC use, brain development, and mental health within a global and developmental framework.