Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental disorder characterized by deficits in social communication and repetitive patterns of behavior (Orefice et al., 2019; Zwaigenbaum et al., 2015). Epidemiological studies consistently demonstrate a substantial male preponderance with a male-to-female ratio of roughly 4.3:1 (Zeidan et al., 2022). This suggests that the pathophysiology of ASD involves sex-specific risk factors and protective mechanisms. Despite the careful consideration of genetic and environmental factors, recent research indicates that sex-specific neurobiological changes may be a predictor of sensitivity to ASD (Napolitano et al., 2022). The brain-derived neurotrophic factor (BDNF), an essential modulator of neuronal development, synaptic plasticity, and survival, has a major impact on early brain maturation and cognitive performance (Wang et al., 2022). Moreover, BDNF is widely distributed throughout the central nervous system (CNS), particularly in regions important in social cognition, emotional regulation, and executive function, such as the hippocampus, prefrontal cortex, and amygdala (Chow et al., 2020).

Numerous neuropsychiatric conditions, including depression, schizophrenia, and ASD, have been linked to the dysregulation of BDNF signaling (Bryn et al., 2015; Gawande et al., 2022). Given its critical role in brain function, BDNF is an interesting target for understanding sex variations in ASD prevalence (He et al., 2024; Santos et al., 2022). Interestingly, recent studies have revealed that individuals with ASD exhibit both increased and decreased levels of BDNF (Carpita et al., 2024; Han et al., 2022). The significant sex differences in BDNF expression and regulation suggest its potential neuroprotective role in females, and raise the question of whether BDNF contributes to the observed resilience of women to ASD. Additionally, one potential mechanism linking BDNF to neuroprotection in females is its interaction with aromatase (CYP19A1), the main enzyme responsible for the local conversion of testosterone to estrogen in the brain (Hill et al., 2013). Furthermore, it is well recognized that estrogen influences neuroimmune response, changes synaptic plasticity, and has neuroprotective effects in ASD (Brown et al., 2010). Aromatase expression and activity have been demonstrated to be regulated by BDNF, and this regulation is suggested to have a feedback mechanism, whereby BDNF-induced estrogen production may increase the resilience of the female brain against neurodevelopmental problems (Barker et al., 2015; Meng et al., 2015).

In view of this background, this review explores the role of BDNF in sex differences in ASD using a multidimensional approach with a particular emphasis on its influence on synaptic plasticity. Moreover, it focuses on BDNF's molecular roles, such as how it interacts with hormone pathways, especially the BDNF-aromatase axis, and how it is dysregulated in ASD. By integrating insights into the regulation of BDNF by estrogen and its impact on neurological and behavioral outcomes, the present review highlights the effective potential of estrogen and aromatase therapies in addressing sex-specific ASD manifestations. Data for this review paper were sourced from previous studies published between 2005 and 2025, accessed via platforms such as PubMed and Medline, with a focus on sex specificity, sex bias, and impairment in synaptic plasticity in preclinical models and clinical studies.