Sex Differences Within The Serotonin Pathway 

Laura Cross 

July 27th, 2025

Edited by the YNPS Publications Team.

Abstract 

The serotonin neurotransmitter system displays extensive sex differences that potentially underlie observed disparities in psychiatric disorder prevalence and treatment response between males and females. This comprehensive review analyzes sex differences upon observing different components of the serotonin pathway, including synthesis mechanisms, receptor expression, neuroimaging findings, and genetic polymorphisms. Evidence from positron emission tomography studies reveals that males demonstrate 52% higher serotonin synthesis rates compared to females, while females exhibit 39% higher 5-HT1A receptor binding and greater stress-related hypothalamic-pituitary-adrenal axis activation. Genetic polymorphisms are associated with sex-specific effects, as the 5-HTTLPR low-expressing alleles heighten the risk of depression in females more strongly via gene-environment interactions, whereas MAOA variants produce opposite effects on aggression between sexes. Sex hormones, including estrogen and testosterone, have the potential to modulate serotonin transporter expression and receptor sensitivity, allowing for a narrower explanation for these differences. The bridging of neurobiological, genetic, and hormonal components unveils that sex differences in the serotonin pathway operate at multiple levels and create distinct vulnerability profiles that may explain sex disparities in psychiatric conditions. These findings may be integral to mesh with standard approaches in psychiatric treatment, where sex differences are minimally highlighted.

Introduction 

The serotonin (5-hydroxytryptamine, 5-HT) system is one of the most extensively studied neurotransmitter pathways in neuroscience due to its incremental roles in regulating mood,  behavior, the gastrointestinal tract, and memory (Bamalan et al., 2023). While many studies have established serotonin’s central importance in brain function and psychiatric disorders, there has been emerging evidence suggesting that the serotonin pathway could function differently between males and females, allowing further explanation for the discrepancy between sexes and mental health vulnerability. Psychiatric disorders have shocking sex disparities in prevalence,  age of onset, symptom presentation, and treatment response. Women are expected to have a twofold chance compared to men to experience major depressive disorder and anxiety disorders, while men show higher rates of certain behavioral disorders and substance abuse (Seedat et al.,  2009). These epidemiological patterns have further suggested that biological sex may influence brain chemistry and vulnerability to psychiatric disorders. The serotonin system has been a target for understanding these sex differences for several reasons. Firstly, serotonin synthesis,  metabolism, and receptor expression are directly influenced by sex hormones, particularly estrogen and testosterone (Rybaczyk et al., 2005). Secondly, the timing of peak depression onset in women corresponds closely with major hormonal transitions, including puberty, postpartum periods, and menopause (Clayton and Ninan, 2010). Thirdly, neuroimaging studies have revealed consistent sex differences in serotonin synthesis rates, receptor binding, and transporter availability (Jovanovic et al., 2008). Recent advances in neuroimaging technology, using apparatus such as positron emission tomography (PET) scanning, have allowed for measurements of serotonin in living humans, revealing associations between previously undetectable sex differences (Erritzoe et al., 2020). Simultaneously, genetic studies have identified key polymorphisms within serotonin pathway genes that exhibit sex-specific effects on psychiatric risk, suggesting complex gene-by-sex interactions that may explain differential vulnerability patterns (Perry et al., 2017). Investigating sex differences is imperative; women have only been included in studies in 1989 (National Institutes of Health, 2024), and most medical knowledge stems from research collected only in men. It is becoming clear that biological sex can make bodily processes distinct. Failure to account for sex differences may obscure important biological mechanisms and lead to incomplete or inaccurate models of serotonin function and thus pollute our understanding of psychiatric disorders. With an understanding of sex-specific patterns, outcomes for both men and women with psychiatric disorders may be improved. This comprehensive review combines current knowledge regarding sex differences within the serotonin pathway, analyzing evidence from multiple levels of analysis, including synthesis mechanisms, receptor subtypes, neuroimaging findings, and genetic polymorphisms. By integrating findings across different research, the aim is to provide a coherent framework for understanding how biological sex influences serotonin system function and contributes to differential psychiatric vulnerability. 

Methodology  

An interpretative meta-synthesis approach was employed to examine sex differences within the serotonin pathway. Relevant studies were systematically searched across multiple databases,  primarily PubMed and ResearchGate, to identify peer-reviewed research investigating sex differences in serotonin system function. The search strategy focused on studies published between 2000-2025 that examined one or more of the following key areas: serotonin synthesis rates, receptor expression patterns, transporter availability, genetic polymorphisms, and hormonal modulation of serotonergic function.

Studies were included if they: (1) directly compared males and females on serotonin-related measures, (2) utilized validated methodologies such as positron emission tomography (PET)  neuroimaging, genetic association analyses, or experimental hormone manipulations, (3)  included both clinical and healthy populations to capture the full spectrum of sex differences,  and (4) provided sufficient statistical information to assess the magnitude and significance of sex differences. Studies using self-report measures alone were excluded unless they included biological validation measures. 

Multiple study designs were incorporated to provide a comprehensive coverage of sex differences,  including cross-sectional studies, longitudinal investigations, meta-analyses, systematic reviews,  and experimental studies. This approach allowed for examination of sex differences from psychological, biological, and clinical perspectives, ensuring a thorough synthesis of available evidence. 

Results 

1. Serotonin Synthesis and Basic Mechanisms 

Across this literature review, there were apparent sex differences observed in multiple components of the serotonin system. Males and females showed patterns of serotonin synthesis,  receptor expression, transporter availability, and genetic vulnerability that bridge fundamentally different serotonergic profiles between the sexes.

Central to understanding the neurobiology of the brain is the role of serotonin (5-hydroxytryptamine, or 5-HT), which is a monoamine neurotransmitter (Baou et al., 2016).  Serotonin is involved in daily operations regarding homeostasis, including regulating mood,  behavior, the gastrointestinal tract, and memory (Bamalan et al., 2023). It is implicated in many functions and processes in the brain, and the equilibrium of normal levels is significant to ensuring typical functioning. This normalcy, however, may differ between the sexes.  

Grasping how the serotonin pathway works is necessary to comprehend these potential sex differences. A critical characteristic of serotonin is that it cannot cross the blood-brain barrier,  making the central nervous system (CNS) and peripheral nervous system (PNS) functionally separate for the pathway (Kanova et al., 2021). This separation means that serotonin produced in the brain operates independently from serotonin produced elsewhere in the body. The distribution of serotonin in the human body is divided into two, where 90% of the body’s serotonin is stored in enterochromaffin cells located in the gastrointestinal tract, which is why it affects the gut, and only 10% is produced by neurons in the central nervous system  (Bakshi & Tadi, 2022). Despite this small percentage, CNS serotonin plays a disproportionately important role in brain function and behavior. 

In the CNS, serotonin is synthesized primarily in the raphe nuclei of the brainstem, which are the major nuclei possessing ascending serotonergic fibers projecting to the forebrain and descending fibers extending to the medulla and spinal cord (Baou et al., 2016). These extensive projections help regulate essential functions, including temperature, appetite, sleep cycles, and more (Walker & Tadi, 2023). The clinical significance of serotonin becomes apparent in most psychiatric disorders, where its absence or dysregulation appears to be related to depression, anxiety, and mania (Bakshi & Tadi, 2022).

The synthesis of serotonin is a two-step process that begins with the amino acid tryptophan,  which serves as the building block of serotonin and is obtained via dietary ingestion (Bakshi &  Tadi, 2022). From the digestive system, tryptophan is either bound to albumin or freely enters the bloodstream (Baou et al., 2016). Only the free tryptophan can be transported into the brain, as it is the form capable of crossing the blood-brain barrier (Baou et al., 2016). Once tryptophan reaches the brain, serotonin synthesis occurs in two steps: the essential amino acid tryptophan is first hydroxylated to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase, then  5-HTP undergoes decarboxylation to form 5-HT (Baou et al., 2016). These reactions occur almost instantaneously in the presence of tryptophan, ensuring rapid serotonin production when needed. 

Once synthesized, serotonin is stored in presynaptic vesicles in axon terminals and released into the synaptic cleft when a neuron is activated (Baou et al., 2016). This is where serotonin binds to various serotonin receptors (5-HT receptors), which affect behaviors and neural communication. The regulation of serotonin availability is modulated by serotonin transporters  (SERT), located on the presynaptic membrane, which removes serotonin from the synaptic cleft  (Baou et al., 2016). 

There are seven major serotonin receptor subtypes, known as 5-HT1 through 5-HT7, each with distinct and separate roles in mood and anxiety regulation (Stiedl et al., 2015). Some receptors,  like 5-HT1A and 5-HT1B, act as autoreceptors in the presynaptic neuron to control serotonin release via feedback mechanisms (Frazer & Hensler, 1999). The interactions of these receptor subtypes determine how serotonin mediates anxiety. As an example, decreased density of 5-HT1A receptors has been linked to increased anxiety symptoms, while dysfunction in 5-HT2C  receptors, which regulate neurotransmitter release, can augment both anxiety and fear responses. Many studies are in progress to observe these subtypes and their effects, with 5-HT1A garnering many publications. 

The 5-HT1A receptor subtype is necessary for serotonin to affect the hypothalamic-pituitary adrenal (HPA) activity (Goel et al., 2014). The HPA axis is typically activated in response to a disruption of homeostasis, and this response is initiated by the release of glucocorticoids, like adrenocorticotropic (ACTH) and corticosteroids (CORT). These hormones are distributed by the adrenal cortex to adapt to the stressor. Within periods of stress, females show greater HPA axis responses to stress compared to males. Sex differences, for instance, gonadal hormones, might have an impact on these distinctions;  estrogens increase glucocorticoid secretion, whereas androgens decrease it (Lund et al.,  2004). Females also have a larger amount of corticotropin-releasing hormone (CRH) and arginine vasopressin, with a lower amount of glucocorticoid receptor gene expression in the paraventricular nucleus of the hypothalamus (PVH) in females (Seale et al., 2004). When revisiting the 5-HT1A receptor, the consensus is that the subtype is heavily involved in stress-related disorders, as presynaptic 5-HT1A receptors diminish the excitability of dorsal raphe neurons, and thus, lower serotonin release (Goel et al., 2014). Pre-synaptic 5-HT1A releases serotonin into the synapse to become postsynaptic 5-HT1A, transmitting 5-HT to various forebrain areas. Antagonists of 5-HT1A reduce stress-induced increases in  CORT and ACTH.  

The research conducted by Goel et al. suggests that females exhibit higher basal ACTH levels and both basal and stress-induced corticosterone (CORT) levels compared to males. Notably,  administration of the 5-HT1A receptor antagonist, called WAY 100635, showcased decreased  peak CORT levels in males only, implicating that sex-specific endogenous requirements for 5-

HT1A receptor regulation of stress responses (Goel et al., 2014). Both sexes showed similar reductions in ACTH release and paraventricular hypothalamic (PVH) neuron activation following WAY treatment (Goel et al., 2014). Females demonstrated greater Fos responses,  which are used as a marker of neuronal activation, than males in both dorsal and ventral dorsal raphe regions, including within serotonergic neurons. This suggests higher serotonergic tone in females may contribute to greater HPA axis stimulation and differences in stress appraisal (Goel et al., 2014). Moreover, WAY treatment revealed sex-specific effects on non-serotonergic dorsal raphe neurons, with males showing potentiated activation, which was lacking in females. The study also identified a negative correlation between estradiol and Fos activation specifically in serotonergic neurons of the dorsal raphe in females treated with WAY (Goel et al., 2014).  Additionally, a positive relationship between estradiol and 5-HT1A mRNA levels was found in the zona incerta, which is a brain region implicated in serotonergic regulation of the HPA axis.  Finally, this study demonstrated that no sex differences were detected in 5-HT1A mRNA expression levels or distribution across forebrain regions and the dorsal raphe nucleus, meaning functional differences may account for the observed sex disparities (Goel et al., 2014). 

2. Serotonin System Analysis Using PET Scans 

Research consistently demonstrates that males display significantly higher rates of serotonin synthesis compared to females across multiple brain regions. PET imaging studies have garnered the results that male serotonin synthesis rates range from 66 to 85 pmol⋅g−1⋅min−1, while female rates range from 47 to 55 pmol⋅g−1⋅min−1, composing a 52% higher synthesis rate in males when averaged across all examined brain regions (Nishizawa et al., 1997). Despite these dramatic differences in synthesis rates, the basic mechanisms of serotonin production appear similar between sexes (Nishizawa et al., 1997). Both males and females follow the same two-step 

synthetic pathway from tryptophan to serotonin, and both show similar regional patterns of synthesis with approximately 1:1 ratios between high and low synthesis brain areas (Nishizawa et al., 1997). This indicates that sex differences in synthesis reflect quantitative rather than qualitative differences in serotonergic function. 

Sex differences in serotonin receptor expression can result in functional differences between males and females. Women show 39% higher 5-HT1A receptor binding compared to men across multiple brain regions, a finding that has been replicated using different analytical approaches and appears robust across age groups (Jovanovic et al., 2008). The 5-HT1A receptor plays a critical role in stress regulation through its effects on the hypothalamic-pituitary-adrenal (HPA)  axis (Goel et al., 2014). Females show greater HPA axis responses to stress compared to males,  with higher basal ACTH levels and both basal and stress-induced corticosterone levels (Goel et al., 2014). When 5-HT1A receptor function is blocked pharmacologically, males show decreased peak cortisol levels while females do not, which allows for an association between sex-specific endogenous requirements for 5-HT1A receptor-mediated stress regulation (Goel et al., 2014). Females also demonstrate greater neuronal activation (Fos responses) than males in serotonergic brain regions, suggesting a higher baseline serotonergic tone that may contribute to enhanced HPA  axis stimulation and different patterns of stress appraisal between sexes (Goel et al., 2014). 

Males show 55% higher serotonin transporter (5-HTT) binding potential compared to women,  which is correlated with higher synthesis rates observed in males (Jovanovic et al., 2008). This pattern suggests coordinated sex differences across many components of the serotonin pathway, with males showing higher serotonergic activity coupled with increased capacity for synaptic serotonin clearance (Jovanovic et al., 2008). The combination of higher synthesis rates and increased transporter density in males may indicate a more efficient serotonin pathway in terms 

of turnover and regulation (Jovanovic et al., 2008). In contrast, lower synthesis rates and transporter density in females can lead to assumptions regarding the serotonin system being more sensitive to external influence and sustained signaling. 

3. Analyzing the Serotonin Pathway via Genetic Polymorphisms 

The serotonin transporter gene polymorphism 5-HTTLPR has sex-specific effects across many domains. Low-expressing alleles (S and L(G)) have complex interactions with early life stress to increase depression risk more strongly in females than males (Goldman et al., 2010).  Many studies are finding stronger stress-gene interactions in females, related to this polymorphism. Mechanistic studies additionally reveal that low-expressing alleles are associated with lower serotonin metabolite levels in males but higher levels in females, indicating opposite effects on serotonin turnover between sexes (Perry et al., 2017). Neuroimaging studies show that depressed women, but not men, exhibit lower serotonin transporter availability compared to healthy controls, which is another potential sex-specific pattern of transporter regulation in psychiatric conditions (Perry et al., 2017). 

The X-linked monoamine oxidase A polymorphism is another target polymorphism with evidence for sex-specific genetic effects due to its chromosomal location (Perry et al., 2017)..  MAOA demonstrates opposite effects between males and females: low-activity alleles (MAOA L) increased risk for aggression and conduct problems in males, particularly when combined with childhood maltreatment, while high-activity alleles (MAOA-H) are associated with increased psychiatric risk in females (Perry et al., 2017). Throughout emotional processing,  amygdala activity increases with childhood stress in male MAOA-L carriers but decreases in male MAOA-H carriers, with females showing the reverse pattern (Perry et al., 2017). These 

opposite neural responses provide biological associations for the opposing behavioral effects observed between sexes (Perry et al., 2017). 

TPH1 and TPH2 polymorphisms show sex-specific associations with depression and anxiety disorders (Perry et al., 2017). The TPH1 A218C polymorphism associates with depression only in males, while other TPH variants confer a stronger risk for depression in women during peripartum phases, suggesting hormonal mediation of genetic effects (Perry et al., 2017). TPH2  variations may have the ability to predict depression and panic disorder in women but not men,  suggesting that central serotonin synthesis may be more genetically influenced in females (Perry et al., 2017). 

Sex hormones potentially regulate multiple components of the serotonin system, providing mechanistic explanations for observed sex differences. Estrogen regulates both serotonin transporter and MAO-A expression, while testosterone demonstrates antidepressant effects in both sexes (Perry et al., 2017). Evidence from transgender individuals undergoing hormone therapy provides direct confirmation of these regulatory relationships: female-to-male individuals receiving androgens show increased serotonin transporter binding, while male-to-female individuals receiving estrogen show decreased binding (Kranz et al., 2015). The timing of peak depression onset in women corresponds closely with major hormonal transitions, including puberty, postpartum periods, and menopause, suggesting that fluctuating hormones interact with genetic vulnerabilities and baseline serotonergic differences to influence psychiatric risk across the female lifespan (Clayton and Ninan, 2010). 

Discussion 

The evidence compiled in this review makes way for a new interpretation of sex differences within the serotonin pathway, as it is clear that the distinctions manifest consistently across 

multiple levels of biological organization. These findings have significant implications for our understanding of psychiatric disorders and highlight the need for sex-specific approaches in both research and clinical practice. 

An apparent finding is the complementary nature of sex differences across different components of the serotonin system. Males were found to have higher synthesis rates and transporter density,  indicating a high-turnover system with efficient serotonin production and clearance (Benkelfat et  

al., 1997). In comparison, females demonstrate higher receptor binding and greater stress responsivity, suggesting that females are equipped with a serotonin pathway with keener sensitivity and sustained signaling (Benkelfat et al., 1997). This pattern suggests that males and females may have evolved different serotonergic strategies, perhaps evolving from different responses to stress during ancient periods, which have distinct advantages and vulnerabilities. 

The genetic findings reveal that the same polymorphisms can have dramatically different effects depending on biological sex. The 5-HTTLPR polymorphism, for example, shows contrasting effects on serotonin metabolism between males and females, while MAOA variants demonstrate completely reversed associations with aggression and emotional processing (Perry et al., 2017). Additionally, the role of sex hormones as modulators of serotonergic function may serve as a potential explanation for observed differences between the sexes. The evidence from transgender individuals undergoing hormone therapy offers insightful support for the causal role of sex hormones in shaping serotonin system function (Kranz et al., 2015). This hormonal modulation may shape the perception of why women experience peak depression onset during periods of hormonal transition and why hormonal contraceptives can influence mood and anxiety symptoms.

These findings introduce reasons for changing clinical approaches to psychiatric disorders. The widespread use of selective serotonin reuptake inhibitors (SSRIs) is based on the goal that all patients will benefit equally. However, given the sex differences in synthesis rates, transporter density, and receptor expression documented in this review, males and females may require different therapeutic approaches or dosing strategies to achieve optimal outcomes. 

These findings additionally may have implications for the timing of interventions. The evidence that hormonal transitions represent periods of vulnerability for women suggests that preventive interventions during puberty, pregnancy, and menopause may make a world of difference.  Similarly, grasping that genetic vulnerabilities may manifest differently across the lifespan depending on sex could inform the timing and nature of genetic counseling and early intervention programs. 

Limitations 

This comprehensive review is subject to several limitations that should be considered when interpreting its findings and thus, its implications. The analysis was restricted to studies published between 2000-2025, which may have excluded earlier foundational research that could provide important historical context for understanding the development of sex differences research in the serotonin pathway. Studies that were written in the 2000s may also be outdated, and new emerging evidence may be more current. Additionally, the focus on peer-reviewed literature from primarily PubMed and ResearchGate databases may have introduced selection bias, potentially missing relevant studies published in other databases or non-English languages. Moreover, the interactions between genetic polymorphisms, environmental factors,  and sex hormones are not fully appreciated within these studies and could indeed be minimizing or maximizing certain effects. Finally, the translation from neurobiological findings to clinical implications remains largely theoretical, as there is a limited amount of research directly testing whether sex-specific treatments based on serotonin system differences lead to improved clinical outcomes. This gap between science and clinical findings is a constant limitation within this specific pathway. 

Conclusions 

This comprehensive review reveals extensive and consistent sex differences within the serotonin pathway. From synthesis rates and receptor expression to genetic polymorphisms and stress responsivity, males and females are observed to have distinct patterns of serotonin pathway function that could manifest into changing the current climate for psychiatric treatment. The evidence displays that males generally show higher serotonin synthesis rates and transporter density, while females exhibit higher receptor binding and greater stress-related HPA axis activation. These differences appear to be mediated by complex interactions between genetic variants, sex hormones, and environmental factors, creating sex-specific patterns of vulnerability. Genetic studies show additional sex-specific effects, with the same polymorphisms typically producing opposite effects in males and females. The 5-HTTLPR polymorphism shows stronger gene-environment interactions in females, while MAOA variants demonstrate opposite effects on aggression and psychopathology between sexes. These findings allow for re-evaluation of considering the serotonin pathway equal between the biological sexes. 

Acknowledging sex differences within the serotonin system could lead to more personalized approaches to understanding brain function and treating psychiatric disorders. With increasing knowledge of these differences, it will become increasingly important to integrate sex-specific considerations into all aspects of neuroscience research and clinical practice.

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