Healing Through Hormones: The Neurobiological Effects of Hormone Replacement Therapy

Written By Michael Silva

Michael Silva

Illustrations by Elsie McKendry

Have you ever felt uncomfortable in your own skin? For most people, this feeling might be fleeting — a momentary discomfort, easily shaken off — but for some individuals, the sense of disconnect between body and gender identity can be both profound and persistent. By and large, sex and gender refer to two concepts that, while often connected, are differentiable [1, 2, 3]. Gender generally refers to socially constructed roles, behaviors, and expectations, whereas sex encompasses biological characteristics such as chromosomes and reproductive anatomy [2, 3, 4]. When an individual’s gender identity diverges significantly from their assigned sex at birth, they may experience gender dysphoria (GD) — a clinically recognized condition marked by distress, discomfort, and a profound sense of incongruence between physical appearance and internal identity [3]. GD is explicitly recognized in the standard American diagnostic manual, whereas other international diagnostic manuals emphasize the broader concept of gender incongruence (GI), focusing less on distress and being more inclusive of the diversity of transgender experiences [5]. Although GD is commonly associated with GI, debate continues within the medical community about whether distress must necessarily accompany incongruence [6].

When treating GD and GI, the discussion often centers around hormones, the chemical messengers that travel through our bloodstream to produce diverse effects throughout the body [7]. Sex hormones produced by the gonads — ovaries in females and testes in males — influence physical development as well as mood, cognition, and emotional regulation [8, 9]. Sex hormones play a crucial role during puberty and continue to exert effects throughout one’s lifespan [9, 10]. Among transgender individuals, hormone replacement therapy (HRT) is a widely prescribed and medically recognized intervention for alleviating GD, allowing one’s body to align more closely with their gender identity [11, 12, 13]. HRT improves overall psychological well-being, with a significant reduction in depression, anxiety, and suicidality in transgender populations [13, 14, 15]. Despite clear clinical benefits, gender-affirming care remains a politically fraught issue [16]. Recent efforts to restrict HRT and puberty blockers, such as federal bans on research funding or laws denying access, threaten the availability of care and undermine public understanding of its medical legitimacy, especially for transgender youth [16, 17, 18]. In the face of mounting misinformation, examining the biological and psychological evidence supporting HRT is not only necessary but urgent. Understanding how hormones and HRT affect the body and brain affirms the importance of transgender healthcare, reinforcing its legitimacy as a medical intervention.

This Is Your Brain on Hormones: The Neurochemical Effects of Estrogen and Testosterone 

Any discussion of HRT begins with a closer look at estrogen and testosterone, hormones present in all humans and virtually all vertebrates, regardless of sex [19, 20, 21]. Estrogen is essential for female sexual development during puberty, such as breast growth and the regulation of the menstrual cycle [22, 23]. Testosterone is typically associated with its role in the development of male sexual characteristics, such as voice deepening and facial hair growth [24]. Additionally, testosterone belongs to a class of hormones called androgens, substances capable of developing and maintaining masculine characteristics in reproductive tissues [25]. Estrogen and testosterone together play a critical role in the overall health of both sexes beyond puberty and sex differences [26, 27]. For example, estradiol, the predominant form of estrogen during reproductive years, is central to maintaining bone density and cardiovascular health in women [27, 28]. Testosterone also enhances bone mineral density in women by increasing the presence of estradiol [27]. In men, a portion of testosterone is converted to estradiol, which is crucial for male bone strength and cardiovascular functioning [27]. Independently, testosterone has an active role in supporting physiological processes like fat distribution [29]. In both sexes, free-floating testosterone and the activation of androgen receptors are positively correlated with muscle mass and strength [30]. The metabolism, bone health, and overall physiological functioning of males and females heavily rely on specific proportions of both estrogen and testosterone [26].

Beyond their effects on the body, sex hormones also influence brain chemistry by interacting with neurotransmitters — chemical messengers that carry signals across the gaps between neurons called synapses [31]. Testosterone and estrogen act as neuromodulators, a class of signaling molecules that regulate neurotransmitter systems [31]. Estradiol boosts neurotransmitter production, including serotonin, associated with mood, and dopamine, associated with reward [31, 32, 33]. Estrogen can help reduce symptoms of anxiety and depression by increasing serotonin synthesis and receptor activity [31, 34, 35]. Estrogen improves dopamine signaling in brain regions that control emotion and reward through similar mechanisms [34]. Furthermore, estradiol promotes synaptic plasticity, or the ability of neurons to change the strength and quantity of their synaptic connections over time [36]. Estradiol also modulates glutamate, the major excitatory neurotransmitter, which in turn mediates the synaptic plasticity essential for learning and memory [31, 37]. The promotion of synaptic plasticity and increase in serotonin and dopamine signaling may help explain why many transgender women report improved mood and mental well-being after beginning estradiol as a form of HRT [13, 38, 39]. Like estrogen, testosterone influences mood and brain function in both sexes, but its effects can differ significantly [31, 40, 41]. Whereas estrogen generally increases dopamine activity in reward pathways, high testosterone levels can suppress these pathways [37, 42]. Although testosterone and estrogen have some contrasting effects on the brain, they are not necessarily opposites; the hormones can have complementary, balancing roles in regulating the brain’s chemistry [37, 42]. Therefore, understanding the effects of sex hormones is crucial, as they may constitute a biological basis for the mood and cognitive changes associated with HRT [43]. 

Beyond the Binary Brain: Sex, Structure, and Brain Biases 

The notion that male and female brains are fundamentally different due to the developmental influences of sex hormones has long been ingrained in public perception and continues to elicit scientific debate [1, 44]. While there are some measurable sex differences in brain structure, many are subtle and do not contribute to functional disparities [1, 45]. Human brains exist on a continuum shaped by hormonal exposure, genetics, and environmental factors [44, 46]. While testosterone and estrogen do play a role in shaping brain development, their effects are often more complex than a simple binary division, especially considering the varying levels of each hormone in both sexes [47, 48]. In reality, male and female brains are mostly similar, with only a small portion of the population that displays substantial sex differentiation between their brains [47]. Emerging research on brain plasticity and the effects of HRT further challenges the assumption of rigid male-female brain distinctions, highlighting that while hormones do influence brain structure and function, they do not operate within a sexual binary [49, 50, 51].

One of the most widely discussed differences between male and female brains is size [52]. Certain regions of male brains tend to exhibit denser gray matter, areas primarily containing neuronal cell bodies [53]. Cisgender women show a lower total gray matter volume and a thinner cortex, the outer layer of the brain [41, 53]. On average, male brains are about 11% larger than female brains, but differences are proportional to body size and do not correlate with cognitive ability [41, 44]. Additionally, the amygdala, a major processing center for emotions, was previously thought to be larger in males due to its role in aggression [54]. However, there are no statistically significant sex differences in the amygdala after controlling for overall brain size [54]. The same is true for the hippocampus, a structure involved in memory that was historically reported as larger in females [55]. Ultimately, absolute differences in brain size are not inherently meaningful, especially regarding the brain’s functional capacity [56, 57]. 

The belief that there is a sex binary in the brain is further disputed by studies on transgender brains. Even before HRT, some transgender individuals seem to show sex-atypical features in brain structure and connectivity that may be indicative of differences in neurodevelopment [58]. Studies on transgender people who have not yet started HRT found that while overall brain volume and structure tend to align with their sex assigned at birth, the organization of their white matter — areas of the brain composed of insulated nerve fibers — more closely resembles their identified gender [59, 60]. Moreover, some brains of people with GI appear intermediate between the binary sexes, suggesting that brain differences are much more nuanced than previously thought [61]. Studies on transgender individuals and HRT have challenged the idea that male-female brain differences are immutable; brain structure is not fixed by biological sex but rather is sensitive to hormonal environments, aligning with the idea that individuals exhibit a mix of sex-associated traits rather than fitting into strict male or female categories [46, 49, 50].

HRT As Gender-Affirming Care: From Puberty Blockers to Hormone Therapy 

HRT is widely recognized as the first line of medical treatment for GD in transgender individuals, significantly reducing psychological distress and improving quality of life [11, 13, 15]. Feminizing hormone therapy for male-to-female (MtF) transgender women typically involves estradiol, which can be administered via several routes, including oral/sublingual tablets, transdermal patches, or injections [63, 64]. Because estrogen alone may not fully suppress internal testosterone production in transgender women, an anti-androgen medication is usually prescribed in tandem to block androgen receptors and reduce testosterone production [64, 65, 66]. Cell receptors function as tiny locks: when the appropriate molecule or ‘key’ is present, they bind together and trigger a cell response. Testosterone and estrogen bind to the same receptor, but testosterone takes priority when both are present [67]. Therefore, androgen blockers are implemented to prevent testosterone from binding, allowing estrogen to bind to the receptor and induce feminization [67]. Combining estradiol with effective testosterone suppression contributes to breast development, fat redistribution, skin softening, and other feminizing changes, typically over many months [68]. Physical changes not only improve gender congruence but also contribute to the mental health benefits seen in transgender women on HRT, such as reduced GD, anxiety, and depression [14]. Meanwhile, masculinizing therapy for female-to-male (FtM) transgender men involves the administration of testosterone to induce male characteristics [69]. Testosterone can be given as injections, gels, creams, patches, or newer long-acting formulations like implants [70]. Unlike MtF individuals, FtM hormone therapy does not necessitate an additional hormone blocker as testosterone is already prioritized over estrogen in binding to receptors [67, 71]. Overall, masculinizing HRT aids in relieving GD by facilitating changes such as a deepening of the voice, growth of facial and body hair, fat redistribution, a halting of the menstrual cycle, and clitoral enlargement [69].

For transgender youth, pubertal suppression is an early intervention that pauses the puberty of their biological sex until they are old enough for HRT [7, 72, 73]. Puberty blockers temporarily halt the signaling that drives puberty, which prevents unwanted development that can worsen dysphoria, such as breast growth or voice deepening [72, 74]. Clinically, puberty blockers have a long history of safe use in treating atypically early puberty and other pediatric hormonal conditions in cisgender youth [73]. In the context of GD, the use of puberty blockers has been endorsed by medical professionals for appropriately assessed youth [7, 11, 75]. The effects of puberty blockers are reversible — if the medication is stopped, puberty of the biological sex will resume [7, 17, 73]. By stalling puberty, transgender youth gain time to mature and consider their options. Because 96.5% to 98.1% of transgender youth who use hormone blockers will proceed to HRT later in life, hormone blockers allow them to do so without having undergone the unwanted, irreversible changes caused by puberty [7, 17, 76]. Altogether, delaying puberty has been associated with better mental health, improved psychosocial functioning, and life satisfaction in transgender youth [15, 77, 78].

Changing Minds: Structural Shifts from Gender-Affirming Hormone Therapy HRT does not just alter secondary sex characteristics — it also produces non-harmful changes in the brain [79]. The brain exhibits remarkable plasticity in response to hormonal changes, undergoing modifications that further support gender alignment and affirmation [49]. Transgender women on estrogen therapy undergo cortical thinning that makes their brain anatomy more similar to that of cisgender women, while transgender men on testosterone therapy show increases in gray matter volume that make their brains more like those of cisgender men [49, 51, 80]. The fact that HRT can reshape brain structures further underscores the brain’s adaptability, supporting the argument that changing hormone levels play a dynamic role in brain function across one's lifespan [81]. Changes in hormone levels have significant implications for transgender individuals undergoing medical transition, as HRT influences not just observable changes in physical appearance but also internal neural structures [81].

When transgender individuals undergo HRT, changes in sex hormones lead to measurable remodeling of brain tissue [49]. Transgender men taking high-dose testosterone have had increases in overall brain volume and growth of certain regions [50, 82]. Conversely, transgender women on estrogen with anti-androgen medication tend to experience volume decreases in some structures, such as the hippocampus [50]. A reduction in hippocampal volume is consistent with the feminization of the brain and may reflect a shift toward a female-typical structure [50, 58, 83]. Over time, HRT appears to be correlated with brain reorganization, a form of structural confirmation that parallels external bodily changes [50, 80]. It is important to note that many of these changes, such as variations in hippocampal or hypothalamic volume, are subtle and not associated with impaired brain function [84]. No cognitive detriment has been identified from HRT; neither transgender men nor transgender women show any impairment in cognitive functioning compared to baseline [85]. Instead, alterations in brain structure likely reflect the brain adapting to function optimally under new hormonal conditions [49].

Hormonal Harmony through HRT: The Connection Between Mind, Body, and Medicine

By alleviating GD and inducing physical changes congruent with one’s identity, HRT is strongly associated with improved mental health in transgender individuals [15]. Transgender individuals often experience chronic dysphoria and minority stress — how society’s mistreatment of stigmatized minority groups results in worse mental and physical health outcomes [86]. Chronic dysphoria and minority stress seem to contribute to the dysregulation of the hypothalamic-pituitary-adrenal axis, a hormonal system crucial in the role of fear and stress as well as sleep, leading to elevated levels of stress hormones and anxiety [87, 88, 89]. Transgender people who are denied gender-affirming care and are experiencing minority stress often exhibit high rates of depression, anxiety, and even potential cognitive detriments as a result of prolonged stress​ [89, 90]. The most crucial mental health outcome to consider is suicidality [91, 92, 93]. Transgender people experience disproportionately high rates of suicidal ideation and suicide attempts, largely due to internalized transphobia and societal stigma [91, 92, 93]. In their lifetime, 81.3% of transgender respondents to a recent survey had reported having suicidal ideation, with 42% having attempted suicide [91]. The heightened levels of psychological distress experienced by transgender people elucidate the necessity of early access to HRT as an important avenue for achieving mental stability and resilience [15, 89]. 

One of the most consistently documented outcomes of HRT is a significant reduction in depressive symptoms and anxiety [14]. In as little as three to six months, many individuals report relief from symptoms of depression and anxiety [13]. By 12 months on HRT, overall mood and general quality of life are improved in most patients [13]. Furthermore, access to hormone therapy is associated with a striking reduction in suicidal thoughts and behaviors [94]. A large study of U.S. transgender adults in 2022 found that those who received hormone therapy had a significantly lower incidence of recent suicidal ideation and past-year suicide attempts than those who desired but could not access HRT [89]. Moreover, individuals who had access to HRT during adolescence were less likely to experience suicidal ideation compared to those without access to HRT until adulthood [89]. Transgender people who started hormonal therapy as teens had fewer lifetime suicide attempts and lower incidence of substance abuse than those who started in their twenties or later [89]. Importantly, mental health improvements may be due not only to the psychological relief of gender affirmation but also to the hormonal effects on brain networks involved with self-perception [95, 96]. The message is clear: early and continued HRT saves lives [15, 89, 94]. 

Gender-affirming hormone therapy holds the potential to alleviate the fundamental discord between brain, body, and identity in some cases of GD by leveraging the brain’s plasticity and the transformative power of hormones [15, 38]. While HRT is not the only route by which transgender individuals can achieve inner peace, it is an evidence-based, life-saving treatment that must be accessible to those who desire it [15, 89, 94]. HRT demonstrates the intimate links between the brain, body, and mind, particularly regarding gender identity. By altering one’s internal hormone levels, HRT can initiate a positive feedback loop of well-being. Such well-being is displayed through improvement of mood and a reduction in suicidality, supporting HRT’s role as a medically necessary and profoundly effective treatment. 

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