November 30, 2018

Gender Dysphoria: Time for a New Model Based on Psychobiology

Literature review shows complex neuropsychiatric processes shape brain-body dichotomy


Gender dysphoria has a neurobiological basis but is closely associated with an individual’s interaction with the external world, according to a poster presented by Cleveland Clinic psychiatrist Murat Altinay, MD, at the 2018 annual meeting of the American Psychiatric Association (APA).


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These findings have the potential to change societal perceptions of what gender is and where it resides, according to Dr. Altinay. “Current belief has been that gender is what your genital organs are,” he explains. “But as shown in the literature, gender is a far more complex concept and the brain seems to play the main role in determining gender identity.”

Scouring the literature on gender dysphoria

He and colleagues performed a PubMed search looking for neuroimaging studies of people with gender dysphoria, including cross-sectional, prospective, retrospective, case-control and randomized controlled studies as well as meta-analyses. They found that previous research shows there is a functional representation of the body in the brain. “There are structural and functional similarities between the transgender brain and its identified gender,” says Dr. Altinay.

These similarities are present prior to initiation of hormone therapies, but such therapies produce further changes. For instance, the hypothalamus, thalamus, orbitofrontal cortex and insula are more active in transgender females (individuals with male genitalia who identify as female) than in cisgender males (individuals with male genitalia who identify as male). In addition, transgender females have greater cortical thickness in the brain’s right and left hemispheres, parietotemporal complex, insula and medial occipital cortices relative to the brains of cisgender individuals.

The literature review also revealed that functional neuroimaging studies show changed resting-state functional connectivity in two notable contexts:

  • Hormonally untreated transgender females showed decreased functional connectivity between the auditory network and the right inferior temporal gyrus and right calcarine gyrus compared with cisgender males. Hormonally treated transgender females showed decreased connectivity between the left frontoparietal cortex and the left dorsolateral prefrontal cortex compared with cisgender males.1
  • Both transgender males and females had less-pronounced functional connectivity within the pregenual anterior cingulate cortex and precuneus compared with cisgender controls, regardless of the subjects’ sexual orientation.2

Increased centrality in the body representation network has also been noted, which suggests that this network could be the neurological biomarker for gender dysphoria, Dr. Altinay says.


A novel model for the concept

“In light of previous research, we introduce the term brain gender, suggesting that the brain and the body (the external genitalia and genetics) can have different maturation patterns when it comes to gender — and that it is brain maturation (brain gender) that determines how an individual identifies,” he explains. “Transgender people frequently find themselves in situations where they have to act or express themselves as opposite gender (the gender they don’t identify with), which creates an ongoing dissonance condition.”

He and his colleagues therefore propose a novel model of gender dysphoria in which its development takes into account the presence of both cognitive dissonance and prediction error. “It appears that gender dysphoria has a neurobiological basis but is also closely associated with the interactions these individuals have with the world, their prediction of those interactions and the feedback they receive in return,” he notes.

Teasing out gender dysphoria from other mood disorders

If it can be shown that distinct functional processes are occurring in the brains of individuals with gender dysphoria, Dr. Altinay believes it will lead to better comprehension of brain function in transgender people who are dysphoric and allow clinicians to differentiate gender dysphoria from other mood conditions, such as major depressive disorder (MDD).

“Currently, most transgender people are labeled ‘depressed’ or ‘anxious’ when some of these symptoms actually stem from gender dysphoria,” he observes. “When we can accurately distinguish MDD and gender dysphoria, we’ll be able to guide patients to the right treatment — for example, hormone therapy and gender affirmation therapies rather than treatment of MDD.” Appropriate treatment may also prevent depression, he adds.

Clinical applications and implications

Dr. Altinay is in the midst of submitting the research from his APA poster for publication, as well as launching a neuroimaging study using 7-tesla functional MRI to test the hypothesis presented in the poster.


Meanwhile, his research observations are influencing how Cleveland Clinic manages gender dysphoria. He has been actively educating medical students, residents, surgeons and psychiatrists about the new psychobiological model, as well as interfacing with Cleveland Clinic’s Lakewood Family Health Center, where providers manage hormone therapy and medical care for transgender individuals, and with Cleveland Clinic’s Section of Urogynecology, where gynecology care is provided for trans males and vaginoplasty for trans females.

“As a society, we have a tendency to pathologize certain conditions rather than understanding them,” he reflects. “This new model attempts to separate gender dysphoria and mood disorders as distinct diagnoses, with the goal of easing the pain and confusion these patients are feeling. Sometimes simply explaining the brain-body dichotomy helps transgender individuals stop thinking there’s something wrong with them and understand that they are not alone in experiencing these issues.”


  1. Clemens B, Junger J, Pauly K, et al. Male-to-female gender dysphoria: gender-specific differences in resting-state networks. Brain Behav. 2017;7:e00691.
  2. Manzouri A, Savic I. Possible neurobiological underpinnings of homosexuality and gender dysphoria. Cereb Cortex. 2018 Jul 31 [Epub ahead of print].

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