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DOI:10.4158/EP14351.RA
2014 AACE.

Review Article

EP14351.RA

EVIDENCE SUPPORTING THE BIOLOGICAL NATURE OF GENDER IDENTITY

Aruna Saraswat, MD1; Megan Weinand, BA, BS; Joshua D. Safer, MD

Running Title: Review: Gender Identity

From: 1Section of Endocrinology, Diabetes and Nutrition Boston Medical Center; 2Boston
University School of Medicine; 3Section of Endocrinology, Diabetes and Nutrition,
Boston University School of Medicine.

Correspondence address: Joshua D. Safer, MD, FACP

Endocrinology, Room M-1016
Boston University School of Medicine
715 Albany Street Boston, MA 02118
Email: jsafer@bu.edu

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Abstract

Objective: To review current literature that supports gender identity having a biologic basis. .

Methods: A traditional literature review.

Results: Evidence that there is a biological basis for gender identity primarily involves 1. data on
gender identity in patients with disorders of sex development along with 2. neuroanatomical
differences associated with gender identity.

Conclusions: Although the mechanisms remain to determined, there is strong support from the
literature that there is a biological basis for gender identity.

Keywords: gender identity, transgender; gender dysphoria

Abbreviations:
MTF = male to female; FTM = female to male.

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Introduction

Gender identity is a fundamental human attribute which has a profound impact on

personal well-being. Transgender individuals are those whose lived and identified gender identity
differs from their natal sex. Various etiologies for transgender identity have been proposed.
Misconceptions which assume that gender identity can be altered still exist. However, clinical
experience with treatment of transgender persons over the years has clearly demonstrated that the
best outcomes with these individuals are achieved with their requested hormone therapy and
surgical sexual transition, as opposed to psychiatric intervention alone (1). In this manuscript we
will review the data which support a fixed, biological basis for gender identity.

Methods

This traditional literature review was conducted using a search of PubMed and Google
Scholar for the following key words: gender identity, gender dysphoria, transsexual, transgender,
transmen, transwomen.

Results

Disorders of Sex Development (DSD)

A seminal study by Meyer-Bahlburg et al involving outcomes of XY individuals raised as

females due to severe non-hormonal, anatomic abnormalities of sex development has provided
the most convincing evidence that gender identity is fixed (2). These congenital abnormalities
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include penile agenesis, cloacal exstrophy, and penile ablation. For many years, female gender
assignment along with surgical feminization was the dominant approach for these patients. In
this study, it was observed that 78% of all female-assigned 46 XY patients were living as females
While the majority of these patients did not initiate a gender change to male, none of the 15 maleraised 46 XY patients initiated a gender change to female. Thus, risk of questioning gender
identity was higher in those patients raised as females than in those raised as males among 46 XY
subjects with one of these conditions. A study by the same group that examined the degree of
satisfaction with surgical intervention reported by patients with 46 XY genotype also found that
those subjects raised as boys were considerably more comfortable with their gender identity (3).
Another seminal study relevant to this topic was by Reiner and Gearhart (4) in their
review of 16 XY genotype subjects with cloacal exstrophy who underwent female gender
reassignment surgery. Out of the 14 individuals raised as girls, 4 announced they were male and
4 later chose to live as boys when they became aware of their genotype. The 2 individuals who
were raised as males identified as males throughout life. The sexual behavior and attitudes of all
16 subjects ultimately reflected strong masculine characteristics regardless of gender assignment.
Thus, children who were born genetically and hormonally male identified as males despite being
raised as females and undergoing feminizing genitoplasty at birth. Although cohort size in these
studies is small, these data provide the strongest evidence for biological underpinnings of gender
identity.
In congenital adrenal hyperplasia (CAH) the adrenal glands produce excessive amounts
of androgens, causing genital virilization with a spectrum of different phenotypes in 46 XX
neonates.

Dessens et al (5) showed that the prevalence of male gender identity in 46 XX

female-raised subjects with CAH is higher than the prevalence of FTM transgender individuals
in the general population of chromosomal females. In this study, the large majority (95%) of 250
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female-raised patients later maintained a female gender identity. However, 13 (5.2%) had serious
problems with their gender identity. 5 alpha-reductase-2 and 17-beta-hydroxy-steroid
dehyrogenase-3 deficiencies are similar conditions in which synthesis and conversion of
testosterone to dihydrotestosterone (DHT) is inhibited, , preventing development of external male
genitalia and resulting in potential genital ambiguity. As with CAH, affected individuals are often
raised as females. In a study of affected subjects, gender role changes were reported in 56-63%
of cases with 5 alpha-reductase-2 and 39-64% of cases with 17-beta-hydroxy-steroid
dehydrogenase-3 who were raised as girls (6). These data support the concept that gender
identity might be attributed to hormone milieu during intrauterine development on some
occasions.
Data from disorders of sexual development highlight the potential influence of abnormal
hormone exposure on development of transgender identity in some individuals. However, it is
important to note that most transgender individuals develop a gender identity which cannot be be
explained by atypical sexual differentiation. It is possible for individuals with normal sexual
differentiation to develop transgender identity later in life.

Neuroanatomical Differences

Many of the current hypotheses for the biological origin of transgender identity are based
on atypical sexual differentiation of the brain. The perception of ones own gender is linked to
sexual differentiation of the brain, which, in transgender individuals, differs from the body
phenotype (7). Regarding transgender identity, Swaab et al have proposed that this discrepancy
could be due to the fact that sexual differentiation of the brain takes place only after sexual

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differentiation of gonads in early fetal life (8). Along these lines, the degree of masculinization of
the genitals may not reflect that of the brain .
The notion of transgender-specific cerebral phenotypes has been further supported by
postmortem brain studies investigating the underlying neuroanatomical correlates of gender
identity (9,10,12). The vast majority of these studies have compared particular regions of interest
only in MTF transgender individuals (13,14,15). These studies support the hypothesis that
atypical cerebral networks in transgender individuals have a neuroanatomical basis. Studies have
examined both grey and white matter areas of the brain, as follows:

Grey Matter Studies

Studies involving grey matter in transgender individuals have provided the strongest
neuroanatomical case for transgender gender identity. Postmortem brain studies suggest that
some subcortical structures are feminized in MTF transgender individuals. One of the earliest
and most influential studies in this area involved the bed nucleus of the stria terminalis (BSTc),
which was reported to be a sexually dimorphic nucleus in humans with a larger volume in males
than in females. In 1995, Zhou et al found that the size and the number of neurons in the BSTc of
6 MTF estrogen-treated transgender individuals was typical for the size and neuron numbers
found generally in control females (9).The authors further reported that these findings could not
be explained by differences in adult sex hormone levels.
A similar study by Kruijver et al provided further data supporting the role of the BSTc in
transgender identity (10). They examined tissue from the same 6 MTF estrogen-treated
transgender persons studied by Zhou et al and found that the number of neurons in the BSTc was
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more similar to genetic XX female controls. BSTc neuron number was also in the male range in
the 1 FTM androgen-treated transgender individual studied.
Most transgender individuals have feelings of gender dysphoria which begin in
childhood. However, in a study of BSTc volume in postmortem brains of 50 control subjects,
Chung et al reported that sexual dimorphism in the BSTc did not develop until adulthood (11).
Yet, the same group remarked that changes in fetal hormone levels could have delayed effects on
BSTc volume and neuron in adulthood, thereby suggesting a role for BSTc as a marker for gender
identity. Still, delayed development of sexual dimorphism in the BSTc would not explain the
early development of gender dysphoria or gender identity discrepancy in childhood.
In 2008, Garcia-Falgueras and Swaab were the first to report a sex reversal in the
uncinate nucleus as part of brain networks involved in gender identity. They examined the
interstitial nucleus of the anterior hypothalamus (INAH 3), which is a sexually dimorphic
component of the uncinate nucleus, in relation to brains of transgender individuals (12). They
reported that INAH3 volume and neuron number in 11 MTF transgender persons was in the
female range.
The above studies are limited by the fact that they involved post-mortem examinations of
a small number of MTF transgender individual brains, some of whom had either received
hormone treatment or surgery. Therefore, study findings may represent confounding effects from
exogenous hormones in a small group of transgender individuals. Nevertheless despite their
small sample size, these studies provide valuable evidence that gender identity has a link to
neuroanatomy.
Studies by Luders et al provided further evidence that transgender identity is associated
with distinct cerebral patterns (13,14). In 2009, the group analyzed MRI data of 24 MTF
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transgender individuals who had not yet begun hormone treatment. These subjects were shown to
have a pattern that was more similar to control men. However, they also revealed a significantly
larger, more feminized volume of regional grey matter in the right putamen in these subjects.
In 2012, the same group observed thicker cortices in 24 MTF transgender individuals who had
not yet received exogenous hormones compared with 24 age-matched control men in a number of
regions across the lateral and medial cortical surfaces. The data supported a dichotomy between
MTF transgender individuals and gender congruent males with regard to brain structure.
Differences in brain volume and cerebral activation patterns have been implicated as
potential explanations for transgender identity. In 2011, Savic et al examined brains of 24 living
MTF transgender individuals and found significant volume reductions of the putamen in MTF
transgender individuals in addition to significant increases in grey matter volumes compared with
male and female controls (15). Although these findings differ from the previous findings of a
smaller, feminized, putamen in MTF transgender individuals, they still reported that certain
brain areas showed characteristic structural features in the transgender group compared with
controls.
The same group investigated 12 living MTF transgender individuals who smelled two
steroidal compounds: the progesterone derivative 4,16-androstadien3-one (AND) and the
estrogen-like compound estra-1,3,5(10),16-tetraen-3-ol (EST). These compounds have been
reported to activate the hypothalamic networks in a sex-differentiated way. MTF transgender
individuals who had not received hormone treatment were found to respond similarly to female
controls with activation of the anterior hypothalamus in response to AND (16). Another study by
Gizewski et al showed a similar cerebral activation in MTF transgender individuals relative to
female controls during viewing of erotic stimuli (17). While the above studies also only

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involved MTF transgender individuals, they nonetheless suggested altered neuroanatomical

pathways as an explanation for transgender identity.
The following two studies were unique from the aforementioned ones because they
included both MTF and FTM transgender individuals who had not received hormone treatment.
Zubiaurre et al reported that FTM transgender individuals showed evidence of subcortical gray
matter masculinization in the right putamen, while MTF transgender individuals had feminized
cortical thickness (18). In 2013, a study by Simon et al found differences in grey matter in 17
living transgender subjects compared with controls (19). Differences were seen in transgender
patients in the cerebellum, angular gyrus, and parietal lobe compared with controls, independent
of their biological gender.

White Matter Studies

Although an early study by Emory et al (20) found no difference in the whole corpus
callosum or the splenium region between MTF and FTM transgender individuals, the following
MRI studies of white matter brain characteristics of transgender individuals have suggested a
strong neuroanatomical explanation for transgender identity . Yokota et al reported that the
pattern of corpus callosum shape in both FTM and MTF transgender individuals was closer to
subjects with shared gender identities than to subjects who shared the same natal sex (21).
Among FTM transgender individuals who had not received hormone treatment, certain white
matter fasciculi involved in higher cognitive functions were closer to the pattern of control males
than to control females (22). Among MTF transgender individuals who had not received

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treatment, diffusion tensor imaging revealed an intermediate white matter pattern that was
between male and female controls (23).

Genetic Factors and Exposures

Although limited in size and scope, the involvement of genetic factors in transgender
identity is supported by small studies of gene abnormalities associated with steroid hormones,
twin case studies, neuroproteins, and prenatal exposures.

Steroid Hormone Genetics

Select genes have been associated with transgender identity. Although these studies have
been small, they represent the most convincing findings to date linking atypical genes with
transgender identity among both MTF and FTM transgender individuals. The CYP17 gene
encodes the 17-alpha hydroxylase enzyme and is associated with elevated serum levels of
estradiol, progesterone, and testosterone. In a case-control study of 151 transgender individuals,
Bentz et al reported a significant association between the CYP17 gene and FTM transgender
individuals but not in MTF transgender individuals (24). Another study by the same group
examined a polymorphism in the gene coding for 5-alpha reductase and found no association in a
sample of both MTF and FTM transgender individuals (25).
Various groups have investigated steroid hormone receptor gene variants to determine if
they confer likelihood of an individual developing transgender identity. Steroid hormones exert
profound influences on fetal sexual development and act via specific receptors. It is therefore
plausible that abnormal development of sex hormone receptor function may predispose to
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transgender identity. The above studies to date on this topic, however, have been contradictory,
and require replication to completely support this hypothesis. Henningson et al found an
association between MTF transgender individuals and a dinucleotide CA polymorphism in the
estrogen receptor beta gene (ERb) (26). However, two subsequent studies by separate groups
showed different results. Hare et al performed a larger study of MTF transgender individuals and
found no relationship with the ERb, but instead found a significant association with the androgen
receptor repeat (27). In a similar study of 242 MTF and FTM transgender individuals, Ujike et al
examined sex steroid receptor genes and found no association with transgender identity (28).
There have been several small case reports of atypical sex chromosomes in transgender
individuals. The most common association reported was with disomy-Y (47, XXY), however no
statistically significant association between particular genes has been noted (29). . Two recent
studies of MTF and FTM transgender individuals reported that aneuplodies are slightly more
common in transgender individuals than in the general population but neither was controlled. In
the first, karyotype abnormalities were found in 2.5% of the 368 transgender individuals studied
(30). A second study of 302 transgender individuals also showed a low overall incidence (1.5%)
of chromosomal abnormalities (31).

Twin studies

Twin literature supports the potential contribution of genetic factors to the development
of transgender identity. In two separate retrospective studies of twin pairs, Bailey et al and
Coolidge et al demonstrated a strong heritable component among twins with transgender identity
(32,33). A similar study by Hylens et al of 23 twin pairs showed that 9 out of 23 monozygotic
twin pairs were concordant for transgender identity, in contrast to no concordance among the
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dizygotic twin pairs (34). Two small studies o studies (35,36) have also demonstrated a higher
concordance for transgender identity among monozygotic twins versus dizygotic twins.
Nevertheless, the overall prevalence of monozyotic twins discordant for transgender identity still
outnumbers those who are condordant.

Neuroproteins

Brain-derived neurotrophic factor (BDNF) is a member of the growth factor

family which is involved in synaptic plasticity and neuronal development. Altered BDNF
signaling is thought to be a contributor to psychiatric conditions. Fontanari et al (37)
reported that serum BDNF levels were 15% lower in an uncontrolled study of 45 MTF
transgender individuals. However, all study subjects were treated with hormones and no
female subjects were included.
Neurokinin B (NKB) is a potent regulator of GnRH secretion, which is essential
for reproductive function. A postmortem brain study of 4 MTF transgender individuals
by Taziaux et al (38) showed an infundibular NKB volume similar to control females.
The feminization observed may have been explained either by medical estrogen therapy
or lack of androgens due to orchiectomy.

Prenatal Exposures

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Dessens et al (39) reported that 3 prenatally anticonvulsant-exposed subjects were

transgender individuals. For many years, researchers have been assessing the impact of prenatal
exposure to the estrogenic anti-miscarriage drug DES (diethylstilbestrol) on development of
gender dysphoria in affected offspring. While the vast majority of DES-exposed children have
not developed transgender identity, a 5 year online study of DES-exposed sons by Kerlin et al
reported at least 150 cases of moderate to severe gender dysphoria among 500 sons with
confirmed or suspected prenatal DES exposure (40).

Conclusion

Current data suggest a biological etiology for transgender identity. Studies of DSD
patients and neuroanatomical studies provide the strongest evidence for the organic basis of
transgender identity. Sample sizes of the majority of studies to date on this subject are small, and
conclusions must be interpreted with caution. Further research is required to assign specific
biological mechanisms for gender identity.

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Table 1. Evidence for a Biologic Basis of Gender Identity

Although no studies to date demonstrate mechanism, multiple studies demonstrate associations with gender
identity that support it being a biological phenomenon. The table below organizes areas studied by type of
study and lists the associations that have been made.

Studies showing rigid gender identity in patients with disorders of sexual development (DSD)

Congenital, non-hormonal conditions

Penile ablation/agenesis, cloacal exstrophy

Studies showing that gender identity may be associated with prenatal hormone exposure in some (perhaps otherwise predisposed)
individuals

Congenital Adrenal Hyperplasia

Hormone deficiencies

5 alpha-reductase-2,
17-beta-hydroxy-steroid dehydrogenase-3

Studies with gender identity associated with neuroanatomical differences

Grey Matter Studies

Bed nucleus of stria terminalis (BSTc)

Uncinate nucleus
Putamen volumes
Cortical thickness
Hypothalamic response to odorous steroids

White Matter Studies

Corpus callosum
Microstructure differences

Studies with gender identity associated with genetic factors and exposures

Steroid Hormone Genetics

Genes: CYP17, SRD5A2, ERb, androgen receptor

Sex Chromosome Aneuploidy

Disomy-Y

Twin case studies

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Neuroproteins

BDNF, NKB

Prenatal exposures

Anticonvulsants, DES

Legend:

CYP17: Cytochrome P-450 17 alpha gene

BDNF: Brain-derived neurotropic factor

SRD5A2: Steroid-5-alpha-reductase, alpha polypeptide 2 gene

NKB: Neurokinin B

ERb: Estrogen receptor beta gene

DES: Diethylstilbestrol

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