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The Link between Estradiol and Neuroplasticity in Transgender Women after Gender-Affirming Surgery: A Bimodal Hypothesis

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For transgender individuals, gender-affirming surgery (GAS) and cross-sex hormone therapy (CSHT) are part of the gender transition process. Scientific evidence supporting the maintenance of CSHT after GAS-related gonadectomy is accumulating. However, few data are available with respect to the impact of CSHT on brain structure following hypogonadism. Thus, we aimed to investigate links between estradiol and brain cortical thickness and cognition in 18 post-gonadectomy transgender women using a longitudinal design. For this purpose, the participants underwent a voluntary period of CSHT washout of at least 30 days, followed by estradiol re-institution for 60 days. High-resolution T1-weighted brain images, hormonal measures, working and verbal memory were collected at two time points: on the last day of the washout (t1) and on the last day of the two-month CSHT period (t2). Between these two time points, cortical thickness increased within the left precentral gyrus and right precuneus but decreased within the right lateral occipital cortex. However, those findings did not survive corrections of multiple comparisons. Nevertheless, there was a significant negative correlation between changes in estradiol levels and changes in cortical thickness. This effect was evident in the left superior frontal gyrus, the left middle temporal gyrus, the right precuneus, the right superior temporal gyrus and the right pars opercularis. Although there was improvement in verbal memory following hypogonadism correction, we did not observe a significant relationship between changes in memory scores and cortical thickness. Altogether, these findings suggest that there is a link between estradiol and cortical thickness.
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ORIGINAL RESEARCH
published: 07 August 2019
doi: 10.3389/fnins.2019.00817
Edited by:
Manuel Tena-Sempere,
Universidad de Córdoba, Spain
Reviewed by:
Alexander Comninos,
Imperial College London,
United Kingdom
Ben Nephew,
Worcester Polytechnic Institute,
United States
*Correspondence:
Maiko A. Schneider
schnmaiko@gmail.com
Specialty section:
This article was submitted to
Neuroendocrine Science,
a section of the journal
Frontiers in Neuroscience
Received: 11 February 2019
Accepted: 22 July 2019
Published: 07 August 2019
Citation:
Schneider MA, Spritzer PM,
Minuzzi L, Frey BN, Syan SK,
Fighera TM, Schwarz K, Costa ÂB,
da Silva DC, Garcia CCG,
Fontanari AMV, Real AG, Anes M,
Castan JU, Cunegatto FR and
Lobato MIR (2019) Effects of Estradiol
Therapy on Resting-State Functional
Connectivity of Transgender Women
After Gender-Affirming Related
Gonadectomy.
Front. Neurosci. 13:817.
doi: 10.3389/fnins.2019.00817
Effects of Estradiol Therapy on
Resting-State Functional
Connectivity of Transgender Women
After Gender-Affirming Related
Gonadectomy
Maiko A. Schneider1,2,3*, Poli M. Spritzer1,4,5 , Luciano Minuzzi2,3,6 , Benicio N. Frey2,3,6,
Sabrina K. Syan2,7 , Tayane M. Fighera1,5, Karine Schwarz1, Ângelo B. Costa8,
Dhiordan C. da Silva1,9 , Cláudia C. G. Garcia1,9, Anna M. V. Fontanari1,9, André G. Real1,9,
Maurício Anes10 , Juliana U. Castan1,11, Fernanda R. Cunegatto11 and
Maria I. R. Lobato1,9,12
1Gender Identity Program (PROTIG), Psychiatric Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, 2Mood
Disorders Program, Women’s Health Concerns Clinic, St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada,
3Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada, 4Department of
Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, 5Division of Endocrinoloy, Hospital de Clínicas
de Porto Alegre, Porto Alegre, Brazil, 6Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada,
7Peter Boris Centre for Addictions Research, McMaster University, Hamilton, ON, Canada, 8Graduate Program in
Psychology, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil, 9Post-Graduation Program,
Universidade Federal do Rio Grand do Sul, Porto Alegre, Brazil, 10 Medical Physics and Radiation Protection Service,
Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, 11 Psychology Service, Hospital de Clínicas de Porto Alegre,
Porto Alegre, Brazil, 12 Psychiatric and Forensic Medical Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
An extreme incongruence between sex and gender identity leads individuals with
gender dysphoria (GD) to seek cross-sex hormone therapy (CSHT), and gender-
affirming surgery (GAS). Although few studies have investigated the effects of CSHT
on the brain prior to GAS, no studies in the extant literature have evaluated its impact
during hypogonadism in post-GAS individuals. Here, we aimed to evaluate the effects
of estradiol on resting-state functional connectivity (rs-FC) of the sensorimotor cortex
(SMC) and basal ganglia following surgical hypogonadism. Eighteen post-GAS (male-
to-female) participants underwent functional magnetic resonance imaging (fMRI) and
neuropsychiatric and hormonal assessment at two time points (t1, hormonal washout;
t2, CSHT reintroduction). Based on the literature, the thalamus was selected as a seed,
while the SMC and the dorsolateral striatum were targets for seed-based functional
connectivity (sbFC). A second sbFC investigation consisted of a whole-brain voxel
exploratory analysis again using the thalamus as a seed. A final complementary data-
driven approach using multivoxel pattern analysis (MVPA) was conducted to identify
a potential seed for further sbFC analyses. An increase in the rs-FC between the left
thalamus and the left SCM/putamen followed CSHT. MVPA identified a cluster within
the subcallosal cortex (SubCalC) representing the highest variation in peak activation
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Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
between time points. Setting the SubCalC as a seed, whole-brain analysis showed a
decoupling between the SubCalC and the medial frontal cortex during CSHT. These
results indicate that CSHT with estradiol post-GAS, modulates rs-FC in regions engaged
in cognitive, emotional, and sensorimotor processes.
Keywords: gender dysphoria, hypogonadism, estradiol, functional connectivity, sensorimotor cortex, putamen,
thalamus
INTRODUCTION
Gender dysphoria (GD) is characterized by incongruence
between the sex assigned at birth and the gender identity.
People who experience profound gender incongruence are
referred for cross-sex hormone therapy (CSHT) and gender-
affirming surgery (GAS) (Hembree et al., 2017). Apart from
their effects on the body, sex hormones are also known
to be neuroactive (Zheng, 2009), and several studies have
demonstrated the impact of CSHT on brain structure and
functional connectivity (Rametti et al., 2012;Mueller et al.,
2016, 2017). Thus far, most of the studies evaluating the
effects of CSHT were conducted before GAS (Nguyen et al.,
2018); as of yet, little is known about its effects on the
brain following gonadectomy. Although there are no estimates
about the worldwide numbers of gonadectomies performed
over previous decades, a 12-year cohort called STRONG (The
study of transition, outcomes, and gender) estimated a total
of 363 orchiectomies/oophorectomies in Georgia, Northern
California and Southern California (United States) (Quinn et al.,
2017). Another survey in Korea reported a total of 115 GAS;
however, that report specified neither how many included
gonadal removal nor the time window in which they had been
performed (Lee et al., 2018). In our outpatient program for
GD, from 2000 to 2016, we completed 174 GAS including
orchiectomy (Schwarz et al., 2017). Considering these numbers,
it is a matter of public health concern to better investigate
the impact of CSHT on a transgender person’s brain after
completion of gonadectomy.
Following removal of the gonads, transgender individuals
experience hypogonadism-related symptoms similar to those
presented by menopause-transitioning women, such as hot
flushes, if CSHT is not continued. A plausible hypothesis
for the development of these symptoms is the disruption of
the functional connectivity between the thalamus (secondary
neuron) and the primary sensorimotor cortex (SMC) (tertiary
neuron) as a result of the decline of circulating sex hormones.
Anatomically, the thalamus is a region contiguous to the
SMC and the basal-ganglia, and functionally, it functions as
a modulator of sensory and motor synapses (Behrens et al.,
2003). The thalamus also conveys and integrates sensory input
within the thalamocorticostriatal circuitry (Butler et al., 1992;
Herrero et al., 2002), and its involvement in the stimulus-
controlled processing stream within this circuitry has also been
proposed in a theoretical frame (Alloway et al., 2017). Of note,
the thalamus, basal ganglia and the SMC express a great number
of estrogen receptors in the human brain (Osterlund et al., 2000;
Osterlund and Hurd, 2001), which contributes to the hypothesis
that these structures are prone to being affected by a deficiency
in sex hormones.
With regard to functional connectivity, Kenna et al. (2008)
had already demonstrated that menopause-related estrogen
decline was associated with a disruption in the integrity of
the thalamostriatal synapses (Kenna et al., 2008). In that
experiment, using [18F] fluorodeoxyglucose positron emission
tomography (18FDG-PET), the investigators found an increase in
the functional connectivity/coupling of this circuit after estrogen
administration. This finding suggested that circulating estradiol
was a modulator of the sensorimotor circuitry, contributing to
the integrity, and function of thalamic synapses after ovarian
failure. Moreover, estradiol replacement therapy was associated
with an improvement in fine motor ability during menopause in
a clinical study from Bayer and Hausmann (2010) (Bayer and
Hausmann, 2010). These results are in line with experimental
data from animal models that showed neuroprotective effects of
estrogen therapy in the face of more adverse conditions such as
stroke and ischemia (Ardelt et al., 2012;Carpenter et al., 2016).
Resting-state functional connectivity (rs-FC) is a
neuroimaging technique used to map the brain that is related
to blood oxygen level-dependent (BOLD) imaging (Hart et al.,
2016;Qiu et al., 2017) that has been applied to investigate several
neurological and psychiatric conditions (Uddin et al., 2009;Chen
and Etkin, 2013). When two or more brain regions present with
temporally correlated changes in the BOLD signal it implies
a “functional connectivity.” Discrete brain regions may have
correlated/coupled connectivity or anticorrelated/decoupled
connectivity. Investigating how the brain works in the resting
state is useful to better understand neuroplastic mechanisms in
response to different physiological and pathological conditions.
Therefore, rs-FC can be helpful to better understand how CSHT
affects functional connectivity after gonadectomy is performed
in transgender people.
As it is still a largely unexplored field, we designed the
present study to investigate the effects of CSHT on transgender
women’s brain functional connectivity after gonadectomy-related
GAS. The principal aim was to determine the effects of
estradiol on the primary SMC and the striatum of transgender
women. To fulfill this objective, region-of-interest to region-
of-interest (ROI-to-ROI) and seed-to-voxel rs-FC analyses were
performed. First, the thalamus was set as a seed region,
while the striatum and the SMC were used as targets in the
ROI-to-ROI approach. The rationale for using the thalamus
as a seed was its already demonstrated anatomical and
functional connection to these structures (Giménez-Amaya
et al., 1995;Herrero et al., 2002;Behrens et al., 2003;Hwang
et al., 2017). We hypothesized that hypogonadism correction
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following estradiol administration increases the rs-FC between
the thalamus, primary SMC, and the dorsolateral striatum. Next,
an additional exploratory seed-to-voxel analysis was done setting
the thalamus as a seed, while whole-brain voxels were defined
as targets. Last, as a secondary objective, a complementary
functional data analysis using whole-brain multivoxel pattern
analysis (MVPA) generated a seed for a last seed-to-voxel
exploratory analysis.
MATERIALS AND METHODS
Patients
Eighteen transgender women (male-to-female) who had already
completed GAS were selected from a specialized outpatient
program for gender incongruence (Programa Ambulatorial
Transdisciplinar de Identidade de Gênero – PROTIG, Hospital de
Clínicas de Porto Alegre, Porto Alegre, Brazil). The recruitment
was done from February 2017 to February 2018. Inclusion criteria
were (1) GD diagnosis according to the DSM-5, (2) age between
18 and 59 years, and (3) at least 1 year post-GAS, without surgical
repairs in the meantime. Exclusion criteria were (1) use of
antidepressant, mood stabilizer, antipsychotic, or anticonvulsant
drugs in the last 90 days; (2) presence of depressed mood,
anxiety, panic or obsessive-compulsive disorder, as assessed
through clinical interviews conducted by a psychiatrist and a
psychologist in accordance with the DSM-5; (3) presence of
current substance use disorder; (4) history of head injury with
loss of consciousness or neuroimaging sequelae; or (5) presence
of any contraindication to MRI. One participant was excluded
due to brain anatomical variation. Anxiety and mood disorders
were chosen as exclusion criteria since these mental health
conditions are known to affect functional brain connectivity
(Yang et al., 2017;Bai et al., 2018;Kunas et al., 2018), and
they could potentially represent confounds to this investigation.
All the patients were right-handed according to the Edinburg
Handedness Inventory (Veale, 2014). After completing the initial
screening, participants ceased CSHT for at least 30 days in
order to promote a standardized hormonal washout among all
participants. On the last day of the washout period (t1), all
participants underwent MRI scans, as well as laboratory, and
mood/anxiety assessments. Notably, this relatively short window
took into consideration ethical concerns regarding depriving
patients of hormonotherapy for longer periods. Afterward,
patients were put back on CSHT regimes according to the
clinical protocols for more 60 (±1 week variance for the visit),
using exclusively estradiol formulations (Hembree et al., 2017).
Then, the participants completed the same MRI, laboratory
and mood/anxiety assessments on the 60th day of CSHT (t2)
as they did at t1.
Sample size was estimated based on the study of Kenna
et al. (2008). We initially expected to recruit 20 volunteers,
although interim analysis revealed sufficient power analysis with
17 individuals. This project was approved by the Ethics Review
Board of the Hospital de Clínicas de Porto Alegre (CEP 15-0199).
All participants gave written informed consent according to the
Declaration of Helsinki.
Neuropsychological Evaluation
At the first and second time points (t1 and t2), participants were
evaluated using the Hamilton Rating Scales for anxiety (HAM-
A), and depression (HAM-D) (Hamilton, 1958, 1959). Paired
t-tests were used to compare differences between mean HAM-
A/HAM-D scores between time points. Although participants
did not present with mood and anxiety disorders when admitted
to the study, these scales were intended to detect potential
somatic anxiety symptoms frequently reported by subjects during
hypogonadal conditions or CSHT adjustment, at a statistical
threshold of p<0.05.
MRI Acquisition Protocol
All subjects were scanned in a Philips Ingenia 3.0 T MR system
(Best, Netherlands, 2015) using a 32-channel head coil. An rs-
fMRI and a high-resolution structural sequence were acquired
from each individual before and after CSHT. The rs-fMRI
sequence was an echo planar imaging (EPI) with 36 slices of
T2weighted images with the following acquisition parameters:
TE = 30 ms, TR = 2000 ms, flip angle 90, 80 ×80 matrix, in-
plane voxel size = 3.5 mm ×3.5 mm, slice thickness = 3.5 mm,
gap slice spacing = 0.35 mm, FOV = 240 mm, lasting for
6:12 min. Structural images were acquired using a T1-weighted
3D magnetization prepared rapid acquisition with gradient echo
(MPRAGE) sequence with 200 sagittal slices, flip angle = 8,
TE = 3.9 ms, TR = 8.5 ms, TI = 900 ms, flip angle = 8,
256 ×256 matrix, matrix size = 272 ×272, in-plane voxel
size 0.94 mm ×0.94 mm, slice thickness 0.94 mm, no gap,
and FOV = 256 mm.
Laboratory Analysis
Venous blood samples were collected between 8 a.m. and 10
a.m. on the same day MRI scans were done. Estradiol was
measured by electrochemiluminescence immunoassay (ECLIA,
Roche Diagnostics, Mannheim, Germany), with assay sensitivity
of 5.0 pg/mL and intra- and interassay CV of 5.7 and
6.4%, respectively. Follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) were measured by chemiluminescence
immunoassay (Centaur XP, Roche Diagnostics, Mannheim,
Germany), with sensitivity of 0.10 mIU/mL, intraassay coefficient
of variation (CV) of (<3% and interassay CV of <5%).
Functional MRI Data Preprocessing
Resting-state functional connectivity data were analyzed with
the CONN toolbox (version 18) (Whitfield-Gabrieli and Nieto-
Castanon, 2012). The preprocessing included the following
steps: functional realignment and unwarp for subject motion
estimation and correction, functional images centering on (0,
0, 0) MNI coordinates and slice-time correction. ART-toolbox
was used for functional outlier detection, using an intermediate
setting of 97th percentile and a 0.9 mm threshold for motion.
The structural and functional images were segmented and
normalized with a simultaneous segmentation and normalization
for gray/white matter and CSF. Structural and functional target
resolutions were 1 and 2 mm, respectively. Functional smoothing
was used to spatial convolution with Gaussian kernel of 8 mm.
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First-level covariates derived from this process were checked for
quality of the data; therefore, motion and outliers could be added
as first-level covariates. A maximum of 35 invalid scans due to
excessive motion per condition was permitted, and no participant
had to be excluded for this reason. Principal component
analysis (PCA) with additional anatomical component-based
noise correction method (aCompCor) (Behzadi et al., 2007;
Whitfield-Gabrieli and Nieto-Castanon, 2012;Muschelli et al.,
2014) was applied to obtain signal from the CSF and WM.
The Harvard-Oxford Atlas (Desikan et al., 2006) was used
to extract signal from the regions of interest using average
time series extraction. The confounds during the denoising
process included signals from white matter and CSF, slice
realignment and scrubbing. A bandpass filter (0.008–0.09) using
linear detrending was applied during noise filtering. Functional
connectivity analysis was carried out using a weighted general
linear model, with a zero-lagged bivariate linear correlation
in order to prepare data for seed-based connectivity analysis.
A block design (estradiol >washout) was defined to compare
conditions on second-level analyses after the completion of the
preprocessing steps.
Additionally, a voxel-to-voxel first-level analysis was prepared
to conduct further data-driven analysis using group-MVPA.
MVPA is a method that uses a low-dimensional representation
of the connectivity values between whole brain voxels in order
to identify reproductible patterns (voxel-to-voxel features) that
differentiate two or more experimental conditions (Mahmoudi
et al., 2012). For each voxel tested as seed a representational
matrix for whole brain connectivity is build, until all voxels
have been tested as seeds. Functional data were prepared using
the first 4 principal components of the PCA and 64-voxel
dimensionality reduction. An omnibus test was carried out to
compared connectivity patterns between the two experimental
conditions. This was a complementary second-level analysis in
order to obtain a new seed from the data for post hoc rs-FC
exploratory analysis (Norman et al., 2006;Peelen and Downing,
2007). As we intended to characterize connectivity patterns
between the data-driven seed and the rest of the brain (post hoc
analysis), no additional cross-validation is needed for the MVPA
algorithm (Whitfield-Gabrieli and Nieto-Castanon, 2012;Beaty
et al., 2015;Thompson et al., 2016).
Statistics
Clinical and laboratory data were analyzed with R software1
(version 3.4.1). Normal distribution for clinical and laboratory
data was assessed by the Shapiro-Wilk test.
Seed-Based FC Using a priori Defined
Seed (ROI-to-ROI and Seed-to-Voxels)
First, ROI-to-ROI analysis was conducted defining the thalamus
as a seed (Kenna et al., 2008), while the SMC and the dorsolateral
striatum were defined as targets (Lanciego et al., 2012;Borich
et al., 2015;Carpenter et al., 2016;Nota et al., 2017). A contrast
between t1 and t2 (estradiol >washout) was designed to
estimate connectivity differences (rs-FC) between the conditions;
1http://www.R-project.org
furthermore, we proceeded with a multiple regression analysis
to test whether there is a relationship between changes in rs-
FC and changes in estradiol serum levels between time points.
Age and variation in anxiety scores between time points were
controlled in both analyses. Including changes in anxiety scores
between time points was considered a reasonable approach,
since they could potentially interfere with the functional
connectivity of the sensory cortex. Compared to the HAM-
D scale, the HAM-A includes more somatic domains, which
are helpful to identify the impact of hypogonadism symptoms
on the sensorimotor connectivity. Multiple comparisons were
corrected for false discovery rate (p-FDR <0.05) according
to the number of functional connectivities tested for the
ROI-to-ROI approach.
Second, a seed-to-voxel whole-brain analysis was conducted
setting the thalamus as a seed, while all brain voxels were set as
targets to estimate connectivity differences between the two time
points (estradiol >washout). As in the ROI-to-ROI approach,
age and changes in anxiety scores between time points were
controlled. We also tested for the relationship between changes
in estradiol levels and changes in rs-FC between time points,
following similar approach as on ROI-to-ROI analysis. Multiple
comparisons were corrected for using a peak height threshold
at p<0.001 plus a sequential cluster-size p-FDR thresholded at
p<0.05, both two-sided.
Post hoc analyses were done to test for the effects of
prior lifetime exposure to CSHT on the rs-FC, since it could
influence the rs-FC responsiveness after estradiol reintroduction,
as well as for lateralization effect on functional connectivity
when comparing left, and right thalami on whole-brain seed-
based analysis.
For both seed-based analyses, we conducted supplementary
exploratory analysis to investigate whether intraindividual
variations in anxiety and depression (changes in HAM-A/HAM-
D scores between time points) are related to changes in rs-FC.
Seed-Based FC Analysis Using a
Data-Driven Seed
Finally, we ran a complementary whole-brain seed-to-voxel
analysis using the seed derived from a data-driven approach
(group-MPVA) in order to estimate connectivity differences
between the two conditions. Statistical significance for this whole-
brain seed-to-voxel analysis was thresholded at <0.001 for peak
height, with further cluster-size correction at 0.05 for FDR
(cluster-size p-FDR <0.05, two-sided).
Briefly, group-MVPA implemented by CONN uses a machine
learning algorithm to classify the voxels that exhibit the greatest
variability in peak activation between two or more conditions.
Here, a contrast between estradiol (CSHT) and the washout
condition was designed to investigate changes in functional
connectivity following reintroduction of estradiol regimes
(estradiol >washout). Statistical significance for group-MVPA
was thresholded at <0.001 for peak height, with additional
cluster-size correction at 0.05 for FDR (cluster-size p-FDR
<0.05), both two-sided. Age differences between subjects were
controlled. When conducting posterior seed-based connectivity
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analysis using the cluster obtained from the MVPA as a seed,
HAM-A variation between time points was added as a covariate,
and following the same approach used for the other seed-
based analysis. Again, we investigated whether intraindividual
changes in HAM-A/HAM-D are related to changes in whole-
brain rs-FC.
RESULTS
Sociodemographic Features
Table 1 presents clinical and hormonal characteristics of the
sample. The mean age of participants was 40.2 years (±8.9 years);
although the inclusion criteria were from 18 to 59 years old,
participants were aged between 27 and 59. The mean for years
of education was 10.2 (±3.3 years), and the mean for lifetime
exposure to CSHT was 17.71 years (±8.62 years). Median time
elapsed from GAS to t1 was 2 years, interquartile interval (IqI)
between 1 and 4 years. The mean of number of days off CSHT
was 35.86 (±3.32 days), and the number of days on CSHT
between time points was 66.1 (±5.49). All participants were right-
handed. As expected, estradiol, LH and FSH serum levels changed
significantly during CSHT.
TABLE 1 | Clinical and laboratory characteristics of the sample.
Clinical and laboratory characteristics of the sample
Age (years, mean/sd) 41.59 (8.66)
Age beginning CSHT
(years, mean/sd)
22 (7.98)
Lifetime exposure to CSHT
(years, mean/sd)
17.71 (8.62)
Time post-GAS (years,
median/IqI)
2 (1–4)
Time off CSHT (days,
mean/sd)
35.86 (3.32)
Time on CSHT after t1
(days, mean/sd)
66.1 (5.49)
Handedness (mean/sd) 98.94 (4.36)
t1 t2 p-value
E2 pg/mL (median/IqI) <5.0 (0–0) 93.23 (25.8–135.30) 0.0002
Testosterone ng/mL
(mean/sd)
0.07 (0.10) 0.11 (0.15) 0.43
LH mIU/mL (mean/sd) 50.85 (22.01) 30.7 (22.99) 0.10
FSH mIU/mL (mean/sd) 91.75 (38.01) 56.56 (33.61) 0.02
HAM-D (median/IqI) 4.0 (1–10) 2 (1–6) 0.51
HAM-A (median/IqI) 5 (1–12) 2 (1–10) 0.16
Pre and post comparisons were done with paired t-test or Wilcox test.
Interpretation of handedness scale: scores <40 indicates predominantly
left handed; scores between 40 and +40 indicates ambidextrous; scores
>+40 indicate predominantly right handed. GD, gender dysphoria; CD, cross-
dressing; CSHT, cross-sex hormone therapy; SHBG, sex hormone binding
globulin; LH, luteinizing hormone; FSH, follicle-stimulating hormone; DHEA-S,
dehydroepiandrosterone sulfate; FSIQ, full-scale intelligence quotient; HAM-D,
hamilton depression rating scale; HAM-A, hamilton anxiety rating scale; IqI,
interquartile interval; sd, standard deviation; t1: washout, t2, CSHT conditions; ,
significant at p <0.05.
Clinical Assessment
Anxiety and depression scores after the washout period (t1) and
after the reintroduction of estradiol (t2) are presented in Table 1.
No significant changes in HAM-D or HAM-A scores were
observed after CSHT reinstitution. Supplementary Figure S1
illustrates individual changes in anxiety and depression scores
between time points (t2 – t1).
Resting-State Functional Connectivity
Seed-Based FC Using a priori Defined Seeds
First, the ROI-to-ROI analysis revealed a significant group effect
of estradiol (CSHT) on rs-FC (Table 2). Compared to the
washout, 60 days of estradiol therapy was associated with a
significant increase in connectivity (coupling) between the left
thalamus and the left SMC (p= 0.016), as well as a coupling
between the left thalamus and the left putamen (p= 0.026)
(Figure 1A). There was no significant relationship between
estradiol levels and changes in the rs-FC regarding the seed
and targets when running the multiple regression analysis. As
well, there was no significant correlation between intraindividual
changes in HAM-A/HAM-D and rs-FC between thalamus and
the respective targets.
Second, the whole-brain seed-to-voxel analysis using the
thalamus as a seed demonstrated an increase in the rs-FC
between the left thalamus and a cluster of voxels from the left
primary motor and sensory cortices (coordinates: 56 04 36;
TABLE 2 | Region-of-Interest to Region-of-Interest analysis.
Seed Target Beta T (14) p-unc p-FDR
L thalamus
L lateral sensorimotor 0.20 3.86 0.002 0.016
R lateral sensorimotor 0.13 2.62 0.020 0.060
S sensorimotor 0.06 0.93 0.286 0.474
L putamen 0.14 3.26 0.006 0.026
R putamen 0.06 0.94 0.264 0.474
L caudate 0.13 1.49 0.158 0.356
R caudate 0.10 1.17 0.262 0.472
L pallidum 0.05 0.76 0.458 0.516
R pallidum 0.03 0.66 0.519 0.519
R thalamus L lateral sensorimotor 0.20 2.87 0.012 0.086
R lateral sensorimotor 0.17 2.65 0.191 0.086
S sensorimotor 0.04 0.73 0.475 0.590
L putamen 0.10 1.61 0.130 0.292
R putamen 0.06 1.30 0.187 0.337
L caudate 0.06 0.73 0.475 0.590
R caudate 0.09 1.10 0.290 0.435
L pallidum 0.11 2.31 0.036 0.109
R pallidum 0.03 0.45 0.658 0.658
Estimated connectivity differences in the resting-state functional connectivity
comparing estradiol and washout time points (t2 >t1). Analyses were controlled for
age differences and changes in anxiety scores according to the Hamilton Inventory.
Beta indicates the average difference on the connectivity values across the regions
of interest. L, left; R, right; S, superior; Rs-FC, resting-state functional connectivity;
unc, uncorrected for multiple comparisons; FDR, false discovery rate; , statistical
significance after FDR <0.05.
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FIGURE 1 | (A) Red regions show an increase in the rs-FC between the left thalamus and the left sensorimotor cortex (beta = 0.20)/left putamen (beta = 0.14) after
estradiol therapy (ROI-to-ROI analysis). Statistical significance thresholded at p-FDR <0.05. (B) Whole-brain seed-to-voxel functional connectivity analysis. Red
cluster indicates increased rs-FC between the left thalamus (seed) and voxels of the pre and post-central gyri (beta = 0.21). Cluster size p-FDR <0.0042. Color bar
shows statistical significance.
cluster size: 239 voxels; peak height uncorrected: 0.00001; size
p-FDR: 0.004) (Figure 1B). Again, there was no statistically
significant relationship between changes in estradiol levels and
changes on rs-FC. Supplementary Material contains spatial
connectivity maps for both time points and connectivity contrast
between t1 and t2 (Supplementary Figure S2). No significant
relationship between intraindividual changes in HAM-A/HAM-
D and changes in whole-brain rs-FC using bilateral thalamus as
the seed were observed.
Post hoc analysis adjusting for lifetime exposure to CSHT as
a second-level covariate did not significantly affect the rs-FC
results, as there was no significant correlation between lifetime
exposure to CSHT and rs-FC changes between time points
when adjusting for age and HAM-A scores. Moreover, post hoc
analysis for lateralization effects on rs-FC using a contrast
between the right and the left thalamus did not show statistically
significant effect.
Seed-Based FC Analysis Using a Data-Driven Seed
Group-MVPA identified a cluster within the subcallosal cortex
(SubCalC) as the most useful for classification between washout
and CSHT (estradiol) conditions; this data-driven seed was
used for posterior seed-to-voxel analysis (MNI peak coordinates:
04 +26 16; cluster size: 94 voxels; p-FDR: 0.00002). Figure 2
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FIGURE 2 | Plots showing changes in whole-brain functional connectivity after a minimum of 60 days of estradiol therapy using multivoxel pattern analysis. (A) Plots
individual changes in FC between the cluster within the subcallosal cortex and the rest of the brain. (B) Shows group average changes in FC (–19.51) between time
points, with a 90% confidence interval (C.I: –25.4 to –13.52). Cluster size p-FDR <0.0013.
shows individual and group changes in functional connectivity
between experimental conditions.
Further whole-brain exploratory analysis using the SubCalC
as a seed found a decreased rs-FC (decoupling) between the
SubCalC and the medial frontal cortex (MNI peak coordinates:
08 +38 20; cluster size: 307 voxels, p-FDR: 0.001) (Figure 3
and Table 3). There was no relationship between intraindividual
changes in HAM-A/HAM-D scores and whole-brain connectivity
using the SubCalC as a seed.
DISCUSSION
Cross-sex hormone therapy prescribed to transgender women
was associated with an increase in the rs-FC between the
left thalamus and the left SMC /left putamen after GAS-
related gonadectomy. This finding was confirmed by a whole-
brain analysis demonstrating an increase in the rs-FC between
the left thalamus and a cluster comprising contiguous voxels
from the sensory and motor cortices. Further, the data-driven
analysis showed a deactivation of a cluster within the subcallosal
cortex during estradiol treatment compared to the hypogonadal
condition. These findings contribute to the understanding of
the relationship between sex hormones and mechanisms of
neuroplasticity, since they provide new evidence regarding rs-FC
plastic adaptations following the correction of hypogonadal state.
The results also showed a coupling effect of hormone
replacement restricted to the left hemisphere (left thalamus –
left SMC/left putamen). Although this lateralization effect did
not remain statistically significant when left and right thalamus
connectivity patterns were directly compared, this finding still
deserves attention. Several studies have demonstrated lateral
specialization of the basal ganglia nuclei and somatosensory
cortex, highlighting the sex differences on lateralization (Pelzer
et al., 2016;Reber and Tranel, 2016;Sarasso et al., 2017;Gordji-
Nejad et al., 2018). Hence, we cannot rule out the possibility that
estradiol therapy influences hemispheric specialization.
To our knowledge, only one previous study by Nota et al.
(2017) investigated the effects of CSHT in brain functional
connectivity due to hypogonadism, however, they did not
study post-gonadectomy individuals. Rather, they induced
hypogonadism using a gonadotropin releasing hormone analog
(GnRHa) for 4 months. According to their results, resting-
state networks were not affected by hormonal status during
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FIGURE 3 | Whole-brain analysis using data-driven seed originated with the MVPA. Slicing view of the cluster within the medial frontal cortex that exhibited a
decrease in the rs-FC (beta = –0.27; Cluster size p-FDR = 0.0013). The blue bar on the right decodes statistical significance.
either GnRHa or GnHRa +CSHT administration. Thus, the
study described is not comparable to this present body of work,
since the SMC was not included as a region of interest in
that study, and the use of GnRHa was considered a potential
confound. As a matter of fact, only a few studies have been
dedicated to the investigation of sex hormone effects on the
sensorimotor circuitry.
Thalamocorticostriatal Circuit
The thalamus is involved in the integration and modulation
of motor and sensory information from (and for) the body
(Roelfsema and Holtmaat, 2018). It plays a role as a gateway for
contralateral body sensory input, and it is connected to ipsilateral
primary sensory and motor cortices (Behrens et al., 2003;
TABLE 3 | Seed-to-voxel whole-brain analysis using the subcallosal cortex
as a seed.
Seed Target Cluster
size
Beta
(cluster
average)
T (cluster
average)
p-FDR
SubCalC
(04 +26 16)
MedFC
(08 +38 20)
307 0.27 6.91 0.0013
The effect of age was controlled. Seed selection was based on previous multivoxel
pattern analysis (MPVA). SubCalC, subcallosal cortex; MedFC, medial frontal
cortex; FDR, false discovery rate.
Mastropasqua et al., 2014). Immunohistochemical and
radiotracer studies have demonstrated that both the thalamus
and primary SMC are rich in ER (Taylor and Al-Azzawi,
2000;Osterlund and Hurd, 2001). This evidence provides a
reasonable background to support our results; i.e., there is a
neuroanatomical and physiological plausibility to explain the
increase in the rs-FC observed between these ROIs. In this
sense, the coupling between the respective brain areas rich in ER
seems to represent a neuroplastic adaptation in the correction
of hypogonadism that follows estradiol treatment. The complete
absence of circulating sex hormones might result in functional
decoupling between these regions, which may contribute to the
development of hypogonadal symptoms exhibited post-GAS.
Indeed, Kenna et al. (2008) showed that estrogen therapy in
menopause was associated with an augmentation in functional
connectivity between the thalamus and the striatum (Kenna
et al., 2008). In that study, the authors considered that the
increase in functional connectivity was due the protection of
cholinergic and dopaminergic neurons after estrogenic therapy.
This hypothesis was based on the fact that the two major
neurotransmitters involved in passing information through the
thalamus are acetylcholine and dopamine, which, respectively,
send and receive information to sensory and motor cortex.
In accordance with the hypothesis expounded in Kenna et al.
(2008),Gardiner et al. (2004) had previously proposed a
neuroprotective role for estradiol in the striatal circuit that was
related to dopamine transporters. Using single-photon emission
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Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
computed tomography (SPECT) and [99mTc]TRODAT-1, a
radiopharmaceutical that binds to the presynaptic dopamine
transporter, they demonstrated that 6 weeks of estrogen therapy
increased the number of dopamine transporters in the left
putamen (Gardiner et al., 2004).
Moreover, the thalamus and the dorsal striatum have also
been implicated in deep learning networks. According to
Roelfsema and Holtmaat (2018), part of the deep learning
mechanism depends on the activation of the sensory cortex
following the reception of sensory input from the thalamic relay.
This activation contributes to the establishment of a complex
learning process that involves the integration of forward and
backward information at different layers of the sensory cortex
(Roelfsema and Holtmaat, 2018). In relation to our results, the
demonstration of the coupling between the left thalamus and the
left putamen/left SMC contributes to the current debate about
the potential role of estradiol in synaptic feedback during the
learning process. For instance, the better performance in a finger-
tapping task following estrogen therapy demonstrated by Bayer
and Hausmann (2010) suggests more than only neuroprotective
effects over simple motor function (Bayer and Hausmann, 2010;
Carpenter et al., 2016). It also suggests additional benefits for
motor learning, since learning more complex finger-tapping tasks
depends on incorporating information that arrives from the
SMC (Herrero et al., 2002). Thus, there seems to be a close
relationship between estrogen therapy and functional coupling in
the sensorimotor-thalamus-striatum circuit.
Connectivity in Subcallosal and Medial
Frontal Cortices
Finally, using a classificatory analysis with group-MVPA, we
identified a decreased activity within the SubCalC after 60 days
of estradiol administration. The SubCalC lies under the anterior
cingulate cortex and receives input from the limbic lobe. It
mediates cognitive and emotional processing – making it a
central component of emotional regulation (Mayberg, 2008).
It has also been claimed to be a potential biomarker to
predict neurocognitive outcomes during treatment of depressive
disorders (Dunlop et al., 2017), as well as a potential target for
treatment of resistant depression (Li et al., 2017;McInerney et al.,
2017). Using the SubCalC as a seed to investigate rs-FC in a
seed-to-voxel analysis, we found it to be functionally decoupled
from the medial frontal cortex (MedFC) following estradiol
administration. Interestingly, deactivation of the SubCalC and
portions of the medial frontal cortex was also demonstrated
following recovery from depressive symptoms in individuals who
responded to cognitive behavior therapy (Goldapple et al., 2004;
Li et al., 2017).
During the gender-affirming process, there is an improvement
in depressive symptoms and a reduction in suicidal ideation
associated with the beginning of CSHT (Gorin-Lazard et al.,
2013;da Silva et al., 2016;Tucker et al., 2018). Although these
improvements can be partially assumed to be a consequence
of the reduction of the body incongruence once CSHT
has started, they might also owe to changes in functional
connectivity of areas involved in emotions and cognition.
Comparatively, in non-transgender individuals, shifts in estradiol
and testosterone levels were demonstrated to negatively impact
mood (Gordon et al., 2018;Ng et al., 2018), anxiety (Hwang
et al., 2015), emotional regulation (Syan et al., 2017;Dan et al.,
2018), and cognitive processes (Maki et al., 2001;Berent-Spillson
et al., 2010). In this sense, there is growing evidence supporting
the existence of a relationship between behavioral, affective
and cognitive measures, and changes in brain anatomy and/or
functionality (Berent-Spillson et al., 2010;Albert et al., 2015;Syan
et al., 2017, 2018;Weis et al., 2017;Dan et al., 2018).
Considering the evidence of increased risk for mood and
anxiety disorders in men and women after deprivation of sex
hormones, our data point to an association between estradiol
administration and rs-FC adaptations involved in emotional and
cognitive processes. The emotional improvement seen following
the beginning of CSHT might be linked to the deactivation of
the SubCalC or to the decoupling between the SubCalC and the
MedFC (Gorin-Lazard et al., 2013;Tucker et al., 2018). Further
studies are needed to better understand the effects of CSHT on
mood and emotional regulation in the transgender population.
Nevertheless, the contrast between washout and CSHT examined
here provides a unique model, since very low to absent
concentrations of sex hormones are found after gonadectomy.
This allows us to investigate the impact of CSHT on the brain
without the interference of native gonadal hormones.
Importantly, hormone therapy for transgender women is
currently limited to the same estradiol formulations worldwide,
such as oral estradiol valerate or non-oral transdermal (gel
or patches) 17β-estradiol. Some countries also have parenteral
estradiol valerate or cypionate for intramuscular administration
while others, including Brazil, may still use oral conjugated
equine estrogens. Dosages are individualized according to clinical
response. Women who had already been submitted to GAS
receive estrogen-only treatment (no anti-androgens are added to
estrogen therapy).
This study is the first longitudinal study demonstrating the
impact of CSHT on the rs-FC of the somatosensory cortex after
GAS. In addition, all participants were not taking psychotropic
medications at baseline, as well as they did not meet current
criteria for major psychiatric disorders. Moreover, ROI-to-ROI
and seed-to-voxel whole-brain analyses were convergent in their
findings regarding the SMC. However, the strengths highlighted
above were accompanied by some limitations which must be
considered. For instance, although heart and respiratory rates
were not altered while HAM-A was assessed, these parameters
were not measured during MRI acquisition. Moreover, the
lack of a control group and of appropriate scales to evaluate
hypogonadal symptoms must also be taken into consideration.
The present study was completed using a within-subjects design
(self-controlled) and therefore lacks a comparison group. Ideally,
a control group should include transwomen left on washout
for more 60 days after 30 days of washout (t1), instead of
reintroducing CSHT for new assessments at time point two
(t2). Although the absence of a comparison group reduces
the specificity of our results, this decision was made due to
ethical considerations, as exposing transgendered women to a
longer washout period for experimental purposes would result
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Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
in prolonged exposure to hypogonadism and its consequences.
The lack of relationship between the behavioral measures and
changes in rs-FC might be partially due to which specific
brain areas were priori defined on this study. Further studies
regarding hypogonadism should also take into consideration the
function of brain areas related to mood and anxiety by employing
more specific scales for the phenomena under investigation.
The sample size is modest, which also limits our ability to
perform secondary analyses. Further, this is a pilot study to
test the modulation of CSHT over the somatosensory network
in transgender women post-GAS, and these results must be
carefully analyzed when extrapolating them to transgender men.
Larger studies employing complementary network measure are
also needed to fully explore the network effects of estradiol on
brain connectivity.
In conclusion, in this study, we found that CSHT in
transgender women after GAS impacted rs-FC over the 3 major
systems of the brain: cognitive, emotional and sensorimotor.
Sensorimotor networks and subcallosal cortex seem to respond
to estradiol administration to compensate for deprivation of
sex hormones after gonadectomy in transgender women. These
results suggest that there is a link between CSHT, mental health,
and neuroplasticity in transgender people.
DATA AVAILABILITY
The datasets generated for this study are available on request to
the corresponding author.
ETHICS STATEMENT
This project was approved by the Ethics Review Board of
the Hospital de Clínicas de Porto Alegre (CEP 15-0199). All
participants gave written informed consent according to the
Declaration of Helsinki.
AUTHOR CONTRIBUTIONS
MS, ÂC, and ML designed the study. MS, MA, and KS
acquired the neuroimage. MS, AF, DS, and CG recruited
the participants. MS, AF, DS, CG, FC, and KS acquired
the clinical data. PS and TF performed the endocrinological
consultations. FC and JC performed the psychological evaluation.
MS, SS, LM, and BF performed the neuroimaging analysis.
MS, PS, and ÂC carried out the statistical analysis. MS, SS,
PS, ML, MA, LM, BF, and JC wrote and critically revised the
manuscript. All authors read and approved the final version
of the manuscript.
FUNDING
This work was supported by grants from the Conselho Nacional
de Desenvolvimento Científico e Tecnológico/Brazilian National
Institute of Hormones and Women’s Health (CNPq/INCT
465482/2014-7), Fundo de Incentivo à Pesquisa (FIPE-HPCA),
and Programa Nacional de Pós-Doutorado – Pró-Reitoria de
Extensão (PNPD-PROEX). The funders had no role in study
design, data collection and analysis, decision to publish, or
preparation of the manuscript.
ACKNOWLEDGMENTS
We thank Prof. Walter J. Koff and Mrs. Esalba M. C. Silveira for
their commitment to PROTIG over the last 20 years.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fnins.
2019.00817/full#supplementary-material
FIGURE S1 | Bar plots (A,B) show intraindividual changes in Hamilton’s
depression and anxiety rating scores from time point 1 to time point 2 (t2–t1).
FIGURE S2 | Blue shows brain regions that exhibit decoupled connectivity with
the left thalamus, while red indicates coupled connectivity with the left thalamus.
(A,B) represent respectively, whole-brain connectivity analysis using left thalamus
as seed at t1 and t2, respectively, while (C) show significant changes on functional
connectivity between t1 and t2. Statistical threshold at peak-height <0.001 and
size p-FDR <0.05.
REFERENCES
Albert, K., Pruessner, J., and Newhouse, P. (2015). Estradiol levels modulate brain
activity and negative responses to psychosocial stress across the menstrual
cycle. Psychoneuroendocrinology 59, 14–24. doi: 10.1016/j.psyneuen.2015.
04.022
Alloway, K. D., Smith, J. B., Mowery, T. M., and Watson, G. D. R. (2017). Sensory
processing in the dorsolateral striatum: the contribution of thalamostriatal
pathways. Front. Syst. Neurosci. 11:53. doi: 10.3389/fnsys.2017.00053
Ardelt, A. A., Carpenter, R. S., Lobo, M. R., Zeng, H., Solanki, R. B., Zhang, A.,
et al. (2012). Estradiol modulates post-ischemic cerebral vascular remodeling
and improves long-term functional outcome in a rat model of stroke. Brain Res.
1461, 76–86. doi: 10.1016/j.brainres.2012.04.024
Bai, T., Zu, M., Chen, Y., Xie, W., Cai, C., Wei, Q., et al. (2018). Decreased
connection between reward systems and paralimbic cortex in depressive
patients. Front. Neurosci. 12:462. doi: 10.3389/fnins.2018.00462
Bayer, U., and Hausmann,M. (2010). Hormone therapy in postmenopaus al women
affects hemispheric asymmetries in fine motor coordination. Horm. Behav. 58,
450–456. doi: 10.1016/j.yhbeh.2010.05.008
Beaty, R. E., Benedek, M., Kaufman, S. B., and Silvia, P. J. (2015). Default and
executive network coupling supports creative idea production. Sci. Rep. 5:10964.
doi: 10.1038/srep10964
Behrens, T. E. J., Johansen-Berg, H., Woolrich, M. W., Smith, S. M., Wheeler-
Kingshott, C. A. M., Boulby, P. A., et al. (2003). Non-invasive mapping of
connections between human thalamus and cortex using diffusion imaging. Nat.
Neurosci. 6, 750–757. doi: 10.1038/nn1075
Behzadi, Y., Restom, K., Liau, J., and Liu, T. T. (2007). A component
based noise correction method (CompCor) for BOLD and perfusion
based fMRI. Neuroimage 37, 90–101. doi: 10.1016/j.neuroimage.2007.
04.042
Berent-Spillson, A., Persad, C. C., Love, T., Tkaczyk, A., Wang, H., Reame,
N. K., et al. (2010). Early menopausal hormone use influences brain regions
Frontiers in Neuroscience | www.frontiersin.org 10 August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 11
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
used for visual working memory. Menopause 17, 692–699. doi: 10.1097/gme.
0b013e3181cc49e9
Borich, M. R., Brodie, S. M., Gray, W. A., Ionta, S., and Boyd, L. A. (2015).
Understanding the role of the primary somatosensory cortex: opportunities for
rehabilitation. Neuropsychologia 79, 246–255. doi: 10.1016/j.neuropsychologia.
2015.07.007
Butler, E. G., Horne, M. K., and Rawson, J. A. (1992). Sensory characteristics
of monkey thalamic and motor cortex neurones. J. Physiol. 445, 1–24. doi:
10.1113/jphysiol.1992.sp018910
Carpenter, R. S., Iwuchukwu, I., Hinkson, C. L., Reitz, S., Lee, W., Kukino, A., et al.
(2016). High-dose estrogen treatment at reperfusion reduces lesion volume
and accelerates recovery of sensorimotor function after experimental ischemic
stroke. Brain Res. 1639, 200–213. doi: 10.1016/j.brainres.2016.01.058
Chen, A. C., and Etkin, A. (2013). Hippocampal network connectivity and
activation differentiates post-traumatic stress disorder from generalized
anxiety disorder. Neuropsychopharmacology 38, 1889–1898. doi: 10.1038/npp.
2013.122
Dan, R., Canetti, L., Keadan, T., Segman, R., Weinstock, M., Bonne, O., et al. (2018).
Sex differences during emotion processing are dependent on the menstrual
cycle phase. Psychoneuroendocrinology 100, 85–95. doi: 10.1016/j.psyneuen.
2018.09.032
da Silva, D. C., Schwarz, K., Fontanari, A. M., Costa, A. B., Massuda, R., Henriques,
A. A., et al. (2016). WHOQOL-100 before and after sex reassignment surgery
in Brazilian male-to-female transsexual individuals. J. Sex. Med. 13, 1–6. doi:
10.1016/j.jsxm.2016.03.370
Desikan, R. S., Segonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker,
D., et al. (2006). An automated labeling system for subdividing the human
cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage
31, 968–980. doi: 10.1016/j.neuroimage.2006.01.021
Dunlop, B. W., Rajendra, J. K., Craighead, W. E., Kelley, M. E., McGrath, C. L.,
Choi, K. S., et al. (2017). Functional connectivity of the subcallosal cingulate
cortex and differential outcomes to treatment with cognitive-behavioral therapy
or antidepressant medication for major depressive disorder. Am. J. Psychiatry
174, 533–545. doi: 10.1176/appi.ajp.2016.16050518
Gardiner, S. A., Morrison, M. F., Mozley, P. D., Mozley, L. H., Brensinger, C.,
Bilker, W., et al. (2004). Pilot study on the effect of estrogen replacement therapy
on brain dopamine transporter availability in healthy, postmenopausal women.
Am. J. Geriatr. Psychiatry 12, 621–630. doi: 10.1176/appi.ajgp.12.6.621
Giménez-Amaya, J. M., McFarland, N. R., las Heras de, S., and Haber, S. N. (1995).
Organization of thalamic projections to the ventral striatum in the primate.
J. Comp. Neurol. 354, 127–149. doi: 10.1002/cne.903540109
Goldapple, K., Segal, Z., Garson, C., Lau, M., Bieling, P., Kennedy, S., et al. (2004).
Modulation of cortical-limbic pathways in major depression: treatment-specific
effects of cognitive behavior therapy. Arch. Gen. Psychiatry. 61, 34–41. doi:
10.1001/archpsyc.61.1.34
Gordji-Nejad, A., Matusch, A., Li, S., Kroll, T., Beer,S., Elmenhorst, D., et al. (2018).
Phosphocreatine levels in the left thalamus decline during wakefulness and
increase after a Nap. J. Neurosci. 38, 10552–10565. doi: 10.1523/JNEUROSCI.
0865-18.2018
Gordon, J. L., Rubinow, D. R., Eisenlohr-Moul, T. A., Xia, K., Schmidt, P. J.,
and Girdler, S. S. (2018). Efficacy of transdermal estradiol and micronized
progesterone in the prevention of depressive symptoms in the menopause
transition. JAMA Psychiatry 75, 149–149. doi: 10.1001/jamapsychiatry.2017.
3998
Gorin-Lazard, A., Baumstarck, K., Boyer, L., Maquigneau, A., Penochet, J.-C.,
Pringuey, D., et al. (2013). Hormonal therapy is associated with better self-
esteem, mood, and quality of life in transsexuals. J. Nerv. Ment. Dis. 201,
996–1000. doi: 10.1097/NMD.0000000000000046
Hamilton, M. (1958). The assessment of anxiety states by rating. Br. J. Med. Psychol.
32, 50–55. doi: 10.1111/j.2044-8341.1959.tb00467.x
Hamilton, M. (1959). Hamilton rating scale for depression. J. Neurol. Neurosurg.
Psychiatry 23, 56–62.
Hart, M. G., Price, S. J., and Suckling, J. (2016). Connectome analysis for pre-
operative brain mapping in neurosurgery. Br. J. Neurosurg. 30, 506–517. doi:
10.1080/02688697.2016.1208809
Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer,
W. J., Murad, M. H., et al. (2017). Endocrine treatment of gender-
dysphoric/gender-incongruent persons: an endocrine society clinical practice
guideline. J. Clin. Endocrinol. Metab. 102, 3869–3903. doi: 10.1210/jc.2017-
01658
Herrero, M.-T., Barcia, C., and Navarro, J. M. (2002). Functional anatomy of
thalamus and basal ganglia. Childs Nerv. Syst. 18, 386–404. doi: 10.1007/s00381-
002-0604-1
Hwang, K., Bertolero, M. A., Liu, W. B., and D’Esposito, M. (2017). The human
thalamus is an integrative hub for functional brain networks. J. Neurosci. 37,
5594–5607. doi: 10.1523/JNEUROSCI.0067-17.2017
Hwang, M. J., Zsido, R. G., Song, H., Pace-Schott, E. F., Miller, K. K., Lebron-Milad,
K., et al. (2015). Contribution of estradiol levels and hormonal contraceptives to
sex differences within the fear network during fear conditioning and extinction.
BMC Psychiatry 15:295. doi: 10.1186/s12888-015-0673-9
Kenna, H. A., Rasgon, N. L., Geist, C., Small, G., and Silverman, D. (2008).
Thalamo-basal ganglia connectivity in postmenopausal women receiving
estrogen therapy. Neurochem. Res. 34, 234–237. doi: 10.1007/s11064-008-
9756-z
Kunas, S. L., Yang, Y., Straube, B., Kircher, T., Gerlach, A. L., Pfleiderer, B., et al.
(2018). The impact of depressive comorbidity on neural plasticity following
cognitive-behavioral therapy in panic disorder with agoraphobia. J. Affect.
Disord. 245, 451–460. doi: 10.1016/j.jad.2018.11.026
Lanciego, J. L., Luquin, N., and Obeso, J. A. (2012). Functional neuroanatomy of
the basal ganglia. Cold Spring Harb. Perspect. Med. 2:a009621. doi: 10.1101/
cshperspect.a009621
Lee, H., Park, J., Choi, B., Yi, H., and Kim, S.-S. (2018). Experiences of and barriers
to transition-related healthcare among Korean transgender adults: focus on
gender identity disorder diagnosis, hormone therapy, and sex reassignment
surgery. Epidemiol. Health 40:e2018005. doi: 10.4178/epih.e2018005
Li, Y., Kong, X., Wei, D., Du, X., Sun, J., and Qiu, J. (2017). Self-Referential
processing in unipolar depression_ distinct roles of subregions of the medial
prefrontal cortex. Psychiatry Res. Neuroimaging 263, 8–14. doi: 10.1016/j.
pscychresns.2017.02.008
Mahmoudi, A., Takerkart, S., Regragui, F., Boussaoud, D., and Brovelli, A. (2012).
Multivoxel pattern analysis for fMRI data: a review. Comput. Math. Methods
Med. 2012, 1–14. doi: 10.1155/2012/961257
Maki, P. M., Zonderman, A. B., and Resnick, S. M. (2001). Enhanced verbal
memory in nondemented elderly women receiving hormone-replacement
therapy. Am. J. Psychiatry 158, 227–233. doi: 10.1176/appi.ajp.158.2.227
Mastropasqua, C., Bozzali, M., Spanò, B., Koch, G., and Cercignani, M. (2014).
Functional anatomy of the thalamus as a model of integrated structural and
functional connectivity of the human brain In Vivo.Brain Topogr. 28, 548–558.
doi: 10.1007/s10548-014- 0422-2
Mayberg, H. (2008). Deep brain stimulation for treatment-resistant depression.
J. Affect. Disord. 107:S23. doi: 10.1016/j.jad.2007.12.153
McInerney, S. J., McNeely, H. E., Geraci, J., Giacobbe, P., Rizvi, S. J., Ceniti,
A. K., et al. (2017). Neurocognitive predictors of response in treatment resistant
depression to subcallosal cingulate gyrus deep brain stimulation. Front. Hum.
Neurosci. 11:74. doi: 10.3389/fnhum.2017.00074
Mueller, S. C., Landré, L., Wierckx, K., and T’Sjoen, G. (2017). A structural
magnetic resonance imaging study in transgender persons on cross-sex
hormone therapy. Neuroendocrinology 105, 123–130. doi: 10.1159/000448787
Mueller, S. C., Wierckx, K., Jackson, K., and T’Sjoen, G. (2016). Circulating
androgens correlate with resting-state MRI in transgender men.
Psychoneuroendocrinology 73, 91–98. doi: 10.1016/j.psyneuen.2016.07.212
Muschelli, J., Nebel, M. B., Caffo, B. S., Barber, A. D., Pekar, J. J., and Mostofsky,
S. H. (2014). Reduction of motion-related artifacts in resting state fMRI
using aCompCor. Neuroimage 96, 22–35. doi: 10.1016/j.neuroimage.2014.
03.028
Ng, H. S., Koczwara, B., Roder, D., and Vitry, A. (2018). Development of
comorbidities in men with prostate cancer treated with androgen deprivation
therapy: an Australian population-based cohort study. Prostate Cancer Prostatic
Dis. 21, 403–410. doi: 10.1038/s41391-018- 0036-y
Nguyen, H. B., Loughead, J., Lipner, E., Hantsoo, L., Kornfield, S. L., and Epperson,
C. N. (2018). What has sex got to do with it? the role of hormones in the
transgender brain. Neuropsychopharmacology 44, 22–37. doi: 10.1038/s41386-
018-0140-7
Norman, K. A., Polyn, S. M., Detre, G. J., and Haxby, J. V. (2006). Beyond
mind-reading: multi-voxel pattern analysis of fMRI data. Trends Cogn. Sci. 10,
424–430. doi: 10.1016/j.tics.2006.07.005
Frontiers in Neuroscience | www.frontiersin.org 11 August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 12
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
Nota, N. M., Burke, S. M., Heijer den, M., Soleman, R. S., Lambalk, C. B., Cohen-
Kettenis, P. T., et al. (2017). Brain sexual differentiation and effects of cross-sex
hormone therapy in transpeople: a resting-state functional magnetic resonance
study. Neurophysiol. Clin. 47, 361–370. doi: 10.1016/j.neucli.2017.09.001
Osterlund, M. K., Grandien, K., Keller, E., and Hurd, Y. L. (2000). The human brain
has distinct regional expression patterns of estrogen receptor alpha mRNA
isoforms derived from alternative promoters. J. Neurochem. 75, 1390–1397.
doi: 10.1046/j.1471-4159.2000.0751390.x
Osterlund, M. K., and Hurd, Y. L. (2001). Estrogen receptors in the human
forebrain and the relation to neuropsychiatric disorders. Prog. Neurobiol. 64,
251–267. doi: 10.1016/s0301-0082(00)00059- 9
Peelen, M. V., and Downing, P. E. (2007). Using multi-voxel pattern analysis of
fMRI data to interpret overlapping functional activations. Trends Cogn. Sci. 11,
4–5. doi: 10.1016/j.tics.2006.10.009
Pelzer, E. A., Melzer, C., Timmermann, L., Cramon, D. Y., and Tittgemeyer,
M. (2016). Basal ganglia and cerebellar interconnectivity within the human
thalamus. Brain Struct. Funct. 222, 381–392. doi: 10.1007/s00429-016-
1223-z
Qiu, T. M., Gong, F. Y., Gong, X., Wu, J. S., Lin, C. P., Biswal, B. B., et al.
(2017). Real-Time motor cortex mapping for the safe resection of glioma: an
intraoperative resting-state fMRI study. AJNR Am. J. Neuroradiol. 38, 2146–
2152. doi: 10.3174/ajnr.A5369
Quinn, V. P., Nash, R., Hunkeler, E., Contreras, R., Cromwell, L., Becerra-Culqui,
T. A., et al. (2017). Cohort profile: study of transition, outcomes and gender
(STRONG) to assess health status of transgender people. BMJ Open 7:e18121.
doi: 10.1136/bmjopen-2017- 018121
Rametti, G., Carrillo, B., Gómez-Gil, E., Junque, C., Zubiaurre-Elorza, L.,
Segovia, S., et al. (2012). Effects of androgenization on the white matter
microstructure of female-to-male transsexuals. A diffusion tensor imaging
study. Psychoneuroendocrinology 37, 1261–1269. doi: 10.1016/j.psyneuen.2011.
12.019
Reber, J., and Tranel, D. (2016). Sex differences in the functional lateralization of
emotion and decision making in the human brain. J. Neurosci. Res. 95, 270–278.
doi: 10.1002/jnr.23829
Roelfsema, P. R., and Holtmaat, A. (2018). Control of synaptic plasticity in deep
cortical networks. Nat. Rev. Neurosci. 19, 166–180. doi: 10.1038/nrn.2018.6
Sarasso, E., Agosta, F., Temporiti, F., Adamo, P., Piccolo, F., Copetti, M., et al.
(2017). Brain motor functional changes after somatosensory discrimination
training. Brain Imaging Behav. 12, 1011–1021. doi: 10.1007/s11682-017-
9763-2
Schwarz, K., da Silva, D. C., Costa, A. B., Fontanari, A. M. V., Rosito, T., da Silva,
G. V. M., et al. (2017). Profile of brazilian transsexual women who underwent
gender affirmation surgery. J. Sexual Med. 14:e287. doi: 10.1016/j.jsxm.2017.
04.349
Syan, S. K., Minuzzi, L., Costescu, D., Smith, M., Allega, O. R., Coote, M., et al.
(2017). Influence of endogenous estradiol, progesterone, allopregnanolone, and
dehydroepiandrosterone sulfate on brain resting state functional connectivity
across the menstrual cycle. Fertil. Steril. 107, 1246–1255.e4. doi: 10.1016/j.
fertnstert.2017.03.021
Syan, S. K., Minuzzi, L., Smith, M., Costescu, D., Allega, O. R., Hall, G. B. C.,
et al. (2018). Brain structure and function in women with comorbid bipolar and
premenstrual dysphoric disorder. Front. Psychiatry 8:301. doi: 10.3389/fpsyt.
2017.00301
Taylor, A. H., and Al-Azzawi, F. (2000). Immunolocalisation of oestrogen receptor
beta in human tissues. J. Mol. Endocrinol. 24, 145–155. doi: 10.1677/jme.0.
0240145
Thompson, W. H., Thelin, E. P., Lilja, A., Bellander, B.-M., and Fransson, P. (2016).
Functional resting-state fMRI connectivity correlates with serum levels of the
S100B protein in the acute phase of traumatic brain injury. Neuroimage Clin.
12, 1004–1012. doi: 10.1016/j.nicl.2016.05.005
Tucker, R. P., Testa, R. J., Simpson, T. L., Shipherd, J. C., Blosnich, J. R.,
and Lehavot, K. (2018). Hormone therapy, gender affirmation surgery, and
their association with recent suicidal ideation and depression symptoms
in transgender veterans. Psychol. Med. 48, 2329–2336. doi: 10.1017/
S0033291717003853
Uddin, L. Q., Kelly, A. M., Biswal, B. B., Castellanos, F. X., and Milham,
M. P. (2009). Functional connectivity of default mode network components:
correlation, anticorrelation, and causality. Hum. Brain Mapp. 30, 625–637. doi:
10.1002/hbm.20531
Veale, J. F. (2014). Edinburgh handedness inventory - short form: a revised version
based on confirmatory factor analysis. Laterality 19, 164–177. doi: 10.1080/
1357650X.2013.783045
Weis, S., Hodgetts, S., and Hausmann, M. (2017). Sex differences and menstrual
cycle effects in cognitive and sensory resting state networks. Brain Cogn. 131,
66–73. doi: 10.1016/j.bandc.2017.09.003
Whitfield-Gabrieli, S., and Nieto-Castanon, A. (2012). Conn: a functional
connectivity toolbox for correlated and anticorrelated brain networks. Brain
Connect. 2, 125–141. doi: 10.1089/brain.2012.0073
Yang, J., Yin, Y., Svob, C., Long, J., He, X., Zhang, Y., et al. (2017). Amygdala
atrophy and its functional disconnection with the cortico-striatal-pallidal-
thalamic circuit in major depressive disorder in females. PLoS One 12:e168239.
doi: 10.1371/journal.pone.0168239
Zheng, P. (2009). Neuroactive steroid regulation of neurotransmitter release in
the CNS: action, mechanism and possible significance. Prog. Neurobiol. 89,
134–152. doi: 10.1016/j.pneurobio.2009.07.001
Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2019 Schneider, Spritzer, Minuzzi, Frey, Syan, Fighera, Schwarz, Costa,
da Silva, Garcia, Fontanari, Real, Anes, Castan, Cunegatto and Lobato. This is an
open-access article distributed under the terms of the Creative Commons Attribution
License (CC BY). The use, distribution or reproduction in other forums is permitted,
provided the original author(s) and the copyright owner(s) are credited and that the
original publication in this journal is cited, in accordance with accepted academic
practice. No use, distribution or reproduction is permitted which does not comply
with these terms.
Frontiers in Neuroscience | www.frontiersin.org 12 August 2019 | Volume 13 | Article 817
... However, no significant effects of GHT were observed; neither in the 22 TM as mentioned above nor in 14 TF undergoing antiandrogen and estrogen treatment. Finally, a recent study by tested functional connectivity in the same 18 TF as in Schneider, Spritzer, Suh, et al. (2019) mentioned above. Participants were measured for a baseline scan after a onemonth wash-out phase, and again in a second scan two months after reintroduction of estradiol treatment. ...
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Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female "characteristics" in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.