ArticlePDF Available

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


Abstract and Figures

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.
Content may be subject to copyright.
fnins-13-00817 August 6, 2019 Time: 17:55 # 1
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
Maiko A. Schneider
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
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
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
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
Frontiers in Neuroscience | 1August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 2
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,
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
Frontiers in Neuroscience | 2August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 3
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
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.
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.
Frontiers in Neuroscience | 3August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 4
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
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).
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;
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
Frontiers in Neuroscience | 4August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 5
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
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.
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,
2 (1–4)
Time off CSHT (days,
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
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.
Frontiers in Neuroscience | 5August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 6
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
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
Frontiers in Neuroscience | 6August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 7
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
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.
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
Frontiers in Neuroscience | 7August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 8
Schneider et al. Hypogonadism, Estradiol and Functional Neuroplasticity
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
T (cluster
(04 +26 16)
(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
Frontiers in Neuroscience | 8August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 9
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
Frontiers in Neuroscience | 9August 2019 | Volume 13 | Article 817
fnins-13-00817 August 6, 2019 Time: 17:55 # 10
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.
The datasets generated for this study are available on request to
the corresponding author.
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.
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.
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.
We thank Prof. Walter J. Koff and Mrs. Esalba M. C. Silveira for
their commitment to PROTIG over the last 20 years.
The Supplementary Material for this article can be found
online at:
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.
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.
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.
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 | 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.
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.
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:
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.
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.
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:
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:
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.
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.
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:
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-
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-
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-
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/
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.
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.
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-
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 | 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-
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.
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-
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.
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.
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.
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.
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/
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:
Veale, J. F. (2014). Edinburgh handedness inventory - short form: a revised version
based on confirmatory factor analysis. Laterality 19, 164–177. doi: 10.1080/
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 | 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. ...
Investigating the effects of the gender-affirming hormone treatment of transgender people using neuroimaging provides a unique opportunity to study the impact of high dosages of sex hormones on human brain structure and function. This line of research is of relevance from a basic neuroscientific as well as from a psychiatric viewpoint. Prevalence rates, etiopathology, and disease course of many psychiatric disorders exhibit sex differences which are linked to differences in sex hormone levels. Here, we review recent neuroimaging studies from others and our group that investigate the effects of gender-affirming hormone treatment in a longitudinal design utilizing structural and functional magnetic resonance imaging and positron emission tomography. Studies point to a general anabolic and anticatabolic effect of testosterone on grey and white matter structure, whereas estradiol and antiandrogen treatment seems to have partly opposite effects. Moreover, preliminary research indicates that gender-affirming hormone treatment influences serotonergic neurotransmission, a finding that is especially interesting for psychiatry. A clear picture of a hormonal influence on brain activity has yet to emerge. In conclusion, the available evidence reviewed here clearly indicates that sex hormone applications influence brain structure and function in the adult human brain.
... Furthermore, our results cannot generalize to ages beyond 12-to 17-years-old. Studies on adults have examined cortical structure related to GD [9,26,[102][103][104][105][106][107][108], but we know of no studies examining cortical structure of GD children. Lastly, we examined three cortical structural brain features; other aspects of adolescent GD brain structure (e.g., white matter microstructure) await investigation. ...
Full-text available
Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Sex-differentiated brain regions are hypothesized to reflect the experienced gender in GD and may play a role in sexual orientation development. Magnetic resonance brain images were acquired from 16 GD adolescents assigned female at birth (AFAB) not receiving hormone therapy, 17 cisgender girls, and 14 cisgender boys (ages 12–17 years) to examine three morphological and microstructural gray matter features in 76 brain regions: surface area (SA), cortical thickness (CT), and T1 relaxation time. Sexual orientation was represented by degree of androphilia-gynephilia and sexual attraction strength. Multivariate analyses found that cisgender boys had larger SA than cisgender girls and GD AFAB. Shorter T1, reflecting denser, macromolecule-rich tissue, correlated with older age and stronger gynephilia in cisgender boys and GD AFAB, and with stronger attractions in cisgender boys. Thus, cortical morphometry (mainly SA) was related to sex assigned at birth, but not experienced gender. Effects of experienced gender were found as similarities in correlation patterns in GD AFAB and cisgender boys in age and sexual orientation (mainly T1), indicating the need to consider developmental trajectories and sexual orientation in brain studies of GD.
The majority of studies attempting to address the healthcare needs of the millions of transgender, non-binary, and/or gender diverse (TNG) individuals rely on human subjects, overlooking the benefits of translational research in animal models. Researchers have identified many ways in which gonadal steroid hormones regulate neuronal gene expression, connectivity, activity, and function across the brain to control behavior. However, these discoveries primarily benefit cisgender populations. Research into the effects of exogenous hormones such as estradiol, testosterone, and progesterone has direct translational benefit for TNG individuals on gender affirming hormone therapies (GAHT). Despite this potential, endocrinological healthcare for TNG individuals remains largely unimproved. Here, we outline important areas of translational research that could address the unique healthcare needs of TNG individuals on GAHT. We highlight key biomedical questions regarding GAHT that can be investigated using animal models. We discuss how contemporary research fails to address the needs of GAHT-users and identify equitable practices for cisgender scientists engaging with this work. We conclude that if necessary and important steps are taken to address these issues, translational research on GAHT will greatly benefit the healthcare outcomes of TNG people.
Full-text available
The availability of phosphocreatine (PCr) and the ratio to inorganic phosphate (Pi) in cerebral tissue has been hypothesized a substrate of wakefulness and the exhaustion thereof a substrate of fatigue. We used 31P-magnetic resonance spectroscopy (31P-MRS) to investigate quantitative levels of PCr, the γ-signal of adenosine triphosphate (ATP) and Pi in 30 healthy humans (18 female) in the morning, in the afternoon, and while napping (n = 15) versus wake controls (n = 10).Levels of PCr (2.40 mM at 9 AM) decreased by 7.0 ± 0.8 % (p = 7.1 × 10-6, t = -5.5) in the left thalamus between 9 AM and 5 PM. Inversely, Pi (0.74 mM at 9 AM) increased by 17.1 ± 5 %, (p = .005, t = 3.1) and pH levels dropped by 0.14 ± 0.07 (p = .002; t = 3.6). Following a 20 min nap after 5 PM, local PCr, Pi and pH were restored at morning levels. We did not find respective significant changes in the contralateral thalamus or in other investigated brain regions. Left hemispheric PCr significantly undercut right only at 5 PM in the thalamus but at all conditions in the temporal region.Thus cerebral daytime- and sleep-related molecular changes are accessible in vivo Prominent changes were identified in the thalamus. This region is highly loaded with a series of energy consuming tasks such as the relay of sensory information to the cortex. Furthermore, our data underline that lateralization of brain function is regionally dynamic and includes PCr.SIGNIFICANCE STATEMENTThe metabolites phosphocreatine (PCr) and inorganic phosphate (Pi) are assumed to inversely reflect the cellular energy load. This study detected a diurnal decrease of intracellular PCr and a nap associated re-increase in the left thalamus. Pi behaved inversely. This outcome corroborates the role of the thalamus as a region of high energy consumption in agreement with its function as a gateway, relaying and modulating the information flow. Conversely to the dynamic lateralization of thalamic PCr, a constantly significant lateralization was observed in other regions. Increasing fatigability in the course of the day may be also a matter of cerebral energy supply and the comparatively fast restoration thereof contribute a biological basis for the recreational value of "power napping".
Full-text available
Despite decades of research on depression, the underlying pathophysiology of depression remains incompletely understood. Emerging evidence from task-based studies suggests that the abnormal reward-related processing contribute to the development of depression. It is unclear about the function pattern of reward-related circuit during resting state in depressive patients. In present study, seed-based functional connectivity was used to evaluate the functional pattern of reward-related circuit during resting state. Selected seeds were two key nodes in reward processing, medial orbitofrontal cortex (mOFC) and nucleus accumbens (NAcc). Fifty depressive patients and 57 healthy participants were included in present study. Clinical severity of participants was assessed with Hamilton depression scale and Hamilton anxiety scale. We found that compared with healthy participants, depressive patients showed decreased connectivity of right mOFC with left temporal pole (TP_L), right insula extending to superior temporal gyrus (INS_R/STG) and increased connectivity of right mOFC with left precuneus. Similarly, decreased connectivity of left mOFC with TP_L and increased connectivity with cuneus were found in depressive patients. There is also decreased connectivity of right NAcc with bilateral temporal pole, as well as decreased connectivity of left NAcc with INS_R/STG. In addition, the functional connectivity of right nucleus accumbens with right temporal pole (TP_R) was negatively correlated with clinical severity. Our results emphasize the role of communication deficits between reward systems and paralimbic cortex in the pathophysiology of depression.
Full-text available
Women are particularly vulnerable to anxiety and depressive disorders. This greater vulnerability has been partly attributed to post-pubertal sex hormone fluctuations, estradiol and progesterone, as well as gender-specific tendencies to engage in maladaptive forms of emotion regulation, particularly rumination. To date, no research has investigated whether sex hormones are associated with emotion regulation in women. In the present study, 61 women participated in a sad mood induction task, involving the viewing of an emotive film. Negative affect was assessed immediately and following recovery, along with self-reported use of rumination, reappraisal, and suppression. Serum levels of estradiol and progesterone were assessed through a blood sample taken at the end of the experiment. Regression analyses were used to examine the relationship between serum hormones and self-reported emotional regulation strategy use, and between serum hormones and the impact of these strategies on negative affect. Estradiol levels positively predicted rumination, but not suppression or reappraisal use. Moreover, estradiol and progesterone interacted with emotion regulation strategies to predict negative affect following the sad mood induction. Reappraisal was associated with greater negative affect only in women with high estradiol, and in women with high progesterone. Conversely, rumination was associated with greater negative affect only in women with low estradiol. Together, these results suggest that sex hormone concentration may be an endogenous contextual factor that is associated with the selection and consequences of emotion regulation strategies in women.
Full-text available
Background The increasing use of androgen deprivation therapy has prompted further evaluation of its potential adverse effects as the treatment may exacerbate or increase the risk of developing new comorbid diseases. This study aims to assess the patterns of comorbidities among Australian men with prostate cancer treated with androgen deprivation therapy. Methods Pharmaceutical Benefits Scheme (PBS) 10% data between 1 January 2003 and 31 December 2014 was utilised in this retrospective cohort study. Men who had received their first androgen deprivation therapy between 2004 and 2010 were selected as the prostate cancer cohort. Comorbidities were identified using the dispensing claims data and classified with the Rx-Risk-V model. Comparisons were made between the prostate cancer cohort and specific control groups (age-matched and sex-matched without any dispensing of anti-neoplastic agents during the study period and without the individual comorbidity of interest evaluated at baseline at 1:10 ratio) for the development of nine individual comorbidities over time using Cox regression models. Results The prostate cancer cohort had a significant higher risk of developing cardiovascular conditions (hazard ratio 1.37, 95% CI: 1.26–1.48), depression (1.86, 95% CI: 1.73–2.01), diabetes (1.30, 95% CI: 1.15–1.47), gastric acid disorders (1.48, 95% CI: 1.39–1.57), hyperlipidaemia (1.18, 95% CI: 1.09–1.29), osteoporosis (1.65, 95% CI: 1.48–1.85) and pain/pain-inflammation (1.47, 95% CI: 1.39–1.55) compared to the control groups. The hazard ratios for cardiovascular conditions and depression were highest in the first year and declined over time. There were no significant differences between the two groups for reactive airway diseases and Alzheimer’s disease. Conclusion Men with prostate cancer treated with androgen deprivation therapy had a higher likelihood of developing new comorbidities than men who did not receive androgen deprivation therapy. Our results support the need for developing coordinated care models that effectively address multiple chronic diseases experienced by prostate cancer survivors.
Full-text available
Objective: The effects of 2 frequently used formulations of menopausal hormone therapy (mHT) on brain structure and cognition were investigated 3 years after the end of a randomized, placebo-controlled trial in recently menopausal women with good cardiovascular health. Methods: Participants (aged 42-56 years; 5-36 months past menopause) were randomized to one of the following: 0.45 mg/d oral conjugated equine estrogen (oCEE); 50 μg/d transdermal 17β-estradiol (tE2); or placebo pills and patch for 4 years. Oral progesterone (200 mg/d) was given to mHT groups for 12 days each month. MRIs were performed at baseline, at the end of 4 years of mHT, and 3 years after the end of mHT (n = 75). A subset of participants also underwent Pittsburgh compound B-PET (n = 68). Results: Ventricular volumes increased more in the oCEE group compared to placebo during the 4 years of mHT, but the increase in ventricular volumes was not different from placebo 3 years after the discontinuation of mHT. Increase in white matter hyperintensity volume was similar in the oCEE and tE2 groups, but it was statistically significantly greater than placebo only in the oCEE group. The longitudinal decline in dorsolateral prefrontal cortex volumes was less in the tE2 group compared to placebo, which correlated with lower cortical Pittsburgh compound B uptake. Rates of global cognitive change in mHT groups were not different from placebo. Conclusions: The effects of oCEE on global brain structure during mHT subside after oCEE discontinuation but white matter hyperintensities continue to increase. The relative preservation of dorsolateral prefrontal cortical volume in the tE2 group over 7 years indicates that mHT may have long-term effects on the brain. Classification of evidence: This study provides Class III evidence that the rates of change in global brain volumes and cognitive function in recently menopausal women receiving mHT (tE2 or oCEE) were not significantly different from women receiving placebo, as measured 3 years after exposure to mHT.
Full-text available
Objectives: Previous literature has documented that transgender people may encounter barriers when they use transition-related healthcare services. This study aims to investigate the experiences of transition-related healthcare and the barriers to those services among transgender adults in South Korea. Methods: In 2017, we conducted a nationwide cross-sectional survey of 278 transgender adults in South Korea. We assessed the prevalence of transition-related healthcare such as Gender Identity Disorder (GID) diagnosis, hormone therapy, and sex reassignment surgery. To understand the barriers to those procedures, we asked the participants for their reason not to receive each of the three procedures. We also examined their experiences of and reasons for using non-prescribed hormone medication. Results: We found that 91.0% have been diagnosed with GID (N=253/278), 88.0% have received hormone therapy (N=243/276), and 42.4% had any type of sex reassignment surgery (N=115/271). Cost was the most common barrier to transition-related healthcare among the Korean transgender adults. Other common barriers were identified: Negative experiences in healthcare settings, lack of healthcare professionals and facilities, and social stigma against transgender people. Among those who have taken hormone therapy, 25.1% (N=61/243) reported that they had experience of purchasing hormone medication without medical prescription. Conclusion: Our findings suggest that transgender people face barriers to transition-related healthcare in South Korea. These barriers may preclude transgender individuals from safely accessing to transition-related healthcare. Improving access to transition-related healthcare requires institutional interventions including expanding national health insurance coverage on those procedures and providing transition-related training programs for healthcare professionals in South Korea.
Full-text available
Humans and many other animals have an enormous capacity to learn about sensory stimuli and to master new skills. However, many of the mechanisms that enable us to learn remain to be understood. One of the greatest challenges of systems neuroscience is to explain how synaptic connections change to support maximally adaptive behaviour. Here, we provide an overview of factors that determine the change in the strength of synapses, with a focus on synaptic plasticity in sensory cortices. We review the influence of neuromodulators and feedback connections in synaptic plasticity and suggest a specific framework in which these factors can interact to improve the functioning of the entire network.
Background:: Depressive disorders are a frequent comorbidity of panic disorder with agoraphobia (PD/AG). Cognitive-behavioral therapy (CBT) for PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbidities. However, as depressive comorbidities can confound fear circuitry activation (i.e. amygdalae, insulae, anterior cingulate cortex) in PD/AG, we investigated whether comorbid depressive disorders alter neural plasticity following CBT. Methods:: Within a randomized, controlled clinical trial on exposure-based CBT, forty-two PD/AG patients including fifteen (35.7%) with a comorbid depressive disorder (PD/AG + DEP) participated in a longitudinal functional magnetic resonance imaging (fMRI) study. A differential fear conditioning task was used as probe of interest. A generalized psycho-physiological interaction analysis (gPPI) served to study functional connectivity patterns. Results:: After CBT, only PD/AG patients without comorbid depressive disorders (PD/AG-DEP) showed reduced activation in the left inferior frontal gyrus (IFG) extending to the insula. While PD/AG-DEP patients showed enhanced functional connectivity (FC) between the left IFG and subcortical structures (anterior cingulate cortex, thalamus and midbrain), PD/AG + DEP patients exhibited increased FC between the left IFG and cortical structures (prefrontal, parietal regions). In both groups, FC decreased following CBT. Limitations:: Primary depressed and medicated patients were excluded. Major depression and dysthymia were collapsed. Conclusions:: Reduced activation in the left IFG, as previously shown in PD/AG, appears to be a specific substrate of CBT effects in PD/AG-DEP patients only. Differential patterns of FC pertaining to fear circuitry networks in patients without depression vs. cognitive networks in patients with comorbid depression may point towards different pathways recruited by CBT as a function of comorbidity.
Sex differences in the neural processing of emotion are of special interest considering that mood and anxiety disorders predominant in females. However, these sex-related differences were typically studied without considering the hormonal status of female subjects, although emotion processing in the brain was shown to differ between phases of the menstrual cycle. In this functional MRI study, we demonstrated the influence of the menstrual cycle phase on sex differences in brain activity and functional connectivity during negative and positive emotions, using two different paradigms: emotion perception and emotion experience. Twenty naturally cycling healthy women without premenstrual symptoms were scanned twice: during the mid-follicular and late-luteal menstrual phases, and compared to a matched group of twenty healthy men. During negative emotion perception, men showed increased neural activity in the right hippocampal formation relative to women in the mid-follicular phase, and increased activity in the right cerebellum relative to women in the late-luteal phase. During experience of amusement, reduced putamen-ventrolateral prefrontal cortex and putamen-dorsomedial prefrontal cortex functional connectivity were observed for women in the late-luteal phase relative to men and associated with levels of sex hormones. These neural and hormonal findings were complemented by behavioral reports of reduced amusement and increased sadness in late-luteal women. Our results demonstrate menstrual phase-dependent sex differences in emotion perception and experience and may suggest a biological tendency for a deficient experience of pleasure and reward during the late-luteal phase. These findings may further shed light on the underlying pathophysiology of premenstrual dysphoric disorder.
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.