Elsevier

Psychoneuroendocrinology

Volume 56, June 2015, Pages 190-199
Psychoneuroendocrinology

Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria

https://doi.org/10.1016/j.psyneuen.2015.03.007Get rights and content

Highlights

  • Puberty suppression does not have an effect on ToL performance.

  • Adolescent boys and girls show sex differences in ToL-load related brain activations.

  • GnRHa treated participants with GD show sex differences similar to the control groups.

  • For the untreated participants with GD no significant sex differences were found.

  • Pubertal hormones induced sex-atypical brain activations in adolescents with GD.

Summary

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n = 8) with untreated MFs (n = 10) or when comparing GnRHa treated female-to-males (suppressed FMs, n = 12) with untreated FMs (n = 10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n = 21) than control girls (n = 24) during high task load ToL items in the bilateral precuneus and a trend (p < 0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD.

Introduction

Gender dysphoria (GD) is a condition in which people suffer from an incongruence between their natal sex and their gender identity, i.e. their experienced gender (American Psychiatric Association, 2013). For young individuals with GD, puberty is a period that causes great distress because it is characterized by unwanted physical changes, the development of the secondary sex characteristics. Therefore puberty inhibiting hormones may be prescribed such as the gonadotropin releasing hormone analogs (GnRHa) leuprolide or triptorelin (Gooren and Delemarre-van de Waal, 1996).

Some researchers expressed concerns about the possible disadvantages of GnRHa administration during adolescence (Spriggs, 2004, Viner, 2005, Houk and Lee, 2006, Korte et al., 2008). They fear that it may lead to misdiagnosis or that adolescents cannot make complex life decisions. Moreover, some have questioned whether hormonal suppression affects psychological functioning and if it may entail medical risks. Indeed, during adolescence the brain is still developing. Furthermore, puberty has been suggested to represent a second organizational period during brain development in rodents (Juraska et al., 2013) and in humans (Romeo, 2003, Sisk and Zehr, 2005). The prefrontal cortex (PFC) in particular appears to develop much later than other brain areas (Huttenlocher, 1979). Histological studies suggest that there is a second wave of synaptic proliferation in the PFC at the onset of puberty (Huttenlocher, 1979, Bourgeois et al., 1994, Woo et al., 1997), followed by a plateau phase and synaptic pruning. Executive functioning (EF), which is believed to depend heavily on prefrontal activation, also develops relatively slowly. For instance, performance on the Tower of London task (ToL), a frequently used EF task, improves with age until early adulthood (De Luca et al., 2003, Huizinga et al., 2006, Asato et al., 2006, Albert and Steinberg, 2011).

Since puberty marks an important period in the development of EF, the question arises if pubertal suppression affects this development. Therefore, in the present study, adolescents with GD who received GnRHa to suppress their puberty were compared with a group of control adolescents regarding ToL performance and brain activation patterns (using functional magnetic resonance imaging, fMRI). To check whether potential differences between the groups were due to the suppression (and not due to GD), we also compared them with a group of age matched adolescents with GD who were not – yet – using GnRHa but were already in puberty.

Most of the previous ToL neuroimaging studies did not report – or perhaps did not look for – any sex effects (Owen et al., 1996, Baker et al., 1996, Dagher et al., 1999, Lazeron et al., 2000, Rowe et al., 2001, Van den Heuvel et al., 2003, Newman et al., 2003, Schall et al., 2003, Wagner et al., 2006, Boghi et al., 2006). However, one study reported sex differences in precuneus and dorsolateral prefrontal cortex (DLPFC) activation (Boghi et al., 2006). Therefore we examined sex differences as well.

Furthermore, it has been hypothesized that sexual differentiation of the brain might be different in individuals with GD (Cohen-Kettenis and Gooren, 1999, Van Goozen et al., 2002, Swaab, 2004). Functional neuroimaging studies comparing adults with GD (before the start of treatment) to controls demonstrated that MFs differed from their natal sex in parietal activation during a mental rotation task (Schöning et al., 2010) and showed female-like activity during processing of erotic stimuli (Gizewski et al., 2009) and after exposure to androstadienone, an odorous steroid compound (Berglund et al., 2008). In a verbal fluency study with adolescents performed by our group (Soleman et al., 2013), activation levels of untreated FMs and MFs fell in between those of the control groups. Structural neuroimaging studies have also shown intermediate values in adult FMs and MFs compared to control groups (Rametti et al., 2011a, Rametti et al., 2011b, Kranz et al., 2014) and several structural studies have shown differences between adults with GD and controls sharing their natal sex (Luders et al., 2009, Luders et al., 2012, Simon et al., 2013, Zubiaurre-Elorza et al., 2013, Hoekzema et al., 2015) although another study reported brain volumes largely in line with their natal sex (Savic and Arver, 2011).

As mentioned above, our group has examined the effect of GD on VF performance and brain activation in untreated adolescents (Soleman et al., 2013). Although the VF task may be considered an executive functioning task, the effect of GnRHa treatment on VF performance and brain activation was not investigated. In this study we examined if ToL-related brain activation of adolescents with GD, before start of GnRHa and while on GnRHa, was more in line with that of individuals of their experienced gender or of their natal sex. We believe that the present study is the first to examine the effects of puberty suppression on executive functioning.

Section snippets

Subjects

Adolescents who were diagnosed with Gender Identity Disorder according to the DSM-IV-TR (American Psychiatric Association, 2000) at VU University Medical Center in Amsterdam were recruited (Kreukels and Cohen-Kettenis, 2011). During preparation of this manuscript the DSM-5 was published (American Psychiatric Association, 2013), therefore DSM-5 terminology is used throughout this manuscript.

Forty-one adolescents with GD were included in this study; 22 female-to-males, 12 of which were using

Sample data

No significant age differences were found between the six groups (F(5, 79) = 1.52, NS), but a difference was observed in IQ (F(5, 79) = 2.32, p < .05). Control boys (M) had significantly higher IQ scores than suppressed MFs (p = .03). Tanner stage and handedness did not differ between the groups (p = 0.207 and p = 0.647, respectively). The means and standard deviations of age, IQ and Tanner stage are presented in Table 1. There was no significant difference in duration of suppression between MFs (mean

Discussion

In this study, we aimed to determine whether puberty suppression affected ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) in either MFs or FMs when compared to untreated adolescents with GD. However, suppressed MFs had the lowest accuracy scores, which, as the analysis of covariance pointed out, did not just reflect their IQ scores, which were the lowest as well. It is possible that this is just a chance finding due to the small

Role of the funding source

The funding sources did not play a role in any component of this study.

Conflicts of interest

The authors report no biomedical financial interest or potential conflicts of interest.

Acknowledgements

The authors thank Thomas D. Steensma for his help during several stages of the study and Paul F.C. Groot for his help with the data analysis. This work was supported by an educational grant from Ferring BV, Hoofddorp, and by a VICI grant (453-08-003) from the Dutch Science Foundation (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) to J. Bakker. J. Bakker is a senior research associate of the Belgian Fonds National de la Recherche Scientifique.

References (60)

  • L. Lemieux et al.

    Modelling large motion events in fMRI studies of patients with epilepsy

    Magn. Reson. Imaging

    (2007)
  • E. Luders et al.

    Regional gray matter variation in male-to-female transsexualism

    Neuroimage

    (2009)
  • J.A. Maldjian et al.

    An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets

    Neuroimage

    (2003)
  • S.D. Newman et al.

    Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception

    Neuropsychologia

    (2003)
  • G. Rametti et al.

    White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study

    J. Psychiatr. Res.

    (2011)
  • G. Rametti et al.

    The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study

    J. Psychiatr. Res.

    (2011)
  • J.B. Rowe et al.

    Imaging the mental components of a planning task

    Neuropsychologia

    (2001)
  • U. Schall et al.

    Functional brain maps of Tower of London performance: a positron emission tomography and functional magnetic resonance imaging study

    Neuroimage

    (2003)
  • S. Schöning et al.

    Neuroimaging differences in spatial cognition between men and male-to-female transsexuals before and during hormone therapy

    J. Sex. Med.

    (2010)
  • C.L. Sisk et al.

    Pubertal hormones organize the adolescent brain and behavior

    Front. Neuroendocrinol.

    (2005)
  • R.S. Soleman et al.

    Sex differences in verbal fluency during adolescence: a functional magnetic resonance imaging study in gender dysphoric and control boys and girls

    J. Sex. Med.

    (2013)
  • T.D. Steensma et al.

    Gender identity development in adolescence

    Horm. Behav.

    (2013)
  • O.A. Van den Heuvel et al.

    Frontostriatal system in planning complexity: a parametric functional magnetic resonance version of Tower of London task

    Neuroimage

    (2003)
  • G. Wagner et al.

    The special involvement of the rostrolateral prefrontal cortex in planning abilities: an event-related fMRI study with the Tower of London paradigm

    Neuropsychologia

    (2006)
  • S. Wojniusz et al.

    Prepubertal gonadotropin-releasing hormone analog leads to exaggerated behavioral and emotional sex differences in sheep

    Horm. Behav.

    (2011)
  • T.U. Woo et al.

    Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex

    Neuroscience

    (1997)
  • T.M. Achenbach et al.

    Manual for the Child Behavior Checklist and Revised Child Behavior Profile

    (1983)
  • D. Albert et al.

    Age differences in strategic planning as indexed by the Tower of London

    Child Dev.

    (2011)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2013)
  • Cited by (0)

    1

    These authors shared senior authorship.

    2

    Deceased (February 2014). Delemarre-van de Waal was the principal investigator of this study and has commented on the penultimate version of this manuscript.

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