Sex steroids and connectivity in the human brain: A review of neuroimaging studies

Institute of Psychology, Brain and Development Laboratory, Leiden University, Leiden, The Netherlands.
Psychoneuroendocrinology (Impact Factor: 4.94). 06/2011; 36(8):1101-13. DOI: 10.1016/j.psyneuen.2011.05.004
Source: PubMed


Our brain operates by the way of interconnected networks. Connections between brain regions have been extensively studied at a functional and structural level, and impaired connectivity has been postulated as an important pathophysiological mechanism underlying several neuropsychiatric disorders. Yet the neurobiological mechanisms contributing to the development of functional and structural brain connections remain to be poorly understood. Interestingly, animal research has convincingly shown that sex steroid hormones (estrogens, progesterone and testosterone) are critically involved in myelination, forming the basis of white matter connectivity in the central nervous system. To get insights, we reviewed studies into the relation between sex steroid hormones, white matter and functional connectivity in the human brain, measured with neuroimaging. Results suggest that sex hormones organize structural connections, and activate the brain areas they connect. These processes could underlie a better integration of structural and functional communication between brain regions with age. Specifically, ovarian hormones (estradiol and progesterone) may enhance both cortico-cortical and subcortico-cortical functional connectivity, whereas androgens (testosterone) may decrease subcortico-cortical functional connectivity but increase functional connectivity between subcortical brain areas. Therefore, when examining healthy brain development and aging or when investigating possible biological mechanisms of 'brain connectivity' diseases, the contribution of sex steroids should not be ignored.

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    • "It is noteworthy that elevated levels of progesterone during fetal development not only play an important role in the maturation of neuronal connections [32], but that progesterone and its metabolite allopregnanolone also protect the vulnerable fetal brain against insults such as hypoxia and hypoglycemia [33] [34] (for review: [6]). As developmental processes are recapitulated after injury, we may expect progesterone to also exert protective and regenerative effects in the adult CNS [35] [36]. "
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    ABSTRACT: Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of progesterone for brain disorders, including traumatic brain injury (TBI). In addition, this steroid has major assets: it easily crosses the blood-brain-barrier, rapidly diffuses throughout the brain and exerts multiple beneficial effects by acting on many molecular and cellular targets. Moreover, progesterone therapies are well tolerated. Notably, increased brain levels of progesterone are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for TBI and stroke patients. The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of progesterone in TBI patients then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 TBI patients enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, progesterone would have become the first efficient neuroprotective drug for brain-injured patients. Thus, progesterone has joined the numerous neuroprotective candidates that have failed in clinical trials. The aim of this review is a reappraisal of the preclinical animal studies, which provided the proof of concept for the clinical trials, and we critically examine the design of the clinical studies. We made efforts to present a balanced view of the strengths and limitations of the translational studies and of some serious issues with the clinical trials. We place particular emphasis on the translational value of animal studies and the relevance of TBI biomarkers. The probability of failure of ProTECT III and SyNAPSE was very high, and we present them within the broader context of other unsuccessful trials.
    Full-text · Article · Nov 2015 · The Journal of steroid biochemistry and molecular biology
    • "Men are hypothesized to show higher amygdala subnuclei RSFC to the prefrontal cortex, which is involved in emotion regulation. Additionally, in line with the results of higher functional connectivity (Peper et al., 2011) and fear extinction memory (Zeidan et al., 2011) with elevated levels of estrogen, we hypothesize women with higher estrogen levels to have a generally higher amygdala subnuclei RSFC, including higher connectivity to the prefrontal cortex. Conversely, women with lower estrogen levels are hypothesized to show higher connectivity to the ACC. "
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    ABSTRACT: The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.
    No preview · Article · Sep 2015 · Psychoneuroendocrinology
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    • "Consistent with these non-human animal studies, exogenous testosterone administration in humans augments ventral striatum activity to financial reward cues (Hermans et al. 2010; Op de Macks et al. 2011), and ventral striatum activity positively correlates with subjective pleasure responses to successful performance in competition (e.g., watching one's team play favorably) as well as aggressive motivation towards opponents (Cikara et al. 2011). This cross-species evidence converges to suggest that a dynamic testosterone increase after a decisive victory may enhance future competitive behavior and subjective task enjoyment through testosterone's effects on reward regions such as the ventral striatum (but other possible neural mechanisms include changes in amygdala, prefrontal cortex, or amygdala-prefrontal cortex connectivity, Peper et al. 2011). Although our study revealed a positive association between testosterone change and decisions to compete in the decisive victory condition, there was a surprising negative association between testosterone change and the propensity to compete against a new opponent in the close victory condition that was accompanied by a similar pattern for task enjoyment (striped lines in Figs. "
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    ABSTRACT: Prior research found that testosterone change after defeat predicted the decision to compete against the same opponent, but testosterone change after victory was unrelated to competitive behavior. The present research tested whether testosterone responses have differential effects on competitive decision-making depending on whether an individual either barely or decisively won a competition. Seventy-one undergraduate males provided an afternoon saliva sample and then participated in a laboratory cognitive contest in which they were randomly assigned to experience a relatively close or decisive victory against a male confederate. Participants provided a second saliva sample after the competition and then chose whether to: (a) compete against the same opponent, (b) compete against a new opponent, or (c) complete an alternative non-competitive task. Participants also reported how much they enjoyed the competitive task. Testosterone change and the propensity to compete were positively related after a decisive victory, but were negatively related after a close victory. These effects were driven by the decision to compete against a new opponent. In fact, very few participants chose to compete against the same opponent. Testosterone change after a decisive victory was also positively associated with participants’ self-reported enjoyment of the competitive task. Together, these results provide new evidence that a close versus decisive victory moderates the effect of testosterone change on future competitive behavior, an effect that may be linked to changes in reward processing systems.
    Full-text · Article · Sep 2015
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