Androgen Modulation of Hippocampal Structure and Function

Atwi, Sarah; McMahon, Dallan; Scharfman, Helen E.; MacLusky, Neil J.

doi:10.1177/1073858414558065

Cited by 68 publications

(53 citation statements)

References 142 publications

(200 reference statements)

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“…Low levels of androgens are involved in a large number of neurodegenerative disorders [ 193 , 194 ]. Testosterone has an important neuroprotective effect [ 195 ], and modulates hippocampal structures, and functions [ 196 ] with a sexual differentiation manner, because in females, hippocampus neurogenesis and cell death is regulated by estrogen [ 197 ]. Androgens stimulate motoneurons and axons’ extension and regeneration [ 198 , 199 ].…”

Section: Discussionmentioning

confidence: 99%

Neurotrophic and Neuroregenerative Effects of GH/IGF1

Bianchi¹,

Locatelli

Rizzi

2017

IJMS

161

109

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Introduction. Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects. Methods. In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: “GH/IGF-1” associated with “neuroregeneration”, “amyotrophic lateral sclerosis”, “Alzheimer disease”, “Parkinson’s disease”, “brain”, and “neuron”. Results. Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results. Conclusions. Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.

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Section: Discussionmentioning

confidence: 99%

Neurotrophic and Neuroregenerative Effects of GH/IGF1

Bianchi¹,

Locatelli

Rizzi

2017

IJMS

161

109

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“…Testosterone is metabolized to the androgen receptor ligand dihydrotestosterone, as well as 5α-androstane-3α17β-diol, a positive allosteric modulator of the GABA A receptor. Loss of the latter would potentially lead to increased excitability (Atwi et al 2015; Scharfman and MacLusky 2014a). Recently it has been shown that estrogen binds to ERα in area CA1 and suppresses GABAergic inhibition via endocannabinoid release, a mechanism which is sexually differentiated (Tabatadze et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Expansion of mossy fibers and CA3 apical dendritic length accompanies the fall in dendritic spine density after gonadectomy in male, but not female, rats

et al. 2016

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Androgen loss is an important clinical concern because of its cognitive and behavioral effects. Changes in androgen levels are also suspected to contribute to neurological disease. However, the available data on the effects of androgen deprivation in areas of the brain that are central to cognition, like the hippocampus, are mixed. In this study, morphological analysis of pyramidal cells was used to investigate if structural changes could potentially contribute to the mixed cognitive effects that have been observed after androgen loss in males. Male Sprague–Dawley rats were orchidectomized or sham-operated. Two months later, their brains were Golgi-impregnated for morphological analysis. Morphological endpoints were studied in areas CA3 and CA1, with comparisons to females either intact or 2 months after ovariectomy. CA3 pyramidal neurons of orchidectomized rats exhibited marked increases in apical dendritic arborization. There were increases in mossy fiber afferent density in area CA3, as well as robust enhancements to dendritic structure in area CA3 of orchidectomized males, but not in CA1. Remarkably, apical dendritic length of CA3 pyramidal cells increased, while spine density declined. By contrast, in females overall dendritic structure was minimally affected by ovariectomy, while dendritic spine density was greatly reduced. Sex differences and subfield-specific effects of gonadal hormone deprivation on the hippocampal circuitry may help explain the different behavioral effects reported in males and females after gonadectomy, or other conditions associated with declining gonadal hormone secretion.

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“…Additionally, the effects of testosterone upon BDNF levels have been found to vary among the sub-regions of the hippocampus. Specifically, castration increased BDNF levels within the mossy fibers extending from the dentate gyrus to the CA3 layer of the hippocampus [186,187], which directly contradicts the hypothesis that testosterone is up-regulating BDNF in the dentate gyrus to, in turn, enhance adult neurogenesis. However, castration decreased BDNF production within CA1 layer of the hippocampus [188], which also has high levels of androgen receptors, suggesting that testosterone may enhance neurogenesis through indirect mechanisms involving enhanced CA1 plasticity.…”

Section: Possible Molecular Pathways Within the Hippocampusmentioning

confidence: 82%

Testosterone and Adult Neurogenesis

Spritzer

Roy

2020

Biomolecules

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It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear. There is considerable evidence that steroid hormones modulate various stages of adult neurogenesis, and this review provides a focused summary of the effects of testosterone on adult neurogenesis. Initial evidence came from field studies with birds and wild rodent populations. Subsequent experiments with laboratory rodents have tested the effects of testosterone and its steroid metabolites upon adult neurogenesis, as well as the functional consequences of induced changes in neurogenesis. These experiments have provided clear evidence that testosterone increases adult neurogenesis within the dentate gyrus region of the hippocampus through an androgen-dependent pathway. Most evidence indicates that androgens selectively enhance the survival of newly generated neurons, while having little effect on cell proliferation. Whether this is a result of androgens acting directly on receptors of new neurons remains unclear, and indirect routes involving brain-derived neurotrophic factor (BDNF) and glucocorticoids may be involved. In vitro experiments suggest that testosterone has broad-ranging neuroprotective effects, which will be briefly reviewed. A better understanding of the effects of testosterone upon adult neurogenesis could shed light on neurological diseases that show sex differences.

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Androgen Modulation of Hippocampal Structure and Function

Cited by 68 publications

References 142 publications

Neurotrophic and Neuroregenerative Effects of GH/IGF1

Neurotrophic and Neuroregenerative Effects of GH/IGF1

Expansion of mossy fibers and CA3 apical dendritic length accompanies the fall in dendritic spine density after gonadectomy in male, but not female, rats

Testosterone and Adult Neurogenesis

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