Daniela Ostatníková

On the effects of testosterone on brain behavioral functions

Testosterone influences the brain via organizational and activational effects. Numerous relevant studies on rodents and a few on humans focusing on specific behavioral and cognitive parameters have been published. The results are, unfortunately, controversial and puzzling. Dosing, timing, even the application route seem to considerably affect the outcomes. In addition, the methods used for the assessment of psychometric parameters are a bit less than ideal regarding their validity and reproducibility. Metabolism of testosterone contributes to the complexity of its actions. Reduction to dihydrotestosterone by 5-alpha reductase increases the androgen activity; conversion to estradiol by aromatase converts the androgen to estrogen activity. Recently, the non-genomic effects of testosterone on behavior bypassing the nuclear receptors have attracted the interest of researchers. This review tries to summarize the current understanding of the complexity of the effects of testosterone on brain with special focus on their role in the known sex differences.

The anxiolytic effect of testosterone in the rat is mediated via the androgen receptor.

Endogenous and exogenous testosterone affects several behavioural traits as shown in human and animal studies. The effects of testosterone can be mediated via androgen or oestrogen receptors, but also via rapid non-genomic effects. The aim of this study was to evaluate whether a single testosterone injection has effects, mediated via the androgen receptor, on anxiety in intact male rats. We hypothesised that administration of testosterone will have an anxiolytic effect, mediated by the androgen receptor. Intact adult male Wistar rats were divided into groups: control, flutamide, testosterone and testosterone with flutamide. Testosterone and flutamide (as an androgen receptor blocker) were applied once, intramuscularly, at a dose of 5mg/kg. Twenty four hours later, rats underwent the following behavioural tests to analyse anxiety: open field test, elevated plus maze and light-dark box. Testosterone was measured in plasma to confirm elevated levels in groups that received testosterone. The levels of testosterone were 2.5-3 fold higher amongst rats administered with testosterone compared to controls. Flutamide did not affect plasma testosterone concentrations. Testosterone administration had no effect on anxiety in the open field and elevated plus maze. In the light-dark transition task, testosterone increased the time spent in the light part of the maze by 80%, an effect which was blocked by flutamide, and which was in support of our hypothesis. Flutamide-treated rats spent more time in the central square of the open field. Using the light-dark box we have shown that a single injection of testosterone decreases anxiety in adult male rats. This effect of increased testosterone was mediated via the androgen receptor as flutamide blocked the anxiolytic effect of exogenous testosterone. Treatment with flutamide blocked the effects of endogenous testosterone and had anxiolytic effects in the open field, suggesting a non-linear relationship between genomic effects of T and anxiety.

Polymorphisms of candidate genes in Slovak autistic patients.

Autism is one of the most genetically influenced neuropsychiatric disorders. However, its detailed genetic basis is far from being clear. Genome-wide association studies have revealed a number of candidate genes, mostly related to synaptogenesis and various neuroendocrine pathways. In our study we have focused on oxytocin (OT), oxytocin receptor (OXTR), GABA receptor gamma 3 (GABRG3), neuroligin (NLGN4X), and reelin (RELN). After signed consent, 90 autistic boys and 85 healthy controls were enrolled in the study. Polymorphisms of OT (rs2740204), OXTR (rs2228485), GABRG3 (rs28431127), and NLGN4X (rs5916338) were analyzed using restriction fragment length polymorphism. (GGC)n STR polymorphism in the 5′ UTR of the RELN gene was genotyped using fragment analysis. The only significant association in autistic boys in Slovakia was found with higher number of GGC repeats in the RELN gene (P=0.001) potentially explaining lower RELN levels in blood and brain of autistic patients.

Reelin and its complex involvement in brain development and function

Reelin is a neuroprotein with crucial role during neurodevelopment and also in postnatal period. It regulates neuronal migration and positioning in developing neocortex and cerebellar cortex. Postnatally it participates in regulation of dendritic and axonal growth, synaptogenesis, neurotransmission and it contribute to synaptic plasticity necessary for learning and memory functions. Role of Reelin seems to be rather complex, profound research gradually uncovers its further functions. Deficits of Reelin were detected in neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism. Pathogenesis of these disorders is far from being clearly understood. Reelin contribution to these diseases seems to be vital, since genetic variants of Reelin were associated with these diseases and often influence symptom severity. Reelin is a promising candidate molecule with potential future use in diagnostics and therapy, however further detailed research is essential.

Ubiquinol Improves Symptoms in Children with Autism

Background. Autism is a spectrum of neurodevelopmental disorders with manifestation within 3 years after birth. Manifestations of autism include behavior problems (hyperactivity, toys destruction, self-harm, and agression) and sleep and eating disorders. Etiology of autism is poorly understood. Oxidative stress and antioxidants can participate in pathobiochemical mechanisms of autism. Methods. Twenty-four children, aged 3–6 years, with autism according to the DSM IV criteria and using CARS were included in the study. Concentrations of CoQ10−TOTAL, γ- and α-tocopherol, β-carotene, and lipid peroxidation were determined in plasma before and after three months of supportive therapy with ubiquinol at a daily dose 2 × 50 mg. Data on behavior of the children were collected from parents at the same time. Results. Ubiquinol supportive therapy improved symptoms in children with autism, as communication with parents (in 12%), verbal communication (in 21%), playing games of children (in 42%), sleeping (in 34%), and food rejection (in 17%), with CoQ10−TOTAL plasma level above 2.5 μmol/L. Conclusions. Beneficial effect of ubiquinol in children with autism has been demonstrated for the first time. We assume that plasma concentration of CoQ10−TOTAL and lipid peroxidation could be used as relevant biomarkers of ubiquinol supportive therapy.

Monosodium Glutamate Toxic Effects and Their Implications for Human Intake: A Review

Monosodium Glutamate (MSG) is one of the world’s most widely used food additives. Its toxic effects have been shown in numerous animal studies, however in most of them, the method of administration and the doses were not similar to human MSG intake. In this paper we review animal and human studies in which MSG effects on central nervous system, adipose tissue and liver, reproductive organs and other systems have been shown and we discuss their implications for human MSG intake.

Endocrine and cognitive effects of short-time soybean consumption in women.

Background: Soy phytoestrogens are known to influence the hormonal status acting as partial estrogen agonists. Soy-derived food supplements are advised for hormone replacement therapy, prevention of atherosclerosis, age-related cognitive decline and even hormone-dependent cancer, although results from clinical studies are controversial. Whether increased soybean intake can affect the endocrine status and cognitive abilities is largely unknown. Aim: To observe the effects of 1 week of increased soybean intake on sex hormone levels and spatial cognitive abilities in women. Subjects and Methods: 16 young healthy female volunteers were asked to eat 900 g of soybeans within 1 week. Salivary testosterone (T), free and total plasma T, salivary and plasma estradiol (E) were measured by radioimmunoassay before and after the study period. Mental rotation (MR) and spatial visualization (SV) psychological tests were done at the days of sampling. Results: Soybean intake increased total plasma T levels (p < 0.02) while decreasing salivary T (p < 0.01) and not altering free plasma T levels. Salivary and plasma E levels were not changed. The results of MR and SV tests were improved after the study period. Conclusion: Short-time increased soybean intake alters the level of total plasma and salivary T and improves spatial cognition in women. Whether this effect is mediated by modulation of estrogen receptors, changes in sex hormone-binding globulin production or changes in activity of steroid-competent enzymes needs further study.

The Effect of Testosterone on the Formation of Brain Structures

It has been confirmed in several studies that testosterone can significantly affect brain development. Following metabolism of this hormone by 5α-reductase to dihydrotestosterone, testosterone may act via androgen receptors, or after conversion by aromatase to estradiol, it may act via estrogen receptors. The parts of the brain which are changed under the influence of sex hormones are known as sexually dimorphic nuclei, especially in the preoptic area of the hypothalamus. Nevertheless, evidence suggests that testosterone also influences the structure of the hippocampus, specifically CA1 and CA3 areas of the hippocampus, as well as the amygdala. These brain areas are designed to convert information from short-term into long-term memory. In this review, we summarize the effects of testosterone on the organization of brain structures with respect to spatial cognitive abilities in small rodents.

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis

Abstract Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.

The effects of saliva collection, handling and storage on salivary testosterone measurement

Several endocrine parameters commonly measured in plasma, such as steroid hormones, can be measured in the oral fluid. However, there are several technical aspects of saliva sampling and processing that can potentially bias the validity of salivary testosterone measurement. The aim of this study was to evaluate the effects caused by repeated sampling; 5 min centrifugation (at 2000, 6000 or 10,000g); the stimulation of saliva flow by a cotton swab soaked in 2% citric acid touching the tongue; different storage times and conditions as well as the impact of blood contamination on salivary testosterone concentration measured using a commercially available ELISA kit. Fresh, unprocessed, unstimulated saliva samples served as a control. Salivary testosterone concentrations were influenced neither by repeated sampling nor by stimulation of salivary flow. Testosterone levels determined in samples stored in various laboratory conditions for time periods up to 1 month did not differ in comparison with controls. For both genders, salivary testosterone levels were substantially reduced after centrifugation (men F=29.1; women F=56.17, p<0.0001). Blood contamination decreased salivary testosterone levels in a dose-dependent manner (men F=6.54, p<0.01, F=5.01, p<0.05). Salivary testosterone can be considered A robust and stable marker. However, saliva processing and blood leakage can introduce bias into measurements of salivary testosterone using ELISA. Our observations should be considered in studies focusing on salivary testosterone.