How Is CYP17A1 Activity Altered in Autism? A Pilot Study to Identify Potential Pharmacological Targets.

Background: Increasing evidence exists that higher levels of androgens can be found in individuals with autism. Evidence yields to a susceptible role of Cytochrome P450 17A1 (CYP17A1) with its catalyzation of the two distinct types of substrate oxidation by a hydroxylase activity (17-alpha hydroxylase) and C17/20 lyase activity. However, to what extent steps are altered in affected children with autism versus healthy controls remains to be elucidated. Methods: Urine samples from 48 boys with autism (BMI 19.1 ± 0.6 kg/m2, age 14.2 ± 0.5 years) and a matched cohort of 48 healthy boys (BMI 18.6 ± 0.3 kg/m2, 14.3 ± 0.5 years) as well as 16 girls with autism (BMI 17.5 ± 0.7 kg/m2, age 13.8 ± 1.0 years) and a matched cohort of 16 healthy girls (BMI 17.2 ± 0.8 kg/m2, age 13.2 ± 0.8 years) were analyzed for steroid hormone metabolites by gas chromatography-mass spectrometry. Results: The activity of 17-alpha Hydroxylase increased by almost 50%, whereas activity of 17/20 Lyase activity increased by around 150% in affected children with autism. Furthermore, the concentration of Cortisol was higher as compared to the average increase of the three metabolites TH-Corticosterone, 5α-TH-Corticosterone and TH-11ß-DH-Corticosterone, indicating, in addition, a stimulation by the CRH-ACTH system despite a higher enzymatic activity. Discussion: As it was shown that oxidative stress increases the 17/20-lyase activity via p38α, a link between higher steroid hormone levels and oxidative stress can be established. However, as glucocorticoid as well as androgen metabolites showed higher values in subjects affected with autism as compared to healthy controls, the data indicate, despite higher CYP17A1 activity, the presence of increased substrate availability in line with the Cholesterol theory of autism.

Stress-induced alterations of social behavior are reversible by antagonism of steroid hormones in C57/BL6 mice.

Various disturbances of social behavior, such as autism, depression, or posttraumatic stress disorder, have been associated with an altered steroid hormone homeostasis and a dysregulation of the hypothalamus-pituitary-adrenal axis. A link between steroid hormone antagonists and the treatment of stress-related conditions has been suggested. We evaluated the effects of stress induction on social behavior in the three chambers and its potential reversibility upon specific steroid hormone antagonism in mice. C57BL/6 mice were stressed twice daily for 8 days by chronic swim testing. Social behavior was evaluated by measuring, first, the preference for sociability and, second, the preference for social novelty in the three-chamber approach before and after the chronic swim test. The reversibility of behavior upon stress induction was analyzed after applying steroid hormone antagonists targeting glucocorticoids with etomidate, mineralocorticoids with potassium canrenoate, and androgens with cyproterone acetate and metformin. In the chronic swim test, increased floating time from 0.8 ± 0.2 min up to 4.8 ± 0.25 min was detected (p < 0.01). In the three-chamber approach, increased preference for sociability and decreased preference for social novelty was detected pre- versus post-stress induction. These alterations of social behavior were barely affected by etomidate and potassium canrenoate, whereas the two androgen antagonists metformin and cyproterone acetate restored social behavior even beyond baseline conditions. The alteration of social behavior was better reversed by the androgen as compared with the glucocorticoid and mineralocorticoid antagonists. This suggests that social behavior is primarily controlled by androgen rather than by glucocorticoid or mineralocorticoid action. The stress-induced changes in preference for sociability are incompletely explained by steroid hormone action alone. As the best response was related to metformin, an effect via glucose levels might confound the results and should be subject to future research.

Are Steroid Hormones Dysregulated in Autistic Girls?

Evidence of altered cholesterol and steroid hormones in autism is increasing. However, as boys are more often affected, evidence mainly relates to autistic males, whereas evidence for affected autistic girls is sparse. Therefore, a comprehensive gas chromatography mass spectrometry-based steroid hormone metabolite analysis was conducted from autistic girls. Results show increased levels of several steroid hormones, especially in the class of androgens in autistic girls such as testosterone or androstenediol. The increase of the majority of steroid hormones in autistic girls is probably best explained multifactorially by a higher substrate provision in line with the previously developed cholesterol hypothesis of autism.

Steroid Metabolites Support Evidence of Autism as a Spectrum.

Objectives: It is common nowadays to refer to autism as a spectrum. Increased evidence of the involvement of steroid metabolites has been shown by the presence of stronger alterations in Kanner's syndrome compared with Asperger syndrome. Methods: 24 h urine samples were collected from 20 boys with Asperger syndrome, 21 boys with Kanner's syndrome, and identically sized control groups, each matched for age, weight, and height for comprehensive steroid hormone metabolite analysis via gas chromatography-mass spectrometry. Results: Higher levels of most steroid metabolites were detected in boys with Kanner's syndrome and Asperger syndrome compared to their matched controls. These differences were more pronounced in affected individuals with Kanner's syndrome versus Asperger syndrome. Furthermore, a specific and unique pattern of alteration of androsterone, etiocholanolone, progesterone, tetrahydrocortisone, and tetrahydrocortisol was identified in boys with Kanner's syndrome and Asperger syndrome. Interestingly, in both matched samples, only androsterone, etiocholanolone, progesterone, tetrahydrocortisone, tetrahydrocortisol, and 5a-tetrahydrocortisol groups were positively correlated. In the Asperger syndrome group, all metabolites showed a positive correlation. In the Kanner's syndrome group, 5-a tetrahydrocortisol with androsterone showed a positive correlation. Conclusions: Due to differences in the level of alteration, the premise that Asperger syndrome is on the mild side of the autism spectrum and that Kanner's syndrome is on the severe side is supported, but alteration patterns yield different phenotypic expressions.

Salt, aldosterone and extrarenal Na+ - sensitive responses in pregnancy.

Outside of pregnancy excessive salt consumption is known to be harmful being linked to increased blood pressure and cardiovascular disease. However, pregnancy represents a major change to a woman's physiology resulting in an intimate adaptation to environmental conditions. It is now becoming apparent that salt is essential for a number of these changes during pregnancy including haematological, cardiac adaptations as well as directly influencing placental development and the uteroplacental immune environment. The present review discusses the important role that salt has during normal pregnancy and evidence will also be presented to show how the placenta may act as a salt sensing organ temporarily, yet substantially regulating maternal blood pressure.