Hyperandrogenism? Increased 17, 20-Lyase Activity? A Metanalysis and Systematic Review of Altered Androgens in Boys and Girls with Autism

Abstract

Introduction: There is increasing evidence that steroid hormone levels and, especially, androgen levels are elevated in autism. An overactivity of 17, 20-lyase with a higher production of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione/androstenediol seems especially present in autism. Methods: An encompassing literature analysis was performed, searching for altered androgens in children with autism and using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Included were all studies published before 31 March 2021 found using the following electronic databases: PubMed, Google Scholar, Cochrane Library, Scopus, and TRIP. Eight studies with boys and three studies with girls where steroid hormone measurements were performed from either plasma, urine, or saliva were found and analyzed. Analyses were performed for DHEA(-S/-C), androstenedione/androstenediol, and testosterone. Effect sizes were calculated for each parameter between mean concentrations for children with autism versus healthy controls. Results: Higher levels of androgens in autism were detected, with the majority of calculated effect sizes being larger than one. Conclusions: We found higher levels of the main testosterone precursors DHEA, androstenedione, and androstenediol, likely causing an additionally higher level of testosterone, and an increased 17, 20-lyase activity is therefore implied. Medications already used in PCOS such as metformin might be considered to treat hyperandrogenism in autism following further research.

Metformin-Treatment Option for Social Impairment? An Open Clinical Trial to Elucidate the Effects of Metformin Treatment on Steroid Hormones and Social Behavior

“…We are aware that the optimal study design would be a placebo-controlled crossover trial, which is, however, for practical reasons, impossible to conduct. Nevertheless, several lines of evidence suggested the involvement of steroid hormones in autism, especially increased androgens [ 15 ]. Just recently, a meta-analysis and systematic review performed by us showed higher androgen levels in hand with increased 17/20 lyase activity in children with autism [ 66 ].…”

“…The following metabolites shall be measured as described above [15,16]: Androgen metabolites: Androsterone, Etiocholanolone, Androstenediol, 11-Oxoetiocholanolone, 11β-Hydroxyandrosterone, 11β-Hydroxyetiocholanolone, Dehydroepiandrosterone, 5-Androstene-3β,17β-diol, 16α-Hydroxydehydroepiandrosterone, 5-Androstene-3β,16α,17β-triol, 5-Pregnene-3β, 16α,17β-triol, Testosterone, 5α-Dihydrotestosterone Estrogen metabolites: Estriol, 17b-Estradiol. Progesterone metabolites: 17-Hydroxypregnanolon, Pregnanediol, Pregnanetriol, 11-Oxo-Pregnanetriol Aldosterone-Metabolites: Tetrahydroaldosterone.…”

“…To date, the etiopathogenesis or the biochemical basis of autism and neurodegenerative diseases has not been conclusively elucidated, and accordingly, the treatment options are not yet exhausted. Furthermore, we know from analyses of children with autism that there appears to be a change in the cholesterol-dependent steroid metabolism yielding to hyperandrogenism [ 15 , 16 , 17 , 18 ]. Causes might be increased oxidative stress resulting in the increased 17,20-lyase-catalyzing activity of adrenal P450c17 through p38α [ 12 ].…”

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

“…Measurements from urine [ 12 , 13 ], plasma [ 14 ] or amniotic fluid [ 4 ] were performed and alterations were detected in pre-pubertal, as well as post-pubertal boys and girls. A recent systematic review and metanalysis from a respectable number of 321 boys and 64 girls with autism indicated that 17/20 Lyase activity is altered in boys as well as girls, implying a relevant role of CYP17A1 [ 15 ]. CYP17A1 is a critically important enzyme in humans that catalyzes the formation of all endogenous androgens via two steps: the 17alpha Hydroxylase step and the 17/20 Lyase step [ 9 ] ( Figure 1 ).…”

“…To date, more than 100 mutations in the CYP17A1 gene have been described and the majority are associated with a classic phenotype of combined 17alpha-hydroxylase and 17/20-lyase deficiency [ 17 , 18 , 19 , 20 , 21 , 22 ]. Interestingly, the reduction of 17alpha-hydroxylase activity and/or 17/20 Lyase activity seems to be a mirror image of the alterations of the steroid hormones detected in affected subjects with autism [ 4 , 12 , 13 , 14 , 15 , 23 , 24 ]. One key question is whether CYP17A1 stops after 17α-hydroxylation or proceeds to 17/20 lyase activity, which is largely dependent on three post-translational factors [ 9 , 16 ].…”