A reply to ‘Alteration of steroidogenesis in boys with autism spectrum disorders’

Buerki

Kurz³

et al. 2021

IJMS

Self Cite

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.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Buerki

Kurz³

et al. 2021

IJMS

Self Cite

“…In principle, metformin has a half-life of 6-8 h and, in consequence, a steady state is reached after around 30-40 h (after five half-lives-as a rule of thumb, the distribution volume is saturated after five half-lives; it does not imply that the pharmaceutical has the maximum effect) [29]. When focusing on reasons for the increased steroid hormones, oxidative stress might be causative, which might result from an increased 17,20-lyase-catalyzing activity of adrenal P450c17 through p38α [11,[30][31][32][33]. It was, in consequence, indicated that these actions contribute to the beneficial effects of metformin [8,34].…”

Section: Discussionmentioning

confidence: 99%

“…As, to date, neither the exact causes nor the biochemical basis of autism have been conclusively elucidated, the treatment options are not yet exhausted. However, we know from analyses of children with autism that there appears to be a change in the cholesterol pathway, yielding altered steroid hormones [30][31][32][33]. Focusing on therapeutic aspects, Bradstreet et al had already, ten years ago, proposed spironolactone for autism in order to target steroid hormones [36], and metformin was considered in the treatment of the side-effects of antipsychotics in autism [37].…”

Section: Discussionmentioning

confidence: 99%

Light in the Rational Treatment of Autism? Effects of Metformin on Steroid Hormones in a Patient with Polycystic Ovarian Syndrome (PCOS)

Calin

Escher

et al. 2022

Life

Self Cite

Background. Metformin is an effective treatment option for type 2 diabetes mellitus, and it is, to this day, the most prescribed oral antiglycaemic drug. Besides its effects mainly on mitochondrial activity, an off-label use came up as a pharmaceutical for subjects with a diagnosis of polycystic ovarian syndrome (PCOS) along with altered steroid hormone homeostasis. Besides these effects, even an influence on mood and social behavior was described, leading to the aim of this case report to elucidate the effects before versus after treatment with metformin on steroid hormones and social behavior. Methods. A female patient with diagnosed PCOS was analyzed three times for steroid hormone levels. The first analysis was performed before treatment; the second, after a period of 71 days with metformin at 2 × 500 mg; and the third, after a total of 144 days with metformin at 2 × 500 mg. Spot urine probes were taken in the morning for a combined gas chromatography–mass spectrometry (GC-MS), and the steroid levels were adjusted for creatinine excretion. A questionnaire on social behavior (Autism Spectrum Questionnaire) was administered before treatment and after 71 days. Results. A decrease in all the steroid hormones measured was detected after 71 and 144 days of treatment with metformin, being more pronounced after 144 days of treatment and highly significant (p < 0.001). Furthermore, in the untreated state, the class of corticosterone metabolites showed increased values compared to the female reference values for TH-11-DH-corticosterone, TH-corticosterone, and 5a-TH-corticosterone. In the class of estrogen metabolites, increased values compared to the reference values were detected for 17b-estradiol; in the class of 11-deoxycortisol metabolites, an increase in TH-11-deoxycortisol was detected. For the class of cortisol metabolites, increased values compared to the reference values were detected for cortisone, TH-cortisone, a-cortolone, b-cortolone, 20b-dihydrocortisone, cortisol, TH-cortisol, 5a-TH-cortisol, a-cortol, 20b-dihydrocortisol, and 6b-OH-cortisol. No increases in androgen metabolites were detected. Interestingly, weight decreased from 93.4 kg to 91.3 kg after 71 days and fell to 82.7 kg after 144 days of treatment. The skeletal muscle mass was 30.1 kg at the first visit, decreasing to 29.9 kg and to 27.5 kg. No significant difference in the social behavior score from baseline to after 71 days of treatment was detected. Discussion. Metformin improved the steroid hormone profiles from levels above the upper reference values to the middle of the reference values after 71 days and to the lower ends of the reference values after 144 days of treatment. This implies not only that metformin has an effect on steroid hormone levels, but in addition that the efficacy of the pharmaceutical seems to depend on the time interval from intake. To summarize, in this patient, steroid hormones were affected but social behavior was not. If no effect of metformin on social behavior exists, this must be supported by further cases.

“…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 ].…”

Section: Background and Need For This Studymentioning

confidence: 99%

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

Kurz²,

Buerki

et al. 2022

Life

Self Cite

Background: Social behavior is mediated by steroid hormones, whereby various lines of evidence indicate that metformin might improve the symptoms of social withdrawal. This directly yields to the aim of the study to correlate the impact of metformin treatment on the potential alterations in steroid hormone homeostasis, which is ultimately impacting social behavior. Therefore, urinary samples of patients before and after treatment with metformin will be correlated to social behavior to elucidate potential changes in steroid hormone profiles and social behavior. Material and Methods: An observational study in healthy adults with a new indication for metformin. Steroid hormone analysis, including the most prominent androgen, estrogen, progesterone, aldosterone, corticosterone, cortisone and cortisol metabolites analyzed with gas chromatography–mass spectrometry and a questionnaire on social behavior (Autism Spectrum Questionnaire (AQ)) will be administered prior to and after around a 12-week phase of metformin treatment. Discussion: It is likely that due to different pathophysiological mechanisms such as an effect on the respiratory chain in mitochondria or via AMP-activated protein kinase, a general alteration of steroid hormone levels can be detected prior to post treatment. The encompassing measurement of steroid hormones shall give hints concerning the involvement of specific cascades yielding potential pharmacological targets for future research.