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11?-hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function.

ABSTRACT: The biological significance of 11?-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as precursor to recognized and novel androgenic steroids. These in vitro findings extend beyond the adrenal, suggesting that 11OHA4 could be metabolized in steroid-responsive peripheral tissues, as is the case for androgen precursor metabolites of adrenal origin. The significance thereof becomes apparent when considering that the metabolism of 11OHA4 in LNCaP androgen dependent prostate cancer cells yields androgenic steroid metabolites. It is thus possible that 11OHA4 may be metabolized to yield ligands for steroid receptors in not only the prostate but also in other steroid-responsive tissues. Future investigations of 11OHA4 may therefore characterize it as a vital steroid with far-reaching physiological consequences. An overview of the research on 11OHA4 since its identification in 1953 will be presented, with specific focus on the most recent works that have advanced our understanding of its biological role, thereby underscoring its relevance in health and disease.

SUBMITTER: Bloem LM

PROVIDER: S-EPMC6270415 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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11β-hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function.

Bloem Liezl M LM Storbeck Karl-Heinz KH Schloms Lindie L Swart Amanda C AC

Molecules (Basel, Switzerland) 20131025 11

The biological significance of 11β-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as precursor to recognized and novel androgenic steroids. These in vitro findings extend beyond the adrenal, suggesting that 11OHA4 could be metabolized in steroid-responsive peripheral tissues, as is the ca ...[more]

PMID: 24165582

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Project description:Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

Project description:Racial minorities, particularly non-Hispanic Blacks in the US, experience weaker effects of family socioeconomic position (SEP) on tangible outcomes, a pattern called Minorities' Diminished Returns (MDRs). These MDRs are frequently shown for the effects of family SEP on immigrant adolescents' school performance. As a result of these MDRs, immigrant adolescents from high SEP families show worse than expected cognitive outcomes, including but not limited to poor school performance. However, the existing knowledge is minimal about the role of executive function in explaining diminished returns of family SEP on adolescents' outcomes. To investigate racial differences in the effects of parental human capital on adolescents' executive function, we compared non-Hispanic White non-immigrant and immigrant adolescents for the effect of parental human capital on adolescents' executive function. This was a cross-sectional analysis that included 2,723 non-twin non-Hispanic White adolescents from the Adolescent Brain Cognitive Development (ABCD) study. The independent variable was parental human capital (parental educational attainment), treated as a continuous measure with a higher score reflecting higher subjective socioeconomic status. The primary outcome was adolescents' executive function measured by the stop-signal task (SST). Age, sex, parental marital status, parental employment, family income, and financial difficulties. Immigration status was the effect modifier. Overall, high parental human capital was associated with higher task-based executive function. Immigration status showed statistically significant interactions with parental human capital on adolescents' executive function outcomes. This interaction term suggested that high parental human capital has a smaller effect on increasing immigrants' executive function compared to non-immigrant adolescents. The boosting effect of parental human capital on executive function is diminished for immigrants compared to non-immigrant adolescents. To minimize the inequalities in executive function-related outcomes such as school performance, we need to address the diminishing returns of existing resources for immigrants. Not only should we equalize groups based on their SEP but also equalize the marginal returns of their existing SEP. Such efforts require public policies that aim for equal processes. As such, social policies should address structural and societal barriers such as xenophobia, segregation, racism, and discrimination that hinder immigrant families' ability to effectively utilize their resources. In a fair society, immigrant and non-immigrant families should be equally able to leverage their SEP resources and turn them into tangible outcomes.

Dataset Information

11?-hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function.

Publications

11β-hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function.

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