Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men
Abstract
Background:
Reliable biomarkers of androgen activity in humans are lacking. The aim of this study was, therefore, to identify new protein markers of biological androgen activity and test their predictive value in relation to low vs. normal testosterone values and some androgen deficiency linked pathologies.
Methods:
Blood samples from 30 healthy GnRH-antagonist treated males were collected at three time points: a) before GnRH antagonist administration; b) 3 weeks later, just before testosterone undecanoate injection, and c) after additional 2 weeks. Subsequently they were analysed by mass spectrometry to identify potential protein biomarkers of testosterone activity. Levels of proteins most significantly associated with testosterone fluctuations were further tested in a cohort of 75 hypo- and eugonadal males suffering from infertility. Associations between levels of those markers and cardio-metabolic parameters, bone mineral density as well as androgen receptor CAG repeat lengths, were explored.
Results:
Using ROC analysis, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6) and fructose-bisphosphate aldolase (ALDOB), as well as a Multi Marker Algorithm, based on levels of 4HPPD and IGFBP6, were shown to be best predictors of low (< 8 nmol/L) vs. normal (> 12 nmol/L) testosterone. They were also more strongly associated with metabolic syndrome and diabetes than testosterone levels. Levels of ALDOB and 4HPPD levels also showed association with AR CAG-repeat lengths.
Conclusions:
We identified potential new protein biomarkers of testosterone action. Further investigations to elucidate their clinical potential are warranted.
Funding:
The work was supported by ReproUnion 2.0 (grant no 20201846), which is funded by the Interreg V EU program.
Data availability
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (60) partner repository with the dataset identifier PXD024448.Supplementary tables (datasets):https://doi.org/10.6084/m9.figshare.14875431Source data of the Figures can be found on:https://doi.org/10.6084/m9.figshare.14875431Supplementary Figure S1 (Figure 2-figure supplement 1):https://doi.org/10.6084/m9.figshare.14876562
-
Supplementary tables, Novel protein markers of androgen activity in humans with potential clinical valuedoi.org/10.6084/m9.figshare.14875431.v2.
-
Supplementary Figure S1, Novel protein markers of androgen activity in humans with potential clinical value.doi.org/10.6084/m9.figshare.14876562.v1.
Article and author information
Author details
Funding
ReproUnion (20201846)
- Aleksander Giwercman
Swedish Governmental Fund for Clinical Research
- Aleksander Giwercman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All subjects were enrolled with informed written consent. The two studies from which they were recruited were approved by the Swedish Ethical Review Authority (Approval number: DNR 2014/311, date of approval 8 May 2014; DNR 2011/1, date of approval 11 January 2011).
Copyright
© 2022, Giwercman et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 923
- views
-
- 158
- downloads
-
- 4
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Medicine
HIV disease remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified signal transducer and activator of transcription (STAT3) as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high levels of HIV-1 gene expression and dysregulation of cytoskeleton-related genes, and these cells dedifferentiated. In injured proximal tubules, cell-cell interaction analysis indicated activation of the pro-fibrogenic PKR-STAT3-platelet-derived growth factor (PDGF)-D pathway. These findings suggest that PKR inhibition and mitochondrial rescue are potential novel therapeutic approaches for HIVAN.
-
- Cancer Biology
- Medicine
Heterogeneity of tumor metabolism is an important, but still poorly understood aspect of tumor biology. Present work is focused on the visualization and quantification of cellular metabolic heterogeneity of colorectal cancer using fluorescence lifetime imaging (FLIM) of redox cofactor NAD(P)H. FLIM-microscopy of NAD(P)H was performed in vitro in four cancer cell lines (HT29, HCT116, CaCo2 and CT26), in vivo in the four types of colorectal tumors in mice and ex vivo in patients’ tumor samples. The dispersion and bimodality of the decay parameters were evaluated to quantify the intercellular metabolic heterogeneity. Our results demonstrate that patients’ colorectal tumors have significantly higher heterogeneity of energy metabolism compared with cultured cells and tumor xenografts, which was displayed as a wider and frequently bimodal distribution of a contribution of a free (glycolytic) fraction of NAD(P)H within a sample. Among patients’ tumors, the dispersion was larger in the high-grade and early stage ones, without, however, any association with bimodality. These results indicate that cell-level metabolic heterogeneity assessed from NAD(P)H FLIM has a potential to become a clinical prognostic factor.