Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men
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Curated by eLife
Evaluation Summary:
This manuscript addresses the important topic of how changes in gonadal testosterone relate to alterations in gonadal physiology. An important aspect of gonadal testosterone is that it can be an imperfect measure of symptoms related to testosterone deficiency. Therefore, biomarkers that are reflective of testosterone physiology might enable us to more deeply understand the connections between testosterone concentrations and eu- and hypogonadism. The authors performed a proteomic analysis in blood from 30 healthy males at baseline, treated with medical castration and again with testosterone replacement. Associated proteins identified using an unbiased approach were studied further in an independent cohort of 75 hypogonadal and eugonadal men with infertility. Overall, the authors found that 4-hydroxyphenylpyruvate dioxygenase, insulin-like growth factor-binding protein 6 and fructose-bisphosphate aldolase are candidate circulating protein biomarkers. This body of work is certainly novel and should be of interest to the field in hormonal regulation and physiology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
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: (1) before GnRH antagonist administration; (2) 3 weeks later, just before testosterone undecanoate injection, and (3) after additional 2 weeks. Subsequently, they were analyzed 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 cardiometabolic parameters, bone mineral density as well as androgen receptor (AR) CAG repeat lengths, were explored.
Results:
Using receiver operating characteristic 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 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 ReproUnion2.0 (grant no. 20201846), which is funded by the Interreg V EU program.
Article activity feed
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Evaluation Summary:
This manuscript addresses the important topic of how changes in gonadal testosterone relate to alterations in gonadal physiology. An important aspect of gonadal testosterone is that it can be an imperfect measure of symptoms related to testosterone deficiency. Therefore, biomarkers that are reflective of testosterone physiology might enable us to more deeply understand the connections between testosterone concentrations and eu- and hypogonadism. The authors performed a proteomic analysis in blood from 30 healthy males at baseline, treated with medical castration and again with testosterone replacement. Associated proteins identified using an unbiased approach were studied further in an independent cohort of 75 hypogonadal and eugonadal men with infertility. Overall, the authors found that 4-hydroxyphenylpyruvate …
Evaluation Summary:
This manuscript addresses the important topic of how changes in gonadal testosterone relate to alterations in gonadal physiology. An important aspect of gonadal testosterone is that it can be an imperfect measure of symptoms related to testosterone deficiency. Therefore, biomarkers that are reflective of testosterone physiology might enable us to more deeply understand the connections between testosterone concentrations and eu- and hypogonadism. The authors performed a proteomic analysis in blood from 30 healthy males at baseline, treated with medical castration and again with testosterone replacement. Associated proteins identified using an unbiased approach were studied further in an independent cohort of 75 hypogonadal and eugonadal men with infertility. Overall, the authors found that 4-hydroxyphenylpyruvate dioxygenase, insulin-like growth factor-binding protein 6 and fructose-bisphosphate aldolase are candidate circulating protein biomarkers. This body of work is certainly novel and should be of interest to the field in hormonal regulation and physiology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Joint Public Review:
This manuscript by Giwercman, et al., pursues the identification of protein biomarkers of androgen activity in humans. These investigators carried out a proteomic analysis in blood from 30 healthy males treated with a GnRH antagonist at baseline, after medical castration and at a third time point after testosterone replacement. Proteins that were most significantly associated with testosterone changes were tested further in a separate cohort of 75 hypo- and eugonadal men with infertility. Associations between these proteins and cardio-metabolic parameters, as well as androgen receptor (AR) CAG repeat length were assessed. The major findings include the observation that 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6) and fructose-bisphosphate aldolase (ALDOB) are …
Joint Public Review:
This manuscript by Giwercman, et al., pursues the identification of protein biomarkers of androgen activity in humans. These investigators carried out a proteomic analysis in blood from 30 healthy males treated with a GnRH antagonist at baseline, after medical castration and at a third time point after testosterone replacement. Proteins that were most significantly associated with testosterone changes were tested further in a separate cohort of 75 hypo- and eugonadal men with infertility. Associations between these proteins and cardio-metabolic parameters, as well as androgen receptor (AR) CAG repeat length were assessed. The major findings include the observation that 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6) and fructose-bisphosphate aldolase (ALDOB) are biomarkers that follow testosterone level and presumably AR activity. Overall, this is a very interesting and novel body of work.
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