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. 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. 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. We identified potential new protein biomarkers of testosterone action. Further investigations to elucidate their clinical potential are warranted. The work was supported by ReproUnion2.0 (grant no. 20201846), which is funded by the Interreg V EU program.
Highlights
The male sex hormone, testosterone (T), plays an important physiological role in regulating function of both reproductive and non-reproductive organs in males as well as in females
We identified potential new protein biomarkers of testosterone action
The study was set up to I) identify new protein markers of biological androgenic activity (BAA) in healthy subjects; II) test the markers’ predictive values in relation to biochemically diagnosed hypogonadism, metabolic syndrome (MetS), cardiovascular risk lipid profile (CVRLP), diabetes mellitus II (DM) and low bone density (LBD) in infertile men; III) analyse androgen dependence of the identified proteins by assessing how their levels associate with androgen receptor gene CAG-repeat length
Summary
The male sex hormone, testosterone (T), plays an important physiological role in regulating function of both reproductive and non-reproductive organs in males as well as in females. The diagnosis of T deficiency (i.e. male hypogonadism) is based on the presence of low serum T levels combined with clinical symptoms, which, are not pathognomonic for this condition (1). Total T does not accurately reflect biological androgenic activity (BAA), which might be considered a more useful biological and clinical marker. The association between T levels and BAA is affected by several biological mechanisms such as the concentration of binding proteins, body mass index, certain diseases (e.g. diabetes), androgen receptor (AR) sensitivity (2), and different co-factors (3). No reliable algorithms for translating T levels into BAA are available, but could be useful for example in the diagnosis of male hypogonadism. The aim of this study was, 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
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