Metabolomics proposes to unveil the molecular machinery involved in each specific disease by the comprehensive analysis of low-molecular-weight metabolites in a biological sample. This narrative mini-review analyzes previous studies applying ultra-high-performance liquid chromatography-high-resolution mass spectrometry (HRMS)-based metabolomics to highlight different metabolic pathways involved in male
hypogonadism and
testosterone replacement
therapy, both in the case of
insulin-sensitive patients with primary
hypogonadism and in the case of
insulin-resistant patients with functional
hypogonadism. In functional
hypogonadism, metabolomics revealed that different biochemical pathways are affected. In detail, glycolysis is the most important biochemical process involved in these patients.
Glucose metabolism is fueled by
amino acid degradation, and gluconeogenesis is widely stimulated. Some important pathways, including
glycerol, are compromised. Furthermore, mitochondrial electron transport is influenced, namely, by a decrease in
ATP production. On the contrary, beta-oxidation of short- and medium-chain
fatty acids does not represent an energy source in hypogonadal patients. Both
lactate and
acetyl-CoA are converted into
ketone bodies, which increased immensely. However,
carnosine and β-
alanine are greatly reduced. These metabolic changes are associated with increased
fatigue and mental
confusion. After
testosterone replacement
therapy, a complete restoration is achieved for only a part of the metabolites. It is of note that only in patients with functional
hypogonadism treated with
testosterone are
ketone bodies produced at high levels, so the symptoms sometimes reported by these patients after the beginning of the
therapy (difficulty in concentrating, depressed mood,
brain fog, and memory impairment) might represent a specific "keto flu-like" syndrome, related to the metabolic ketonic state.