Zolla, L., Grande, G., & Milardi, D. (2022). Plasma Metabonomics in Insulin-Resistant Hypogonadic Patients Induced by Testosterone Treatment. International journal of molecular sciences. https://doi.org/10.3390/ijms23147754
Zolla L, Grande G, Milardi D. Plasma Metabonomics in Insulin-Resistant Hypogonadic Patients Induced by Testosterone Treatment. International journal of molecular sciences. 2022. doi:10.3390/ijms23147754
Zolla, Lello, et al. "Plasma Metabonomics in Insulin-Resistant Hypogonadic Patients Induced by Testosterone Treatment." International journal of molecular sciences, 2022.
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Author affiliations
2 institutions
Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy.
Division of Endocrinology, Centre for Natural Reproductive Medicine "ISI - Paul VI", Fondazione Policlinico Universitario "Agostino Gemelli" Scientific Hospitalization and Treatment Institute (IRCC...
RRM Academy Synopsis
Testosterone therapy raised ketone production in insulin-resistant men
Testosterone therapy increased ketone production in men with insulin resistance and low testosterone. The study measured blood chemicals made by metabolism in 20 such men before and after 60 days of gel treatment. The men reported new symptoms similar to the keto flu after treatment.
Key Findings
The study enrolled 20 men with low testosterone and insulin resistance and 20 healthy controls, and analyzed plasma from the patients before and after 60 days of testosterone gel.
The authors report normal testosterone levels in these men after 40 days. Approximately 20 canonical biochemical pathways were affected, and 12 were implicated to a significant extent.
In these men after 60 days, triglycerides decreased and free fatty acids increased. The authors attribute the rise in fatty acids to reduced β-oxidation, the breakdown of fats for energy.
Glycolysis improved slightly, the Krebs cycle was not activated, and gluconeogenesis, the main energy source before treatment, stopped. Lactate and acetyl CoA increased significantly, and ketone bodies increased greatly.
In these men, proline and lysine, amino acids involved in collagen synthesis, were reduced after treatment, and carnosine increased.
Interpretation
Metabonomics measures many small molecules in the blood at once. This exploratory study followed 20 men with low testosterone and insulin resistance from one clinic in Rome. Their blood was compared before and after 60 days of treatment. The only comparison group was 20 healthy men. The authors note that 60 days may be too short for complete metabolic restoration. Separately, they report that insulin resistance does not improve with testosterone therapy. They conclude that insulin resistance status should be taken into account when testosterone therapy is planned.
RRM Context
Restorative Reproductive Medicine (RRM) looks for the cause of a hormone problem. The authors describe a two-way link between low testosterone and insulin resistance. The link places a man's metabolic health beside his reproductive hormones. RRM evaluates the male partner as part of the couple.
Our editorial summary of this paper, not the article's abstract.
Abstract
Hypogonadic subjects with insulin resistance (IR) showed different metabonomic profiles compared to normo-insulinemic subjects (IS). Testosterone replacement therapy (TRT) may have a different impact on the metabolisms of those with the presence or absence of insulin resistance. We evaluated the changes in the metabolism of IR hypogonadic patients before and after 60 days of TRT. The metabonomic plasma profiles from 20 IR hypogonadal patients were recorded using ultra-high-performance liquid chromatography (UHPLC) and high-resolution mass spectrometry (HRMS). Plasma metabolites, before and after 60 days of TRT, were compared. In hypogonadic patients, carnosine, which is important for improving performance during exercise, increased. Conversely, proline and lysine-amino acids involved in the synthesis of collagen-reduced. Triglycerides decreased and fatty acids (FFAs) increased in the blood as a consequence of reduced FFA β-oxidation. Glycolysis slightly improved, while the Krebs cycle was not activated. Gluconeogenesis (which is the main energy source for hypogonadal IR before TRT) stopped after treatment. As a consequence, lactate and acetyl CoA increased significantly. Both lactate and acetyl CoA were metabolized into ketone bodies which increased greatly, also due to leucine/isoleucine degradation. Ketone bodies were derived predominantly from acetyl CoA because the reaction of acetyl CoA into ketone bodies is catalyzed by mtHMGCoA synthase. This enzyme is inhibited by insulin, which is absent in IR patients but overexpressed following testosterone administration. Ketosis is an alternative route for energy supply and provides the same metabolic effects as insulin but at the metabolic or primitive control level, which bypasses the complex signaling pathway of insulin. After treatment, the hypogonadic patients showed clinical symptoms related to ketonuria. They presented similarly to those following a ketogenic diet, the so-called 'keto flu'. This must be taken into account before the administration of TRT to hypogonadic patients.
