Interactive Effect of Corticosterone and Lactate on Regulation of Testosterone Production in Rat Leydig Cells

Chen, Chih-Chieh; Chen, Chien‐Wei; Lin, Po-Han; Chou, Jou-Chun; Weng, Ting-Chun; Jian, Cai-Yun; Hu, Sindy; Lai, Wei-Ho; Lieu, Fu-Kong; Wang, Shyi-Wu; Wang, Paulus S.

doi:10.1002/jcp.25700

Cited by 16 publications

(12 citation statements)

References 42 publications

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“…Interestingly, lactate increased significantly after TRT, in agreement with Burns [21]. In fact, there is a correlation between lactate and testosterone production in rat Leydig cells, [22] and in these patients the testosterone production was stimulated by lactate and vice versa. Thus, lactate accumulation might not imply a state of anaerobic glycolysis but simply a state of accelerated glycolysis (glycolytic flux is higher than the tricarboxylic acid cycle flux) [23], and/or higher lactate production.…”

Section: Discussionsupporting

confidence: 81%

Plasma Metabolomics Profile of “Insulin Sensitive” Male Hypogonadism after Testosterone Replacement Therapy

Zolla

Ceci

2022

IJMS

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Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while β-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.

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Section: Discussionsupporting

confidence: 81%

Plasma Metabolomics Profile of “Insulin Sensitive” Male Hypogonadism after Testosterone Replacement Therapy

Zolla

Ceci

2022

IJMS

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“…Surprisingly, lactate was high in IS hypogonadal males, at variance with IR hypogonadism 16 . Consequently, in view of the correlation between lactate and testosterone production in rat Leydig cells 21 , in these patients the testosterone production seems to be still stimulated 22 .…”

Section: Discussionmentioning

confidence: 98%

Metabolic patterns in insulin-sensitive male hypogonadism

et al. 2018

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Male hypogonadism is a disorder characterised by low levels of the hormone testosterone. At beginning subjects with low levels of testosterone do not show insulin resistance (insulin-sensitive patients), which develops over time (insulin-resistance patients). To analyse the metabolic alterations mainly related to decreased testosterone, we performed metabolomics investigations on the plasma of males with hypogonadism who showed normal insulin levels. Plasma from patients with low testosterone (<8 nmol/l) and homeostatic model assessment for insulin-resistance-index (HOMAi) < 2.5, as well as matched controls, was analysed by UHPLC and mass spectrometry. Then metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathways. Glycolysis was not altered, as expected for the presence of insulin activity, but imbalances in several other pathways were found, such as the pentose phosphate pathway (PPP), glycerol shuttle, malate shuttle, Krebs cycle (TCA) and lipid metabolism. The PPP was significantly upregulated. Moreover, while the first steps of the Krebs cycle were downregulated, 2-oxoglutarate was replenished via glutaminolysis. Since glutaminolysis leads to an activation of the malate aspartate cycle, greater amounts of NADH and ATP with respect to the control were recorded. The activation of the glycerol shuttle was also recorded, with consequent lower triglyceride production and downregulation of beta-oxidation. This explained the moderately increased dyslipidaemia, as well as the mild increase in body mass index (BMI) observed in insulin-sensitive hypogonadism. Finally, a significant decrease in carnosine was recorded, explaining the muscle weakness commonly observed.

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“…However, upon TRT, lactate increases, independently from insulin activity, given that it was also observed following TRT in IS hypogonadic patients [ 31 ]. This is probably related to the fact that lactate and testosterone cause reciprocal effects in Leydig cells [ 32 , 33 ], where lactate stimulates testosterone production and testosterone stimulates lactate production. Thus, a lactate increase represents the first response to testosterone supplementation.…”

Section: Discussionmentioning

confidence: 99%

Plasma Metabonomics in Insulin-Resistant Hypogonadic Patients Induced by Testosterone Treatment

Zolla

Grande

Milardi

2022

IJMS

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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.

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Interactive Effect of Corticosterone and Lactate on Regulation of Testosterone Production in Rat Leydig Cells

Cited by 16 publications

References 42 publications

Plasma Metabolomics Profile of “Insulin Sensitive” Male Hypogonadism after Testosterone Replacement Therapy

Plasma Metabolomics Profile of “Insulin Sensitive” Male Hypogonadism after Testosterone Replacement Therapy

Metabolic patterns in insulin-sensitive male hypogonadism

Plasma Metabonomics in Insulin-Resistant Hypogonadic Patients Induced by Testosterone Treatment

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