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

Abstract

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.

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

“…Gluconeogenesis is strongly active in IR hypogonadic patients [ 19 ] but is stopped upon TRT, as revealed here. 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, TRT induced a significantly higher production of acetyl CoA both in IR and IS [ 31 ] hypogonadic patients. It is of note that the increased acetyl CoA did not enter the Krebs cycle ( Figure 3 C) in both groups of patients, but instead was used in other pathway metabolisms.…”

“…Thus, the production of KB is exclusive to IR hypogonadism, in which insulin is inactive and cannot inhibit ketogenesis. This is for the most part due to the prevention of the breakdown of triglycerides into FFAs and glycerol [ 44 , 45 ], as well as Cori cycle activation, as revealed in TRT of IS-hypogonadism [ 31 ].…”

“…It is of note that ketone bodies were produced only in IR [ 19 ] hypogonadism, and more so upon TRT, while their production was not observed in IS hypogonadism both before and after TRT [ 31 ], suggesting that insulin plays a role. On the other hand, the permanence of insulin resistance upon TRT compromises the correct use of glucose, and it is reasonable to suggest that ketone bodies can offer an alternative route, which acts directly on the same metabolic pathways, without requiring the action of the complex signaling insulin pathways.…”

On the Need to Distinguish between Insulin-Normal and Insulin-Resistant Patients in Testosterone Therapy

“…Upon the administration of TRT for three months, testosterone levels were restored in both IS and IR hypogonadal patients [ 53 , 54 ], but in IR insulin was slightly reduced (decreasing from 17 to 15 µU/mL), in agreement with Kapoor [ 23 ]. Since synergic and/or antagonistic action between testosterone and insulin exists [ 55 , 56 ], it is not surprising that this partial insulin reduction can limit the total restoration of all metabolisms, except for those in muscle and adipose tissue, which were shown to benefit.…”