University of Tuscia, 01100 Viterbo, Italy.
Unit of Andrology and Reproductive Medicine, University of Padua, 35122 Padua, Italy.
Int J Mol Sci. 2022 Jul 14;23(14):7754. doi: 10.3390/ijms23147754.
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.
患有胰岛素抵抗（IR）的性腺功能减退症患者与正常胰岛素血症患者（IS）的代谢组学特征不同。睾酮替代疗法（TRT）对存在或不存在胰岛素抵抗的患者的代谢可能有不同的影响。我们评估了 20 例 IR 性腺功能减退症患者在 TRT 治疗 60 天后代谢的变化。使用超高效液相色谱（UHPLC）和高分辨率质谱（HRMS）记录了 20 例 IR 性腺功能减退症患者的代谢组学血浆图谱。比较了 TRT 治疗前 60 天和治疗后 60 天的血浆代谢物。在性腺功能减退症患者中，肉毒碱增加，肉毒碱对改善运动表现很重要。相反，脯氨酸和赖氨酸——参与胶原蛋白合成的氨基酸减少。由于 FFAβ-氧化减少，血液中的甘油三酯减少，脂肪酸（FFA）增加。糖酵解略有改善，而三羧酸循环未被激活。在接受治疗之前，作为主要能量来源的糖异生（这是 TRT 前 IR 性腺功能减退症的主要能量来源）停止。结果，乳酸和乙酰辅酶 A 显著增加。由于亮氨酸/异亮氨酸降解，乳酸和乙酰辅酶 A 都代谢成酮体，酮体也大大增加。酮体主要来自乙酰辅酶 A，因为乙酰辅酶 A 转化为酮体的反应是由 mtHMGCoA 合酶催化的。这种酶被胰岛素抑制，而胰岛素在 IR 患者中不存在，但在睾酮给药后过度表达。酮症是一种能量供应的替代途径，它提供了与胰岛素相同的代谢效果，但在代谢或原始控制水平，绕过了胰岛素的复杂信号通路。治疗后，性腺功能减退症患者出现了与酮尿相关的临床症状。他们表现与酮饮食患者相似，即所谓的“酮流感”。在对性腺功能减退症患者进行 TRT 治疗之前，必须考虑到这一点。
