Male but not female mice in which the aromatase gene has been deleted (ArKO) develop hepatic steatosis that can be normalized by estrogen treatment . Thus, although it is widely recognized that estrogens regulate liver lipid metabolism and reduce triglyceride accumulation in the liver mainly via ER-α 47, 48, both ER-α and GPER are required to be present in the liver to maintain lipid homeostasis. Additionally, treatment of the specific ER-α agonist PPT decreases weight, fat mass, and TG in the liver in both wild-type mice and obese ob/ob mice 39, 40. One study of genome-wide analyses demonstrated that the subtle oscillations of estrogens occurring during the estrous cycle are sufficient to influence liver gene expression, and that ERs are involved in the pulsatile synthesis of fatty acids and cholesterol in the liver . In another E2-deficient aromatase knockout (ArKO) mouse model, spontaneous obesity and hepatic steatosis result from impaired fatty acid β-oxidation and elevated fatty acid synthase (FAS) in the liver in both female and male mice . Epidemiological studies have showed higher plasma level of LDL-C and lower plasma level of HDL-C in men and postmenopausal women compared with premenopausal women, suggesting that lower circulating estrogen levels may promote fat deposition in the liver .
In particular, a marked induction of UCP1 and UCP2 was observed in PADs derived from adipose tissue of T-treated hypogonadal obese men. Noteworthy, the ability of preadipocytes to respond to increasing concentrations of insulin was tightly dependent upon T level, measured at the pre-surgery visit 1. Lipid handling and lipid droplet formation are closely related to mitochondria processes . Therefore, our data further corroborated the positive effects of T on mitochondrial function. Noteworthy, given that TFAM, one of the most important mitochondrial DNA transcription factors 67–69, contains AR-responsive elements, it is now considered a relevant AR target gene through which testosterone might regulate mitochondrial homeostasis . In unhealthy cells, division (fission) becomes predominant and the mitochondrial network fragments, thus reducing energy efficiency, ATP production and fitness to respond to environmental stress buffering reactive oxygen species (ROS) 57–62. Mitochondria constantly undergo fusion and division processes to form a tubular network, which is crucial for health in most eukaryotic cells 55, 56.
Low testosterone may make it easier for fat to collect in the liver. There is also a close connection between testosterone levels and how the body handles fat and sugar. People with low testosterone may also have more belly fat, high blood pressure, or insulin resistance. Many people who start testosterone therapy (also called TRT) may already have NAFLD and not know it. Even without symptoms, very high liver enzyme levels—especially if they rise fast or stay high—need medical review. Some people may need to stop therapy for a while to see if the enzyme levels go back to normal. But if liver enzyme levels stay high or keep rising over time, this can be a warning sign.
If blood tests show that liver enzymes are high, doctors usually repeat the test after a few weeks. Ongoing elevation may point to liver inflammation or fatty liver disease. These body changes may cause a mild rise in liver enzymes without real liver damage.
We have also demonstrated in this study that the mRNA expression of Glucose-6-phosphate dehydrogenase (G6pd), the gateway enzyme in the pentose phosphate shunt pathway, is elevated in the liver of Tfm mice suggesting that glucose may also be utilised down this route during testosterone deficiency. Improved glucose utilisation in muscle, liver and SAT by testosterone may reduce the conversion of glucose to fat in times of excess and improve insulin sensitivity thus reducing lipid accumulation in these and other tissues. Protein expression of selected targets of lipid and glucose regulation in muscle and liver of Tfm mice. Gene expression of targets of lipid and glucose regulation in muscle, liver, subcutaneous and visceral adipose tissue of Tfm mice
It can lead to side effects like acne, hair loss, mood changes, and heart or liver problems. However, too many red blood cells can also be a problem, which is why doctors often monitor this closely during treatment. When testosterone levels are low, some people may develop a type of anemia. After therapy starts, many people notice better mood, improved energy, and a return of muscle strength.
A greater glycogen storage rate may be due to increased muscle glucose uptake and enhanced signaling pathways made possible by the influx of amino acids. Postexercise muscle glycogen concentrations were similar among treatments, but 24 hours later, less glycogen had been replenished with resistant starch compared with the other treatments. For that reason, waxy starches have been studied to assess how their ingestion influences glycogen metabolism and exercise performance.119–121 In 1996, Jozsi et al.121 published the results of a study in which 8 male participants completed 4 exercise trials in which they cycled for 60 minutes at 75% VO2max, followed by six 1-minutes sprints, a protocol that lowered muscle glycogen content. The authors attributed improved run performance to higher muscle (and possibly liver) glycogen levels prior to the final sprints. It is true that fructose better stimulates liver glycogen restoration and glucose does the same for muscle glycogen,104 but most physically active people normally ingest enough fructose and glucose in foods and beverages to restore liver glycogen. Immediately after physical activity, muscle cells that sustained a substantial decrease in glycogen content are metabolically prepared for rapid glycogenesis.. Numbers examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed are reported in the "Study design and treatment" subsection The outcomes reported in the present manuscript were changes over time between and within HYPO and HYPO + TTh groups in insulin sensitivity, adipogenic potential and mitochondrial function of preadipocytes (hPADs) isolated from adipose tissue biopsies and in the severity of NAFLD evaluated by triglycerides assay and liver biopsies histology|The main aim of this study was to evaluate the association between testosterone concentrations and NAFLD in adult men, in terms of noninvasive indices of NAFLD and hepatic fibrosis. An additional orchidectomised XY littermate group receiving testosterone treatment would also allow us to control for pharmacological and dosing effects in animals with fully functional AR. Such administration may explain the influence of testosterone treatment on gene expression above and beyond that observed in wild-type controls. Tfm mice also had reduced SAT and VAT expression of Pparg mRNA, indicating a potential mechanism by which testosterone deficiency may lead to metabolic dysregulation and adverse fat distribution. Rather than inducing hepatic steatosis as with many LXR agonists, testosterone additionally protects against diet-induced hepatic lipid accumulation in this model . LXRs are key transcriptional regulators of lipid and carbohydrate metabolism known to control molecular pathways including cholesterol efflux, glucose regulation, fatty acid synthesis and inflammation . Testosterone altered the expression of master metabolic regulators as a potential signalling mode of action to influence lipid and glucose regulation.|Testosterone treatment to cells for 120 min, and insulin treatment 10 ng ml−1 and 250 ng ml−1 for 60 min, without removing testosterone; the data were analyzed by two-way repeated measures ANOVA test followed by Bonferroni post hoc analysis; data represent mean±s.d. We gave exogenous insulin treatment to the animals, and then checked for P-AKT (Ser-473) and FOXO1 levels in the liver of the two groups. In normal subjects, PEPCK level rises during fasting periods to attain normoglycemia, and in increased insulin resistance conditions also, its level increases resulting in increased hepatic glucose output. Thus, we investigated the effect of testosterone on gluconeogenesis pathway and insulin responsiveness in the liver. Instead, it could have altered signaling in the liver, which led to reduced hepatic glucose output in the testosterone-administered T2DM males.|Interestingly, in this study we observed that GH alone restored total SFAs in TXOX rats to the same levels of INTACTSO animals, a situation where SFAs levels dropped and MUFA levels increased. Hypothyroidism in non-castrated male rats highly increased the hepatic level of total SFAs compared to euthyroid INTACTSO rats (33). Fourth, in this study, T replacement in TXOX rats was not able to increase the transcription of hepatic genes linked to hepatic FA uptake, transport, activation or CHO removal nor PPARα target genes which, however, were positively regulated by E2 (33, 64). However, our data demonstrated that neither T nor GH, nor their combinatory treatment increased the levels of ERα mRNA in TXOX rats at the end-time point. Furthermore, T can functionally cooperate with GH to enhance its physiological effects on protein and energy metabolism, an effect that is developed mainly in the liver rather than in peripheral tissues (13, 15).|From the above studies, ARs are vital in regulating liver lipid homeostasis in both males and females , although hepatic ARs have greater impact in males than in females 102, 108. The total AR knockout mice develop liver steatosis and insulin resistance in both male and female mice . Besides androgen level, ARs are also critical in maintaining lipid metabolism in the liver.|But not all high liver enzyme levels mean there is something wrong. If liver enzymes stay high or go much higher than normal, the doctor may stop or lower the dose of testosterone. Sometimes exercise, muscle injury, or other medications can raise liver enzymes for a short time. If liver enzyme levels go above the normal range, the doctor will try to find out why. If the liver enzymes are still in a safe range, the therapy can usually continue. Before someone begins testosterone therapy, a doctor will usually order a baseline blood test. While testosterone does not always cause liver damage, it can sometimes affect liver enzymes.}
Action is needed when liver enzymes are high and other warning signs are present. The ratio between AST and ALT can also help tell what kind of liver problem might be happening. For example, a slight rise in ALT alone may mean mild liver stress, while a high AST and ALT together could suggest more serious injury.
Next, we went on to check the level of P-GSK3α (Ser-21) in the liver of Treated and Control animals as glycogen synthase kinase-3 (GSK3) also has an important role in PEPCK regulation and glucose homeostasis in the liver. Thus, all the above experiments suggest that testosterone is increasing hepatic insulin resistance. Testosterone had negatively affected insulin-induced AKT activation, but there was significant difference in P-AKT (Ser-473) levels of I(−)T(−) and I(+)T(+) samples, possibly because prolonged insulin treatment was not given to induce insulin resistance.

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