Table 1.

Summary of Treatment Strategies for Improving Testosterone Levels

Intervention Strategy	Main Mechanism	Current Evidence	Clinical Application	Sources
Lifestyle Modifications (e.g., Exercise)	Enhances overall health and reduces inflammation, indirectly improving testosterone levels	Studies suggest moderate exercise can improve testosterone, especially in older men	Supplementary strategy for managing testosterone decline, suitable for health management	[131] [132]
LIPUS	Provides non-invasive physical stimulation to enhance testosterone secretion	Early studies show it can improve testosterone synthesis in aging Leydig cells, but more research is needed	Potential non-pharmacological strategy, pending further clinical evidence	[133]
Stem Cell Transplantation	Transplantation of SLCs restores Leydig cell function and increases testosterone synthesis	Animal studies show effective testosterone increase; clinical studies still limited	Promising for reversing age- or damage-related testosterone decline in the future	[134] [135] [136]
TRT	Provides exogenous testosterone to compensate for age- or disease-related testosterone deficiency	Multiple RCTs confirm effectiveness, but concerns about misuse and long-term safety exist	Commonly used for age-related testosterone decline; safety needs monitoring	[137] [138] [139]
SERMs	Blocks estrogen’s negative feedback on the HPG axis, stimulating testosterone production	Systematic reviews show it raises testosterone but increases thrombosis risk and reduces bone density with long-term use	Potential TRT alternative, requires more long-term safety and efficacy studies	[140] [141]
Melatonin	Protects Leydig cells through antioxidant and anti-inflammatory effects, delaying aging processes	Animal studies show protective effects, but convincing evidence of testosterone elevation is lacking	May help improve Leydig cell function; more clinical studies needed for validation	[142] [143] [144]
TSPO Ligands	Activates TSPO protein, promoting cholesterol transport to mitochondria, enhancing testosterone synthesis	Animal studies show increased testosterone in aged rats, but TSPO is expressed in multiple tissues, posing a challenge	Promising for endogenous testosterone enhancement, but tissue-specific activation is a challenge	[67] [145]
VDAC1 Peptide	Binds to 14–3-3ε, reducing its interaction with VDAC1, increasing cholesterol transport to mitochondria, enhancing testosterone synthesis	Animal studies show subcutaneous and oral administration safely increases testosterone levels in male rats	Promising strategy for testosterone increase; more research needed for clinical application	[146] [147]

HPG Hypothalamic-Pituitary–Gonadal, LIPUS Low-Intensity Pulsed Ultrasound, RCT Randomized Controlled Trial, StAR Steroidogenic Acute Regulatory protein, SLCs Stem Leydig Cells, TSPO Translocator Protein, VDAC1 Voltage-Dependent Anion Channel 1