Table 1 Summary of Treatment Strategies for Improving Testosterone Levels

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]