Mechanisms of Leydig Cell Aging and Obesity-Related Hypogonadism in Men: A Review

Abstract

The rising prevalence of overweight, obesity, and late-onset hypogonadism (LOH) is seriously affecting the quality of life of middle-aged and older men. LOH is a testosterone deficiency syndrome that is closely associated with aging. Its main symptoms are erectile dysfunction, loss of libido, fatigue, and loss of bone density. Testicular Leydig cells are located in the connective tissue between the spermatogenic tubules and are the primary sites producing testosterone. Metabolic disorders such as obesity and hyperlipidemia accelerate Leydig cell aging, reduce testosterone levels, and contribute to the development of LOH. The pathogenesis of LOH mainly includes oxidative stress, inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress. The treatments for LOH include testosterone replacement therapy, senolytic therapy, stem cell therapy, and traditional Chinese medicine therapy. Obesity may be one of the important mechanisms of obesity-related LOH by promoting Leydig cell aging, changing the endocrine environment, and worsening chronic inflammation, and research in this field is still deepening. Therefore, this article reviews the mechanisms of testicular interstitial cell senescence and obesity-related delayed hypogonadism, as well as possible obesity management methods.

Figure 1

Mechanisms of testicular leydig cell senescence in obesity-related late-onset hypogonadism. Illustration: From left to right, they are endoplasmic reticulum stress, oxidative stress, senescence-associated secretory phenotype (SASP), cellular senescence, hypothalamic-pituitary-gonadal axis injury, immune cell activation, autophagy, and mitochondrial dysfunction in sequence. In the middle is the process of obesity – aging – testicular Leydig cell dysfunction.

Figure 2

Treatment of testicular leydig cell senescence in obesity-related late-onset hypogonadism. Illustration: From left to right are exercise therapy, stem cell therapy, traditional Chinese medicine therapy, drug therapy, and testosterone replacement therapy (TRT). In the middle is the process of obesity – aging – testicular Leydig cell dysfunction.