Restoring testosterone homeostasis: The therapeutic potential of stem Leydig cells for late-onset hypogonadism

Late-Onset Hypogonadism (LOH), also known as male menopause syndrome, is a common health problem plaguing middle-aged and elderly men. Its core pathophysiological change lies in the progressive decline of testosterone levels in men with age. This leads to a series of symptoms involving sexual function, physical, and psychological aspects, seriously affecting the quality of life and overall health of patients. The core pathophysiological link of LOH lies in the progressive decline of testosterone levels caused by the reduction in the number and functional decline of Leydig cells (LCs). As the cell source of LCs, Stem Leydig cells (SLCs) play an indispensable role in maintaining testosterone homeostasis and testicular endocrine function. Compared to other stem cells, the localization of SLCs in testicular tissue enables them to directly sense and respond to various paracrine factors and signaling molecules from adjacent somatic cells and the testicular interstitial fluid, thereby achieving precise regulation of their self-renewal and differentiation potential. The functional decline of SLCs and the impaired adaptability in the aging microenvironment are the key intrinsic mechanisms for the occurrence and development of LOH. The discovery of SLCs and the clarification of their biological characteristics have opened up a brand-new perspective for understanding the pathogenesis of LOH and exploring innovative treatment strategies. The aim of this review is to systematically sort out the research progress of SLCs in LOH, with a view to providing a deeper theoretical basis and potential targets for the prevention and treatment of LOH.