Mularoni et al. biopsied testicular tissue from 24 organ donors and observed no significant change in LC number between ages 19–45, but a significant decrease thereafter . Owing to the scarcity of fresh, disease-free adult testicular tissue, evidence regarding the effect of aging on LC number in humans primarily comes from testicular biopsies of organ donors. This deterioration of the testicular microenvironment adversely affects other cell types. It is characterized by an increased population of macrophages, particularly those exhibiting a pro-inflammatory phenotype. Researchers obtained LCs from organ donors of different ages and stimulated them with human chorionic gonadotropin (hCG) in vitro. A stable testicular microenvironment is a prerequisite for the normal survival and function of LC.
(C) Representative result of RIA of plasma testosterone concentration on day 4 of EE2 injection. These results were in accordance with the finding that the AUCs of all EE2-injected rat groups were significantly decreased as compared with the control group (Fig. 3D). The AUCs of all EE2-injected groups were significantly decreased as compared with the control group (Fig. 3B). Compared to the control group, a dramatic decrease in the testosterone level of approximately 70% was observed after injection for 3 days with EE2 (Fig. 3A). To examine how EE2 was involved in interfering with testosterone biosynthesis, the two critical steps of steroidogenesis were detected. At the end of the incubation, culture media were collected for testosterone RIA. The results showed that the range of EE2 from 0.1 to 1000 nM did not cause any significant cell death as compared with the vehicle control.
Dysregulation of this microenvironment during aging plays a crucial role in LC dysfunction . The study found that increasing age led to decreased GnRH outflow, while pituitary responsiveness to GnRH remained normal. Early biomathematical models predicted a 33–50% decline in GnRH secretion in males from ages 20 to 80 years 26, 27. Aging can impair testosterone synthesis through its effects on the hypothalamic-pituitary–gonadal axis and direct actions on LCs 2, 24.
Cellular senescence is a highly stable state of cell cycle arrest , characterized by a decline in cellular function. A recent 2023 study in male cynomolgus macaques demonstrated a significant age-related reduction in the number of LCs . While these studies provide evidence of age-related changes in LC number through testicular biopsies, their main limitations include relatively small sample sizes and insufficient information on potential confounding variables. However, contradictory findings were reported by Gougeon et al., who biopsied testes from 26 men aged 16–80 and found no significant change in LC number with aging . Neaves et al. performed testicular biopsies on 30 men aged 20–76 who died from trauma or heart disease and found a 44% reduction in the total number of LCs in older males . In adult mice, complete depletion of Sertoli cells results in a 75% reduction in the number of LCs .
However, this stimulated effect was reduced in the presence of EE2 at 10 to 1000 nM (Fig. 1A). Its underlying molecular mechanism was a reduction of luteinizing hormone receptor (LHR)-regulatory activity, which in turn suppressed the process of steriodogenesis. Notably, a previous animal study reported that abnormal development of the external genitalia was observed in female offspring exposed to EE2 at 50 μg/kg during the neonatal period. Numerous studies have indicated that EDCs interfere with endogenous endocrine processes by mimicking hormonal action, leading to infertility, metabolic syndrome, and the rise of cancer incidence3–5.