Peripubertal orchidectomy transitorily affects age-associated thymic involution in rats

Abstract

The role of gonadal hormones in induction and, particularly, maintenance/progression of rat thymic involution, which normally starts around puberty, was reassessed by examining the effects of peripubertal orchidectomy on thymic weight and morphometric parameters at different times up to the age of 10 months. Up to 6 months postcastration both thymic weight and cellularity in orchidectomized (Cx) rats were greater than in age-matched control rats, sham Cx (Sx). The increase in thymic cellularity reflected an increase in thymocyte proliferation rate (the proportion of proliferating cells was 18.6 ± 0.7% in 2-month-old Cx (N = 5) vs 13.4 ± 0.3% (N = 5) in age-matched Sx rats) followed by reduced sensitivity to apoptotic signals (apoptotic thymocytes were 9.8 ± 0.9% in 2-month-old Cx (N = 5) vs 15.5 ± 0.3% (N = 5) age-matched Sx rats). However, 9 months post-orchidectomy, neither thymic weight and cellularity nor any of the morphometric parameters analyzed differed between Cx and control rats. The reduction of thymic cellularity in Cx rats to control values may be related to increased sensitivity of their thymocytes to apoptotic signals in culture (72.6 ± 1.2% in 10-month-old vs 9.8 ± 0.9% in 2-month-old Cx rats) followed by reduced responsiveness to proliferative stimuli (14.1 ± 0.2% in 10-month-old vs 18.6 ± 0.7% in 2-month-old Cx rats). Thus, the study indicates that the effects of peripubertal orchidectomy on thymic weight and cellularity, as well as on the main morphometric indices, are long-lasting but not permanent, i.e., that removal of the testes can only postpone but not prevent age-related organ atrophy and consequently functional deterioration of the immune system.

Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way

“…This could be ascribed to the age-related decline in thymopoietic efficacy. This is consistent with the previous studies indicating that the effects of orchidectomy on the rodent thymus are long lasting but transitory [11,12]. In other words, our findings indicated that withdrawal of testicular hormones beginning from the late prepubertal stage only postponed the initiation of thymic involution, so that, despite a notably greater number of CD4+CD8+ DP thymocytes, as also reported previously [35,36], and RTEs in young ORX rats compared to age-matched controls, there was no significant difference in the value of these parameters between aged ORX and control rats.…”

“…In the same line were data indicating increased thymic size in rodents following surgical ablation of testicular hormones [8,9], as well as in male mice showing inherited androgen receptor (AR) insensitivity [10]. However, subsequent reassessment of the role of androgens in thymic involution in mice [11] and rats [12] showed that the beneficial effects of androgen ablation on thymic size and cellularity are of limited duration. This led to the hypothesis that androgens contribute to the initiation of thymic involutive changes, whereas they do not have a role in the maintenance/progression of this process [13].…”

Age-Associated Remodeling of Thymopoiesis: Role for Gonadal Hormones and Catecholamines

“…In favor of the notion that the peripubertal rise in the circulating levels of sex steroid hormones and initiation of involutive changes in thymus are 2 disassociated events, they pointed to the data obtained almost 20 years ago that the thymus weight in C57BL/6 female mice returns to the level in age-matched controls by 20 months after gonadectomy [50] . We have also noted that effects of castration performed at 30 days of age on thymus of Wistar rats are long lasting but not permanent, so that the volume of lymphoid so-called true thymic tissue and thymic cellularity returns to the corresponding levels in the sham-Cx rats by the age of 10 months [52,53] . To further support the same hypothesis, Min et al [51] have stated that there is no increase in thymus cellularity in old animals at the time of andropause or menopause despite the decline in circulating sex steroids.…”

“…Collectively, these data, together with findings indicating that CAs acting via ␣ -and ␤ -adrenoceptors have diminishing effects on thymic cellularity and thymopoiesis [45,46,48,275,276] , may suggest that peripubertal rise in gonadal steroid levels provides increased levels of NA in adult rat thymus, thereby insuring thymus involution through adrenoceptor-mediated mechanisms. However, at the first glance, this hypothesis does not offer an explanation for the transitory effects of peripubertal gonadectomy on thymus [50,51,53] , which have challenged the commonly held view that thymus involution is a gonadal steroid-dependent event.…”

“…Finally, it should be pointed out that the commonly held view that the peripubertal rise in gonadal steroid hormone level is causally linked with thymus involution has recently been challenged by findings showing that effects of peripubertal gonadal ablation on thymic weight and cellularity in mice of both sexes [50,51] and male rats [52,53] are long lasting, but not permanent. Accordingly, it has been speculated that the peripubertal increase in the levels of gonadal steroid hormones and thymic involution are 2 dissociated events, and that gonadal steroids are only potent modulators of thymic size and function, but not responsible for the age-associated thymic changes [51] .…”