Background and aim: Androgens and glucocorticoids are regulated via the hypothalamus-pituitary-gonadal (HPG) and hypothalamus-pituitary-adrenal (HPA) axis, respectively. We aimed to check possible interference of androgen deprivation with the HPA axis and circulating glucocorticoid levels. Androgen deprivation is most widely used in the treatment of prostate cancer, but is also applied in gender-affirming care and males with hypersexual disorder. Current insights on the possible impact of androgen deprivation on the HPA axis are limited.
Material and methods: We chemically castrated 14-wk-old male mice using the GnRH-receptor antagonist degarelix (DGX) and supplemented them for 2 weeks with either vehicle (VEH) or the androgen dihydrotestosterone (DHT). The control group received no intervention (SHAM). We evaluated the HPA axis in basal condition as well as after stress, where we used the novelty-induced stress test and measured total serum corticosterone levels 10 and 120 minutes after stress induction.
Results: Androgen deprivation was confirmed by 5-fold reduction of seminal vesicle weight in DGX-VEH compared to SHAM, and supplementation of DHT treatment restored this parameter. Total serum corticosterone (CORT) levels at baseline were similar in the 3 different groups (SHAM, DGX, DGX-VEH). After 10 min of induced stress, DGX-VEH had higher total serum CORT compared to SHAM and DGX-DHT. Total serum CORT levels returned to baseline after 120 min in all groups. Furthermore, after 2 weeks of treatment no changes were observed in hypothalamic glucocorticoid receptor (GR) and androgen receptor (AR) mRNA expression. However, hypothalamic corticotropin releasing hormone (CRH) mRNA expression was increased by DGX, but was not affected by DHT treatment. Hepatic corticosteroid binding globulin (CBG) mRNA was 4-fold higher in DGX-VEH and restored to SHAM levels by DHT treatment. Protein levels of CBG in liver were unaffected, but serum levels of CBG were increased in the DGX group and restored to SHAM levels by supplementation of DHT.
Conclusion: Importantly, although androgen deprivation has no effect on basal total serum CORT levels, serum levels of CBG were increased. Even more, androgen deprivation leads to increased total serum CORT in circumstances of stress. We hypothesize that androgen deprivation might additionally sensitize the negative feedback loop of the HPA axis.