Androgen deprivation therapy and side effects

Abstract

Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones (FSH), thereby lowering testosterone to castrate levels. This is associated with adverse events (AEs), including cardiovascular (CV) disorders, bone fractures, metabolic dysfunction, and impaired cognitive function. This literature review discusses these AEs, with a focus on CV and bone-related events. A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix. While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome, one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health, whereas antagonists do not. GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists, no differences in risk are predicted. Other common AEs with ADT include injection site reactions, which are much more common with degarelix than with GnRH agonists, which may reflect differing administration and injection techniques. Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists, especially in patients with pre-existing CV disease and other co-morbidities. Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.

CTHRC1 is a prognosis-related biomarker correlated with immune infiltrates in colon adenocarcinoma

“…Additionally, many cancer cells abnormally express GPCRs, including those from lung, prostate, colon, pancreas, and mesenchymal cancer cells, which stimulate cell proliferation, migration, invasion, and angiogenesis [ 27 ]. Among members of the GPCR family, gonadotropin-releasing hormone receptor (GnRH) has been reported to be overexpressed in various tumor cells such as melanoma, prostate and endometrial cancer, leiomyoma, breast cancer, choriocarcinoma, epithelial ovarian tumor, and stromal ovarian tumor [ 28 ]. Therefore, the GnRH receptor is a reliable target for the clinical treatment of cancer [ 29 ].…”

Systemic ablation of Camkk2 impairs metastatic colonization and improves insulin sensitivity in TRAMP mice: Evidence for cancer cell-extrinsic CAMKK2 functions in prostate cancer

“…While CAMKK2 is an interesting therapeutic target due to its role in prostate cancer cell biology, prior reports indicate that CAMKK2 inhibitors may have additional benefits for prostate cancer patients [20]. One of the most common comorbidities for men undergoing ADT is metabolic syndrome [21].…”

“…Fourth, we did not have a HFD-fed, castrated TRAMP cohort. In prostate cancer patients, ADT is known to increase the risk of metabolic syndrome [20,21,57]. We would predict that castrated mice fed a HFD-diet may benefit even more from CAMKK2 inhibition, a scenario that remains to be tested.…”

“…In addition, CAMKK2 inhibition protects mice from developing metabolic syndrome shown through a decrease in blood glucose and insulin resistance as well as regression of nonalcoholic fatty liver disease (NAFLD) [17][18][19]. This phenomenon was of interest to us because a major comorbidity for prostate cancer patients is an increased risk of metabolic syndrome [20,21]. Thus, in addition to testing CAMKK2's role in an aggressive prostate cancer GEMM, we sought to simultaneously assess its impact on systemic metabolism to determine if targeting CAMKK2 could be dually beneficial in both treating the tumor and its linked comorbidities.…”

Einflussfaktoren bei der Wahl der Androgendeprivationstherapie für Patienten mit hormonsensitiven Prostatakarzinom

“…Das Patientenkollektiv war in dieser Studie zu klein, um zuverlässige Aussagen bezüglich des Einflusses der ADT auf das kardiovaskuläre Risiko ableiten zu können. Verschiedene Publikationen [ 2 , 3 , 15 , 23 ] und aktuelle Reviews [ 5 , 6 , 10 , 24 ] deuten jedoch auf die Vorteile der GnRH-Antagonisten bei Patienten mit kardiovaskulären Vorerkrankungen hin.…”