Follicle-Stimulating Hormone Exacerbates Cardiovascular Disease in the Presence of Low or Castrate Testosterone Levels

[Display omitted] •Hypogonadism and PC are common in aging men and associate with cardiovascular disease. ADT to suppress T in PC patients also affects FSH.•We defined a hormonal state characterized by an elevated FSH/T ratio that correlated with the amount of aortic atherosclerotic and necrotic plaque in mice after ADT and clinically associated with the risk of developing a CVE following a stressful cardiovascular trigger.•ADT modalities which optimally suppress FSH (GnRH-antagonists) appear to have an inherent superior cardiovascular risk profile.•Larger studies that prospectively collect CVEs and serum are needed to validate our results in ADT recipients. Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T, modulates the cardiovascular effects associated with low T or castration. FSHβ−/−:low-density lipoprotein receptor (LDLR)−/− mice, untreated or castrated (orchiectomy, gonadotropin-releasing hormone agonist or antagonist), demonstrated significantly less atherogenesis compared with similarly treated LDLR−/− mice, but not following FSH delivery. Smaller plaque burden in LDLR−/− mice receiving gonadotropin-releasing hormone antagonists vs agonists were nullified in FSHβ−/−:LDLR−/− mice. Atherosclerotic and necrotic plaque size and macrophage infiltration correlated with serum FSH/T. In patients with prostate cancer, FSH/T following androgen-deprivation therapy initiation predicted cardiovascular events. FSH facilitates cardiovascular disease when T is low or eliminated.