1821P - High serum FSH/T ratio as a marker for the development of cardiovascular disease in ADT recipients

Background

Cardiovascular disease (CVD) is a leading cause of death in men with prostate cancer (PC). Androgen deprivation therapy (ADT) may increase this risk. GnRH agonists or antagonists induce equivalent castration but have a distinctive effect on follicle-stimulating hormone (FSH). We hypothesize that FSH mediates the atherogenic and cardiovascular effects associated with testosterone (T) deficiency.

Methods

We investigated mouse models of atherosclerosis using gain and loss of FSH and two clinical studies with primary CVD endpoints. Low-density lipoprotein receptor-deficient (LDLR-/-) and FSHβ-/-;LDLR-/- mice were treated with different modes of ADT for 14 weeks and aortic atherosclerotic plaque, its necrotic and inflammatory content and serum hormones were determined. In a prospective cohort of PC patients commencing on ADT, serum FSH and T were determined after three and six months and related to the development of cardiovascular events. In a prospective nested case-control study of 848 men undergoing surgery, serum FSH and T were related to the development of cardiovascular event.

Results

Compared to LDLR-/- mice, FSHβ-/-;LDLR-/- mice, untreated or castrated, demonstrated significantly less atherosclerosis, but not following delivery of FSH. The significant differences in necrotic core and total atherosclerotic plaque in mice treated with GnRH-agonists vs. antagonists were nullified by loss of FSH in the FSHβ-/-;LDLR-/- mice. Atherosclerotic plaque, its necrotic and inflammatory content, correlated significantly with the serum FSH/T ratio. In PC patients commencing on ADT, serum FSH/T after three and six months significantly predicted the development of cardiovascular event. In men undergoing surgery, high FSH/T ratio increased odds of a postoperative cardiovascular event by 39% (95% CI 3-87%).

Conclusions

FSH facilitates CVD in men with low or castrated T. Serum FSH/T ratio associates with the risk of developing a cardiovascular event following a stressful cardiovascular trigger such as ADT or surgery. Accordingly, GnRH-antagonists associated with lower necrotic and atherosclerotic plaque burden in mice and clinically, with significantly lower serum FSH/T levels and fewer cardiovascular events compared to GnRH-agonists.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

J. H. Pinthus.

Funding

Ferring.

Disclosure

J.H. Pinthus, D. Margel: Financial Interests, Personal, Research Grant: Ferring. All other authors have declared no conflicts of interest.