Role of FSH in the musculoskeletal side effects associated with androgen deprivation therapy (ADT) for prostate cancer

Introduction: In the treatment of advanced prostate cancer, gonadotropin releasing hormone/luteinizing hormone releasing hormone (GnRH/LHRH) receptor agonists and antagonists both reduce testosterone to castrate levels. 
However, much evidence shows that the GnRH antagonist (degarelix), more effectively suppresses follicle stimulating hormone (FSH) levels. FSH has been implicated in some of the pathophysiologic effects associated with canonical ADT, including bone loss; however, the mechanism of action has yet to be elucidated.

Methods: To further explore the relationship between FSH and ADT unwanted effects, a panel of world key opinion leaders in the treatment of prostate cancer was convened, and a review of the literature in Medline and PubMed was conducted.

Results: Several potential mechanisms mediated by FSH which may contribute to adverse musculoskeletal effects were identified. FSH stimulates osteoclastogenesis by promoting the expression of receptor activator of nuclear factor-kappaB (RANK) on osteoclast precursor cells, as well as the activation of RANK through the stimulation of RANK-ligand secretion. FSH also promotes the release of tumor necrosis factor (TNF)-α from mononuclear cells, which likewise differentiates precursors cells into osteoclasts. Additionally, osteoclast survival time was shown to increase following FSH-mediated stimulation of interleukin (IL)-1β from monocytes, allowing ongoing promotion of bone resorption. Also, patients with bone metastases demonstrate increased concentrations of the bone resorption marker, N-telopeptide, which has been correlated with morbidity and mortality outcomes.

Conclusions: These findings suggest that possible undesired effects of ADT may be precipitated from the result of FSH escape. Additional research is required to confirm a causal relationship between the FSH pathway and the adverse effects associated with ADT.

Funding source: The studies reported were funded by Ferring Pharmaceuticals Inc.

E. David Crawford MD1, Andrew V. Schally PhD MDhc (Multi) D.Sc hc2*, John H. Hoenemeyer MD1, Neal D. Shore MD FACS CPI3, Phillip A. Saccone PhD4*, Thomas J. Beveridge PhD4*, Dennis C. Marshall RN MS PhD4*.
1Aurora, CO, 2Miami, FL, 3Myrtle Beach, SC, 4Parsippany, NJ.


Beveridge IPCU2017 Poster 1.13.17c 301x