Possible link between FSH and RANKL release from adipocytes in men with impaired gonadal function including Klinefelter syndrome

Introduction: The FSH receptor (FSHR) has been found to be expressed in human bone cells and bone marrow-adipocytes, and highly-debated mouse studies have suggested extra-gonadal effects of gonadotropins on glucose, adipocyte and bone homeostasis. These putative effects could be direct or indirectly mediated by endocrine factors released from bone-cells or adipocytes. Here, we investigated whether gonadotropins are linked with glucose- and lipid-metabolism in hypergonadotropic men.

Methods: Single centre, cross-sectional study of 307 men with idiopathic infertility and 28 men with Klinefelter syndrome (KS).

Outcome: associations between serum LH and FSH with soluble-RANKL (sRANKL), osteoprotegerin (OPG), osteocalcin, fasting glucose and insulin, sex steroids, and body composition. Expression of FSHR was studied in human-derived adipocyte-cell-models (hMADS, TERT-hWA) and FSH stimulation of RANKL expression and secretion in hMADS in vitro.

Results: Serum FSH was not directly linked with glucose- and lipid-metabolism. However, FSH was inversely associated with sRANKL in both infertile men and KS men (p = .023 and p = .012). Infertile men with elevated FSH (>11 U/L) had significantly lower sRANKL (p = .015). sRANKL was positively associated with fat percentage, fasting insulin, and glucose (all p < .05). Men with prediabetes had higher sRANKL (p = .021), but lower testosterone (p < .0001) and Inhibin B (p = .005). The FSHR was expressed in the investigated human derived adipocytes, and 3-6 h treatment with FSH markedly increased RANKL release (p < .05).

Conclusion: KS and infertile men with prediabetes have low Inhibin B, and testosterone but elevated RANKL compared with non-prediabetic men despite comparable levels of serum gonadotropins. Serum FSH and sRANKL was inversely associated in both infertile and KS men, but the increased release of RANKL from FSH treated adipocytes suggest a direct effect of FSH on RANKL production in some tissues. Further studies are required to clarify whether FSH targets RANKL in the skeleton. ClinicalTrial_ID:NCT01304927.