The Heart: A Novel Gonadotrophin-Releasing Hormone Target

Abstract

Gonadotrophin-releasing hormone (GnRH) is a hypothalamic hormone transported by the hypophyseal portal bloodstream to the pituitary gland, where it binds to GnRH receptors. However, GnRH receptors are expressed in multiple extrapituitary tissues, although their physiological relevance is not fully understood. GnRH agonists are employed extensively in steroid deprivation therapy, especially to suppress testosterone in prostate cancer. Because GnRH agonist treatment is associated with increased coronary heart disease and myocardial infarction, we investigated the impact of GnRH on cardiomyocyte contractile function. Cardiomyocytes were isolated from mouse hearts and mechanical and intracellular Ca(2+) properties were evaluated, including peak shortening amplitude (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90) ), maximal velocity of shortening/relengthening (± dLdt), electrically-stimulated rise in Fura-2 fluorescence intensity (ΔFFI) and Ca(2+) decay. GnRH (1 ng/ml) increased PS, ± dL/dt, resting FFI and ΔFFI, and prolonged TPS, TR(90) and Ca(2+) decay time, whereas 1 pg/ml GnRH affected all these cardiomyocyte variables, except TPS, resting FFI and ΔFFI. A concentration of 1 fg/ml GnRH and the GnRH cleavage product, GnRH-[1-5] (300 pg/ml), had no effect on any cardiomyocyte parameter. The 1 pg/ml GnRH-elicited responses were attenuated by the GnRH receptor antagonist cetrorelix (10 μm), the protein kinase A (PKA) inhibitor H89 (1 μm) but not the protein kinase C inhibitor chelerythrine chloride (1 μm). These data revealed that GnRH is capable of regulating cardiac contractile function via a GnRH receptor/PKA-dependent mechanism. If present in the human heart, dysfunction of such a system may play an important role in cardiac pathology observed in men treated with GnRH agonists for prostate cancer.

The Effects of Androgen Deprivation Therapy on Cardiac Function and Heart Failure: Implications for Management of Prostate Cancer

“…35 In mice, GnRH-ags might modulate contractile function via a mechanism dependent on GnRH receptor and protein kinase A. 36 …”

Gonadotropin-releasing hormone antagonist: A real advantage?

“…Inflammatory events during plaque rupture include the production of various cytokines, and activated macrophages and lymphocytes further degrade the fibrous cap, leading to plaque instability and increased risk of CVD [26]. Treatment with GnRH agonists could lead to dysfunction of the cardiac receptors regulating cardiac contractile function, and this could thereby play an important role in cardiac pathology [29]. In contrast, GnRH antagonists do not activate T-cell proliferation and activity and thus are unlikely to contribute to plaque destabilization through this mechanism [27,28].…”

Kardiovaskuläre Risikopatienten unter Androgenentzugstherapie

“…Weiterhin ist denkbar, dass LHRH-Agonisten direkt auf das kardiovaskuläre System wirken, indem sie die Herzkontraktilität und die Konzentration intrazellulä-rer Kalziumionen regulieren. Dies könn-te über eine vom GnRH-Rezeptor ausgehende Aktivierung der Proteinkinase A (PKA) erfolgen, deren Substrate wie Phospholamban, der L-Typ-Kalziumkanal und Komponenten des kontraktilen Apparates sich in den Kardiomyozyten befinden [10].…”