Existing literature addressing the effects of fenugreek and spironolactone on the uterus is either lacking or yielding inconsistent results. Relevant molecular mechanisms have not been sufficiently studied. Thus, adult female rats were orally administered fenugreek or spironolactone for 30 days. Blood flow of the uterine artery and uterine microstructure were examined. Dose responses of isolated uterine contraction and relaxation were performed. Uterine estradiol (E2), anti-müllerian hormone (AMH), triiodothyronine (T3), thyroxine (T4), vascular endothelial growth factor (VEGF), and endothelial-selectin (E-selectin) as well as the expression of estrogen receptor alpha (E2Rα), thyroid hormone receptor alpha (THRα), adenosine receptor 2 (A2AR), and melatonin receptor 2 were assessed. Molecular docking was performed to identify the binding affinities of the investigated drugs to the assessed receptors. Fenugreek increased the peak systolic velocity (PSV) (+39.82%, P < 0.05), opposite to spironolactone (-42.94%, P < 0.0001). Unlike spironolactone which increased uterine tension during relaxation (+213.05%, P < 0.05), fenugreek reduced it (-170.69%, P < 0.0001). Opposite to spironolactone which increased T4 and THRα (+26.85% and +64.17%, respectively, P < 0.0001), fenugreek reduced them (-48.89% and -44.73%, respectively, P < 0.0001). Spironolactone increased E-selectin (+923.06%) against reducing VEGF (-45.58%, P < 0.0001), opposite to fenugreek (-81.61%, P < 0.001 against +226.81%, P < 0.05). Molecular docking revealed that fenugreek exhibited strong binding affinities to the assessed receptors, weak for spironolactone, especially for THRα and MT2R (ΔG of -12.59 kcal/mol and -11.28 kcal/mol, respectively). Fenugreek and spironolactone have distinct effects on the uterus. Direct drug-receptor interaction could be implicated.
Abdelmissih et al. (Sun,) studied this question.