Metformin Attenuates Spontaneous and Stimulated Myometrium Contractions in Rat Uterine Strips

Metformin, an adenosine monophosphate activated protein kinase activator, is indicated in pregnant and non-pregnant women for glucose dysregulation-associated conditions. Its role in various smooth muscle functions was documented. As the myometrium, crucial in fertility and pregnancy, is overlooked, the aim was to investigate the modulation of spontaneous and stimulated myometrium contractions by metformin.

The uterus of the adult female Sprague-Dawley rats (N=15) was excised and 4 full thickness myometrium strips (2 × 10 mm) were sectioned. The strips (n=57) were challenged with KCl (80 mM) to confirm viability and determine the reference maximum response. The spontaneous contractions and dose- response curves for oxytocin (10-11-10-4M) and carbachol (CCh, 10-8-10-4M) were recorded. Additionally, CCh-induced curves were re-obtained in M2-muscarinic receptor blocker, methoctramine (10-5M) and M3-muscarinic receptor blocker, and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (10-7M) exposed strips. The responses were obtained alone or in combination with metformin (10-4M).

Metformin attenuated both the amplitude and frequency of spontaneous contractions (P < .005) as well as those stimulated by oxytocin and CCh (P < .005). This effect was comparable to M2-receptor blockage, whereas the most potent inhibition was with M3-receptor blocker and/or combinations involving it. The 90% inhibition of contraction in metformin, 4-DAMP, and methoctramine exposed strips suggests a synergistic action.

Metformin may be beneficial in conditions favorable to fertilization, implantation, and prevention of preterm labor by reducing myometrial contractility during pregnancy and in non-pregnant indications. However, use of metformin should be approached with caution when strong myometrium contractions are required near term or postpartum.