Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is now recognized to be the most common endocrinopathy in women of reproductive age with a prevalence of 6.6-6.8%. PCOS, a syndrome of unknown etiology, was initially regarded as a reproductive disorder. However, in the last 15 years the role of insulin resistance (IR) has been identified as a significant contributor to the pathogenesis of PCOS, and the metabolic and cardiovascular sequelae of the syndrome have been increasingly appreciated. The coexistence and interaction of reproductive and cardiometabolic abnormalities in the context of PCOS have created a need for a modified therapeutic management of affected women. Insulin sensitizers, particularly metformin, have been introduced as a pharmaceutical option targeting not only IR, but several other aspects of the syndrome, including reproductive abnormalities. The landscape of the multifaceted actions of metformin evolves to broaden the therapeutic implications of this old drug in a new fashion for patients with PCOS. Most recently, the spectrum of metformin's targets has been expanded, and molecular studies have explored the tissue-specific mechanisms of metformin in the liver, the muscle, the endothelium, and the ovary. The use of metformin in pregnant women with PCOS comprises another scarcely explored, but promising area of research. This review attempts to cover the spectrum of metformin's cellular actions in different tissues and to summarize the current literature regarding the potential medical value of this medication in PCOS. Even if many of these actions are individually modest, they seem to be collectively sufficient to confer therapeutic benefits not only in cardiometabolic aspects but also in reproductive aspects of PCOS.

Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome

“…Metformin suppresses lipolysis, modulates adipokine secretion and decreases lipogenesis in adipose tissue [32]. In skeletal muscle, metformin increases basal and insulinmediated glucose uptake possibly because of the reduction in glucotoxicity and lipotoxicity resulting from its actions in the liver and adipose tissue [32].…”

“…In skeletal muscle, metformin increases basal and insulinmediated glucose uptake possibly because of the reduction in glucotoxicity and lipotoxicity resulting from its actions in the liver and adipose tissue [32]. In the ovary, metformin is presumed to exert both direct and indirect effects on androgen production.…”

A clinical study to determine metformin as a cause of serum vitamin B12 decrease and effect of combination of metformin and mecobalamin on serum vitamin B12 levels in type 2 diabetics

“…7,8 It is known that metformin demonstrates an effect of hepatic gluconeogenesis suppression. 9 Further, reduction in serum glucose is also a consequence of its action on several tissues via activation of the adenosine monophosphateactivated protein kinase (AMPK) system, reducing insulin resistance. 9 Additionally, metformin has beneficial effects on carbohydrate metabolism, weight loss, and vascular protection.…”

“…9 Further, reduction in serum glucose is also a consequence of its action on several tissues via activation of the adenosine monophosphateactivated protein kinase (AMPK) system, reducing insulin resistance. 9 Additionally, metformin has beneficial effects on carbohydrate metabolism, weight loss, and vascular protection. 10 Despite its known efficacy and satisfactory safety profile, it has non-negligible side effect such as decreased serum vitamin B12 levels.…”

“…There are certain postulations demonstrating that vitamin B12 deficiency is due to either alteration in small bowel motility, which stimulate small bowel bacterial overgrowth and/or by decreasing vitamin B12 absorption. 14,15 Drop in vitamin B12 concentrations in turn, might results in rise in homocysteine (Hcy) concentrations, an independent risk factor for cardiovascular disease, particularly among individuals with T2DM. 16 Vitamin B12 is one of the vital nutrients required for the proper functioning of the nervous system, cardiovascular system and hemopoesis.…”