Abstract
Maintenance of gestation implicates complex function of multiple endocrine mechanisms, and disruptions of the global metabolic environment prompt profound consequences on fetomaternal well-being during pregnancy and postpartum. Polycystic Ovary Syndrome (PCOS) and gestational diabetes mellitus (GDM) are very frequent conditions which increase risk for pregnancy complications, including early pregnancy loss, pregnancy-induced hypertensive disorders, and preterm labor, among many others. Insulin resistance (IR) plays a pivotal role in the pathogenesis of both PCOS and GDM, representing an important therapeutic target, with metformin being the most widely prescribed insulin-sensitizing antidiabetic drug. Although traditional views neglect use of oral antidiabetic agents during pregnancy, increasing evidence of safety during gestation has led to metformin now being recognized as a valuable tool in prevention of IR-related pregnancy complications and management of GDM. Metformin has been demonstrated to reduce rates of early pregnancy loss and onset of GDM in women with PCOS, and it appears to offer better metabolic control than insulin and other oral antidiabetic drugs during pregnancy. This review aims to summarize key aspects of current evidence concerning molecular and epidemiological knowledge on metformin use during pregnancy in the setting of PCOS and GDM.
Highlights
Infertility currently affects approximately 48.5 million of women aged 20–44 years around the world [1], with severe implications in their physical and mental well-being [2]
insulin resistance (IR)-hyperinsulinemia-hyperandrogenemia cycle involved in the endocrine disruptions in Polycystic Ovary Syndrome (PCOS) [7] leads to the typical clinical picture of PCOS—featuring oligoanovulation and hyperandrogenic manifestations—and to diverse cardiometabolic comorbidities, such as impaired glucose tolerance [8], dyslipidemia [9], hypertension [10], central obesity [11, 12], accelerated atherosclerosis [13], and metabolic syndrome [14], which can appear as a myriad of distinct metabolic phenotypes [15] including mild, moderate, and severe forms of PCOS
Utilizing the HOMA-IR index as a surrogate for IR quantification, Huidobro et al [18] reported this condition to be associated with gestational diabetes mellitus (GMD), which supports the notion that this pregnancy-related metabolic disorder may be part of International Journal of Reproductive Medicine
Summary
Infertility currently affects approximately 48.5 million of women aged 20–44 years around the world [1], with severe implications in their physical and mental well-being [2]. Insulin resistance, defined as a decrease in cellular responsiveness to insulin signaling [31], triggers increased insulin secretion, a phenomenon termed “compensatory hyperinsulinemia” [32] This mechanism attempts to maintain lipid, carbohydrate, and protein metabolism homeostasis, it contributes to multiple aggregate consequences, such as the cardiovascular PCOS comorbidities [33], and favors hyperandrogenemia through various pathways. The elevated serum levels of free fatty acids triggered by IR represent an important adaptive mechanism in order to increase the glucose offer for fetal metabolism, they serve as a selfreinforcing pathway for IR (Figure 2) [76] These pro-IR phenomena are counterbalanced by several pancreatic function-enhancing signals, which allow for the typical over twofold increase in insulin secretion during the second and third trimesters of gestation [77].
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