The Pathophysiological Mechanism and Clinical Treatment of Polycystic Ovary Syndrome: A Molecular and Cellular Review of the Literature

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder among women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The pathogenesis of PCOS involves a complex interplay of genetic and environmental factors, including insulin resistance (IR) and resultant hyperinsulinemia. Insulin receptors, primarily in skeletal muscle, liver, and adipose tissue, activate downstream signaling pathways like PI3K-AKT and MAPK-ERK upon binding. These pathways regulate glucose uptake, storage, and lipid metabolism. Genome-wide association studies (GWASs) have identified several candidate genes related to steroidogenesis and insulin signaling. Environmental factors such as endocrine-disrupting chemicals and lifestyle choices also exacerbate PCOS traits. Other than lifestyle modification and surgical intervention, management strategies for PCOS can be achieved by using pharmacological treatments like antiandrogens, metformin, thiazolidinediones, aromatase inhibitor, and ovulation drugs to improve insulin sensitivity and ovulatory function, as well as combined oral contraceptives with or without cyproterone to resume menstrual regularity. Despite the complex pathophysiology and significant economic burden of PCOS, a comprehensive understanding of its molecular and cellular mechanisms is crucial for developing effective public health policies and treatment strategies. Nevertheless, many unknown aspects of PCOS, including detailed mechanisms of actions, along with the safety and effectiveness for the treatment, warrant further investigation.

Keywords: hyperandrogenism; hyperinsulinemia; insulin resistance; polycystic ovary syndrome.

Figure 1

The clinical presentations and comorbidities of PCOS.

Figure 2

The etiology, pathophysiology, and hallmarks of PCOS.

Figure 3

The flowchart of database searching, screening, selection, and inclusion of eligible articles from the literature.

Figure 4

A summarized process of the biosynthesis of cholesterol. Cholesterol is either absorbed through diet uptake or more often produced by the de novo pathway, which takes place at the endoplasmic reticulum of the hepatocyte (the arrows depicted a cascade of the step-by-step biosynthesis). The initial reactants are two acetyl-CoA molecules, which merge and convert into acetoacetyl-CoA. Acetoacetyl-CoA then merges with another acetyl-CoA molecule to form HMG-CoA. HMG-CoA goes through a series of complex chemical reactions (displayed as “…”) and is eventually converted to cholesterol.

Figure 5

The process of human steroidogenesis. Through a series of different chemical reactions, cholesterol can be converted into cortiocosterone/aldosterone, cortisol and sex hormones, respectively. The process is delicately regulated by various catalysts and signaling pathways. The arrows indicate the direction of the biosynthesis, catalyzed by different enzymes. Androgens such as androstenedione and testosterone can be converted into female sex hormones such as estrone and estradiol by CYP19A1. Dihydrotestosterone can be converted into androsterone through a series of different reactions with multiple catalysts involved, shown with “…” below the lowest arrow.

Figure 6

The cell signaling pathway of steroidogenesis.

Figure 7

The PI3K-AKT cell signaling pathway of insulin and glucose utilization, which is one of the most significant intracellular signaling cascades involving phosphorylation of mediators (a). The muscle (b), liver (c) and adipose tissue (d) are the three main target organs of insulin action. Insulin enhances protein synthesis via the mTORC1 pathway, which facilitates muscle growth and repair (b). Once the PI3K-AKT pathway is triggered, it leads to the activation of glycogen synthase and in turn the formation of glycogen in hepatocytes. Concomitantly, insulin suppresses lipolysis and encourages fatty acid synthesis (c). Insulin can also enhance lipid storage, known as de novo lipogenesis—through mechanisms such as upregulation of the activity of lipogenic enzymes like fatty acid synthase and acetyl-CoA carboxylase and the inhibition of the breakdown of triglycerides. The arrows in the flow chart are used to describe the directions of the chemical reactions in the signaling pathway. The ↑ and ↓ arrow symbols, displayed next to glycogen synthase, lipogenic enzymes and lipolysis refer to an increase in glycogen synthase and lipogenic enzymes, as well as decrease in lipolysis, respectively.

Figure 8

The action mechanism of metformin in the liver and gastrointestinal (GI) tract. Metformin boosts the AMPK pathway in the liver through the lysosomal pathway and an increase (↑) of ADP:ATP and AMP:ADP ratios. A series of reactions can lead to the decrease (↓) of gluconeogenesis. On the other hand, metformin causes a change in gut microbiota in the GI tract, as well as an increase (↑) in GLP-1 secretion, which further enhances (↑) the glycolytic pathway. Finally, the action of metformin results in increased sugar consumption and decreased sugar production.