Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies

Abstract

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited.

Scope of review: This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions.

Major conclusions: Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.

Keywords: Androgen excess; GLP-1; Insulin resistance; Obesity; PCOS; Poly-agonists.

Figure 1

Potential pathogenic factors of PCOS. During gestation, multiple factors including increased AMH levels, growth restriction, endocrine disruptors such as BPA, and androgen excess may predispose to the development of a PCOS-like phenotype in adulthood. During the postnatal period, exposure to endocrine disruptors and androgen excess and the development of obesity and insulin resistance are considered pathogenic factors that may also cause PCOS. Genetic and epigenetic factors may also increase the risk of developing PCOS. The figure was designed using tools provided by Servier Medical Art (https://smart.servier.com).

Figure 2

Metabolic impact of androgen excess in PCOS. In women with PCOS, androgen excess has a detrimental impact on different metabolic tissues, including the adipose tissue (white and brown), liver, pancreas, and skeletal muscle. Androgen excess also impairs systemic metabolism via the brain, primarily increasing adiposity and reducing insulin sensitivity. The figure was created using tools provided by Servier Medical Art (https://smart.servier.com).