Review
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jul 15, 2025; 16(7): 108789
Published online Jul 15, 2025. doi: 10.4239/wjd.v16.i7.108789
Decoding androgen excess in polycystic ovary syndrome: Roles of insulin resistance and other key intraovarian and systemic factors
Neervana Rambaran, Md Shahidul Islam
Neervana Rambaran, Md Shahidul Islam, Department of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, Durban 4000, KwaZulu-Natal, South Africa
Author contributions: Rambaran N contributed to the collation of information and wrote the manuscript; Islam MS contributed to the study design, co-wrote the manuscript, and critiqued the draft to finalize the manuscript. Both authors contributed to the conceptualization, read and approved the final version of the manuscript before submission.
Supported by Incentive Funding for Rated Researchers from the National Research Foundation, Pretoria, No. 145943; and Research Reward from the Research Office of the University of KwaZulu-Natal, Durban, South Africa.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Md Shahidul Islam, PhD, Department of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, University Road, Chiltern Hills, Durban 4000, KwaZulu-Natal, South Africa. islamd@ukzn.ac.za
Received: April 23, 2025
Revised: May 19, 2025
Accepted: June 23, 2025
Published online: July 15, 2025
Processing time: 83 Days and 16 Hours
Abstract

Recent studies have potentiated the essential role of androgens in normal folliculogenesis and, therefore, female fertility. Contrastingly, excess androgen levels, i.e., hyperandrogenism (HA), a hallmark characteristic of polycystic ovary syndrome, overrides the delicate balance of folliculogenesis, leading to follicular arrest and ovulatory issues. Insulin resistance (IR) has a profound effect on elevating androgen secretion and is considered one of the primary factors driving both ovarian androgen production and metabolic dysfunction in polycystic ovary syndrome. Together with IR, disruptions in key intraovarian and systemic factors, including activin, inhibin, follistatin, anti-Mullerian hormone, bone morphogenetic proteins, growth differentiation factor-9 and Kit ligand, as well as dysregulation in both the insulin and the transforming growth factor-β superfamily signaling pathway, contribute to follicular arrest, elevated androgen levels and metabolic dysfunction, exacerbating HA. Additionally, suppression of sex hormone-binding globulin, disrupted adipose-neuroendocrine signaling and altered microRNA expression heighten HA, with IR serving as the fundamental contributor. Emerging evidence implicates impaired atresia together with non-apoptotic cell death, such as ferroptosis and pyroptosis, which have also been associated with ovarian dysfunction. A comprehensive understanding of the most significant factors, particularly IR, which amplifies androgen production through hyperinsulinemia-mediated stimulation of theca cells, is essential for identifying targeted therapeutic strategies.

Keywords: Polycystic ovary syndrome; Hyperandrogenism; Insulin resistance; Oxidative stress; Obesity; Folliculogenesis; Ovary

Core Tip: Polycystic ovary syndrome is a multifactorial disorder characterized by excess ovarian androgen production, frequently amplified by insulin resistance. This review explores how insulin resistance intersects with systemic and intraovarian factors such as activin, inhibin, follistatin, anti-Mullerian hormone, bone morphogenetic proteins, growth differentiation factor-9 and Kit ligand, as well as the dysregulation in both the insulin and the transforming growth factor-β superfamily signaling pathway, to create a vicious cycle of reproductive and metabolic dysfunction. A deeper understanding of these factors and pathways emphasizes the need for individualized, multi-targeted therapeutic approaches beyond conventional treatments.