Polycystic ovary syndrome: pathophysiology and therapeutic opportunities Original paper

What Was Reviewed?

This comprehensive review synthesized current evidence on the pathophysiology of polycystic ovary syndrome (PCOS) and emerging therapeutic opportunities. It explored how PCOS results from a combination of polygenic susceptibility, environmental influences, and developmental programming. The review paid particular attention to neuroendocrine disruption, androgen biosynthesis, insulin resistance, and the role of gut microbiota and adipose tissue function. It integrated findings from clinical and experimental models to explain the disease’s reproductive and metabolic features and offered a detailed examination of therapeutic agents in development, including kisspeptin agonists, neurokinin 3 receptor antagonists, AKR1C3 inhibitors, GLP-1 receptor agonists, and microbiota-based interventions. These insights provided a modern framework for targeting PCOS not just as a reproductive disorder, but as a systemic, multifactorial syndrome with metabolic and microbial roots.

Who Was Reviewed?

The review analyzed studies involving a broad population of women with PCOS from various ethnic backgrounds and phenotypic subtypes. It included data from clinical cohorts, epidemiological studies, and preclinical models such as letrozole- and androgen-induced rodent models. Patients ranged in metabolic phenotype, encompassing lean and obese subtypes with or without insulin resistance. The review also drew on human genome-wide association studies (GWAS), metagenomic studies, and randomized controlled trials investigating microbiota and hormonal therapies. The diversity of sources allowed the authors to assess pathophysiological mechanisms relevant to both early onset and chronic PCOS progression.

What Were the Most Important Findings?

One of the most critical findings is the multifaceted etiology of PCOS, with gut microbiota emerging as a pivotal player. Women with PCOS exhibit increased levels of Bacteroides vulgatus and decreased concentrations of beneficial bile acids such as glycodeoxycholic acid and tauroursodeoxycholic acid. In mouse models, oral gavage with B. vulgatus or fecal samples from PCOS patients induced insulin resistance, ovarian morphological disruption, and hyperandrogenism. These effects were mediated partly through suppressed interleukin-22 (IL-22) production and altered bile acid metabolism. Supplementation with IL-22 or bile acids reversed some PCOS-like features, reinforcing the causal role of microbial dysbiosis. Other major microbial associations (MMAs) include increased LPS-producing gram-negative bacteria and reduced SCFA-producing species like Faecalibacterium prausnitzii, which impair gut barrier integrity and promote systemic inflammation.

The review also underscored that hyperinsulinemia not only drives androgen production but suppresses SHBG, creating a feedback loop of worsening endocrine dysfunction. Adipose tissue contributes actively to androgen synthesis, particularly via AKR1C3, which converts adrenal-derived precursors into potent 11-oxygenated androgens. These metabolites have comparable potency to testosterone and correlate strongly with metabolic risk in PCOS. Additionally, neuroendocrine irregularities, particularly increased kisspeptin and GnRH pulsatility, exacerbate LH-driven androgen excess. The convergence of these pathways—microbial, hormonal, metabolic—solidifies PCOS as a systemic condition requiring holistic intervention strategies.

What Are the Implications of This Review?

This review reframes PCOS as a neuro-metabolic disorder deeply intertwined with gut microbial composition and function. Clinicians should consider integrating microbiome assessment into PCOS diagnostics, especially in patients with lean phenotypes or atypical presentations. Therapeutically, the review paves the way for microbiota-targeted strategies such as IL-22 modulation, bile acid supplementation, and personalized probiotics. The consistent microbial shifts identified—especially involving Bacteroides vulgatus and SCFA-producing taxa—could serve as biomarkers or therapeutic targets. Moreover, understanding the role of AKR1C3 in adipose-driven androgen synthesis opens a novel therapeutic avenue for endocrine normalization. This work also highlights the value of targeting kisspeptin and neurokinin pathways, providing hormone-specific modulation without systemic suppression. In totality, the review advocates for multi-system treatment strategies that address not just fertility and cosmetic concerns, but long-term cardiometabolic health.