Serum Copper Level and Polycystic Ovarian Syndrome: A Meta-Analysis Original paper

What was reviewed?

This meta-analysis reviewed the association between serum copper levels and polycystic ovary syndrome (PCOS) by pooling data from nine cross-sectional studies encompassing a total of 2,274 women (1,168 with PCOS and 1,106 healthy controls). The goal was to clarify inconsistent findings in previous literature regarding whether circulating copper levels differ significantly in women with PCOS and whether elevated copper might play a role in the pathophysiology of the disorder.

Who was reviewed?

The reviewed studies included adult women diagnosed with PCOS based on the Rotterdam criteria, alongside matched control participants without PCOS. These studies were conducted across diverse geographical regions, including China, Turkey, India, Iran, Sudan, and the USA, and were published between 2012 and 2020. The studies employed either atomic absorption spectrophotometry or inductively coupled plasma mass spectrometry to quantify serum copper. All were assessed as high quality using the Newcastle–Ottawa Scale.

What were the most important findings?

The meta-analysis found that women with PCOS have significantly higher serum copper levels than healthy controls, with a standardized mean difference (SMD) of 0.51 µg/mL. This effect remained statistically significant even after conducting sensitivity analyses and omitting a single contradictory study, which showed an inverse trend. Subgroup analyses by country (China vs. Western) confirmed that elevated copper was consistently observed in both populations, suggesting a robust association independent of geographic or ethnic background.

Biologically, copper acts as a cofactor in several enzymatic reactions involving oxidative metabolism and plays a role in hormone receptor regulation, including acting as a metalloestrogen capable of activating estrogen receptor alpha. Increased copper levels may contribute to oxidative stress in PCOS through enhanced ROS generation, glutathione depletion, and lipid peroxidation. These processes can disrupt endocrine function and potentially influence ovarian physiology, although more research is needed to clarify copper’s direct role in PCOS pathogenesis.

From a microbiome perspective, copper excess disrupts the gut microbiota by decreasing beneficial taxa such as Bifidobacterium spp. and Faecalibacterium prausnitzii, while favoring pro-inflammatory genera like Proteobacteria. These changes contribute to leaky gut, systemic inflammation, and insulin resistance, which are core features of PCOS. As such, elevated copper may not only be a marker of oxidative and inflammatory stress but also a mediator of microbiome-endocrine dysregulation.

What are the implications of this review?

This meta-analysis provides clear evidence that elevated serum copper is associated with PCOS and may play a mechanistic role in its pathophysiology. The findings support the hypothesis that copper acts as an endocrine disruptor by generating oxidative stress and modulating hormone activity, including via metalloestrogenic pathways. For clinicians, this raises the potential for serum copper to serve as a biomarker for metabolic and inflammatory status in PCOS patients. Moreover, it opens new avenues for therapeutic strategies aimed at modulating copper levels through diet, chelation, or supplementation with competing trace elements like zinc. Given copper’s known effects on microbiota, this study further strengthens the case for including trace element monitoring in microbiome-focused PCOS interventions. Future research should explore longitudinal relationships between copper exposure, microbiota changes, and hormonal dysregulation, as well as whether copper modulation improves clinical outcomes in PCOS.