PMOS is far more than a reproductive inconvenience. The condition, which affects an estimated one in ten to one in five women worldwide depending on the diagnostic criteria applied, weaves together irregular ovulation, elevated male hormones called androgens, insulin resistance, obesity and long-term risks including type 2 diabetes and cardiovascular disease. In 2026, an international consensus process published in The Lancet formally renamed the condition to reflect its true nature as a multi-system endocrine and metabolic disorder rather than a purely gynaecological one. Yet despite decades of research, the initiating mechanisms that tie these seemingly disparate defects together have remained elusive, leaving clinicians to manage symptoms rather than root causes.

The new study began with a clue from clinical chemistry. Analysing follicular fluid, the nutrient-rich liquid that surrounds developing eggs within the ovary, the researchers found that the metabolism of methionine, an essential amino acid that fuels a cellular process called methylation, was dysregulated in women with PMOS. They also observed that nicotinamide metabolism was disturbed, and that NNMT, the enzyme responsible for methylating nicotinamide, was markedly elevated in granulosa cells, the somatic cells that nurture developing follicles and support ovulation. The pattern held up across public gene-expression datasets and an expanded clinical cohort of 21 patients with PMOS compared with 16 controls, and NNMT levels correlated with serum anti-Müllerian hormone concentrations and the ratio of luteinizing hormone to follicle-stimulating hormone, both hallmarks of the syndrome.

What makes NNMT so consequential is its peculiar biochemistry. The enzyme consumes methyl groups from S-adenosylmethionine, the universal methyl donor of the cell, and transfers them to nicotinamide, producing N1-methylnicotinamide. In doing so, NNMT acts as what researchers have called a metabolic methylation sink: it drains the cell’s pool of available methyl groups, starving the machinery that decorates histones, the protein spools around which DNA is wound. When histone methylation falters, genes that should be silenced can spring into activity. NNMT had previously been implicated in epigenetic remodelling in cancer cells and in metabolic dysfunction in the liver, but its role in the ovary had never been systematically explored.

To test whether NNMT could actually drive disease, the team used an adeno-associated virus to overexpress Nnmt specifically in the granulosa cells of mice. The results were striking. The animals developed a constellation of PMOS-like features, including disrupted oestrous cycles, altered follicle development, elevated luteinizing hormone and an increased luteinizing hormone to follicle-stimulating hormone ratio, mirroring the endocrine profile seen in affected women. Transcriptomic analysis of the ovaries revealed that the gene programmes activated by Nnmt overexpression overlapped significantly with genes known to respond to luteinizing hormone and to dihydrotestosterone, a potent androgen, suggesting that the enzyme had pushed the ovary into an androgen-dominated state.

The mechanistic core of the study lies in a specific histone mark: trimethylation of lysine 27 on histone H3, abbreviated H3K27me3. This mark, deposited by the enzyme EZH2 as part of the Polycomb repressive complex 2, is a classic silencing signal that keeps developmental and metabolic genes in check. The researchers showed that NNMT overexpression in granulosa cells reduced H3K27me3 across the genome, and that pharmacologically blocking EZH2 with the inhibitor GSK343 reproduced the same PMOS-like hormonal and ovarian phenotypes in mice. In other words, the loss of this single repressive mark was sufficient to push the ovary toward the disease state, establishing H3K27me3 as a critical downstream effector of NNMT.

Which gene, then, does the loss of H3K27me3 unleash? The team’s search converged on retinoic acid receptor beta, or RARB, a nuclear receptor whose expression rose when the repressive mark was stripped away. RARB had previously been linked to the regulation of human androgen biosynthesis, and the new data confirmed its role: when the researchers overexpressed Rarb in primary theca-interstitial cells, the ovarian cells responsible for producing androgens, testosterone accumulated in the culture medium and steroidogenesis-related genes were upregulated. In mice, ovarian Rarb expression correlated with both Nnmt levels and serum testosterone concentrations, and granulosa cells from women with PMOS showed elevated RARB compared with controls.

Perhaps the most compelling aspect of the findings is that the circuit does not merely run downhill from enzyme to hormone. The researchers demonstrated that androgen itself suppresses H3K27me3 in granulosa cells, feeding back on the very epigenetic landscape that unleashed RARB in the first place. This creates a self-reinforcing feedforward loop: NNMT erodes histone methylation, which activates RARB, which drives androgen synthesis, which further erodes histone methylation. Once the loop is established, the cell becomes locked into a hyperandrogenic identity that persists even if the original metabolic trigger subsides, providing a plausible explanation for the chronicity of PMOS and for why the disorder can be transmitted across generations through epigenetic mechanisms, as earlier work in mice and sheep has suggested.

Crucially, the loop appears to be breakable. When the researchers treated mice with a DHEA-induced model of the syndrome using a pharmacological inhibitor of NNMT, H3K27me3 levels were restored, the RARB-androgen circuit was disrupted, and both the metabolic and hormonal phenotypes improved. Glucose tolerance normalized, oestrous cycles stabilized, and serum concentrations of testosterone, anti-Müllerian hormone and luteinizing hormone all declined. Parallel experiments in mice lacking Nnmt specifically in granulosa cells confirmed that the enzyme’s presence was required for the full manifestation of the DHEA-induced phenotype. NNMT inhibitors have already been developed and tested in other contexts, including obesity and metabolic syndrome in preclinical models, which raises the prospect of repurposing or refining these compounds for PMOS.

The study does not claim to have solved PMOS in its entirety. The syndrome is heterogeneous, with distinct genetic subtypes and environmental contributions, and mouse models capture only part of the human condition. Human sequencing data from the study are available only under controlled access, and translating findings from granulosa cells in mice to the ovaries of diverse patient populations will require further validation. Nevertheless, by identifying the NNMT-H3K27me3-RARB-androgen axis as a mechanistic nexus linking methionine metabolism, epigenetic dysregulation and excess androgen production, the work provides both a unifying framework for understanding how reproductive, endocrine and metabolic defects intertwine, and a concrete, druggable target for interventions that could, for the first time, address the epigenetic roots of the disorder rather than merely its symptoms.

Subject of Research: The role of NNMT-driven epigenetic remodelling in hyperandrogenism of polyendocrine metabolic ovarian syndrome

Article Title: NNMT enhances hyperandrogenism in polyendocrine metabolic ovarian syndrome through epigenetic remodelling

Article References: NNMT enhances hyperandrogenism in polyendocrine metabolic ovarian syndrome through epigenetic remodelling. (n.d.). https://doi.org/10.1038/s42255-026-01625-6

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01625-6

Keywords: NNMT, polyendocrine metabolic ovarian syndrome, PCOS, epigenetics, H3K27me3, RARB, hyperandrogenism, granulosa cells, methionine metabolism, androgen biosynthesis, EZH2, Nature Metabolism