PMOS rethink reframes a common hormone disorder as a whole-body disease

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Jun 18 2026

Once seen mainly as a fertility disorder, PCOS is being recast as a whole-body endocrine and metabolic condition, opening the door to earlier diagnosis, sharper risk profiling, and more individualized care.

PCOS/PMOS pathophysiology. PCOS/PMOS is a complicated syndrome, involving multiple feedback loops in the anterior pituitary, liver, pancreas, and ovary, ultimately contributing to a hyperandrogenic state. In the pituitary, LH is released in higher quantities than FSH, simulating theca cells of the ovary to increase production of androgens. The androgens, in turn, stimulate the pituitary to release LH and FSH. The increased androgen also acts on the liver, decreasing SHBG and increasing circulating free androgens. Finally, at the level of the pancreas, androgens lead to hyperinsulinemia, which, in turn, decreases SHBG. Insulin also acts on theca cells to promote androgen release. All of these factors lead to HA, which leads to anovulation and PCOM in the ovary. LH, luteinizing hormone; FSH, follicle-stimulating hormone; SHBG, sex hormone–binding globulin. AI-assisted redrawing based on Figure 1 from Chan JL, Masini I, and Pisarska MD, “Polyendocrine metabolic ovarian syndrome (PMOS)/polycystic ovary syndrome (PCOS): current and future trends,” Journal of Clinical Investigation, 2026;136(12). https://www.jci.org/articles/view/202824. Original article published under the Creative Commons Attribution 4.0 International License.

In a recent comprehensive review published in the Journal of Clinical Investigation, researchers synthesized decades of research on polycystic ovary syndrome (PCOS) to elucidate the shifting diagnostic paradigms surrounding the disease. It outlines the interplay among genetic, epigenetic, environmental, metabolic, and neuroendocrine factors that may together contribute to disease development, phenotypic variation, and long-term complications, as well as emerging targeted approaches to improve patient outcomes.

The review findings highlight how the management of PCOS, recently proposed to be renamed polyendocrine metabolic ovarian syndrome (PMOS), has long been hampered by diagnostic inconsistency and symptom-focused treatments. It concludes by suggesting that PMOS treatment is transitioning from its “one-size-fits-all” roots toward personalized, multi-system medicine that could support more targeted future care for this highly prevalent yet poorly understood endocrinological disorder.

Background

Decades of research and clinical reports have identified polycystic ovary syndrome (PCOS) as the most common endocrine disorder among reproductive-aged women worldwide. Currently, studies estimate that the condition impacts between 5% and 20% of the global female population, depending on the diagnostic criteria used.

Unfortunately, despite its widespread prevalence, the exact biological mechanisms driving the condition remain incompletely understood. Consequently, researchers believe that current prevalence estimates may underrepresent the true prevalence, potentially leaving millions of patients misdiagnosed or inadequately treated.

PCOS has culturally and historically been viewed primarily as a fertility issue due to its association with irregular menstrual cycles and polycystic ovarian morphology. However, modern clinical insights reveal a far more systemic reality. Recent research has established that the disorder is underpinned by hormonal and metabolic disturbances, often involving elevated androgens and/or insulin resistance.

Scientists now know that this combination of reproductive, endocrine, and metabolic dysfunction is associated with a patient's risk for lifetime metabolic complications, including insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD), although a definitive causal link between PCOS itself and CVD has not been established. Emergent research is further linking the condition to clinically significant mental health struggles like depression and anxiety.

To better reflect this multi-system metabolic nature, an international consortium recently advocated renaming the condition polyendocrine metabolic ovarian syndrome (PMOS).

About the review

The present comprehensive review aimed to elucidate the complex architecture of PMOS by synthesizing findings from clinical studies, genetic analyses, mechanistic research, animal models, and emerging in vitro platforms.

It specifically evaluated the implementation of the updated 2023 international evidence-based guidelines, which recommend the Rotterdam criteria for adults. These criteria require individuals to meet two out of three primary diagnostic features: ovulatory dysfunction (OD), biochemical or clinical hyperandrogenism (HA), and polycystic ovary morphology (PCOM), with exclusion of other hormonal disorders.

Within the realm of diagnostic data, the review details advanced biochemical tracking, such as using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure total testosterone, and pelvic transvaginal ultrasonography with high-bandwidth transducers (8 MHz or higher) to map antral follicle counts. Additionally, the paper evaluates the validity of serum anti-Müllerian hormone (AMH) levels as an objective, non-invasive surrogate (“proxy”) for ultrasound mapping, while emphasizing that AMH should not be used as a stand-alone diagnostic test.

The review further explores advanced methodologies driving contemporary PMOS research, such as genome-wide association studies (GWAS) investigating risk alleles across diverse human ancestries, and advanced microfluidic platforms (e.g., the "LATTICE" organ-on-a-chip framework) that allow researchers to study three-dimensional cellular interactions and accelerate automated, high-throughput drug testing under PMOS-like hormone levels.

Review findings

The review revealed that, diagnostically, research using an automated AMH assay found that, in women aged 23 to 35, a serum AMH level above 3.2 ng/mL could serve as a potential surrogate for PCOM assessment, with a sensitivity of 88.6% and a specificity of 80.3%. In diagnostic bioinformatic research, machine learning models utilizing specific hormone values, specifically luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and sex hormone-binding globulin (SHBG), successfully predicted PMOS development prior to clinical onset with an area under the curve (AUC) of up to 0.85 in an out-of-sample test.

The review further identified a strong heritable component, noting that 60% to 70% of daughters born to mothers with PMOS develop the condition themselves. It also highlighted how distinct reproductive and metabolic phenotypes may carry different risk profiles, reinforcing the need for more precise classification.

On the therapeutic front, clinical updates show that the aromatase inhibitor “letrozole” achieves significantly higher live birth rates for ovulation induction compared to the traditional choice, clomiphene citrate (27.5% versus 19.1%). Drug-repurposing studies also highlighted that the antimalarial agent artemether alleviated hyperandrogenism, irregular estrous cycles, PCOM, and subfertility in PCOS-like rodent models by targeting ovarian enzymes to inhibit excess androgen synthesis. In a small human pilot trial, the related compound dihydroartemisinin was associated with reduced hyperandrogenism, lower AMH levels, reduced PCOM, and normalized menstrual cycles.

Conclusions

The present review highlights that PMOS is a multifaceted, highly heritable condition requiring individualized, precision care rather than a one-size-fits-all approach. While current treatments primarily manage symptoms like abnormal bleeding or metabolic dysfunction through combined hormonal contraceptives (CHC), lifestyle intervention, and metformin, the review’s findings indicate that the future of PMOS treatments may depend on identifying shared biological pathways and clinically meaningful subtypes.

Encouragingly, novel therapies such as neurokinin 3 (NK3) receptor antagonists and glucagon-like peptide-1 (GLP-1) receptor agonists or multi-agonists are showing early or context-specific clinical potential in reducing hyperandrogenism or improving metabolic and reproductive features, although several approaches remain preclinical, and GLP-1 therapies require caution around conception and pregnancy. Addressing current diagnostic gaps through machine learning and validating distinct reproductive-metabolic sub-phenotypes could allow future clinicians to intervene early, thereby altering the long-term health trajectory for millions of women.

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