How a Common Hormonal Disorder Disrupts the Placenta and Programs Disease in Offspring

Polycystic ovary syndrome has just been given a new name, and with it a new scientific identity. In a sweeping consensus process, an international panel of experts renamed the condition polyendocrine metabolic ovarian syndrome, or PMOS, a change that reflects what researchers have long suspected: this is not merely an ovarian disorder but a multisystem endocrine and metabolic disease. A new review published in Reproductive Sciences by Mina Amiri of Tehran University of Medical Sciences and colleagues now pulls together the evidence for what that means during one of the most vulnerable periods in human biology, pregnancy. The verdict is sobering. Women with PMOS face elevated risks of early pregnancy loss, gestational diabetes, hypertensive disorders, preterm birth, and abnormal fetal growth, and these risks persist partly independently of obesity, the factor most often blamed for them.

The review begins with the metabolic fingerprint that defines the syndrome. Women with PMOS characteristically display insulin resistance, meaning their tissues respond weakly to the hormone that shuttles glucose into cells; hyperandrogenemia, an excess of circulating male hormones; dyslipidemia, an unhealthy profile of blood fats; and chronic low-grade inflammation. Each of these disturbances has been documented repeatedly in clinical studies, including meta-analyses of euglycemic-hyperinsulinemic clamp studies, the gold-standard method for measuring insulin sensitivity. Crucially, adipose tissue itself appears dysfunctional even in normal-weight women with the syndrome, releasing inflammatory signals and lipid mediators that poison the metabolic environment well before conception occurs. The disease, in other words, is already operating systemically before a pregnancy begins.

Pregnancy then throws fuel on the fire. In every pregnancy, the placenta secretes hormones such as human placental lactogen, progesterone, and prolactin that deliberately induce a state of insulin resistance in the mother. This is not a malfunction; it is an evolutionary strategy to divert glucose toward the growing fetus while the mother shifts her own metabolism toward fat oxidation. But in a woman whose insulin signaling is already impaired, this physiological challenge can push the system past its breaking point. The review describes how the normal insulin resistance of pregnancy amplifies the pre-existing metabolic disturbances of PMOS, disrupting endometrial receptivity, the window during which the uterine lining can accept an embryo, and compromising placental function from the earliest weeks of gestation.

At the molecular level, the review identifies a set of conserved signaling pathways where maternal metabolic insults converge and do their damage. The first is the phosphoinositide 3-kinase, protein kinase B, and mechanistic target of rapamycin axis, the central relay for insulin action and nutrient sensing. When this pathway is deranged in trophoblast cells, the specialized cells that invade the uterine wall and build the placenta, the consequences ripple outward: trophoblast invasion falters, the spiral arteries that must be remodeled to feed the placenta remain narrow and muscular, and the angiogenic balance that governs blood vessel formation tips toward dysfunction. Evidence linking altered PI3K-AKT signaling to both PMOS and recurrent spontaneous abortion is highlighted as a key mechanistic thread.

A second convergence point is the inflammatory signaling hub built around nuclear factor kappa B and c-Jun N-terminal kinase. Chronic low-grade inflammation, a hallmark of PMOS, activates these pathways in endometrial and placental tissue, where they interfere with insulin signaling in a vicious feedback loop. Studies cited in the review show that pro-inflammatory markers directly suppress insulin receptor substrate 1 in endometrial cells, effectively blunting the uterus’s ability to respond to insulin. Meanwhile, the placenta itself can become an inflammatory organ, with activated STAT3 signaling observed in placentas from women with the syndrome. The result is a maternal-fetal interface bathed in cytokines rather than the carefully calibrated immune environment a healthy pregnancy requires.

Perhaps the most striking mechanistic story involves androgens and mitochondria. Excess androgens, the review explains, act through the androgen receptor inside mitochondria, the energy-producing organelles of the cell, and overactivation of this receptor is coupled to mitochondrial defects in the decidua, the specialized uterine tissue of pregnancy. In animal models of PMOS-like disease, hyperandrogenism combined with insulin resistance triggers ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, in both the gravid uterus and the placenta. Recent work suggests a specific mechanism: excess androgens induce trophoblast ferroptosis by promoting the degradation of ferritin heavy chain 1, the cell’s iron-storage protein, through chaperone-mediated autophagy. The placenta, deprived of its antioxidant defenses, accumulates lethal oxidative damage.

Lipid metabolism adds a third layer of injury. The review examines the role of peroxisome proliferator-activated receptors, nuclear receptors that regulate fatty acid handling in the placenta, and of fatty acid transporters such as CD36 and fatty acid-binding protein 4. In a dysmetabolic maternal environment, these systems become dysregulated, and the placenta is exposed to lipotoxic injury, the accumulation of harmful lipid intermediates that damage cellular machinery. Studies of first-trimester placental tissue show that obesity downregulates lipid metabolism genes, and metabolomic profiling of PMOS pregnancies has identified a unique metabolic signature associated with low birth weight. Elevated maternal androgens have also been linked to placental dysfunction and lipid disorders in newborns, suggesting that the hormonal and metabolic arms of the syndrome reinforce each other at the placental interface.

The consequences of this cascade are visible in the delivery room. Large population studies, including one analysis of 9.1 million births, confirm that PMOS is associated with increased risks of gestational diabetes, preeclampsia and other hypertensive disorders, preterm delivery, and both restricted and excessive fetal growth. But the story does not end at birth. The review devotes substantial attention to fetal programming, the process by which the intrauterine environment leaves lasting epigenetic marks on the developing offspring. Children exposed to a dysmetabolic, hyperandrogenic womb show elevated risks of metabolic and reproductive dysfunction later in life, and animal studies demonstrate that prenatal androgen exposure produces ovary-independent uterine dysfunction and placental inflammation that a high-fat diet worsens. In this way, PMOS risks perpetuating itself across generations, a cycle the authors describe as metabolic disease transmission.

What can be done? The review appraises the current therapeutic arsenal with a critical eye. Lifestyle modification remains the foundation, improving insulin sensitivity before and during pregnancy, but adherence is difficult and evidence for hard pregnancy outcomes is thin. Metformin, the most studied insulin-sensitizing drug, has shown benefits in some trials, including reduced early pregnancy loss and lower gestational diabetes incidence in high-risk populations, yet meta-analyses of preconception and first-trimester metformin in PMOS report inconsistent results across outcomes, and questions remain about long-term effects on offspring. A recent randomized trial of myo-inositol supplementation published in JAMA found it did not prevent pregnancy complications in PMOS. Bariatric surgery in obese patients improves metabolic parameters, but its effects on pregnancy outcomes require further study. The authors are blunt: rigorous preconception trials are needed before any intervention can be recommended with confidence.

The larger message of the review is that the placenta deserves far more attention than it has historically received, described in the literature as the forgotten organ. By mapping how insulin resistance, hyperandrogenemia, dyslipidemia, and inflammation converge on specific molecular pathways, PI3K-AKT-mTOR, NF-kappaB-JNK, androgen receptor-mediated mitochondrial dysfunction and ferroptosis, and PPAR-regulated lipid handling, the authors provide a mechanistic framework that could guide targeted therapies rather than blunt metabolic correction. Emerging data on adipose-derived lipid mediators and inflammatory-metabolic crosstalk at the maternal-uteroplacental interface point toward biomarkers that could refine risk stratification long before complications appear. If the cycle of metabolic disease transmission is to be broken, the review argues, the intervention window may need to open before conception, when the metabolic milieu that will shape the placenta, and through it the next generation, is still modifiable.

Subject of Research: Maternal metabolic dysfunction and uteroplacental adaptation in polyendocrine metabolic ovarian syndrome pregnancy

Article Title: Maternal Metabolic Dysfunction and Uteroplacental Adaptation in Polyendocrine Metabolic Ovarian Syndrome Pregnancy

Article References: Amiri, M., Kamrani, M. A., Qaderi, K., & Ammoli, M. M. (2026). Maternal Metabolic Dysfunction and Uteroplacental Adaptation in Polyendocrine Metabolic Ovarian Syndrome Pregnancy. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02226-0

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02226-0

Keywords: polyendocrine metabolic ovarian syndrome, polycystic ovary syndrome, placenta, insulin resistance, hyperandrogenemia, trophpblast invasion, fetal programming, gestational diabetes, ferroptosis, endometrial receptivity, inflammation, metformin