Assessment of Metabolic Changes in Response to Glcuose Intake in Women With Polyendocrine Metabolic Ovarian Syndrome (PMOS)

Официальное название

METabolic FLEXibility in PMOS

Обзор

Polyendocrine metabolic ovarian syndrome (PMOS), previously known as polycystic ovary syndrome (PCOS), is a common endocrine and metabolic condition affecting women of reproductive age. It is associated with hormonal imbalances, irregular menstrual cycles, elevated androgen levels, and metabolic disturbances such as insulin resistance. These metabolic changes can increase the risk of type 2 diabetes and cardiovascular disease. Insulin resistance means that the body's cells respond less effectively to insulin, a hormone that regulates blood glucose. This leads to compensatory increases in insulin levels, which can further disrupt hormonal balance and contribute to the clinical features of PMOS. This study aims to investigate how the bodies of women with PMOS respond dynamically to glucose intake compared with women without PMOS. A standard clinical test, the oral glucose tolerance test (oGTT), will be used. Participants consume a glucose solution, and blood samples are collected before and two hours afterward. This procedure is routinely used in clinical practice. Women with PMOS will be compared with age- and body mass index (BMI)-matched control participants without PMOS. Blood and urine samples will be analyzed using advanced multi-omics technologies to measure proteins, metabolites, extracellular vesicles, and immune-related signals. The main objective is to understand how metabolic, hormonal, and immune pathways respond over time to a glucose challenge and whether these responses differ in PMOS. Special attention is given to inter-organ communication and systemic metabolic regulation. The study includes two visits. The first visit involves health assessments, questionnaires, and body composition measurements. The second visit includes the glucose tolerance test and blood sampling. In total, approximately 100 mL of blood will be collected across both visits. Participation is voluntary, and participants may withdraw at any time without affecting their medical care. The procedures involve minimal risk and consist of standard clinical methods. The results of this study may improve understanding of PMOS and contribute to better diagnostic and therapeutic strategies in the future.

Подробное описание

Background and Rationale: Polyendocrine metabolic ovarian syndrome (PMOS), previously referred to as polycystic ovary syndrome (PCOS), is a common endocrine disorder in women of reproductive age. PMOS is characterized by a heterogeneous clinical phenotype involving reproductive, endocrine, and metabolic disturbances, including hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology.

A central feature of PMOS is insulin resistance. Compensatory hyperinsulinemia can enhance ovarian androgen production and reduce hepatic sex hormone-binding globulin synthesis, thereby increasing circulating free androgen levels. This endocrine-metabolic interaction contributes to the reproductive and metabolic manifestations of PMOS.

Beyond reproductive dysfunction, PMOS is associated with impaired glucose metabolism, dyslipidemia, low-grade inflammation, and an increased long-term risk of type 2 diabetes and cardiovascular disease. Metabolic dysfunction in PMOS may not be fully captured by fasting measurements alone, because fasting assessments provide only a static snapshot of systemic physiology.

The oral glucose tolerance test provides a standardized metabolic challenge for assessing dynamic glucose homeostasis. Glucose ingestion induces coordinated physiological responses involving pancreatic insulin secretion, hepatic glucose regulation, peripheral glucose uptake, endocrine adaptation, and immune-metabolic signaling. Dynamic molecular profiling during an oral glucose tolerance test may therefore reveal regulatory abnormalities that are not apparent under fasting conditions.

Plasma represents an integrative biological compartment reflecting metabolic, endocrine, inflammatory, and inter-organ communication processes. Advances in high-resolution molecular profiling now allow simultaneous characterization of circulating metabolites, plasma proteins, steroid hormones, inflammatory mediators, and extracellular vesicle-associated molecular cargo. Extracellular vesicles are of particular interest because extracellular vesicles may contribute to intercellular and inter-organ communication by transporting proteins, nucleic acids, lipids, and metabolites between tissues.

The study is based on the concept that dynamic perturbation testing can provide additional biological information compared with steady-state measurements. A standardized oral glucose tolerance test is used as a controlled metabolic perturbation to characterize systemic molecular response patterns in PMOS and matched control participants.

Study Design: The study is a single-center, exploratory, matched case-control study. Participants with PMOS and age- and body mass index-matched control participants undergo standardized clinical and metabolic assessments. The study is designed to generate high-dimensional molecular data describing dynamic systemic responses to acute glucose ingestion.

Study Procedures: Participants attend a baseline assessment visit and a metabolic challenge visit. The baseline assessment includes clinical characterization, anthropometric measurements, body composition assessment, questionnaire-based phenotyping, and gynecological assessment as applicable.

During the metabolic challenge visit, participants undergo a standardized 75 g oral glucose tolerance test after an overnight fasting period. Blood samples are collected in the fasting state and 2 hours after glucose ingestion. The timing of the metabolic challenge is standardized in the morning, and menstrual cycle timing is controlled where applicable.

Biological Sampling and Molecular Analyses: Blood-derived biospecimens are processed for clinical chemistry and molecular profiling. Plasma is used for metabolomic profiling, proteomic profiling, targeted steroid hormone analysis, inflammatory protein profiling, and extracellular vesicle characterization. Extracellular vesicle analyses include assessment of vesicle concentration, vesicle size distribution, and extracellular vesicle-associated molecular cargo.

Inflammatory and immune-related proteins are measured using a predefined multiplex protein panel. Buffy coat-derived or blood cell-associated material may be used for immune-related analyses, depending on the final laboratory workflow.

Metabolomic analyses focus on circulating small molecules involved in glucose metabolism, lipid metabolism, amino acid turnover, and energy homeostasis. Proteomic analyses focus on circulating proteins related to insulin signaling, inflammatory pathways, lipid metabolism, endocrine regulation, and inter-organ communication. Targeted steroid profiling is performed using mass spectrometry to characterize endocrine regulation in PMOS.

Analytical Approach: The primary analytical focus is the characterization of molecular changes between the fasting state and the post-glucose state. Molecular response patterns are compared between PMOS and matched control participants to identify dynamic differences in metabolic, endocrine, inflammatory, and extracellular vesicle-associated signaling pathways.

The study is exploratory and hypothesis-generating. Integrated analysis of clinical, biochemical, and molecular data is intended to identify systemic response patterns associated with PMOS, insulin resistance, and altered metabolic flexibility.

Вмешательства

• Процедура Oral Clucose Tolerance Test (oGTT)
  After an overnight fasting period (≥8 hours), participants ingest a 75 g oral glucose solution. Venous blood samples are collected at predefined time points (fasting and typically 2 hours post-ingestion) to measure plasma glucose and insulin levels. The test evaluates whole-body glucose tolerance and insulin response under controlled metabolic conditions and is routinely used in clinical and research settings.

Первичные конечные точки

• Change in Normalized Relative Plasma Metabolite Abundance From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline (fasting, Visit 2) and 2 hours post-glucose ingestion (Visit 2).]
• Change in Normalized Relative Plasma Protein Abundance From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline (fasting, Visit 2) and 2 hours post-glucose ingestion (Visit 2).]

Вторичные конечные точки (11)

• Change in oGTT-Derived Glucose and Insulin Response Indices From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline and 2 hours post-glucose ingestion (Visit 2).]
• Change in Concentration of Plasma Extracellular Vesicles From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline and 2 hours post-glucose ingestion (Visit 2).]
• Change in Median Diameter of Plasma Extracellular Vesicles From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline and 2 hours post-glucose ingestion (Visit 2).]
• Change in Normalized Relative Abundance of Extracellular Vesicle-Associated Proteins From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline and 2 hours post-glucose ingestion (Visit 2).]
• Change in Normalized Relative Abundance of Extracellular Vesicle-Associated Metabolites From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: aseline and 2 hours post-glucose ingestion (Visit 2).]
• Change in Normalized Relative Abundance of Plasma Inflammatory Proteins From Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline and 2 hours post-glucose ingestion (Visit 2).]
• Concentrations of Circulating Steroid Hormones from Baseline to 2 Hours Post-Glucose Ingestion [Срок оценки: Baseline (fasting state, Visit 1 or Visit 2).]
• Total Body Bone Mineral Density Measured by DXA at Baseline [Срок оценки: Baseline assessment (Visit 1).]
• Total Body Fat Mass Measured by DXA at Baseline [Срок оценки: Baseline assessment (Visit 1).]
• Score on the State-Trait Anxiety Inventory at Baseline [Срок оценки: Baseline assessment (Visit 1).]
• Score on the Beck Depression Inventory-II at Baseline [Срок оценки: Baseline assessment (Visit 1).]

Критерии участия

Критерии включения

• Age: 18-35 years
• Body weight (BMI): between BMI 18.5-39.9 kg/m2
• Ability to consent and to provide written informed consent
• CG: History of regular MCs (21 to 35 days) 3 months prior to study enrollment
• PCOS-G: Existing or new established diagnosis of PCOS. Diagnosis is verified in accordance with the ESHRE/ASRM Rotterdam consensus (2003)23, phenotype A (hyperandrogenism, oligo-/anovulation, and polycystic ovarian morphology). PCOS is diagnosed when at least the following three criteria are present, after exclusion of other etiologies:

• Oligo- or anovulation
• Clinical and/or biochemical signs of hyperandrogenism
• Polycystic ovaries on ultrasound (≥12 follicles per ovary measuring 2-9 mm in diameter and/or ovarian volume >10 mL)

Критерии исключения

• Use of systemic hormonal contraceptives within the last 3 months prior to study enrollment. Use of levonorgestrel-releasing intrauterine devices is permitted; all other hormonal contraceptive methods are excluded.
• CG: A clinically diagnosed or history of a menstrual disorder (e.g., polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD) or amenorrhea)
• A clinically diagnosed mental disorder (e.g. major depression, anxiety disorder)
• history of epileptic seizure
• history of or current manic or psychotic episode
• existing/current eating disorders (bulimia nervosa, anorexia nervosa) within the past 5 years
• inability to communicate adequately in speech
• inability to follow instructions
• regular use of medication other than thyroxine
• alcohol consumption as equivalent doses of more than 12 g of pure alcohol per day
• vegan diet
• daily nicotine consumption
• currently or history of (regular) consumption of illegal drugs within the last year
• pregnancy or breastfeeding
• known diseases of the cardiovascular system
• arterial hypertension above 160/90 mm/Hg at rest
• known pulmonary diseases
• Arthritis and rheumatic diseases and conditions
• Hematologic diseases
• surgery less than 1 month ago
• having given birth within 12 months before the start of the study

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Швейцария · 1 центр

• University Hospital Zurich — Zurich

Публикации

• Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004 Jan;19(1):41-7. doi: 10.1093/humrep/deh098. PMID 14688154
• Ferdosi S, Tangeysh B, Brown TR, Everley PA, Figa M, McLean M, Elgierari EM, Zhao X, Garcia VJ, Wang T, Chang MEK, Riedesel K, Chu J, Mahoney M, Xia H, O'Brien ES, Stolarczyk C, Harris D, Platt TL, Ma P, Goldberg M, Langer R, Flory MR, Benz R, Tao W, Cuevas JC, Batzoglou S, Blume JE, Siddiqui A, Hornburg D, Farokhzad OC. Engineered nanoparticles enable deep proteomics studies at scale by leveragin PMID 35275789
• Mansournia MA, Jewell NP, Greenland S. Case-control matching: effects, misconceptions, and recommendations. Eur J Epidemiol. 2018 Jan;33(1):5-14. doi: 10.1007/s10654-017-0325-0. Epub 2017 Nov 3. PMID 29101596
• Tkach M, Thery C. Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell. 2016 Mar 10;164(6):1226-1232. doi: 10.1016/j.cell.2016.01.043. PMID 26967288
• Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HY, Chen R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, Cheng Y, Clark MJ, Im H, Habegger L, Balasubramanian S, O'Huallachain M, Dudley JT, Hillenmeyer S, Haraksingh R, Sharon D, Euskirchen G, Lacroute P, Bettinger K, Boyle AP, Kasowski M, Grubert F, Seki S, Garcia M, Whirl-Carrillo M, Gallardo M, Blasco MA, Greenberg PL, Snyder P, Klein TE, Altma PMID 22424236
• Ozer OF, Ibrahimoglu AZ, Gul AZ, Demirel M, Ates S, Taha HS, Ibrahimoglu M, Selek S. Mass spectrometry-based untargeted metabolomics study of polycystic ovary syndrome. J Ovarian Res. 2025 Nov 12;18(1):255. doi: 10.1186/s13048-025-01842-9. PMID 41225634
• Stener-Victorin E, Eriksson G, Mohan Shrestha M, Rodriguez Paris V, Lu H, Banks J, Samad M, Perian C, Jude B, Engman V, Boi R, Nilsson E, Ling C, Nystrom J, Wernstedt Asterholm I, Turner N, Lanner J, Benrick A. Proteomic analysis shows decreased type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS. Elife. 2024 Jan 5;12:RP87592. doi: 10.7554/eLife.87592. PMID 38180081
• Rajska A, Buszewska-Forajta M, Rachon D, Markuszewski MJ. Metabolomic Insight into Polycystic Ovary Syndrome-An Overview. Int J Mol Sci. 2020 Jul 9;21(14):4853. doi: 10.3390/ijms21144853. PMID 32659951

Идентификаторы

NCT: NCT07687264 · MF26

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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