This single-center, prospective, observational, cross-sectional mechanistic pilot study will evaluate whether polycystic ovary syndrome (PCOS) contributes to hepatic steatosis in adolescent girls independently of adiposity. A total of 150 girls aged 10-18 years will be enrolled into three groups of 50: girls with PCOS and obesity, age- and body mass index-matched girls with obesity but without PCOS, and healthy normal-weight girls. Each participant will undergo a single evaluation comprising anthropometry, clinical and biochemical phenotyping, transient elastography with controlled attenuation parameter and two-dimensional shear wave elastography, and a single venous blood sample.
An extended biomarker panel will be measured by enzyme-linked immunosorbent assay (Fetuin-A, fibroblast growth factor 21, adiponectin, visfatin, cytokeratin-18 M30 and M65, soluble CD163, growth differentiation factor 15, 11-ketotestosterone, and 11beta-hydroxyandrostenedione), together with liquid chromatography-tandem mass spectrometry measurement of testosterone and sex hormone-binding globulin, and genotyping of PNPLA3 rs738409 and HSD17B13 rs72613567. The primary objective is to compare hepatic steatosis and the hepatokine/adipokine profile between the PCOS with obesity group and the adiposity-matched obesity control group, adjusting for body mass index z-score, insulin resistance, and free androgen index. No therapeutic intervention is assigned by the study protocol.
Female, aged 10 to 18 years, with written informed consent from a parent or legal guardian and written assent from the child.
Group 1 (PCOS with obesity): both hyperandrogenism and oligo-anovulation required, based on adolescent-adapted Rotterdam criteria; body mass index at or above the 95th percentile.
Group 2 (Obesity control): body mass index at or above the 95th percentile, without features of PCOS, matched to Group 1 for age and body mass index.
Group 3 (Healthy control): healthy normal-weight girls (body mass index between the 5th and 84th percentile) without chronic disease, hyperandrogenism, or menstrual irregularity.
Known acute or chronic liver disease (including viral, autoimmune, or Wilson disease) or use of hepatotoxic medication.
Endocrine disorders or secondary hyperandrogenism, including Cushing syndrome, hypothyroidism, uncontrolled diabetes mellitus, congenital adrenal hyperplasia, androgen-secreting tumour, or hyperprolactinaemia.
Syndromic or monogenic obesity (including Prader-Willi syndrome, Bardet-Biedl syndrome, Alström syndrome, MC4R or LEP variants) or a known genetic disorder.
Use of relevant or hepatotoxic medication within the preceding three months, including corticosteroids, metformin, oral contraceptives, valproic acid, or antiandrogens.
Adolescent girls aged 10 to 18 years presenting to the Departments of Pediatric Endocrinology and Pediatric Gastroenterology and Hepatology of Kayseri City Hospital, Kayseri, Türkiye. The study population comprises girls with polycystic ovary syndrome and obesity, girls with obesity without polycystic ovary syndrome matched for age and body mass index, and healthy normal-weight girls. Participants will be enrolled prospectively by consecutive sampling of eligible admissions.
Case-control
Prospective
Extended Serum Biomarker and Hormonal Panel
Diagnostic testA single fasting venous blood sample is obtained at the study visit. Enzyme-linked immunosorbent assay measurement of Fetuin-A, fibroblast growth factor 21, adiponectin, visfatin, cytokeratin-18 M30, cytokeratin-18 M65, soluble CD163, growth differentiation factor 15, 11-ketotestosterone and 11beta-hydroxyandrostenedione is performed. Total testosterone and sex hormone-binding globulin are measured by liquid chromatography-tandem mass spectrometry. Routine biochemistry and hormonal profiling are performed from the same sample. Observational only; no therapeutic agent is administered.
Liver Elastography with Controlled Attenuation Parameter
Diagnostic testHepatic steatosis and liver stiffness are assessed non-invasively at the same study visit. Vibration-controlled transient elastography with controlled attenuation parameter yields attenuation (dB/m) and stiffness (kPa) values; two-dimensional shear wave elastography provides an independent stiffness estimate. Predefined validity criteria are applied to all acquisitions. No sedation, contrast agent or ionizing radiation is used; the procedure is observational.
Targeted Genotyping of PNPLA3 rs738409 and HSD17B13 rs72613567
GeneticGenomic DNA is isolated from the same single venous blood sample; no additional venipuncture is required. TaqMan allelic discrimination assays are used for genotyping of PNPLA3 rs738409 and HSD17B13 rs72613567. Genotype call rate and Hardy-Weinberg equilibrium are reported. Genotyping is performed for research purposes only; results are not used to guide clinical management.
Hepatic Steatosis Measured by Controlled Attenuation Parameter (CAP)
Controlled attenuation parameter obtained during vibration-controlled transient elastography, compared between girls with PCOS and obesity and adiposity-matched girls with obesity, and across all three study groups, with adjustment for body mass index z-score, homeostatic model assessment of insulin resistance, and free androgen index. Unit of measure: dB/m.
Serum Fetuin-A Concentration
Serum Fetuin-A measured by enzyme-linked immunosorbent assay and compared across the three study groups with adjustment for body mass index z-score, homeostatic model assessment of insulin resistance, and free androgen index. Unit of measure: µg/mL.
Serum Fibroblast Growth Factor 21 (FGF-21) Concentration
Serum FGF-21 measured by enzyme-linked immunosorbent assay and compared across the three study groups with adjustment for body mass index z-score, homeostatic model assessment of insulin resistance, and free androgen index. Unit of measure: pg/mL.
Serum Adiponectin Concentration
Serum adiponectin measured by enzyme-linked immunosorbent assay and compared across the three study groups with adjustment for body mass index z-score, homeostatic model assessment of insulin resistance, and free androgen index. Unit of measure: µg/mL.
Serum Soluble CD163 Concentration
Serum soluble CD163, a marker of macrophage activation, measured by enzyme-linked immunosorbent assay and compared across the three study groups; evaluated as a candidate mediator of the association between hyperandrogenism and hepatic steatosis. Unit of measure: ng/mL.
Serum Cytokeratin-18 M30 and M65 Concentrations
Serum cytokeratin-18 M30 (apoptotic fragment) and M65 (total cell death) measured by enzyme-linked immunosorbent assay and compared across the three study groups to characterise the mode of hepatocyte death. Unit of measure: U/L for each analyte.
Liver Stiffness Measurement
Liver stiffness assessed by vibration-controlled transient elastography and by two-dimensional shear wave elastography, compared across the three study groups. Unit of measure: kPa.
Discriminatory Performance of the Biomarker Panel for Hepatic Steatosis
Receiver operating characteristic analysis of individual biomarkers and of a composite preliminary risk score for the identification of hepatic steatosis. Measures include area under the receiver operating characteristic curve with 95% confidence intervals, sensitivity, and specificity at the Youden index.
Serum Growth Differentiation Factor 15 (GDF-15) Concentration
Serum GDF-15, a marker of mitochondrial stress, measured by enzyme-linked immunosorbent assay and compared across the three study groups. Unit of measure: pg/mL.
Serum 11-Oxygenated Androgen Concentrations
Serum 11-ketotestosterone and 11beta-hydroxyandrostenedione measured by enzyme-linked immunosorbent assay and evaluated for association with hepatic steatosis measures independently of body mass index and insulin resistance. Unit of measure: ng/dL for each analyte.
PNPLA3 rs738409 and HSD17B13 rs72613567 Genotype Distribution and Gene-Gene Interaction
Genotype frequencies of PNPLA3 rs738409 and HSD17B13 rs72613567 determined by TaqMan assay, and evaluation of gene-gene interaction with respect to hepatic steatosis measures. Measure: genotype counts and interaction estimates; Hardy-Weinberg equilibrium will be assessed.
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Kayseri City Hospital
Lead sponsor
Presidency of the Health Institutes of Türkiye
Collaborator
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