P325 - ECE_3527 - Metabolomic profiling reveals distinct metabolic signatures in women with functional hypothalamic amenorrhoea (FHA) and polycystic ovary syndrome (PCOS)

Abstract

Reproductive endocrine disorders are tightly linked to alterations in energy balance and metabolism, with functional hypothalamic amenorrhoea (FHA) associated with reduced energy availability, and polycystic ovary syndrome (PCOS) with metabolic dysfunction and insulin resistance, further exacerbated by obesity. Metabolomics provides comprehensive analysis of small-molecule metabolites offering an integrated assessment of systemic metabolic activity. Herein, we describe the first direct comparison of metabolomic signatures in these two common causes of menstrual disturbance. Metabolomic evaluation was conducted in healthy controls (n = 32), women with FHA (n = 37) and women with PCOS (n = 54). PCOS was further stratified into lean PCOS (BMI < 25 kg/m2; n = 30) and obese PCOS (BMI ≥30 kg/m2; n = 24). Serum was analysed using nuclear magnetic resonance (NMR) spectroscopy, with metabolites categorised into amino acid, carbohydrate, and lipid pathways. Metabolites are presented as normalised expression values and compared by Kruskal-Wallis test. Amino acid profiles: Branched-chain amino acids (BCAA) were increased in PCOS, with higher leucine and isoleucine than healthy controls (P < .0015) and FHA (P < .0099), whilst valine was higher in PCOS than in healthy controls (P = .0034). Glycine was lower in PCOS than other groups (P < .0001), whereas tyrosine was higher in PCOS than FHA (P = .0076). Aromatic amino acids (AAA) including phenylalanine and tyrosine were higher in obese PCOS (P < .036). Carbohydrate metabolites were also altered, with lower lactate in FHA than healthy controls (P = .01) and lower citrate in PCOS than FHA (P < .0001) and healthy controls (P = .048). Lipid profiling demonstrated higher triglycerides in PCOS than healthy controls (P = .001), while total cholesterol (P = .008) and polyunsaturated fatty acids (P = .009) were higher in FHA than PCOS. Citrate concentrations were lower in obese PCOS than healthy controls (P = .02) and FHA (P < .0001) and triglyceride levels were higher than in healthy controls (P = .003) and FHA (P = .02). PCOS is characterised by a distinct metabolomic signature consistent with insulin resistance, demonstrated here by elevated BCAA and AAA, reduced glycine, altered carbohydrate metabolism, and triglyceride enrichment. By contrast, FHA exhibits a metabolic profile consistent with energy conservation, reduced glycolytic activity and preserved lipid composition. Collectively, these findings indicate that PCOS and FHA represent fundamentally divergent metabolic states, with obesity acting as a key modifier of metabolic dysfunction in PCOS.