Serum contains many metabolites whose variations can provide biochemical clues about diseases and may offer information about the pathogenesis and treatment of each disease. Hypothyroidism has been shown to be related to many metabolic disorders. Thyroid hormones, especially triiodothyronine, have been widely demonstrated to cause insulin resistance in the liver, and hepatic glucose output is pathologically increased by enhanced gluconeogenesis and glycogen breakdown . Therefore, PCOS can only be diagnosed after hypothyroidism has been ruled out. The relationship between insulin resistance and hypothyroidism has been studied for decades; however, the influence of SCH on clinical and metabolic parameters has not been sufficiently investigated in the setting of PCOS [13–15]. Thyroid hormones are involved in the metabolism of various substances in the body and may regulate gonadal development and female reproductive endocrine function through the hypothalamic–pituitary–ovarian axis. Elevated TSH levels and SCH are common in PCOS patients. PCOS patients with SCH are at a risk of having endocrine and metabolic abnormalities, which worsen with increasing body weight. In our study, there were significant differences in body weight, volume of the right ovary, HOMA-IR value, insulin level at 2 h after a meal, and triglyceride level between the overweight and normal weight groups of PCOS patients with SCH. Ambrosi et al. reported that an elevated TSH level affects thyroid hormones in adipose tissue, resulting in activation of the thyroid hormone receptor, increased production of cytokines, elevated levels pro-reactive proteins, and mediation of the inflammatory response. It also decreases insulin sensitivity and increases insulin production. Long-term high insulin levels accelerate the conversion of fatty acids and enhance the synthesis of lipase .
Our study identified 26 differential metabolites, mainly fatty acids, phosphatidyl choline, choline phosphate, cholesterol, and androsterone sulphate, in serum of normal weight and overweight PCOS patients with SCH, showing the effect of BMI on metabolic pathways in these patients. Through KEGG analysis, a total of 18 metabolic pathways related to the differential metabolites were detected, mainly biosynthesis of fatty acids and unsaturated fatty acids, digestion and absorption of proteins, and ABC transporters. Because fatty acids are a class of metabolites that could be used to evaluate stearoyl-CoA desaturase activity, the increased unsaturated fatty acids observed in PCOS patients indicate that stearoyl-CoA desaturase activity could be a potential marker for this disease . Follicular fluid metabonomics can be used to predict oocyte quality. Several spectroscopy-based studies have reported that the levels of specific free fatty acids in serum and follicular fluid are altered in women with PCOS [18, 19]. In mammals, the composition of fatty acids in oocytes and the levels of fatty acids in the follicular fluid environment may affect oocyte development and subsequent embryo implantation [20–21]. Phospholipids are the main component of biological membranes and play roles in maintaining human life activities, promoting cell metabolism, maintaining material exchange between cellular compartments, accelerating the transport of fat and preventing fat accumulation in the liver, maintaining brain development, inhibiting brain ageing, and exerting anti-tumour effects. In patients with SCH, altered thyroid hormone levels have slight and lasting effects, despite the absence of obvious clinical manifestations. The study by Roos et al. suggested that thyroid hormones are involved in the regulation of cholesterol and lipoprotein metabolism, and abnormal thyroid hormone levels affect the production and degradation of blood lipids . Glintborg et al. showed that SCH was associated with higher BMI, diastolic hypertension, higher total cholesterol and triglyceride levels, and higher total cholesterol/high-density lipoprotein cholesterol ratio, resulting in lipid regulation disorders, hemodynamic and endothelial dysfunction, hypercoagulation states, and atherosclerosis . The active ABC superfamily is one of the largest protein families in biological systems. Its function is to use the energy generated by ATP hydrolysis to transport molecules, such as sugars, amino acids, nucleotides, peptides, lipids, steroids, bile salts, toxins, and chemotherapeutic drugs, through biological membranes. It has a protective effect by allowing toxic exogenous substances, endogenous metabolites, and amphiphilic compounds to flow out of cells. The imbalance of this protein in granulosa cells may impair follicle development and steroid production. Another study also suggested that ABC transporters and follicular fluid high-density lipoprotein jointly regulate the cholesterol content of oocytes, which is related to the quality of oocytes . Glutamic acid and glutamine are the precursors of arginine, and arginine is the precursor of nitric oxide and polyamines (putrescine, spermidine, spermine, and agmatine), which are involved in the regulation of key events in early pregnancy, such as angiogenesis, placenta formation, and embryonic development. Taurine and hypotaurine act as antioxidants and cell osmotic pressure regulators in a variety of cell types.
The association of PCOS and thyroid function is not clear. It remains to be elucidated whether the disorder in thyroid hormone secretion is the cause of PCOS, whether the occurrence of PCOS affects the abnormal secretion of thyroid hormones, or whether the hypothalamic–pituitary–gonad and hypothalamic–pituitary–thyroid axes together cause abnormal lipid metabolism and insulin resistance, resulting in weight gain. In our study, the comparison of metabolites and metabolic pathways between normal weight and overweight PCOS patients with SCH suggested that PCOS causes disordered thyroid hormone secretion, which affects lipid, sugar, and protein generation and degradation, and accelerates the occurrence and development of disease. Therefore, it is important to investigate the prevalence of primary thyroid dysfunction in obese and overweight patients with PCOS. In addition, lifestyle intervention, early treatment with levo-thyroid hormone, reducing the TSH level, and maintaining the metabolic balance of the body are important strategies for PCOS patients with SCH.