Is thyroid function associated with polycystic ovary syndrome? A bidirectional Mendelian randomization study.

OBJECTIVE: Some observational studies have suggested the association between thyroid function and polycystic ovary syndrome (PCOS). However, it remains to be determined whether these associations are causal or not. The aim of this study was to investigate the underlying causal association between different thyroid function status and PCOS. METHODS: Bidirectional Mendelian randomization (MR) analysis was conducted to explore the impact of different thyroid function statuses on PCOS. The study included 10,074 individuals with PCOS and 103,164 controls for the primary analysis, with validation analysis repeated in the FinnGen R9 and EstBB PCOS cohorts. Female-specific thyroid function GWAS data were obtained from European population, including Hyperthyroidism (22,383 cases and 54,288 controls) and Hypothyroidism (27,383 cases and 54,288 controls) from the UK Biobank, and TSH (54,288 cases and 72,167 controls) and FT4 (49,269 cases and 72,167 controls) within the reference range from the ThyroidOmics Consortium. Inverse variance weighting (IVW) was chosen as the principal method, and sensitivity analysis was conducted to test for the presence of horizontal pleiotropy or heterogeneity. RESULTS: The IVW analysis indicated nominal significance between normal TSH levels and PCOS after adjusted for age and BMI [OR (95% CI) = 0.78(0.62,0.97), P = 0.029], suggesting that maintaining normal TSH levels might act as a protective factor against the pathogenesis of PCOS. Besides, in order to increase the statistical power, we pooled PCOS GWAS above together by meta-analysis and found PCOS contributed to the occurrence of hyperthyroidism [OR(95%CI) = 1.37(0.73,2.57), P = 0.012]. However, no causal relationship was found after Bonferroni correction (P-value < 0.0031). CONCLUSION: Although the MR analysis didn't indicate genetic causal association between thyroid function and PCOS after Bonferroni correction. Further efforts are needed to interpret the potential causal relationship between thyroid function and PCOS in different age and BMI subgroup.

Association between radioactive iodine uptake and neutropenia in untreated Graves' disease.

Objective: Neutropenia is a complication of Graves' disease (GD), but there is currently no means by which to predict its occurrence. This study aimed to investigate the risk factors for the development of neutropenia in untreated GD. Methods: This was a retrospective cohort study. Between January 1, 2010, and July 31, 2020, 1000 patients with new-onset or relapsing GD without treatment were enrolled in the study and divided into two groups: neutropenia group (neutrophil count < 2 × 109/L) and non-neutropenia group (neutrophil count ≥ 2 × 109/L). Clinical characteristics of subjects were compared between the two groups, and logistic regression analysis was applied to determine risk factors for neutropenia. To further explore the correlation of radioactive iodine uptake (RAIU) with neutropenia, subjects were first classified according to quartile of 3 h RAIU and 24 h RAIU prior to logistic regression analysis. Results: Of all patients recruited, 293 (29.6%) were diagnosed with neutropenia. Compared with non-neutropenic patients, those with neutropenia had a higher level of free thyroxine (FT4) (56.64 ± 31.80 vs 47.64 ± 39.64, P = 0.001), 3 h RAIU (55.64 ± 17.04 vs 49.80 ± 17.21, P < 0.001) and 24 h RAIU (67.38 ± 12.54 vs 64.38 ± 13.58, P < 0.001). Univariate logistic regression analysis revealed that FT4, 3 h RAIU, 24 h RAIU, creatinine, and low-density lipoprotein were risk factors for development of neutropenia in GD. After adjusting for confounding factors of age, BMI, and sex, we determined that 3 h RAIU and 24 h RAIU (Model 1: OR = 1.021, 95% CI: 1.008-1.033, P = 0.001; Model 2: OR = 1.023, 95% CI: 1.007-1.039, P = 0.004), but not FT4, were associated with the development of neutropenia. Conclusions: RAIU is associated with neutropenia in patients with untreated GD.

High concentration of estradiol has a negative correlation with free thyroxine during the second trimester of pregnancy.

Objective: To explore the relationship between estradiol (E2) and thyroid function during the second trimester of pregnancy and the effect of E2 on sodium iodide transporter (NIS) expression in cultured thyroid cells. Materials and methods: We analyzed relationships between E2 and thyroid function in 196 pregnant women during the second trimester. Multiple linear regression analysis was performed between E2 and thyroid function. The human thyroid Nthy-ori3-1 cells were cultured in different E2 concentrations, and the mRNA levels of NIS, estrogen receptor (ER)-α, and ER-ß were measured by quantitative real-time PCR. Their protein levels were assessed by western blot. Results: E2 was positively correlated with thyroid-stimulating hormone (TSH) and negatively correlated with free thyroxine (FT4) (P < 0.05). When we corrected for age, BMI, alanine aminotransferase, and serum creatinine, E2 was still negatively correlated with FT4 (P < 0.5) during the second trimester. In Nthy-ori3-1 cells treated with 10 nM E2, NIS and ER-ß mRNA levels were significantly reduced, while ER-α mRNA level was not altered (P > 0.5). Moreover, 10 nM E2 significantly decreased protein levels of ER-ß, phosphorylated versions of protein kinase A (p-PKA), phosphorylated versions of cAMP response element-binding protein (p-CREB), and NIS, while treatment with the ER-ß inhibitor restored the expression of p-PKA, p-CREB, and NIS (P < 0.05). Conclusion: High concentration of E2 has a negative correlation with FT4. High concentration of E2 can inhibit the NIS expression through the ER-ß-mediated pathway, which may cause thyroid hormone fluctuations during pregnancy.

Serum cystatin C is closely associated with euthyroid Hashimoto's thyroiditis in adult female Chinese patients.

OBJECTIVE: The aim of our study was to explore the association between serum cystatin C (CysC) and euthyroid Hashimoto's thyroiditis. METHODS: There were 119 female euthyroid Hashimoto's thyroiditis patients and 225 healthy controls who were recruited. Serum CysC, thyroid function, thyroid autoantibodies, fasting glucose, liver enzymes, and lipid profile were determined. Clinical parameters were compared between two groups. RESULTS: Serum CysC levels were significantly higher in euthyroid Hashimoto's thyroiditis patients compared with controls. In the lowest, middle, and highest tertile groups of CysC, the percentage of Hashimoto's thyroiditis was 15.9%, 34.2%, and 53.5%, respectively. The percentage of Hashimoto's thyroiditis was significantly higher in the highest tertile than in the lowest and middle tertiles. Spearman's correlation analysis showed that serum CysC levels were negatively correlated with free triiodothyronine (FT3), and positively correlated with serum thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb). Logistic regression analysis showed that serum CysC was independently related to the status of euthyroid Hashimoto's thyroiditis. CONCLUSIONS: The present study shows the first evidence suggesting that serum CysC levels are positively correlated with TPOAb and TGAb. Serum CysC might underlie the pathophysiologic features of euthyroid Hashimoto's thyroiditis.

25-Hydroxyvitamin D serum level in Hashimoto's thyroiditis, but not Graves' disease is relatively deficient.

Vitamin D is a modulator of both the innate and adaptive immune system. As vitamin D deficiency was a risk factor for some autoimmune diseases, we aimed to evaluate the serum vitamin D levels in autoimmune thyroid diseases (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) and investigated the association between serum vitamin D levels and AITD. 175 AITD patients including 51 GD, 61 euthyroid HT (mild HT), 63 euthyroid HT patients with hypothyroidism receiving hormone therapy (treated HT) were recruited from the outpatient department. 51 controls were from the physical checkup center of the hospital. 25-Hydroxyvitamin D levels, thyroid function, antithyroid antibodies, IL-4, IL-17, and TNF-α were determined. Compared with the controls, treated and mild HT patients had significantly lower 25(OH)D levels (45.77±3.48 vs. 83.49±6.24 nmol/L, p<0.001) and (55.25±3.88 vs. 83.49±6.24 nmol/L, p<0.001), respectively. However, GD patients had similar 25(OH)D levels (81.77±5.60 vs. 83.49±6.24 nmol/L, p=0.808). Compared to 24.1% controls with prevalent vitamin D deficiency, mild HT and treated HT patients were significantly different (55.4%, p<0.001) and (70.3%, p<0.001), respectively; no difference was seen in the GD patients (22.9%, p=0.797). Serum 25(OH)D levels were not associated with thyroid function, antithyroid antibodies, and serum cytokines IL-4, IL-17, and TNF-α in patients with AITD. We observed relatively low vitamin D level in mild and treated HT patients, while GD patients had similar 25(OH)D levels to those of healthy individuals. Further studies are imperative to explore the complex etiology of vitamin D deficiency in AITD.