Association Between Thyroid Hormone Sensitivity and Dyslipidemia in Elderly Women

doi:10.21203/rs.3.rs-4908179/v1

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Association Between Thyroid Hormone Sensitivity and Dyslipidemia in Elderly Women

https://doi.org/10.21203/rs.3.rs-4908179/v1

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Context:

This study investigates the relationship between thyroid hormone sensitivity indices and dyslipidemia in elderly Chinese women. Given the potential impact of thyroid hormones on lipid metabolism, understanding this relationship could improve dyslipidemia management in this population.

Materials and Methods

We conducted a retrospective case-control study involving 1,312 elderly women who underwent health examinations at the Health Examination Center of the 305 Hospital of the Chinese PLA. Thyroid hormone sensitivity indices, including Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), Thyrotroph Thyroxine Resistance Index (TT4RI), and Free Triiodothyronine/Free Thyroxine ratio (FT3/FT4), were assessed alongside dyslipidemia markers. Statistical analyses included logistic regression and restricted cubic spline models to evaluate the associations and dose-response relationships between these indices and dyslipidemia.

Results

The study found a U-shaped dose-response relationship between TFQI, TSHI, and TT4RI levels and dyslipidemia risk, indicating that both very high and very low levels of these indices were associated with increased risk. The FT3/FT4 ratio was positively correlated with dyslipidemia risk but lost significance when adjusting for additional confounders.

Conclusions

Elevated and reduced thyroid hormone sensitivity indices are associated with a higher risk of dyslipidemia in elderly women, while moderate levels may be protective. These findings suggest that a comprehensive approach to thyroid function assessment, incorporating sensitivity indices, could enhance the management of dyslipidemia in older women. Further research is needed to confirm these results and explore the underlying mechanisms.

Elderly Women

Thyroid Hormone Sensitivity Indices

Dyslipidemia

Dose-Response Relationship

Cardiovascular disease (CVD) is the most prevalent chronic non-communicable disease globally, posing a significant health risk. Despite advancements in therapeutic medications that reduce heart disease mortality, cardiovascular disorders still account for one-third of all deaths worldwide(1). Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD)(2). In women, the prevalence of dyslipidemia—including high blood pressure, elevated triglycerides, and low-density lipoprotein cholesterol—increases with age. In contrast, this trend is stable or even decreases in men(3). Early identification and treatment of dyslipidemia can mitigate or delay the risk of cardiac events(4). As dyslipidemia is a modifiable risk factor for coronary heart disease, managing lipid metabolism is particularly crucial for elderly women.

Thyroid hormones play a vital role in regulating lipid metabolism, including processes such as lipid synthesis, mobilization, and breakdown through complex regulatory systems(5). Previous research on the relationship between thyroid hormone fluctuations and dyslipidemia has yielded inconsistent results(6–8). Changes in thyroid hormones can cause dyslipidemia both within and outside the normal range, indicating that drawing conclusions from standard serological test results alone may be unreliable. Given the complexity of hormone interactions within the hypothalamic-pituitary-thyroid axis and the unique metabolic characteristics of thyroid hormones in circulation, evaluating thyroid function with a single serological marker is insufficient. Incorporating thyroid hormone sensitivity indices—such as the Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating hormone Index (TSHI), Thyrotroph Thyroxine Resistance Index (TT4RI), and Free Triiodothyronine /Free thyroxine (FT3/FT4)—provides a new perspective on the relationship between dyslipidemia and thyroid function(9). Only one study has examined the relationship between thyroid hormone sensitivity indices and dyslipidemia, focusing on a general population with coronary heart disease. This study found that elevated levels of TSHI, TT4RI, and TFQI were significantly associated with an increased risk of dyslipidemia, while FT3/FT4 was associated with a decreased risk(10). However, thyroid hormone sensitivity in the general population differs from that of the elderly(11). The relationship between thyroid hormone sensitivity and dyslipidemia in older women has not been studied.

This study aims to investigate the relationship between thyroid hormone sensitivity and dyslipidemia in elderly women to provide a reference for future research on thyroid function and lipid management in this population.

Study Population

This retrospective case-control study included participants (n = 6,390) who underwent health examinations at the Health Examination Center of the 305 Hospital of the Chinese PLA between January 2021 and July 2023. Inclusion criteria:1. Individuals aged 60 years and older.2. Completion of tests for serum triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and other metabolism-related indicators (including blood routine, uric acid, creatinine, fasting blood glucose, and glycated hemoglobin).Exclusion criteria:1. Male individuals.2. Any abnormal values in TSH, FT3, FT4, TT3, or TT4.3. History of using thyroid medications, lipid-lowering drugs, amiodarone, or chemotherapy drugs.4. History of thyroid disease, neck radiotherapy, or malignant tumors, or those who did not undergo thyroid function tests.5. Incomplete physical examination data.(Fig. 1).All participants provided written informed consent, and the study protocol was approved by the Ethics Committee of our hospital.the Ethical Committee of the 305 Hospital of the Chinese PLA approved this study with the approval number KYLL-SPJ-2024-09.

Measurement of Laboratory Parameters

General data, including age, height, weight, and blood pressure, along with laboratory test results, were collected through the health screening system of the 305 Hospital of the Chinese PLA. The laboratory tests included triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The reference ranges for thyroid function indicators, as established by the 305 Hospital’s laboratory, are as follows:TSH: 0.56–5.91 mIU/L,FT3: 3.28–6.47 pmol/L,FT4: 7.64–16.03 pmol/L,T3: 1.01–2.48 nmol/L,T4: 69.97-152.52 nmol/L.

Diagnostic Standards and Categorization

A diagnosis of dyslipidemia was made if any of the following conditions were met:Low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol/L;High-density lipoprotein cholesterol (HDL-C) < 1.0 mmol/L;Total cholesterol (TC) ≥ 5.2 mmol/L;Triglycerides (TG) ≥ 1.7 mmol/L.A patient was diagnosed with dyslipidemia if any one of these four markers was abnormal(12). Based on these diagnostic criteria, the study population was divided into two groups: the dyslipidemia group and the normal lipid group.

Thyroid hormone sensitivity indices Calculation Formula:

$$\:\text{T}\text{F}\text{Q}\text{I}=\text{c}\text{d}\text{f}\text{F}\text{T}4-(1-\text{c}\text{d}\text{f}\text{T}\text{S}\text{H})$$

After calculation, the range for TFQI values is from − 1 to 1

$$\:\text{T}\text{T}4\text{R}\text{I}=\text{F}\text{T}4\times\:\text{T}\text{S}\text{H}$$

$$\:\text{T}\text{S}\text{H}\text{I}=\text{l}\text{n}\text{T}\text{S}\text{H}+0.1345\times\:\text{F}\text{T}4$$

$$\:\text{F}\text{T}3/\text{F}\text{T}4=\text{F}\text{T}3/\text{F}\text{T}4$$

Units:TSH: mIU/L、FT3༚pmol/L、FT4༚pmol/L

Statistical Analysis

Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables were represented by counts and percentages. For normally distributed continuous variables, t-tests were used to determine differences between groups, while U tests were applied for non-normally distributed continuous variables. Categorical variables were compared using chi-square tests.Thyroid hormone sensitivity indices were divided into quartiles, with the median of each quartile used as a continuous variable in the regression model for trend testing. Multivariate logistic regression was employed to explore the relationship between thyroid hormone sensitivity indices and dyslipidemia in elderly women.Additionally, a restricted cubic spline model was used to analyze the dose-response relationship between thyroid hormone sensitivity indices and dyslipidemia, plotting the restricted cubic spline curve for these indices and dyslipidemia. A P-value less than 0.05 for the thyroid hormone sensitivity index indicated a dose-response relationship between the index and dyslipidemia. If the P-value for the thyroid hormone sensitivity index was less than 0.05 and the P-value for nonlinearity was greater than 0.05, it indicated a linear dose-response relationship. If both the P-value for the thyroid hormone sensitivity index and the P-value for nonlinearity were less than 0.05, it indicated a nonlinear dose-response relationship.A two-sided P-value of less than 0.05 was considered statistically significant. Data processing was performed using R 4.3.0 statistical software.

Baseline Characteristics of the Study Population

A total of 1,312 participants were enrolled in the study, with an average age of 69.34 years (standard deviation 6.91). Table 1 presents the baseline characteristics of the study population. In the dyslipidemia group, levels of hyperuricemia, total protein, globulin, T3, FT3, FT3/FT4, red blood cells, white blood cells, and platelets were significantly higher compared to the normal lipid group (P < 0.05). Additionally, the dyslipidemia group exhibited lower albumin/globulin ratios and a statistically significant difference in age compared to the normal lipid group (all P < 0.05).

Table 1

Baseline characteristics of the study population
variable	Total(n = 1312)	dyslipidemia(n = 862)	normal(n = 450)	t/X²	p
age	69.34 ± 6.91	68.89 ± 6.85	70.20 ± 6.96	-3.25	< 0.01
BMI	24.01 ± 3.44	24.05 ± 3.25	23.95 ± 3.79	0.47	0.64
ALB	42.84 ± 4.41	42.90 ± 4.53	42.72 ± 4.15	0.70	0.48
GLB	29.32 ± 4.45	29.66 ± 4.41	28.67 ± 4.46	3.86	< 0.001
A/G	1.48 ± 0.21	1.47 ± 0.20	1.52 ± 0.22	-3.94	< 0.0001
WBC	5.93 ± 1.38	6.04 ± 1.41	5.71 ± 1.28	4.20	< 0.0001
RBC	4.38 ± 0.37	4.43 ± 0.36	4.30 ± 0.36	6.15	< 0.0001
PLT	220.54 ± 53.60	226.32 ± 54.78	209.49 ± 49.47	5.63	< 0.0001
N	3.45 ± 1.07	3.49 ± 1.10	3.37 ± 1.01	1.94	0.05
TP	70.81 ± 12.26	71.45 ± 11.72	69.58 ± 13.17	2.53	0.01
CR	60.46 ± 15.23	60.58 ± 16.75	60.23 ± 11.80	0.44	0.66
T4	116.22 ± 18.10	115.69 ± 18.36	117.22 ± 17.56	-1.47	0.14
T3	1.61 ± 0.27	1.62 ± 0.27	1.58 ± 0.27	2.53	0.01
FT3	4.88 ± 0.58	4.91 ± 0.57	4.81 ± 0.59	2.86	< 0.01
FT4	11.28 ± 1.64	11.25 ± 1.67	11.35 ± 1.58	-1.07	0.28
TSH	2.48 ± 1.21	2.51 ± 1.25	2.42 ± 1.12	1.29	0.20
TFQI	-0.03 ± 0.37	-0.03 ± 0.38	-0.03 ± 0.35	-0.01	0.99
TSHI	2.30 ± 0.51	2.30 ± 0.52	2.30 ± 0.47	0.04	0.97
TT4RI	27.55 ± 13.30	27.80 ± 13.80	27.06 ± 12.29	1.00	0.32
FT3/FT4	0.44 ± 0.08	0.45 ± 0.08	0.43 ± 0.08	2.87	< 0.01
diabetes				0.12	0.73
yes	209(15.93)	140(16.24)	69(15.33)
no	1103(84.07)	722(83.76)	381(84.67)
hypertension				0.39	0.53
yes	572(43.60)	370(42.92)	202(44.89)
no	740(56.40)	492(57.08)	248(55.11)
hyperuricemia				21.05	< 0.0001
yes	84( 6.40)	75( 8.70)	9( 2.00)
no	1228(93.60)	787(91.30)	441(98.00)

For continuous variables, data are expressed as the mean ± SD or median (interquartile range). For categorical variables, data are presented as percentages.Abbreviations:BMI, body mass index;ALB, albumin;GLB, globulin;A/G, albumin-to-globulin ratio;WBC, white blood cells;RBC, red blood cells;PLT, platelet count;N, neutrophil count;TP, total protein;CR, creatinine;T4, thyroxine;T3, triiodothyronine;FT3, free triiodothyronine;FT4, free thyroxine;TSH, thyroid-stimulating hormone;TSH, thyroid-stimulating hormone;TFQI, Thyroid Feedback Quantile-based Index;TSHI, Thyroid-Stimulating Hormone Index;TT4RI, Thyrotroph Thyroxine Resistance Index;FT3/FT4, free triiodothyronine/free thyroxine ratio.

Thyroid Hormone Sensitivity Indices and Dyslipidemia in Elderly Women: A Logistic Regression Analysis

After categorizing the thyroid hormone sensitivity indices into quartiles, logistic regression analysis was performed. The results are as follows:Model 1:Without adjusting for confounding factors, the risk of dyslipidemia in the Q4 group of FT3/FT4 was 1.62 times that of the Q1 group (P < 0.05).Model 2:After adjusting for age, the risk of dyslipidemia in the Q4 group of FT3/FT4 was 1.54 times that of the Q1 group (P < 0.05).Model 3:After adjusting for body mass index, albumin, globulin, and other confounding factors, the risk of dyslipidemia in the Q2 group of TFQI was 0.69 times that of the Q1 group (P < 0.05).(Table 2)

Table 2

Logistic Regression Analysis of thyroid hormone sensitivity indices and Dyslipidemia in Elderly Women
character	Model 1		Model 2		Model 3
character	95%CI	P	95%CI	P	95%CI	P
TFQI
Q1	1.00		1.00		1.00
Q2	0.72(0.52,1.00)	0.05	0.72(0.52,1.00)	0.05	0.69(0.49,0.97)	0.03
Q3	0.8(0.58,1.11)	0.18	0.8(0.58,1.11)	0.18	0.76(0.54,1.07)	0.12
Q4	0.89(0.64,1.23)	0.47	0.87(0.63,1.22)	0.43	0.81(0.58,1.14)	0.23
p for trend		0.61		0.56		0.31
TSHI
Q1	1.00		1.00		1.00
Q2	0.84(0.61,1.16)	0.30	0.83(0.60,1.15)	0.26	0.84(0.60,1.18)	0.32
Q3	0.81(0.59,1.12)	0.21	0.8(0.58,1.10)	0.17	0.81(0.58,1.14)	0.23
Q4	1.09(0.78,1.51)	0.61	1.07(0.77,1.48)	0.70	1.01(0.71,1.43)	0.96
p for trend		0.7		0.79		0.97
TT4RI
Q1	1.00		1.00		1.00
Q2	0.85(0.62,1.17)	0.32	0.84(0.61,1.16)	0.29	0.89(0.63,1.24)	0.48
Q3	0.77(0.56,1.06)	0.10	0.75(0.54,1.03)	0.08	0.75(0.54,1.05)	0.10
Q4	1.15(0.83,1.61)	0.40	1.13(0.81,1.57)	0.48	1.1(0.78,1.57)	0.57
p for trend		0.28		0.35		0.51
FT3/FT4
Q1	1.00		1.00		1.00
Q2	1.16(0.84,1.59)	0.36	1.15(0.84,1.58)	0.40	1.03(0.74,1.44)	0.85
Q3	1.16(0.84,1.59)	0.37	1.11(0.81,1.53)	0.51	1.08(0.77,1.51)	0.66
Q4	1.62(1.17,2.25)	0.004	1.54(1.11,2.14)	0.01	1.4(0.99,1.99)	0.06
p for trend		0.004		0.01		0.05

Model 1: unadjusted. Model 2: adjusted by age.Model 3: adjusted by age, BMI, ALB, GLB, A/G, WBC, RBC, PLT, N, TP, CR.

Dose-Response Association between Dyslipidemia and Thyroid Hormone Sensitivity Indices in Elderly Women

In elderly women, the Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating hormone Index (TSHI), and Thyrotroph Thyroxine Resistance Index (TT4RI) all exhibited a U-shaped nonlinear dose-response relationship with dyslipidemia in Model 1. This relationship persisted even after adjusting for confounding factors in Models 2 and 3 (P-TFQI, TSHI, TT4RI all < 0.1294, P-Nonlinear < 0.05) (Fig. 2, Fig. 3, Fig. 4). However, the FT3/FT4 index showed a linear dose-response relationship with dyslipidemia in both the unadjusted model and after adjusting for age (P-FT3/FT4 < 0.05, P-Nonlinear < 0.05). After adjusting for body mass index, albumin, globulin, and other confounding factors, the FT3/FT4 index did not show a dose-response relationship with dyslipidemia (P-FT3/FT4 = 0.1483, P-Nonlinear = 0.0122) (Fig. 5).

This study is the first to examine the relationship between thyroid hormone sensitivity indices and dyslipidemia specifically in older Chinese women. Previous research, including a review by Debbie W. Chen's team published in The Lancet,indicates that approximately 75% of thyroid cancer patients are female, though the disease can affect both genders. Thyroid cancer can occur at any age, but the median age at diagnosis is just over 50 years(13). This study's focus on older women is thus particularly novel. By using a restricted cubic spline model, this research extends previous methods to visually illustrate the dose-response relationship between thyroid hormone sensitivity and lipid metabolism in this demographic. This approach will provide valuable insights for future studies on thyroid function and lipid management in older women.

Research on the relationship between thyroid hormones and blood lipids has produced varied results. For instance, Yanqiu Wang's team found that free thyroxine (FT4) is positively correlated with high-density lipoprotein cholesterol (HDL-C) levels and negatively correlated with triglycerides, while free triiodothyronine (FT3) is positively correlated with total cholesterol and low-density lipoprotein cholesterol (LDL-C)(14). Conversely, Bruce H. R. Wolffenbuttel's research showed that waist circumference and triglycerides in women were positively correlated with the lowest FT4 quartile, while in men, higher FT3 levels were associated with lower HDL-C levels(8). Yeqing Gu's study found no correlation between FT4 and dyslipidemia, but FT3 was negatively correlated with total cholesterol and LDL-C, and TSH was negatively correlated with HDL-C(15). These mixed findings underscore the complex relationship between thyroid hormones and blood lipid levels.

Previous studies have suggested that assessing TSH or thyroid hormone levels alone may not fully elucidate the relationship between dyslipidemia and thyroid function. Composite indices may provide a more systematic reflection of thyroid hormone regulation. For example, prior research indicated that peripheral thyroid hormone sensitivity indices are linked to a lower risk of dyslipidemia, while central indices are associated with an increased risk(10). This study demonstrates a U-shaped dose-response relationship between TFQI, TSHI, and TT4RI levels and dyslipidemia risk, suggesting that both excessively high and low levels of these indices may increase the risk of dyslipidemia, with moderate levels potentially offering protection. The FT3/FT4 ratio showed a positive correlation with dyslipidemia risk, which was significant after adjusting for age but not after accounting for additional confounding variables such as blood pressure, blood glucose, and uric acid. This indicates that elevated FT3/FT4 levels warrant close monitoring in the context of lipid control.

As individuals age, alterations in thyroid hormone signaling and receptor expression affect thyroid hormone metabolism. Reduced thyroid hormone transport and receptor number result in decreased receptor occupancy and weaker responses to thyroid hormones. Epigenetic modifications, such as DNA methylation, also impact gene expression related to thyroid hormone response(16–18). Aging can slow thyroid hormone metabolism and decrease sensitivity, leading to changes in the hypothalamic-pituitary-thyroid (HPT) axis. These changes include altered TSH secretion patterns, increased hypothalamic sensitivity to TSH feedback inhibition, and variations in thyroid hormone metabolism in peripheral tissues. Older individuals may have higher TSH levels without a corresponding decrease in FT4(19–20). Research by Arshag D. Mooradian suggests that age-related thyroid hormone resistance may result from changes in gene expression, tissue transport, nuclear receptor occupancy, and T3 activation of thyroid hormones(21). Some studies have shown that thyroid hormone sensitivity decreases with age, with peripheral sensitivity indices (FT3/FT4 ratio) negatively correlated with age, while central indices (TT4RI, TSHI, TFQI) are positively correlated(11).

Women generally have lower FT3/FT4 ratios and higher TSH levels compared to men across all age categories. Women's FT4 levels decrease more sharply than men's before middle age, and only women's FT4 levels modestly increase after age 60(11). These findings, along with this study's results, highlight the distinct thyroid traits associated with dyslipidemia in middle-aged and older women.

However, this study has limitations. Although it suggests a potential link between thyroid hormone sensitivity indices and dyslipidemia in older women, it does not establish a causal relationship. Additionally, the findings may not be generalizable beyond the healthy screening population in China. Future large-scale, prospective studies are needed to validate these results.

In conclusion,this study is the first to explore the association between thyroid hormone sensitivity indices and dyslipidemia specifically in elderly Chinese women. Our results reveal that elevated and reduced levels of TFQI, TSHI, and TT4RI are both associated with an increased risk of dyslipidemia, suggesting a U-shaped dose-response relationship. In contrast, while the FT3/FT4 ratio showed a positive association with dyslipidemia risk, this relationship was influenced by additional confounding factors.

Compliance with ethical standards

Conflict of interest The authors declare no competing interests.

Consent to participate

Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Ethics approval

the Ethical Committee of the 305 Hospital of the Chinese PLA approved this study with the approval number KYLL-SPJ-2024-09.

Funding

This work was supported by the 2024 Independent Research Fund of the 305th Hospital of the Chinese People's Liberation Army (24ZZJJLW-025).

Author Contribution

Jinpin Zhang and Jianxin Ma contributed to the study conception and design.Data collection were performed by Binghua Zhu and Zhipeng Liu.Statistical analysis was performed by Hezhi Li.Yiling Zhou prepared the tables.The first draft of the paper was written by Hezhi Li.All authors reviewed the manuscript.

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No competing interests reported.

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Association Between Thyroid Hormone Sensitivity and Dyslipidemia in Elderly Women

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