The present study focused more on the alterations of lipid profiles in patients with hypothyroidism than previous studies. We found that the degree of abnormal lipid metabolism in patients with IH patients was more pronounced, mainly in the form of higher levels of TC, TG, LDL-C, and Apo B. Previous research showed that FT4 and TSH play separate functions in lipid metabolism [28, 29]. IH is characterized by normal range TSH levels and only a low level of FT4. In the control group, we observed a negative association between FT4 and TG levels, which was more significant in patients with IH. Our findings are consistent with those of another cross-sectional study that found a negative association between TG and normal range FT4 levels in 2315 euthyroid adults [30]. However, some studies have noted that variations in TC are associated with variations in TSH, regardless of whether FT4 levels were normal or abnormal [31]. However, this phenomenon was not observed based on the present study. This may be related to the fact that IH is associated with a slight degree of hypothyroidism and a small sample size.
Experts have begun to explore the relationship between BMI and thyroid function. Evidence suggests that changes in thyroid hormone levels result from weight change rather than a cause [4]. A negative relationship between normal-range FT4 levels and BMI was found in a large-sample retrospective study [1]. A study in China reported a negative correlation between FT4 levels and prepregnancy BMI in patients with IH [32]. The close relationship between hypothyroidism and dyslipidemia with obesity indicates that the association between maternal thyroid function and metabolic markers may also be mediated by obesity [1]. However, there is no clear evidence supporting this inference. In our study, pregnant women with IH had a higher prepregnancy BMI than controls. Although no specific link was identified, stratification based on BMI levels revealed that pregnant women with a higher prepregnancy BMI (those who were relatively overweight) had lower FT4 levels. Due to the nonavailability of all individuals' prepregnancy thyroid function results, we could only hypothesize that those with a higher prepregnancy BMI had a higher risk of developing IH during pregnancy, consistent with previous research. This is partly because obesity increases the levels of adipokines expressed by adipocytes, such as leptin and adiponectin. Leptin can affect the hypothalamic-pituitary-thyroid axis via the JAK2/STAT3 pathway, influencing thyroxine secretion [33, 34]. ΔBMI and GWG reflect, to some extent, maternal fluid expansion, fat accumulation, and placental and fetal growth, and appropriate gain is necessary [34]. We found that patients with IH had a higher ΔBMI and GWG, which was associated with a lower maternal basal metabolism rate. These findings suggest that attention should be given to healthy dietary habits, which reduce the risk of developing thyroid dysfunction during pregnancy. Additionally, weight control should be encouraged throughout pregnancy.
After excluding the disturbance of prepregnancy BMI, we found that in patients with IH, a linear relationship between FT4 and TG still existed and was more significant, further confirming that low FT4 levels may interfere with lipid metabolism alone in pregnant women. Simultaneously, the difference in ΔBMI and GWG remained, indicating that pregnancy weight gain was relatively high in patients with IH, however, it was unrelated to the initial BMI. Pop also found that pregnant women may experience low FT4 levels when they gain weight too quickly, even with a normal prepregnancy BMI [34]. These studies suggest that weight management becomes more complicated during pregnancy in women with low FT4 levels. Perhaps thyroid function should also be considered in those who have difficulty managing their weight during pregnancy or have abnormally high lipid indicators.
Age [31] was positively correlated with TSH [35] and negatively correlated with FT4 in individuals with normal thyroid function; however, serum lipid levels tended to increase with age. Therefore, age is an independent factor affecting thyroid function and lipid metabolism. However, in our study, the occurrence of IH was independent of age, probably because the participants were fertile women, and the age was relatively concentrated. There is no clear evidence that gravidity and parity affect the occurrence of IH during pregnancy. Therefore, more factors still need to be explored in further prospective, large-sample, multicenter studies.
We established that despite the absence of medication in the dietary treatment group, the data proved that getting more iodine-containing food, such as kelp, could slightly improve thyroid function, mainly by increasing FT4 levels. This phenomenon may indicate that, in IH, the alteration of FT4 levels after small amounts of iodine supplementation may be more sensitive than that of TSH. After L-T4 intervention, the levels of FT4 and TSH greatly improved and were more significant than those of the other groups. Although TSH levels were normal, the L-T4 treatment reduced TSH levels. These results confirm the effectiveness of L-T4 in the treatment of thyroid function.
We investigated the effects of L-T4 treatment on the blood lipid profile and the possible link between thyroid function recovery and lipid metabolic changes. This is because traditional lipid-lowering drugs are not the preferred treatment for hyperlipidemia during pregnancy [27]. Based on the treatment group’s lowest raised TC levels, L-T4 intervention can partly hinder the elevation of physiological cholesterol in pregnancy. This finding demonstrates that serum TC levels during pregnancy are sensitive to thyroid regulation. Furthermore, we found that both interventions marginally reduced LDL-C by boosting thyroid function, however, L-T4 did not show a distinct therapeutic impact. Changes in TG levels in the IH group were greater than those in controls. This could be because of the poor overall thyroid function on retesting in late pregnancy compared with controls, despite intervention with L-T4 or dietary iodine supplementation. We hypothesized that the long-term effects of decreased FT4 levels on lipids would outweighe the benefits of better thyroid function in terms of lipid alleviation. L-T4 has been shown to directly activate the expression of the LDL receptor and cholesterol 7 alpha-hydroxylase (CYP7A1) and stimulate the breakdown of LDL-C and cholesterol into bile acids in the liver, returning partial lipid levels to normal levels [26, 36]. This may be due to the direct effects of TH and TSH on TC and LDL-C regulation [37, 38] and their indirect effects on TG [39,40,41]. We found that after thyroid function improved, TC and LDL-C levels returned to normal first, while TG lagged.
We further explored the factors influencing the therapeutic effects of L-T4. First, stratification based on FT4 and TSH levels indicated that the baseline level of thyroid function could partly affect the therapeutic effect of L-T4. This means that the more severe the low FT4 and high TSH levels are, the greater the improvement in thyroid function following L-T4 intervention, as seen in patients with clinical hypothyroidism (CH) and subclinical hypothyroidism (SCH) [42, 43]. Currently, there is no diagnostic standard for hyperlipidemia during pregnancy [44]. However, we used the 50th percentile of lipid distribution to establish subgroups to determine the relative lipid levels. In the subgroup with high TG levels (TG ≥ 2.41 mmol/L), the treatment effect was relatively poor, with less improvement in thyroid function and a higher degree of dyslipidemia. Despite not finding statistically significant differences and the lack of consensus on the lipid-lowering effect of L-T4 in patients with IH, we believe there is a connection between the therapeutic effect and the severity of the disease, with the main factors being FT4, TSH, and TG levels before treatment.
The present study has several strengths. These results were adjusted for known or potential confounders to minimize errors. And it was devoted to an in-depth exploration of lipid alterations in patients with IH during pregnancy. At the same time, this study was the first study to explore the effect of L-T4 on these patients in this region, proved that drug treatment has a certain degree of improvement in some metabolic indicators to a certain extent, which was of great significance for guiding the monitoring and treatment of IH in clinical work. However, as this was a single-center study, caution should be exercised when extrapolating the results to the general pregnant population. This study had some other limitations in data collection: the cases included in this study may have had both thyroid function and blood lipid profile results in the second and third trimesters, affecting the accuracy of calculation for the incidence and consequently impacting the experimental results. Moreover, maternal weight was not included as a metabolic indicator, making it difficult to further speculate on the role of maternal weight factors in the alteration of thyroid function and serum lipids. In the future, this center will conduct prospective cohort studies and test some adipokines to further explore the mechanism. We only studied the effects of levothyroxine treatment on lipid metabolism in IH during pregnancy. However, whether all patients will benefit from levothyroxine therapy, including improving pregnancy outcomes and offspring neurointellectual development, determining the need for clinical intervention and long-term prognosis, or whether such therapy should be given to specific subgroups, remains a major question, and no definitive recommendation can be made at this time [2]. The potential side effects of medicine should also be considered, which were not identified in this study.