Thyroid diseases are a major medical and biological concern because of the wide range of systemic effects they have on the human body. They are associated with an increased risk of cardiovascular diseases and accelerated atherogenesis, leading to rising mortality rates. Thyroid hormones play a key role in the regulation of metabolism, with the cardiovascular system being particularly sensitive to their fluctuations.

The relationship between thyroid function and the components of metabolic syndrome (MS) is still not fully understood, although it is believed to be mediated by genomic and non-genomic mechanisms.^[1] Several hypotheses have been proposed regarding this connection: thyroid hormones are involved in the pathogenesis of insulin resistance^[2], which in turn is considered a major etiological factor in the development of MS.^{[3, 4]} Furthermore, there are closely related interactions between the individual components of metabolic syndrome and thyroid function, suggesting the possibility that MS may arise as an end phenotype in the context of thyroid dysfunction.

For example, hypothyroidism contributes to increased body weight, and thyroid-stimulating hormone (TSH) has been shown to positively correlate with body mass index (BMI) and the presence of obesity, even within reference ranges.^[5] Both overt and subclinical hypothyroidism are associated with unfavorable lipid profiles, including hypercholesterolemia, reduced HDL-cholesterol levels, and elevated blood pressure.^[6]

To investigate the correlations between thyroid dysfunction and metabolic syndrome, with a specific focus on age- and sex-specific patterns, and to evaluate whether elevated TSH levels—even within the reference range—are associated with increased metabolic risk.

This study is a retrospective cross-sectional analysis involving 726 patients with thyroid pathology who were hospitalized in the Clinic of Endocrinology at St. George University Hospital in Plovdiv between October 2019 and December 2021. All procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki and the established Good Clinical Practice guidelines. The study was approved by the Ethics Committee of the Medical University of Plovdiv (protocol No. 5/24.04.2025). Among the patients, 499 were diagnosed with Hashimoto’s thyroiditis (HT). The remaining 227 patients were distributed according to the following diagnoses: non-toxic thyroid nodule (n=24), multinodular goiter (MNG) (n=59), diffuse toxic goiter (n=79), toxic multinodular goiter (n=11), malignant thyroid diseases (n=19), and postoperative hypothyroidism(n=35). All participants met the established inclusion criteria. The diagnosis of Hashimoto’s thyroiditis was based on a combination of clinical features, supported by the presence of thyroid autoantibodies (anti-Tg, anti-TPO), elevated or altered TSH levels, characteristic ultrasound findings, and, in rare cases when required, fine-needle aspiration biopsy (FNAB). Hyperthyroidism was diagnosed through typical clinical presentation and confirmed by thyroid hormone tests (TSH, T3, and T4). Graves’ disease was identified by diffuse goiter, positive family history, ophthalmopathy, and elevated TRAb or TSI levels. High-resolution thyroid ultrasound was used to evaluate nodules with suspicious features, including hypoechogenicity, irregular margins, microcalcifications, a taller-than-wide shape, and abnormal cervical lymph nodes. FNAB was performed for definitive diagnosis of malignancy. Thyroid scintigraphy was applied in nodules >1 cm with suppressed TSH. Patients included both newly diagnosed and previously diagnosed individuals, with or without ongoing treatment.

During their hospitalization, all patients had their anthropometric, instrumental, and biochemical parameters measured. Body height (cm) and weight (kg) were measured, and BMI was calculated using the standard formula: weight (kg)/[height (m)]².

Fasting blood samples were collected between 07:00 and 09:00 AM, in accordance with all standard patient preparation requirements. Serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured using chemiluminescent immunoassay on the fully automated Access 2 Immunoassay System (Beckman Coulter Inc., USA). Metabolic parameters—total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoproteins (HDL), as well as fasting plasma glucose (FPG)—were analyzed enzymatically using the AU 480 clinical chemistry analyzer (Beckman Coulter, USA) with validated standard methods. Reference ranges for the laboratory parameters used were as follows: TSH: 0.34–5.60 mIU/L; FT3: 3.8–6.0 pmol/L; FT4: 7.86–14.41 pmol/L; TC: 3.0–5.2 mmol/L; TG: 0.4–1.70 mmol/L; LDL: 2.6–4.1 mmol/L; HDL: 1.03–1.60 mmol/L; and FPG: 2.8–6.1 mmol/L.

A statistical analysis of the data was conducted using univariate and bivariate distributions and descriptive statistics methods. The Student’s t-test was employed to compare two independent groups with normal distribution. The results were graphically represented using Microsoft PowerPoint, and statistical analyses were performed using SPSS software, version 19.0 (Chicago, IL, USA). A p-value of less than 0.05 was considered to be statistically significant.

Given the well-documented differences in the prevalence of thyroid gland disorders between sexes, a percentage-based distribution of patients by sex was performed (Fig. 1).

Analysis of the overall sample showed that thyroid pathology was significantly more common in women—83.3%, whereas men represented only 16.7% of the studied cases. This approximately 5:1 female-to-male ratio corresponds with established epidemiological trends and may partly be explained by the higher frequency of healthcare-seeking behavior and preventive checkups among women. In addition to behavioral factors, biological mechanisms also contribute to the observed female predominance in thyroid disorders. Women generally exhibit a more active immune response, which predisposes them to autoimmune conditions, including Hashimoto’s thyroiditis and Graves’ disease. Furthermore, hormonal fluctuations—particularly during pregnancy, the postpartum period, and menopause—can influence thyroid function and autoimmunity, thereby increasing the risk of thyroid dysfunction in females.

A clear predominance of female patients was observed across all forms of thyroid pathology, with prevalence increasing progressively with age. Thyroid hormones exert pleiotropic effects on lipid and glucose metabolism, blood pressure regulation, and energy expenditure, which is why thyroid dysfunction is regarded as an independent risk factor for cardiovascular disease.

The growing interest in the interaction between thyroid dysfunction and the components of metabolic syndrome (MetS) is justified by the fact that both conditions are associated with considerable morbidity and mortality. Recent studies suggest that elevated levels of thyroid-stimulating hormone (TSH), even within the reference range, may be linked to an unfavorable lipid profile. It has been demonstrated that both clinical and subclinical hypothyroidism are associated with an increased risk of developing MetS.^[7] Particularly relevant are findings indicating that even within the euthyroid range, TSH levels >2.5 mIU/L may be linked to adverse metabolic outcomes. Ruhla et al.^[8] observed that TSH levels below 2.5 mIU/L correlated with a more favorable metabolic profile, while Oh et al.^[9] recommended screening for MetS in apparently healthy women with TSH levels exceeding 2.5 mIU/L. Nonetheless, some studies report conflicting evidence and do not support a statistically significant association between TSH and MetS prevalence^{[10, 11]}, which may reflect differences in study design, population characteristics, or MetS diagnostic criteria. These inconsistencies underscore the need for further investigation, and future analyses could benefit from sensitivity assessments using different TSH thresholds.

Over the past decades, global lifestyle patterns have undergone a profound transformation, characterized by increasing consumption of high-calorie foods and reduced physical activity. As a result, there has been a sharp rise in the prevalence of obesity, hyperglycemia, and arterial hypertension—trends that have reached pandemic proportions worldwide.^[23] According to data from the World Health Organization, over 1 billion adults globally are overweight, and more than 300 million suffer from obesity.

As early as 2008, Misra and Khurana^[24] reported high prevalence rates of MetS in various regions: Sub-Saharan Africa (33.5%), India (28.8%), Turkey (33.4%), Iran (33.7%), Venezuela (31.2%), and Brazil (25.4%). MetS is associated with an increased risk of developing type 2 diabetes and serious cardiovascular events, including myocardial infarction, stroke, and heart failure. According to Huang et al.^[25], obesity and smoking are leading risk factors for chronic non-communicable diseases. Obesity alone accounts for more than 363,000 deaths and 12.3 million years lived with disability.

Metabolic regulation demonstrates a marked sex dimorphism, which determines the differing cardiovascular risk profiles in men and women. Premenopausal women are in a more favorable metabolic position due to lower visceral adiposity, mediated by estrogenic activity.^[26] After menopause, the decline in circulating estrogens leads to changes in the lipid profile and fat distribution, shifting toward a central (android) pattern similar to that in men.^[27]

The results of the present study confirm a positive correlation between advancing age and the prevalence of metabolic syndrome, as well as a linear relationship between age and thyroid-stimulating hormone levels. The physiological decline in ovarian function leads to estrogen deficiency, while androgen production by the adrenal cortex remains relatively preserved. This hormonal imbalance contributes to adverse changes in the metabolic profile. Menopause is associated with increased frequency of all components of MetS—central obesity, arterial hypertension, atherogenic lipid profile, and insulin resistance.^[28]

Available data indicate that the overall prognostic value of MetS for cardiovascular events and all-cause mortality is higher in women compared to men.^[29] In addition, there are distinct sex differences in the prevalence of thyroid diseases, particularly autoimmune disorders, which are significantly more common in women and increase with age in both sexes. It should be emphasized that even subclinical forms of thyroid dysfunction are associated with an increased risk of coronary artery disease and all-cause mortality, supporting the need for screening, especially in patients with MetS.

Aging is a complex process involving morphological and functional changes that lead to a progressive decline in biological functions. In women, this process is marked by a sharp decline in sex hormones accompanying the cessation of reproductive function, whereas in men, androgen reduction is more gradual and progressive.^[30] Age is a significant moderating factor in the relationship between thyroid function and MetS. Lao et al.^[31] identify population aging as a key factor in the rising prevalence of MetS. Sex differences in the distribution, age of onset, and severity of MetS, as well as its cardiovascular consequences, are likely due to the differing pace of hormonal decline between the sexes. Our findings confirm the progressive increase in both the prevalence of MetS and thyroid dysfunction with advancing age.

Recent guidelines from the American Thyroid Association (ATA) and other expert consensus panels emphasize the importance of considering age-related changes in thyroid physiology when interpreting thyroid-stimulating hormone (TSH) levels. While the standard reference range for TSH in adults is generally 0.4–4.0 mIU/L, several studies and expert groups suggest that TSH values tend to increase with age, even in the absence of overt thyroid disease. Consequently, applying a uniform reference interval across all age groups may lead to overdiagnosis of subclinical hypothyroidism in the elderly. The ATA recommends individualized interpretation of TSH results, particularly in adults over 65 years of age, and supports higher upper reference limits in this population to avoid unnecessary treatment. These age-adjusted thresholds are increasingly being recognized in clinical practice to ensure more accurate diagnosis and management decisions.

In addition to screening considerations, the American Thyroid Association (ATA) provides guidance on the treatment of subclinical hypothyroidism, emphasizing a personalized approach based on age, TSH levels, and symptomatology. Treatment is generally recommended for patients under 65 years with a TSH level ≥10 mIU/L, even if asymptomatic, due to the increased risk of cardiovascular events and progression to overt hypothyroidism. For patients with TSH levels between 4.5 mIU/L and 9.9 mIU/L, treatment may be considered in younger individuals, especially in the presence of symptoms, positive anti-thyroid antibodies, or risk factors such as dyslipidemia, infertility, or goiter. However, in older adults (≥65 years), the ATA advises a more conservative approach. In this population, treatment is typically reserved for those with TSH ≥10 mIU/L, and individualized decisions should be made for those with lower elevations due to the lack of clear evidence of benefit and potential risk of overtreatment, including atrial fibrillation and bone loss.^{[32, 33]}

The results of this study highlight a significant association between metabolic syndrome (MetS) and thyroid dysfunction, with age and sex playing a substantial moderating role. It was found that older women, particularly those in the postmenopausal period, were at an increased risk of developing MetS in the presence of elevated thyroid-stimulating hormone levels. This likely reflects the combined influence of estrogen deficiency and the higher prevalence of thyroid disorders in women.

The findings underscore the need for targeted screening for thyroid dysfunction in patients with MetS, with particular attention to vulnerable age and sex subgroups. These insights may contribute to a deeper understanding of the pathophysiological mechanisms underlying cardiometabolic risk and support early identification and appropriate management of high-risk individuals. Early identification of thyroid dysfunction through routine screening in primary care is essential for timely intervention, especially in high-risk groups such as older adults and women. Preventive strategies, including regular monitoring and patient education, can help reduce the burden of metabolic and cardiovascular complications associated with undiagnosed or subclinical thyroid disorders.

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the institutional Ethics Committee of St George University Hospital in Plovdiv, Bulgaria. All data were obtained through retrospective analysis of medical records, ensuring full anonymity and confidentiality of patient information. The requirement for written informed consent was waived due to the retrospective nature of the study and the use of de-identified data, in line with local regulations and institutional guidelines.

This research received no external funding.

The authors declare no conflict of interest.