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Prevalence of Residual Symptoms Following Thyroid-Stimulating Hormone Normalization in Patients with Hypothyroidism
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Seyed Mohammad Aria1    , Maryam Zahedi2 , Fatemeh Mohmmadzade *3 , Alireza Seyedi Niaki4 , Somayeh Ghorbai5 |
1- Medical Student, Golestan University of Medical Sciences, Gorgan, Iran.
2- Assistant Professor, Golestan University of Medical Sciences, Gorgan, Iran.
3- Assistant Professor, Ischemic Disorders Research Center, Faculty of Medicine, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Iran. , msoheila66@yahoo.com
4- Anesthesiologist, Anesthesiology Ward, Sayad Shirazi Hospital, Golestan University of Medical Sciences, Gorgan, Iran.
5- Assistant Professor of Biostatistics, Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran. |
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Keywords: Hypothyroidism [MeSH], Thyrotropin [MeSH], Thyroxine [MeSH]
Article ID: Vol27-34 |
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Type of Study: Original Articles |
Subject:
Endocrinology
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Abstract: (32 Views) |
Extended Abstract
Introduction
Hypothyroidism is a clinical syndrome characterized by the inadequate production of thyroid hormones, typically managed with levothyroxine (LT4) to maintain serum thyroid-stimulating hormone (TSH) levels within the normal range. In the majority of patients, this approach successfully alleviates symptoms of overt hypothyroidism through the endogenous conversion of thyroxine (T4) into triiodothyronine (T3), the biologically active thyroid hormone. A variety of thyroid function tests (TFTs) are available, enabling clinicians to diagnose thyroid disorders with a high degree of sensitivity and specificity. The application of these tests, particularly the assessment of serum TSH levels, renders the diagnosis of overt thyroid dysfunction relatively straightforward in most cases.
Nevertheless, a small percentage of patients (10–20%) continue to experience residual symptoms despite maintaining normal serum TSH levels. These symptoms encompass cognitive, mood, and metabolic impairments that significantly impact psychological well-being and quality of life. While the standard of care has traditionally focused on the normalization of TSH levels, emerging research highlights the importance of considering T3 deficiency in patients undergoing LT4 monotherapy. Although clinical trials comparing LT4 monotherapy with combination therapy (LT4 plus liothyronine [LT3]) have demonstrated both approaches to be safe and comparably effective, these trials often lacked adequate enrollment of patients specifically exhibiting residual symptoms. More recent studies suggest that symptomatic patients may indeed derive benefit from combination treatment. Consequently, a pragmatic approach to managing patients with residual symptoms involves considering the initiation of combination therapy with both LT4 and LT3.
In most patients, hypothyroidism is a chronic condition necessitating lifelong management. Treatment primarily involves thyroid hormone replacement therapy, except in cases where the hypothyroidism is transient or reversible. The therapeutic objective is to achieve a euthyroid state, which is readily attainable in nearly all patients through the oral administration of synthetic T4 (LT4). However, a significant proportion of patients continue to experience symptoms despite treatment and achieving biochemical targets (i.e., maintaining serum TSH levels within the normal range). This raises the question of whether LT4 monotherapy is sufficient for all patients, or if alternative approaches-such as combination therapy with LT4 and LT3-might offer superior efficacy in certain individuals. Despite standard LT4 treatment and the normalization of TSH levels in hypothyroidism, a substantial number of patients still suffer from certain symptoms, including fatigue, dry skin, cold intolerance, muscle cramps, and constipation. The present study was conducted to determine the prevalence of residual symptoms following TSH normalization among patients with hypothyroidism in Gorgan, Iran.
Methods
This descriptive-analytical study was conducted on 200 patients with hypothyroidism (193 females and 7 males) who were under regular treatment, had achieved normalized TSH levels, and were recruited from an endocrinology subspecialty clinic in Gorgan, Iran, in 2022.
Inclusion criteria consisted of an age range of 25–65 years, regular LT4 consumption for at least 6 months, and TSH levels within the normal range (0.4–4 mIU/L). Exclusion criteria included suffering from incurable diseases, pregnancy, thyroid malignancy, and poor general health status.
Initially, the patients' height, weight, and blood pressure were measured. Subsequently, the instructions for completing the questionnaire were explained to each participant individually. The questionnaire comprised 8 items regarding common symptoms of hypothyroidism, including fatigue, dry skin, weight changes, cold intolerance, constipation, muscle cramps, facial puffiness, and hair loss. Responses were recorded and collected using a 4-point Likert scale (ranging from 'absent' and 'rarely present' to 'present' and 'severely present').
Paraclinical data, including T4, T3, TSH, and thyroid peroxidase antibody (anti-TPO) levels, were extracted from the most recent laboratory reports in the patients' medical records. These assays were performed using the Siemens Immulite 2000 analyzer (Siemens Co., Germany) via the chemiluminescence immunoassay (CLIA) method. The intra-assay percentage of repeatability for T4, T3, TSH, and anti-TPO were reported to be 7.1, 3.53, 6.13, and 2.7, respectively.
Results
The most prevalent symptoms were identified as fatigue (74.2%), cold intolerance (73.7%), dry skin (73.2%), constipation (70.4%), hair loss (67.2%), facial puffiness (63.3%), muscle cramps (62.8%), and weight changes (48%), respectively.
A statistically significant correlation was observed between body mass index (BMI) and dry skin (P<0.027). More than 40% of individuals with a BMI of less than 25 kg/m2 reported severe dry skin, whereas this figure was approximately 21% for those with a BMI of 25 kg/m2 or higher. No significant statistical correlation was found between BMI and other symptoms.
No statistically significant correlations were observed between anti-TPO levels and residual symptoms of hypothyroidism and between TSH levels and residual symptoms of hypothyroidism. A statistically significant difference was observed in the mean age of participants across different categories of hair loss, so that individuals with severe hair loss had a higher mean age (P<0.001). Furthermore, a significant difference was noted in the mean age of individuals across various levels of cold intolerance, where those with no symptoms of cold intolerance were significantly younger and had a lower mean age (P<0.010). A statistically significant difference was observed in the mean age across different categories of weight changes, with younger individuals reporting greater weight changes (P<0.022). The mean and standard deviation of systolic blood pressure (SBP) among individuals in various categories of hair loss-including 'absent,' 'rarely present', 'present', and 'severely present'-were 112.30±14.72 mmHg, 108.15±62.01 mmHg, 104.51±11.50 mmHg, and 113.19±59.89 mmHg, respectively. A significant statistical difference was found in the mean SBP across categories of hair loss, indicating that individuals with lower SBP reported higher levels of hair loss (P<0.032). No significant statistical difference was observed in the mean SBP regarding other residual symptoms of hypothyroidism.
The mean and standard deviation of diastolic blood pressure (DBP) across different categories of weight changes-including 'absent,' 'rarely present,' 'present,' and 'severely present'-were determined to be 70.8±25.81 mmHg, 70.35±6.76 mmHg, 78.12±44.34 mmHg, and 69.71±10.44 mmHg, respectively. A significant difference was observed in the mean DBP across these categories of weight changes, so that individuals with higher DBP reported the presence of weight changes (P<0.007). No statistically significant difference was found in mean DBP regarding the residual symptoms.
The mean and standard deviation of serum T4 levels across different categories of hair loss-including 'absent,' 'rarely present,' 'present,' and 'severely present'-were determined to be 8.91±1.81 ng/dL, 9.1±23.71 ng/dL, 8.68±1.55 ng/dL, and 9.50±1.60 ng/dL, respectively; no significant difference was observed among these groups. Furthermore, there was no statistically significant difference in mean T4 levels regarding different categories of hair loss. In contrast, mean T4 levels showed a statistically significant difference across categories of fatigue (P<0.002) and muscle cramps (P<0.036), with individuals exhibiting lower T4 levels reporting higher fatigue levels and muscle cramps. No significant statistical difference was observed in mean T4 levels concerning the residual symptoms.
Conclusion
According to the results of this study, despite achieving normalized TSH levels through LT4 therapy, a significant proportion of patients continued to experience symptoms such as fatigue, hair loss, weight changes, dry skin, cold intolerance, constipation, and muscle cramps. No statistically significant correlation was observed between post-narmalization of TSH levels and the persistence of clinical symptoms. These findings suggest that TSH levels alone may not serve as a sufficient biomarker for the comprehensive assessment of patient recovery.
The restoration of a normal biochemical state does not necessarily equate to the resolution of symptoms, particularly energy-related manifestations like fatigue. Hair loss was reported by 67.2% of patients, a finding consistent with extant literature on hypothyroidism. This symptom is directly linked to metabolic disturbances resulting from thyroid hormone deficiency. The persistence of such symptoms despite normalized TSH levels suggests that LT4 monotherapy may not fully restore systemic thyroid function at the tissue level, which is essential for metabolic regulation.
Our findings challenge the traditional reliance on TSH as the sole indicator of therapeutic success in patients with hypothyroidism. While TSH serves as a sensitive biomarker for thyroid function, it may fail to fully capture the complexity of thyroid hormone regulation at the tissue level. In our study, no significant correlation was observed between TSH levels (whether below or above 2.5 mIU/L) and the persistence of symptoms. This suggests the possibility of localized tissue-level thyroid hormone deficiency, even when serum TSH levels remain within the normal range.
The present study found no significant correlation between varying TSH levels and the incidence of diverse clinical symptoms. It should be noted that despite the current preference for TSH measurement as the primary indicator of treatment adequacy, no clinical parameter correlates more effectively with TSH levels than with free T4 (FT4) or T3/free T3 (FT3) levels. Although evidence suggests that FT4 is a superior marker for euthyroidism, this does not necessarily imply a required shift from TSH measurement to another solitary test (i.e., FT4 levels). A notable limitation of this study is the absence of a control group.
Ethical Statement
This study was approved by the Ethics Committee at Golestan University of Medical Sciences (IR.GOUMS.REC.1401.295).
Funding
This article has been derived from the doctoral dissertation (approval code: 113099) by Seyed Mohammad Aria in Doctor of Medicine (MD) at the School of Medicine, Golestan University of Medical Sciences.
Authors' Contributions
Seyed Mohammad Aria: Project execution, Data collection, Drafting of the initial manuscript, Approval of the final manuscript.
Maryam Zahedi (M.D): Project execution, Approval of the final manuscript.
Fatemeh Mohmmadzade (M.D): Project administration and design, Project execution, Data analysis, Interpretation of the results, Drafting of the initial manuscript, Approval of the final manuscript.
Alireza Seyedi Niaki (Ph.D): Project execution, Approval of the final manuscript.
Somayeh Ghorbai (Ph.D): Data collection, Data analysis, Interpretation of the results, Approval of the final manuscript.
Conflicts of Interest
No conflicts of interest.
Acknowledgement
The authors would like to thank the Vice-Chancellor for Research and Technology at Golestan University of Medical Sciences and the Ischemic Disorders Research Center for their support in the implementation and completion of this study.
Key Message: The most prevalent residual symptoms of hypothyroidism include fatigue, cold intolerance, and dry skin.
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Aria S M, Zahedi M, Mohmmadzade F, Seyedi Niaki A, Ghorbai S. Prevalence of Residual Symptoms Following Thyroid-Stimulating Hormone Normalization in Patients with Hypothyroidism. J Gorgan Univ Med Sci 2025; 27 (4) :35-44 URL: http://goums.ac.ir/journal/article-1-4560-en.html
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