Assessment of Quality of Life Among Patients with Hypothyroidism on Levothyroxine: A Review

Abstract

Hypothyroidism is the most common endocrine disorders that significantly impacts patient health related quality of life (HRQoL). Levothyroxine (LT4) is the primary treatment used alone to restore normal thyroid hormone levels. This review examines how levothyroxine (LT4) treatment influences the quality of life in individuals diagnosed with hypothyroidism. It assesses the effectivity of levothyroxine in symptom resolution, explore factors influencing QoL, and identify possible shortcomings in the current treatment plan. This review evaluates recent observational studies and meta-analyses that investigated HRQoL, daily functioning of hypothyroid patients on LT4 therapy. Studies were focused on patient-reported outcomes, biochemical markers and different assessment tools like SF-36 and ThyPRO questionnaires. Findings shown that while LT4 therapy normalize thyroid hormone levels, a significant patient proportion reports residual symptoms which negatively affect HRQoL. Emerging evidence suggests that a combination therapy involving LT4 and liothyronine (LT3) may offer superior symptom relief for certain patients, particularly those who continue to experience residual symptoms despite achieving biochemical euthyroidism with LT4 alone Although levothyroxine (LT4) monotherapy is widely regarded as the standard treatment for hypothyroidism, its effectiveness in fully restoring health-related quality of life (HRQoL) has been questioned. Patients with persistent symptoms suggest a need for individualized treatment strategies, further research on alternative therapies and optimization of dosing regimen.

Keywords

Introduction

Hypothyroidism is a common endocrine condition marked by insufficient production of thyroid hormones. The condition arises from any structural or functional abnormality that disrupts the synthesis or secretion of thyroid hormones that may result from defects occurring anywhere along the hypothalamic-pituitary-thyroid (HPT) axis. ^[1,2] Although it is typically easy to diagnose and manage with appropriate treatment, untreated or severe cases can lead to life threatening complications.^[3] The prevalence and distribution of hypothyroidism vary significantly across regions and are influenced by several factors, including age, gender and dietary iodine intake.^[4] Globally, hypothyroidism affects approximately 4-10% of the general population, with a notably higher incidence among women and older adults.^[5] Subclinical hypothyroidism affects 4-20% adults while overt hypothyroidism affects 0.3-5% of the population.^[6]  Hypothyroidism can arise from a variety of etiologies, most commonly autoimmune thyroiditis such as Hashimoto’s thyroiditis.^[7] Other causes include iodine deficiency, which remains a significant contributor in certain regions.^[8,9] Iatrogenic factors such as thyroid surgery, radioactive iodine therapy, radiation therapy of head or neck or medications (amiodarone, thalidomide, rifampin, lithium, phenytoin).^[10,11,12] In some cases, congenital hypothyroidism occurs due to thyroid gland dysgenesis or inborn errors of thyroid hormone synthesis.^[13] Secondary hypothyroidism are less common which results from pituitary or hypothalamic dysfunction affecting TSH secretion.^[14]  Levothyroxine serves as a synthetic substitute for thyroxine (T4), the hormone synthesized by the thyroid gland. It is the standard treatment for hypothyroidism preferred by clinicians nowadays. The typical replacement dose of levothyroxine is around 1.6 micrograms per kilogram of body weight per day, administered once daily. ^[15,16]

QUALITY OF LIFE AND HYPOTHYROIDISM.

Quality of life (QoL) refers to an individual’s comprehensive sense of well-being, encompassing physical health, psychological status, social interactions, and engagement with the surrounding environment.^[17] The World Health Organization (WHO) defines quality of life as an individual's assessment of their life situation, taking into account cultural and value-based contexts, as well as their personal goals, expectations, and concerns. ^[18] Hypothyroidism is commonly linked to adverse health outcomes including metabolic, cognitive, and psychological disturbances and poses a major burden on patients' health-related quality of life (HRQoL).^[19] The clinical definition of hypothyroidism is primarily based on biochemical reference ranges particularly levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4), but these parameters remain a topic of ongoing debate, especially in subclinical cases.^[3] Despite biochemical correction of thyroid hormone levels with levothyroxine therapy, numerous studies have demonstrated that a considerable proportion of patients continue to report diminished QoL.^[20] This discrepancy highlights the limitations of relying solely on serum thyroid-stimulating hormone (TSH) levels as a marker of treatment adequacy and underscores the importance of incorporating patient-reported outcomes into routine clinical evaluation and research. ^[20,21] Evaluating QoL is essential in hypothyroidism, as it offers a patient-centred perspective that extends beyond clinical assessments and biochemical measurements. It provides valuable insight into the personal impact of the disease and its treatment, thereby reflecting the subjective experiences and challenges faced by individuals living with hypothyroidism. ^[18,19]

MULTIDIMENSIONAL IMPACT ON QOL.

Hypothyroidism significantly affects multiple dimensions of health and well-being, leading to considerable deterioration in quality of life (QoL). There are various sub domains which illustrate the broad spectrum of QoL impairments in patients with hypothyroidism:

1. Physical health

Common physical symptoms experienced by patients with hypothyroidism include fatigue, weight gain, cold intolerance, dry skin, constipation, and generalized muscle weakness. These symptoms reduce physical stamina and energy, hindering patients’ ability to perform routine tasks and maintain an active lifestyle. Studies consistently demonstrate that individuals with hypothyroidism report lower physical functioning and vitality scores compared to healthy controls, as measured by standardized QoL instruments such as the SF-36 and ThyPRO. Notably, these physical limitations often persist despite normalized thyroid-stimulating hormone (TSH) levels under levothyroxine therapy. ^[20,22]

2. Mental and emotional well being

Mood disturbances are frequently reported among patients with hypothyroidism. Anxiety, irritability, low mood, and depressive symptoms are prevalent and can significantly impact emotional stability. These mental health issues contribute to social isolation, impaired interpersonal relationships and decreased overall life satisfaction. ^[19,23,24] Many hypothyroid patients on levothyroxine (L-T4) therapy report persistent mood and cognitive issues despite having normal TSH levels. While evidence is mixed, a large study of over 25,000 individuals found no overall link between thyroid function and depression or anxiety. However, those with known thyroid disease had a higher risk of mood disorders even with normal TSH. Another study noted reduced quality of life and mood—especially in women on L-T4 replacement therapy.^[25]

3. Social functioning.

The cumulative burden of physical and mental symptoms often leads to social withdrawal and reduced participation in occupational, familial, and recreational activities. Many patients report difficulties in maintaining employment or fulfilling social obligations due to persistent fatigue, low self-esteem, or emotional instability??. Feelings of isolation and diminished self-worth are commonly reported, further compounding the decline in social functioning and QoL. ^[25,26]

4. Cognitive function.

Cognitive impairment, frequently described by patients as "brain fog," represents a significant contributor to the decline in quality of life (QoL) associated with hypothyroidism. This constellation of cognitive symptoms often includes difficulties with attention, memory, information processing, and executive functioning, such as problem-solving. ^[27,28] Some studies highlight the persistence of these cognitive issues even in patients who are adequately treated with levothyroxine, suggesting that QoL assessments should include evaluations of cognitive health in addition to physical and emotional parameters. ^[20,21]

5. Occupational and Daily Role Functioning.

The combined effect of physical fatigue, mental sluggishness, and emotional distress often leads to reduced work productivity and challenges in fulfilling occupational or academic duties. Patients may struggle to maintain employment, manage household responsibilities, or meet caregiving demands. The burden of navigating daily life with fluctuating symptoms leads to feelings of inadequacy and frustration, which further diminish perceived QoL.^[29] A study examined the prevalence of body image disturbances among individuals with hypothyroidism. This study reported that such impairments led to significantly diminished occupational functioning and daily productivity?.^[30]

6. Sleep Disturbances.

Patients with hypothyroidism frequently report disrupted sleep patterns, including insomnia, hypersomnia, difficulty initiating or maintaining sleep, and non-restorative sleep. Poor sleep quality exacerbates daytime fatigue, reduces alertness, and contributes to mood instability, creating a cyclical pattern that perpetuates physical and psychological symptoms.^[31] A population-based study examined the association between sleep quality and QoL in patients with subclinical hypothyroidism. The researchers found that impaired sleep quality was significantly correlated with decreased cognitive function, social relationships, and overall QoL scores.^[32] Furthermore, a systematic review explored the relationship between subclinical thyroid disease and sleep quality in older men. The findings indicated that subclinical thyroid disease was not associated with altered sleep quality in this demographic, suggesting that the impact of thyroid dysfunction on sleep may vary across different populations.^[33]

7. Sexual Health.

Thyroid dysfunction has a direct impact on reproductive health and sexual functioning. Women with hypothyroidism may experience menstrual irregularities, infertility, and diminished libido, while men may report erectile dysfunction and reduced sexual satisfaction. These issues can negatively affect self-esteem and intimate relationships, creating additional psychological stress and further impairing overall well-being.^[30] A comprehensive meta-analysis examined the impact of hypothyroidism and subclinical hypothyroidism on female sexual function. The study analysed data from seven studies involving 2,481 women and found that those with overt hypothyroidism had significantly lower scores in several domains of the Female Sexual Function Index (FSFI), which evaluates domains like desire, arousal, lubrication, orgasm, satisfaction, and pain, reveals significant impairment in sexual function among women with hypothyroidism.^[34]

8. Body Image and Self-esteem.

While direct studies specifically linking hypothyroidism to body image concerns are limited, many physical manifestations of hypothyroidism, such as weight gain, puffiness, hair thinning, and skin changes, can negatively affect body image. These visible symptoms often lead to embarrassment, low self-confidence, and dissatisfaction with one’s appearance. The resulting impact on self-esteem may contribute to social withdrawal, depression, and reluctance to engage in public or professional settings.^[30] A study the prevalence of impaired body image among individuals with hypothyroidism. The findings revealed that female patients exhibited significantly higher levels of appearance anxiety compared to their male counterparts, suggesting a greater prevalence of body image concerns among women with hypothyroidism. The study emphasized the importance of incorporating body image assessments into routine management of hypothyroid patients to facilitate timely psychological interventions.^[35]

QOL GAPS DESPITE STANDARD THERAPY.

Despite normalization of thyroid function tests with levothyroxine (LT4) therapy, many hypothyroid patients continue to report impaired quality of life (QoL). This discrepancy between biochemical control and patient-perceived well-being highlights the need to address additional factors that may influence treatment outcomes.

1. Residual Symptoms in Biochemically Euthyroid Patients

Several studies have demonstrated that even when TSH levels are within the target range, patients often report ongoing symptoms such as fatigue, depression, cognitive dysfunction, and reduced energy??. This suggests that normalization of serum TSH alone does not guarantee resolution of tissue-level hypothyroidism or improvement in patient-perceived health. ^[31,36]

2. Inadequacy of TSH as a Sole Biomarker.

TSH has long been used as the primary indicator of treatment adequacy. However, it reflects pituitary sensitivity rather than peripheral tissue thyroid hormone activity. Studies indicate that normal TSH may coexist with suboptimal T3 concentrations in target tissues such as the brain and liver?. This biochemical discrepancy may explain persistent symptoms in some LT4-treated individuals. ^[36,37]

3. Genetic and Physiological Variability.

Individual variations in deiodinase enzymes (especially DIO2 polymorphisms like Thr92Ala) may affect intracellular T3 conversion, thereby influencing symptom persistence despite standard LT4 monotherapy?. Such genetic differences are not accounted for in standard treatment protocols, which may explain interindividual variability in QoL outcomes.^[38]

4. Psychological and Emotional Burden of Chronic Illness.

The psychological impact of chronic disease, including anxiety over lifelong medication dependence, fear of relapse, or frustration due to unmet expectations, can negatively affect QoL. A prospective cohort study noted that emotional susceptibility remained elevated even after 12 months of therapy?. These psychological stressors are often independent of hormonal status. ^[31,39]

5. Treatment Satisfaction and Patient Expectations

A mismatch between patient expectations and therapeutic outcomes may also play a role. Some patients anticipate complete symptom resolution, and when this is not achieved, dissatisfaction may lead to perceived QoL deficits. Survey studies highlight growing concern over the patient experience with LT4 therapy.^[40]

EVALUATING QoL IN HYPOTHYROID PATIENTS.

Evaluating quality of life (QoL) in individuals with hypothyroidism is essential, as the condition often impacts both physical and psychological well-being, even with treatment. To evaluate quality of life (QoL), standardized assessment tools are commonly used to capture various aspects of health.^[41]

1. Thyroid Specific Patient-Reported Outcome (ThyPRO)

ThyPRO (Thyroid-Related Patient-Reported Outcome) is the most widely recognized disease-specific tool developed specifically for patients with benign thyroid disorders, including hypothyroidism. It was designed to capture the full spectrum of thyroid-related symptoms and their impact on quality of life.^[29] The original version, ThyPRO-84, consists of 84 items distributed across 13 scales such as goitre symptoms, tiredness, cognitive complaints, anxiety, depression, impaired social life, and cosmetic concerns. Each domain reflects a key aspect of living with a thyroid condition, allowing researchers and clinicians to pinpoint areas of concern with high specificity. A shorter version, ThyPRO-39, is also available and retains good psychometric properties while being more practical for use in busy clinical settings. The tool has been validated in multiple languages and cultural contexts, reinforcing its global utility in thyroid-related QoL assessment. ^[29,42,43]

2. Short form-36 Health Survey

SF-36 (Short Form Health Survey – 36 items) is a more comprehensive version of SF-12 and remains one of the most frequently used generic health-related QoL instruments. It systematically assesses eight distinct health domains: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations resulting from emotional challenges, and mental health status. This level of detail enables a deeper understanding of how hypothyroidism affects different aspects of a patient's life.^[41] SF-36 has been used extensively in comparative studies and clinical trials to monitor QoL changes before and after treatment. Despite its broader scope, its length may limit its use in routine clinical practice.^[44]

3. Short Form-12 Health Survey

SF-12 (Short Form Health Survey – 12 items) is a brief, generic QoL instrument derived from the longer SF-36 questionnaire. It provides a quick overview of an individual's physical and mental health through two main summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). These scores are derived from responses related to limitations in physical activities, emotional problems, pain, vitality, social functioning, and general health perceptions. In hypothyroid populations, SF-12 helps identify persistent issues such as fatigue, reduced energy, and mood disturbances, which are not always captured by biochemical measures. Although not disease-specific, its brevity and ease of administration make it suitable for large population studies and routine monitoring. ^[44,45]

4. EQ-5D (EuroQol-5 Dimension)

The EQ-5D is a widely used generic quality of life (QoL) measure in health economics and clinical research, assessing five domains: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Patients rate each domain on a three- or five-level scale, depending on the version used. In addition, the EQ-5D includes a visual analogue scale (VAS), enabling patients to rate their overall health on a scale from 0, representing the worst imaginable health, to 100, indicating the best imaginable health. The EQ-5D is particularly useful for cost-utility analyses and for comparing QoL outcomes across different health conditions. In hypothyroid patients, it can help quantify the burden of persistent symptoms, such as fatigue and mood changes, and their impact on daily functioning.^[46]

5. RAND-36 (Research and Development 36-Item Health Survey)

The RAND-36 is a general health-related quality of life tool, comparable to the SF-36, comprising 36 items that evaluate eight key domains: physical functioning, limitations due to physical health, emotional role limitations, energy and fatigue, emotional well-being, social functioning, pain, and overall health perception. While the item content of RAND-36 and SF-36 is nearly identical, RAND-36 uses a different scoring algorithm, particularly for the pain and general health subscales. One of the advantages of RAND-36 is that it is in the public domain, making it freely available for non-commercial research.^[47]

6. WHOQOL-BREF (World Health Organization Quality of Life – BREF)

WHOQOL-BREF is a widely used generic instrument developed by the WHO to assess QoL across multiple cultural contexts. It consists of 26 items grouped into four broad domains: physical health, psychological well-being, social relationships, and environmental factors. Unlike other tools, WHOQOL-BREF emphasizes the individual’s subjective perception of their position in life, which can be particularly relevant in chronic conditions like hypothyroidism that often affect emotional and social well-being. Although not specific to thyroid disorders, WHOQOL-BREF allows for a holistic assessment of how hypothyroidism interferes with multiple aspects of a patient’s life. ^[18,48]

IMPORTANCE OF QoL IN HYPOTHYROID CARE

• Holistic Approach to Patient Care: Managing hypothyroidism should extend beyond achieving biochemical targets such as TSH normalization. By actively addressing quality of life (QoL), healthcare providers adopt a more patient-centred approach that considers emotional, physical, and psychological well-being ultimately delivering comprehensive care. ^[41,49]
• Treatment optimization: Persistent symptoms despite optimal lab values may signal the need to revisit treatment strategies. Regular evaluation of QoL can guide clinicians in fine-tuning therapy, including considering alternative formulations or adjunctive treatments, to better align with patients’ individual responses and needs. ^[50,51]
• Promoting Patient Satisfaction and Medication Adherence: Improved QoL is closely associated with higher levels of patient satisfaction. When patients feel better and perceive tangible improvements in their daily functioning, they are more likely to adhere to prescribed treatments, thereby enhancing long-term therapeutic outcomes. ^[52,53]
• Early Identification of Residual Symptoms: Even when laboratory parameters appear normal, patients may continue to experience fatigue, mood disturbances, or cognitive issues.^[54] Routine QoL assessments help in the early detection of such residual symptoms, enabling timely interventions and preventing a decline in overall health. ^[55,56]

CONCLUSION

Although levothyroxine remains the cornerstone of hypothyroidism management and is effective in restoring biochemical euthyroidism, it does not consistently alleviate the full spectrum of symptoms experienced by patients. Evidence from multiple studies indicates that a significant proportion of individuals continue to report impaired quality of life (QoL) despite achieving normalized thyroid-stimulating hormone (TSH) levels. This discrepancy highlights the limitations of relying solely on biochemical markers to assess treatment adequacy and patient recovery. Persistent clinical manifestations such as fatigue, cognitive impairment, emotional lability, and reduced social functioning indicate that standard monotherapy may not sufficiently address the multifaceted burden of the disease. Contributing factors may include residual hypothyroid symptoms, individual variability in peripheral T3 conversion, genetic polymorphisms, and the psychological impact of chronic illness and lifelong medication dependence. Thyroid-specific quality of life tools, such as the ThyPRO and ThyPRO-39 questionnaires, are effective in detecting areas of impairment that may be missed during routine clinical evaluations. These tools offer a more patient-centered perspective and should be incorporated into routine monitoring and management strategies. To enhance therapeutic efficacy and patient satisfaction, there is an imperative need to adopt more individualized treatment paradigms that encompass clinical presentation, biochemical indices, and patient-reported outcomes. Future investigations should focus on the potential benefits of alternative therapeutic strategies, such as levothyroxine-liothyronine combination therapy or symptom-guided dose titration, and their long-term effects on quality of life. Ultimately, optimizing care for hypothyroid patients requires a shift toward a more holistic, individualized model that prioritizes not just biochemical normalization, but also patient well-being and satisfaction.

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