What Is the Quality of Life in Patients Treated with Levothyroxine for Hypothyroidism and How Are We Measuring It? A Critical, Narrative Review

Thyroid hormone replacement therapy (THRT, generally using oral levothyroxine (LT4)) is a safe, effective means of treating hypothyroidism. However, a proportion of LT4-treated patients with biochemically normal thyroid function tests complain of persistent symptoms that impact their health-related quality of life (QoL). The objectives of this critical, narrative review of the literature were to identify studies of QoL in LT4-treated patients with hypothyroidism, examine the instruments used to measure QoL, determine whether normal QoL is restored by THRT, and identify factors associated with QoL. The PubMed database was searched from 1 January 2000 to 31 December 2020. A total of 809 publications were screened, 129 full-text articles were retrieved, and 58 were analyzed. The studies of overt hypothyroidism evidenced an improvement in psychological and emotional well-being after three to six months of THRT with LT4, although contrasting results were found for patients with subclinical hypothyroidism. Combination treatment with LT4 and liothyronine was not generally associated with better QoL. In hypothyroidism, QoL appears to be influenced by a number of physiological, behavioral, cognitive and/or lifestyle factors that are not strictly related to thyroid hormone levels.


Introduction
Hypothyroidism (mainly caused by autoimmune thyroiditis, surgery for cancer or benign thyroid disease, or radioiodine therapy) impacts many physiological functions [1]. Although the definition and prevalence of hypothyroidism depend on biochemical reference ranges measured in the general population, it has been estimated that~4% of adults in Western countries suffer from overt hypothyroidism [2,3]. The prevalence rises to~15% when subclinical hypothyroidism (SCH, defined as a serum thyroid-stimulating hormone (TSH) level above the upper limit of normal (typically >4.0 mU/L) and a normal serum free thyroxine (FT4) level) is included [4][5][6].
Thyroid hormone replacement therapy (THRT, generally based on oral levothyroxine (LT4)) is a safe, effective means of treating hypothyroidism [7][8][9][10][11]. The clinical objective is to relieve symptoms and then normalize thyroid hormone levels. TSH is considered to be the most sensitive and specific marker of thyroid status [12]. Most LT4-treated patients experience fewer symptoms of hypothyroidism at a serum TSH level of between 0.4 and 4.0 mU/L. Nevertheless, a small proportion of LT4-treated patients (around 5 to 10%, depending on the study) complain of persistent symptoms of hypothyroidism, mood disturbances, and poor health-related quality of life (QoL) even when thyroid function is biochemically normal [13][14][15].
Well-being and QoL do not simply equate to adequate material living standards or the absence of disease. QoL has been defined as how an individual's well-being is affected over time by a disease, disability, or disorder [13][14][15] but can also be viewed as the difference between an individual's hopes and his/her actual status [16]. Hence, QoL is a subjective variable that covers affective, cognitive, and behavioral domains [17,18]. This subjectiveness means that inter-individual and inter-group comparisons of QoL (e.g., between actively treated and placebo-treated patients or with general population samples) are problematic [19]. Researchers have sought to codify QoL with psychometrically valid generic or disease-specific instruments. The fact that a large number of QoL instruments have been developed reflects the complexity of this variable and the differences in its definition.
The objectives of this critical, narrative review of the literature were to (i) identify studies of QoL in LT4-treated adults and children with hypothyroidism (including SCH), (ii) examine the instruments used to measure QoL in the identified studies, (iii) determine whether normal QoL is restored by THRT, and (iv) identify physiological, genetic, demographic and behavioral factors associated with QoL in patients with hypothyroidism. To this end, we searched the literature for quantitative reports on QoL in patients undergoing THRT with LT4 alone or in combination with other thyroid hormones. We focused on the results of randomized clinical trials (RCTs) but did not exclude nonrandomized studies.
All authors discussed and decided on the study inclusion and exclusion criteria. Only publications that reported numerical QoL data on patients receiving THRT for benign overt hypothyroidism or SCH were included. We excluded studies of patients with differentiated thyroid carcinoma (DTC) because their baseline status and TSH targets differ from those in benign hypothyroidism [20] and because a diagnosis of cancer may be associated with poor QoL for psychological reasons [21,22]. Lastly, we excluded case reports, reviews, and editorials. All abstracts were screened for relevance by the lead author (FBC). If an abstract was found to be relevant, the full-text article was retrieved and reviewed. The full-text articles for review were divided between all the authors, who extracted the data. The lead author checked the extracted data. Any disagreements were resolved by consensus.
The PubMed search initially identified a total of 809 potentially relevant publications ( Figure 1). The main reasons for excluding publications were (i) the absence of original, quantitative data on QoL, and (ii) the absence of data on patients with hypothyroidism. A total of 129 full-text articles were retrieved; 58 of these met the inclusion criteria and were analyzed. It should be noted that we did not seek to determine independently whether the QoL reported for a given study group was truly "good" or "normal"; we relied on the study investigators' statements and the results of their statistical analyses.

How Has QoL Been Measured in Patients on THRT for Hypothyroidism?
When considering the selected studies, we noted the use of 12 generic QoL questionnaires and five disease-specific QoL questionnaires. The questionnaires' characteristics are summarized in Table 1. The severity of the discomfort or problem during the preceding month is specified on a 5-point scale ranging from "not at all" (1 point) to "all the time" (5 points). The overall score ranges from 29 (worst QoL) to 145 (best QoL).
ThyTSQ, Underactive Thyroid Treatment Satisfaction Questionnaire [26] 10 items covering satisfaction with current treatment, convenience, and understanding of treatment.
Patients respond to each item by circling a number on a scale from 6 to 0, indicating their degree of satisfaction with that aspect of treatment e.g., from very satisfied to very dissatisfied.
The original Chronic Thyroid Questionnaire [28] contains up to 104 items grouped into four domains: physical; energy and wellbeing; mood/ emotions; and cognitive functioning. The patient identifies applicable items (potentially ranging from 0 to 104, making intra-and inter-patient comparisons difficult) and rates the corresponding degree of discomfort on a zero-to-five scale, where zero is the most favorable.
Kaminski et al. [27] selected 29 items from the Chronic Thyroid Questionnaire and added four items (palpitation, insomnia, irritability, and anxiety). The 33 items were grouped into three categories: physical complaints (12 items), energy, and general well-being (11 items), and mood and emotions (10 items). Each item is scored on a zero-to-five scale. The items are rated from 0 to 3. The total score ranges from 0 (best QoL) to 36 (worst QoL). The original GHQ had 60 items. The 12-item version is most frequently used but 28-and 30-item versions are also available [34,35].
PedsQL, Pediatric Quality of Life Inventory [36] 23 items in 4 domains: physical functioning, emotional functioning, social functioning, school functioning Each item is a score on a Likert scale from 0 to 4. A Psychosocial Health Summary Score and the Physical Health Summary Score can be computed, along with a total score ranging from 0 (worst QoL) to 100 (best QoL).
WHOQoL-Bref, the Abbreviated World Health Organization Quality of Life Instrument [37] 26 items in four broad domains: physical health, psychological health, social relationships, and environment.
Each section is scored from 0 (worst QoL) to 100 (best QoL). An overall score, computed using an algorithm, also ranges from 1 (worst) to 100 (best).

Abbreviated and Full Name [Reference] Score Items or Domains Scoring and Scale
EQ-5D, EuroQol five-dimensional questionnaire [38] Two components: health state description (in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and evaluation (overall health status, on a visual analog scale).
The level of severity for each dimension is rated on three levels (EQ-5D-3L) or five levels (EQ-5D-5L), generating 243 unique health states. These states are converted into an index utility score, ranging from −0.59 (worst QoL) to 1.00 (best QoL). The 20 cm visual analog scale is rated from 0 to 100 EORTC QLQ-C30, European Organization for Research and Treatment Core Quality of Life Questionnaire [39] 30 items with 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. The core questionnaire was developed for use with cancer patients.
Each item is rated on a scale of 1 to 4. The overall score ranges from 30 (best QoL) to 120 (worst QoL).

COOP/WONCA, Primary Care Cooperative Information Project/World
Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians functional status questionnaire [40,41] Six single-item scales: physical fitness, feelings, daily activities, social activities, change in health, and overall health Each chart is rated on a 5-point scale ranging from 1 (best functional status) to 5 (worst functional status). The developers do not recommend the use of a summative (total) score.
For each package: 0 (best QoL) to 100 (worst QoL). A total score is obtained by averaging the package score, and so also ranges from 0 (best QoL) to 100 (worst QoL).

KINDL-R [43]
A self-reported or parent-reported questionnaire with 24 items assessing 6 dimensions: physical well-being, emotional wellbeing, self-esteem, family, friends, and everyday functioning Each item is a score on a five-point Likert scale (1 to 5). The total score is transformed into a value of between 0 (worst QoL) and 100 (best QoL).
The most frequently applied generic instrument was the well-known Short Form (36) Health Survey (SF-36) [31]. The five thyroid-specific instruments were the Underactive Thyroid-Dependent Quality of Life Questionnaire (ThyDQoL) [23], the Thyroid-Specific Patient-Reported Outcome Measure (ThyPRO) [24], the Hypothyroid-Specific Health-Related Quality of Life Questionnaire (HRQL) [25], and the Underactive Thyroid Treatment Satisfaction Questionnaire (ThyTSQ) [26] and a modified version of the Chronic Thyroid Questionnaire [28]. Although the ThyTSQ probes treatment satisfaction, the investigators of a recent study referred to it as a "dedicated QoL questionnaire"; hence, we included the ThyTSQ in our list of disease-specific instruments [44]. A systematic review has recommended the ThyPRO for administration in benign thyroid diseases [45]. It should be noted that QoL questionnaires often comprise "physical" items (which may overlap with symptoms, for example) and "mental" items (which may overlap with mood, for example). For example, the SF-36 features a physical composite score (PCS) and a mental composite score (MCS) calculated from the individual section scores, using a proprietary algorithm [31]. These considerations illustrate the complexity of measuring (and distin-guishing between) specific symptoms, nonspecific symptoms, QoL, treatment satisfaction, and patient preference.
Fifty of the 58 reviewed publications featured a single QoL instrument, and eight featured two instruments (Tables 2 and 3).      Lastly, it should be borne in mind that QoL was rarely the primary study outcome, and so many of the interventional trials were not powered to reveal a putative effect on this variable.

Randomized Studies
We found very few RCTs of patients treated with LT4 soon after being diagnosed with overt hypothyroidism (Table 2). This is not surprising because newly diagnosed patients require effective treatment and thus (for ethical reasons) cannot be put on a placebo. However, Samuels et al. studied a high-dose LT4 group vs. a standard-dose (control) group in a double-blind cross-over RCT [55]. The intergroup differences in several SF-36 domains were inconsistent; at the end of the study, the mean ± SEM score in the high-dose group was significantly higher for the PCS (p = 0.01) but not for the MCS (p = 0.15). The changes in the MCS (but not in the PCS) were associated with changes in FT3 and FT4 levels. In a double-blind crossover trial, Bolk et al. (2010) randomized adult patients to morning or evening LT4 administration for 3 months but did not compare the QoL scores with controls or with normative data. QoL improved significantly over time but there were no significant intergroup differences in the SF-36 domain scores [58].

Nonrandomized Studies
The great majority of studies of patients newly treated with LT4 following a diagnosis of overt hypothyroidism had observational designs (Table 3). Two studies found that QoL was normal (i.e., not impaired, relative to general population samples). In a study of German children and adolescents with various thyroid diseases, Hirtz et al. observed a normal KINDL-R score in the subsamples of participants with overt hypothyroidism or SCH [91], and Quinque et al. (2013) did not find a difference in the ThyDQoL score when comparing treated patients with autoimmune thyroiditis and a group of healthy controls [69]. Other nonrandomized studies found small but statistically significant impairments in QoL (using SF-36 and/or the ThyPRO) among LT4-treated patients with overt hypothyroidism, relative to general population samples [68,92]. Lastly, three studies reported significantly worse QoL in LT4-treated patients with overt hypothyroidism, relative to control patients with other diseases and to general population samples ( [66,73,86].

Summary
Overall, the literature results suggest that QoL is markedly improved-but not always normalized-by several months of LT4 treatment in newly diagnosed patients with overt hypothyroidism. The sometimes conflicting or inconsistent findings might be due to major interstudy differences in designs, patient populations, and control populations. The absence (for ethical reasons) of control (i.e., non-treated) groups of patients newly diagnosed with overt hypothyroidism means that the full effect of LT4 on QoL might be underestimated.

Randomized Studies
Some LT4-treated patients have relatively low serum T3 levels, i.e., an abnormally high, nonphysiological T4/T3 ratio that might be related to abnormally low T3 secretion by the thyroid or low peripheral T3 production (due to decreased deiodinase activity in depression or in metabolic diseases) [94][95][96][97]. From the early 2000s onwards, it has often been suggested that patients who experience persistent symptoms of hypothyroidism and/or poor QoL during treatment with LT4 alone may benefit from LT4 + LT3 combination treatment. However, almost 20 years later, the merits and limitations of this strategy are still subject to debate [97][98][99].
In most of the double-blind randomized studies, LT4 + LT3 combination therapy was not associated with better QoL (vs. LT4 alone) ( Table 2) [27]. Similarly, Hoang et al.'s (2013) double-blind, crossover RCT (using the 12-item General Health Questionnaire (GHQ-12)) did not find an advantage for dried thyroid extract (which contains variable, non-standardized amounts of T3) over LT4 [60]. Nygaard et al.'s (2009) double-blind crossover RCT reported significant intergroup differences for the SF-36 General Health and Vitality domains but not for the Social functioning and Mental Health domains [56].

Summary
Most studies of combination therapy did not evidence a difference in QoL for LT4 + LT3 combination therapy, relative to LT4 alone [25,47,48,50,51,60]. When benefits were found, they concerned some but not all QoL domains [56,82,83]. The majority subjective patient preference for LT4 + LT3 combination therapy (typically expressed by~50-70% of the treated patients [50,51,56]) cannot be explained by the QoL data per se. The basis for this patient preference has yet to be determined. As discussed below, we hypothesize that today's QoL instruments do not necessarily capture subtle changes (e.g., in mood) related to patient preference and wellbeing. Lastly, the presence of an additional placebo effect (perhaps due to the novelty of taking a combination treatment after months or years of taking LT4 alone) cannot be ruled out.

Randomized Studies
In contrast to treated overt hypothyroidism, the relationship between LT4 treatment and QoL in SCH has been frequently evaluated in double-blind, placebo-controlled RCTs ( Table 2). In a study of LT4 (a fixed 100 µg/day) vs. placebo, Razvi et al. (2007) studied 100 previously untreated patients [median (range) TSH level at baseline: 5.3 mU/L (3.7-15.8)] [53]. The mean ± SD ThyDQoL scores in the LT4 and placebo phases did not differ significantly. In a double-blind study performed in Brazil, Reuters et al. (2012) assigned treatment-naïve patients with SCH to either LT4 (n = 35) or placebo (n = 36) for 6 months [59]. In the LT4 group, the Role-emotional and Pain SF-36 scores improved markedly over time and differed significantly from placebo. In the large, double-blind, randomized Thyroid Hormone Replacement for Subclinical Hypothyroidism (TRUST) study of communitydwelling patients aged ≥ 65 with SCH, an association between treatment and improved thyroid-specific QoL (as measured with the ThyPRO) or general QoL (as measured with the EuroQol five-dimensional questionnaire (EQ-5D)) was not observed [65,100]. Mooijaart et al. (2019) studied pooled data from patients aged 80 and over with SCH in the Institute for Evidence-Based Medicine in Old Age (IEMO) and TRUST RCTs [88]. The few small changes in the mean ± SD ThyPRO subscores were not statistically significant. Lastly, Pollock et al. performed a double-blind, placebo-controlled RCT of LT4-treated patients with symptoms of hypothyroidism but who were biochemically euthyroid; there were no significant intergroup differences in any of the QoL (SF-36) scores [46].

Nonrandomized Studies
The results of nonrandomized studies [either cross-sectional or longitudinal (Table 3)] were disparate: some studies found no significant differences in QoL between treated patients and healthy controls [69,101], others observed better scores in some but not all QoL domains in treated patients [13,68,84,89], and yet others reported the presence or persistence of significantly worse QoL in treated patients [23,58,66,73,86].

Summary
With a few exceptions, studies of patients with SCH indicate that LT4 treatment does not markedly improve QoL and that the latter is not correlated with thyroid hormone concentrations. However, age might be a factor. As mentioned below, older age is [inconsistently] associated with poor QoL. It is possible that in older adults with comorbidities, today's QoL instruments are not sensitive enough to measure subtle effects of changes in LT4. Studies of QoL in younger adults with SCH are warranted.

TSH Levels
Several groups have looked at whether steady-state or target TSH levels/LT4 dose levels in treated patients are correlated with QoL [102]. In an observational study and an RCT, Samuels et al. found that high-normal (>2.5 mU/L) vs. low-normal (≤2.5 mU/L) TSH levels [75] or low normal, high-normal, and mildly elevated target TSH levels [81] did not significantly influence the SF-36 MCS and PCS scores and did not differ significantly, apart from a higher Physical Functioning score in the high-normal TSH group. Dos Santos Vigario et al.'s cross-sectional study (2013) of 2057 LT4-treated patients with primary hypothyroidism [70] concluded that only "undertreatment" (TSH > 4.0 mU/L) was associated with poor SF-36 scores. A similar lack of influence of the target TSH level was obtained in Roos et al.'s (2005) double-blind RCT [49] and in Walsh et al.'s crossover RCT (69). In contrast, Moron-Diaz et al. found that even within the TSH reference range, lower TSH levels were associated with better QoL with adequately treated primary hypothyroidism [93]. Similarly, Mithal et al. (2014) observed that the mean SF-36 Emotional Health and Physical Health scores were worse (p = 0.0278 and 0.0763, respectively) among "undertreated" patients (TSH > 4 mU/L) and "overtreated" patients (TSH < 0.40 mU/L) patients when compared with patients with a normal TSH level [71]. In view of these studies' sometimes conflicting conclusions, the exact nature of the relationship between QoL and steady-state or target TSH levels is still unclear and requires further investigation.

Genetic Factors (Transport Proteins and Metabolic Enzymes)
In view of the possible importance of differences or fluctuations in plasma and/or tissue FT3 levels on symptoms and QoL, a few research groups have genotyped patients for the genes coding for deiodinases or for proteins that transport thyroid hormones in vivo. Van der Deure et al. (2008) screened patients for polymorphisms in the OATP1C1 gene coding for the brain-specific thyroid hormone transporter called organic anion transporting polypeptide 1C1 [103]; there were a few significant differences in the RAND-36 score (e.g., for the rs10770704 variant), with the greatest difference seen for homozygotes. In LT4-treated individuals from the LifeLines cohort study, Wouters et al. (2017) did not find an association between poor QoL (RAND-36) and the rs225014 Thr92Ala genotype of the DIO2 gene coding for deiodinase (DIO) 2 [79]. After adjustment for age and sex, Young Cho (2017) found significantly lower median SF-36 PCS scores in hypothyroid patients who were homozygous for two DIO1 variants (rs11206244 and rs2294512) [78]. By scoring the GHQ-12 in LT4-treated patients, Panicker et al. found that the CC genotype of the rs225014 polymorphism in the DIO2 gene was associated with impaired psychological well-being and a better response to combination therapy [57].
Older age was inconsistently associated with poor QoL. In Sawicka-Gutaj et al.'s (2018) open-label study of QoL and an impaired sex life in patients with autoimmune hypothyroidism, the impairment was worse in older patients [84]. Djurovic et al.'s (2018) study of LT4-treated patients with Hashimoto thyroiditis found that QoL was more impaired in patients aged over 50 [86], and Recker et al. (2019) observed partial and inconsistent impairments in ThyPRO and SF-36 in both older patients (aged 60-75) and younger patients (under 40) with SCH before and after treatment [89]. However, a post-hoc analysis of Djurovic et al.'s data suggested that poor QoL was related to weight gain [73].
Other factors that may influence QoL in hypothyroidism include endurance exercise [62], dietary intervention (a diet with green vegetables, beef, whole milk, and butter) [64], higher level of antibodies against thyroid peroxidase [86], the occurrence of severe adverse drug reactions [77], tablet vs. liquid LT4 formulations [44,80], morning vs. evening LT4 administration [58,85], male gender, the duration of hypothyroidism, frequent visits to the general practitioner before diagnosis, negative experiences with LT4, high expectations of LT4, and the provision of support by the general practitioner [104]. However, these factors have not been extensively characterized, and their specificity and selectivity remain to be determined.

Summary
None of the reviewed physiological, genetic, clinical, demographic, or behavioral factors were unambiguously and strongly associated with poor or good QoL. However, some reports suggested that QoL might be influenced by weight gain, the presence of antithyroid peroxidase antibodies, physical exercise, marital status, pain levels, employment status, and diet; the exact nature of the relationship between these factors and QoL in hypothyroidism requires further investigation. The diversity of potential influencing factors illustrates the complexity of the relationships between hormone levels, symptoms of hypothyroidism, and QoL. We do not feel that there is a particular age cut-off (65 or otherwise) for effective LT4 replacement therapy. However, older age is always a factor to be taken into account because it is [inconsistently] associated with poor QoL. It is possible again that in older adults with comorbidities, today's QoL instruments are not always sensitive enough to measure the effects of changes in THRT.

Discussion
Our review of the literature showed that some aspects of QoL in patients with hypothyroidism have been widely studied over the last 20 years. However, a number of important questions have yet to be addressed. To the best of our knowledge, QoL in patients with benign thyroid disorders was last reviewed by Watt et al. in 2006 [105]. The researchers concluded that "impairments . . . are also frequent in the long term", i.e., during treatment of hypothyroidism. However, the body of literature on overt hypothyroidism has grown considerably since 2006. Unsurprisingly, most of the studies reviewed here were performed in Western Europe and the USA. Some European countries were particularly well represented (e.g., The Netherlands, and Denmark), whereas others were notably absent (e.g., France). Data from Asia, Africa, and South America (with the notable exception of Brazil) were lacking or scarce (see below). We noted a wide range of cross-sectional and longitudinal study designs, with a relatively low proportion of double-blind, placebo-controlled RCTs (accounting for around a quarter of the studies reviewed). Many of the randomized studies were prompted by the advent of LT4 + LT3 combination treatment in the early 2000s. There was a notable absence of large, multicenter trials. One of the largest studies was based on a network of 150 general practitioners [71].
Generic and thyroid-specific QoL instruments were applied concomitantly in only 8 of the 58 publications. It should be noted that by virtue of their design, thyroid-specific instruments incorporate both disease symptom ratings and classical QoL domains. This may be problematic because the relationship between symptoms, QoL, and treatment satisfaction is complex. For example, Karmisholt et al.'s (2019) open-label longitudinal study of LT4-treated patients with SCH found that the threshold for a true change in the SF-36 score (20%) was much lower than that for a change in a mood-related symptom score (140%) [87].
A key issue in QoL research is what constitutes "good QoL" in a given population [16,18,19]. This issue is addressed in one of two ways, i.e., by consisting of a local group of euthyroid controls (from the general population or from patients with diseases other than hypothyroidism (e.g., [68,69,72,101]) or by referring to normative data previously collected in the general population [13,14,66]. For example, Wekking et al. (2005) compared their QoL data patients with primary hypothyroidism with normative data from a Dutch general population sample but suggested that a comparison with a control group would have been preferable [66]. The definition of "good" QoL is less of an issue in double-blind, placebo-controlled RCTs that focused on changes over time with treatment or in active treatment vs. placebo groups.
With a few exceptions, most of the reviewed studies included broad populations (with regard to age and the diagnosis or etiology of hypothyroidism) and did not check for the presence of "LT4 nonresponders". The bulk data suggest that overall QoL is good in LT4treated patients with hypothyroidism-even when symptoms are present (or persist)-but do not explain why a few percent of biochemically corrected patients complain of poor QoL. A few studies (such as those by Mooijaart et al. [88] and Recker et al. [89]) focused on older patients with SCH, in whom the definition of hypothyroidism differs [106]; we suggest that the assessment of other well-defined patient populations might facilitate the identification of risk factors for poor QoL.
Although we formally excluded studies of LT4-treated patients with differentiated thyroid carcinoma, it is clear from the literature published before the introduction of recombinant TSH that the severe (albeit transient) hypothyroidism following thyroidectomy plus radioiodine ablation therapy is associated with very poor QoL [107]; this may serve as a marker of the "worse possible" QoL experienced in the absence of treatment. However, the relationship between less severe (treated) hypothyroidism (and above all SCH) and poor QoL is less clear. Firstly, the literature data are contradictory with regard to the relationship between the recommended target range for serum TSH (0.4 to 4.0 mU/L) and QoL. On one hand, Walsh et al. [52] and Samuels et al. [81] did not observe differences in QoL between subgroups of treated patients with low normal, high-normal, and/or mildly elevated TSH levels. On the other hand, Dos Santos Vigario et al. [70], Samuels et al. [55], and Mithal et al. [71] concluded that "undertreatment" and "overtreatment (in terms of LT4 dosing) were correlated with significantly worse aspects of QoL.
The randomized studies of LT4 + LT3 combination treatment failed to identify marked differences in QoL after a switch from LT4 alone. During combination treatment (with two types of pill to be taken, etc.), most of the investigators felt that the potential benefits for QoL did not provide a clear clinical rationale in favor of LT4 + LT3. However, the frequent patient preference for LT4 + LT3 (for as-yet unknown reasons) [51] reinforces Wiersinga's suggestion that robust clinical trials in selected patient subpopulations are essential for making progress in this field [99].
In randomized studies of patients with SCH, THRT did not greatly improve QoL, and QoL was not correlated with thyroid hormone levels-suggesting that residual, treatmentrefractory, poor QoL is not solely related to biochemical parameters. This is in line with Feller et al.'s review of SCH [108]. However, the large double-blind, placebo-controlled RCTs in SCH (like IEMO and TRUST) assessed populations of elderly adults [65,100]. This age group does not correspond to the middle-aged adults with SCH who tend to complain of poor QoL-raising the question of whether studies of other patient groups could provide more information on QoL in SCH. In this respect, THRT in SCH might be therefore primarily preventive in nature (to stop or slow progression to overt or clinical hypothyroidism), with the goal of reducing the risk of certain (mainly cardiovascular) complications. However, the absence of an obvious, immediate benefit on QoL might be a crucial argument against treating SCH with LT4.
In most of the studies reviewed here, thyroid function parameters, symptom scores, and hormone concentrations were not correlated with QoL-except in patients with profound hypothyroidism. A few studies identified prognostic factors for QoL. Sowinski et al.'s (2016) prospective case-control study found not only that an increase in the LT4 dose level was associated with changes in symptom scores and QoL among patients with hypothyroid symptoms and normal TSH levels but also that the circulating FT3 concentration was inversely and significantly associated with several domain scores in the ThyPRO (where a lower score indicates better QoL) [74]. A role for T3 is also suggested by trials in which combination therapy was associated with better QoL [56,76,82,83]. Djurovic et al. found that the total SF-36 score was negatively correlated with anti-thyroid peroxidase antibody levels in LT4-treated patients with Hashimoto thyroiditis [86]. It has been suggested that autoimmune disease per se might be associated with poor QoL in hypothyroidism [102]. A few other studies mentioned weight gain, diet, physical exercise, and certain symptoms of hypothyroidism (carpal tunnel syndrome, dry skin, and a feeling of weakness) [62,90]. It is widely accepted that mood, memory, and cognition are affected in hypothyroidism [67,109]. Samuels et al. found that even SCH was associated with specific decrements in working memory and cognitive function [54]-although this relationship is subject to debate in the literature [110]. Given that the standard recall period for the SF-36 is four weeks, one can hypothesize that memory and cognitive impairments may be a confounding factor in some studies. Interestingly, Rezaei et al. recently reported that cognitive-behavioral therapy can improve some aspects of QoL (including emotional health problems, energy, and general health) in patients with hypothyroidism [63]. Lastly, the time of day at which LT4 was taken (morning vs. evening) did not appear to change QoL in adults [58] or children [85].
The present study had a number of limitations. Firstly, only the PubMed database was searched. Secondly, only publications in English were screened. These possible sources of bias might explain why few of the selected publications came from the Asia-Pacific region. Thirdly, the results obtained with a given QoL questionnaire in one study cannot be directly compared with those obtained in a different study. The study also had some strengths: it notably constituted the first extensive review of QoL in hypothyroidism and identified some important topics for further research.

Conclusions
Our review of the literature indicated that THRT restores QoL to often near-normal levels within 3 to 6 months. However, discordant results were found-especially in patients with SCH. Combination treatment with LT4 + LT3 does not appear to lead to better QoL. Very few prognostic factors for QoL have been identified but these may include weight gain, physical activity, autoimmunity, and diet, and may not necessarily be related to thyroid endocrine status. However, the factors that influence QoL in hypothyroidism-especially in "treatment-resistant" poor QoL observed in symptomatic SCH-require further characterization. Perspectives for further research on QoL in hypothyroidism might include (i) concomitantly evaluations with both a thyroid-specific questionnaire and a generic HR-QoL questionnaire, (ii) studies of QoL in nonelderly populations with SCH, (iii) the choice of control patient groups as a guide to "normal" QoL, (iv) investigations of why QoL subdomain scores sometimes change in opposite directions (e.g., an improvement in physical QoL and a worsening in mental QoL) and (v) investigation of the relationships between QoL questionnaires, symptoms, and other patient-reported outcomes (e.g., the apparent patient preference for LT4 + LT3 combination treatment [51]).
Author Contributions: All authors made substantial contributions to the identification, review, and analysis of relevant publications. Likewise, all authors were involved in drafting the manuscript and revising it critically for important intellectual content. All authors have read and agreed to the published version of the manuscript.