Table 3.
Reviewed nonrandomized studies, by year of publication.
| First Author |
Publication Year and Journal |
Topic | Study Design | Country (Number of Investigating Centers) | Indication/Population | Qol Instrument(S) Scored, and Rank of Qol Outcome * | Difference or Change in Qol |
|---|---|---|---|---|---|---|---|
| Wekking [66] | Eur J Endocrinol 2005 | QoL in treated hypothyroidism | Cross-sectional study | The Netherlands (13 general practices, 1 referral center) |
Primary hypothyroidism during LT4 treatment (n = 141) |
RAND-36 (secondary outcome) |
↓ in LT4-treated patients vs. general population |
| Gulseren [67] | Arch Med Res 2006 | QoL in treated hypothyroidism | Cross-sectional study vs. controls | Turkey (1) | Overt hypothyroidism and SCH (also overt hyperthyroidism and subclinical hyperthyroidism) (n = 76 (43 SCH, 33 overt)) |
SF-36 (secondary outcome) | ↑ on treatment |
| Samuels [68] | Thyroid 2007 | QoL in LT4-treated patients | Cross-sectional comparative study | USA (1) | Primary hypothyroidism (autoimmune hypothyroidism or Graves’ disease or benign thyroid cancer) (n = 34) |
SF-36 (secondary outcome) | ↓ for lower LT4 dose vs. usual LT4 dose |
| McMillan [23] | Value Health 2008 | QoL in LT4-treated overt or SCH | Study of psychometric properties of ThyDQoL | UK (1) | Overt hypothyroidism and SCH (n = 110, (103 treated)) | ThyDQoL (primary outcome) |
↓ in LT4-treated patients |
| Quinque [69] | Health Qual Life Outcomes 2013 | Adequately treated hypothyroidism |
Scale validation study and then a longitudinal study vs. healthy controls | Germany (1) | Diagnosed hypothyroidism (n = 18). | ThyDQoL (primary outcome) |
⇔ for patients vs. controls |
| dos Santos Vigario [70] | Endocrine 2013 | TSH levels (“overtreated” etc.) | Cross-sectional study | Brazil (4) | Consecutive primary hypothyroidism patients on LT4 replacement (n = 33) |
SF-36 (primary outcome) | ↓ in “under-treated” patients (TSH >4.0 mIU/L, i.e., insufficient LT4) |
| Mithal [71] | Indian J Endocrinol Metab 2014 | LT4 dosing after treatment initiation |
Cross-sectional study | India (150 physicians from 10 cities) |
Primary hypothyroid patients with abnormal thyroid function despite being prescribed LT4 for at least 2 months (n = 1950) |
SF-36 (secondary outcome) | ↓ in “under-treated” patients (i.e., insufficient LT4) |
| Samuels [72] | J Clin Endocrinol Metab 2014 | “Over-treated” hypothyroidism | Cross-sectional study | USA (1) | Women receiving chronic TSH-suppressive LT4 doses (low-risk thyroid cancer or overtreatment of hypothyroidism), chronic replacement LT4 doses, or no LT4 (n = 59) |
SF-36 (primary outcome) | ↓ for LT4-treated patients vs. healthy controls |
| Kelderman-Bolk [73] | Eur J Endocrinol 2015 | Factors associated with QoL (weight gain) | Baseline survey before a cross-over trial |
The Netherlands (1) | Treated primary hypothyroidism (n = 90) |
SF-36 (primary outcome) | ↓ for LT4-treated patients vs. healthy controls |
| Winther [13] | PLoS One 2016 | QoL in newly treated patients | Prospective cohort study | Denmark (2) | Hypothyroidism due to autoimmune thyroiditis (n = 78) |
SF-36 and ThyPRO (primary outcomes) |
↑ in LT4-treated patients |
| Sowinski [74] | Pol Arch Med Wewn 2016 | Relationship between QoL and the dose level of LT4 | Prospective case-control study | Poland (1) | Patients with hypothyroidism (Hashimoto thyroiditis, thyroidectomy, radioiodine) before and after a dose increase in LT4 (n = 33) |
ThyPRO (primary outcome) | ↑ in LT4-treated patients |
| Samuels [75] | Thyroid 2016 | Relationship between TSH levels and QoL |
Cross-sectional study | USA (1) | Healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) (n = 132, (85 low-normal TSH + 47 high-normal TSH)) |
SF-36 (primary outcome) | ⇔ for different TSH levels |
| Jonklaas and Burman [76] | Thyroid 2016 | Switch from LT4 to LT3 | Open-label, single-arm study | USA (1) | Hypothyroidism of any etiology, no significant medical problems, LT4 dose of 75 µg (n = 18) |
SF-36 (secondary outcome) | ↑ (slight) for LT3 monotherapy |
| Rolfes [77] | Drug Saf 2016 | Changes in QoL after an ADR | Cross-sectional survey | The Netherlands (1) | Patients who experienced an ADR after a packaging change and who reported this to a pharmacovigilance center (n = 1167) | COOP/WONCA questionnaire (primary outcome) |
↓ after an ADR due to a packaging change |
| Young Cho [78] | Endocrine 2017 | Polymorphisms in iodothyronine deiodinase | Open-label cross-sectional study | Korea (1) | Chronic autoimmune thyroiditis and thyroid cancer (n = 136 and n = 60) |
SF-36 and ThyPRO (primary outcomes) | ↓ for DIO1 variants ⇔ for DIO2 and 3 variants |
| Wouters [79] | Thyroid 2017 | Polymorphisms in iodothyronine deiodinase (DIO) | Cross-sectional study | The Netherlands (regional population-based cohort) | Patients taking LT4 (n = 364 LT4 users (146 Thr/Thr, 140 Thr/Ala, 35 Ala/Ala)) |
RAND 36-Item Health Survey (primary outcome) | ⇔ in LT4-treated patients ⇔ no significant effect of the D2-Thr92Ala polymorphism |
| Lombardi [80] | Endocrine 2017 | Tablet vs. liquid formulations of LT4 | Open-label longitudinal study | Italy (1) | Total thyroidectomy (n = 155 (77 liquid, 78 tablet)) |
GHQ-12 (secondary outcome) |
↑ for a liquid formulation vs. tablet |
| Samuels [81] | J Clin Endocrinol Metab 2018 | Targeting TSH levels | Open-label longitudinal study |
USA (1) | Hypothyroidism (n = 138) | ThyDQoL, SF-36 (primary outcomes) |
⇔ for different TSH levels |
| Werneck study 1 [62] | Arch Endocrinol Metab 2018 | SCH and exercise |
Open-label cross-sectional study SCH vs. euthyroid | Brazil (1) | SCH (n = 22) | SF-36 (primary outcome) | ⇔ for SCH vs. euthyroid individuals |
| Michaelsson [82] | Eur Thyroid J 2018 | LT4 vs. combination therapy LT4 + LT3 in SCH | Open-label longitudinal cohort study |
Denmark (1) | SCH (n = 23) | ThyPRO (primary outcome) | ↑ for a switch to LT4 + LT3 from LT4 |
| Tariq [83] | South Med J 2018 | Switch from LT4 to LT4 + LT3 or DTE | Observational retrospective study |
USA (1) | Hypothyroidism on “optimal” LT4 only (n = 100 (40 switched to LT4/LT3, 60 switched to DTE)) |
MOS Short Form-20 (primary outcome) |
↑ for a switch to LT4 + LT3 from LT4 |
| Sawicka-Gutaj study 1 [84] | Thyroid 2018 | Impaired sex life | Open-label cross-sectional study | Denmark (2) | Autoimmune hypothyroidism (one subgroup) (n = 189) |
SF-36 and ThyPRO (primary outcomes) |
↓ before LT4 treatment |
| Sawicka-Gutaj study 2 [84] | Thyroid 2018 | Impaired sex life | Open-label longitudinal study |
Denmark (2) | Autoimmune hypothyroidism (one subgroup) (n = 86) |
SF-36 and ThyPRO (primary outcomes) |
↑ with LT4 treatment |
| Guglielmi [44] | Endocr Metab Immune Disord Drug Targets 2018 | Tablet vs. liquid formulations of LT4 | Open-label longitudinal study |
Italy (2) | Hypothyroidism with stable TSH levels on LT4 (n = 102) |
ThyTSQ (primary outcome) | ↑ for liquid LT4 taken at breakfast |
| Akın [85] | J Pediatr Endocrinol Metab 2018 | Regimen timing–pediatric hypothyroidism |
Open-label cross-sectional study of bedtime vs. evening LT4 regimens | Turkey (not reported) |
Acquired hypothyroidism (n = 163) | PedsQL (secondary outcome) |
⇔ for morning vs. bedtime dosing |
| Djurovic [86] | Endocrine 2018 | Factors associated with QoL (Hashimoto thyroiditis) |
Open-label cross-sectional study vs. controls | Serbia (1) | Hashimoto thyroiditis (n = 130 (59 20–49 years old + 71 >50 years old)) |
SF-36 (primary outcome) | ↓ in LT4-treated patients vs. controls |
| Karmisholt [87] | Eur Thyroid J 2019 | SCH | Open-label longitudinal cohort study | Denmark (1) | SCH (n = 15) | SF-36 (primary outcome) | ⇔ vs. TSH levels |
| Mooijaart [88] | JAMA 2019 | SCH–older patients |
Cross-sectional study | Several European countries. 1st trial: The Netherlands and Switzerland. 2nd trial: Netherlands, Switzerland, Ireland, and the UK (not reported) |
SCH (n = 93) | ThyPRO (primary outcome), EuroQol-5D, EuroQol VAS (secondary outcomes) | ⇔ for LT4-treated patients |
| Recker [89] | Horm Metab Res 2019 | SCH–older patients |
Open-label longitudinal cohort study |
Germany (6 endocrine practices) |
Newly diagnosed, untreated, overt endogenous hypothyroidism or SCH (n = 28 (11 > 60 years + 17 < 40 years )) |
ThyPRO and SF-36 (primary outcomes) |
↑ for LT4-treated patients |
| Tan [90] | Fam Pract 2019 | Factors associated with QoL | Cross-sectional survey |
Singapore (1) | Hypothyroidism (n = 229) |
EuroQol-5D-5L (primary outcome) | ↓ for patients with symptoms and comorbidities |
| Hirtz [91] | Front Endocrinol (Lausanne) 2020 | QoL in children and adolescents with thyroid disease | Cross-sectional survey |
Germany (not reported) |
Subclinical and overt hypothyroidism, Subclinical and overt hyperthyroidism, Hashimoto’s thyroiditis (n = 351; 331 (subclinical) + 20 (overt) |
KINDL-R (primary outcome) |
⇔ for the various disease groups |
| Ur Rehman [92] | J Ayub Med Coll Abbottabad 2020 | QoL in treated hypothyroidism | Cross-sectional survey |
Pakistan (1) | Patients aged 18–60 with confirmed hypothyroidism (n = 52) |
ThyPRO (primary outcome) | ↑ upon LT4 treatment |
| Moron-Diaz [93] | Endocrine 2020 | QoL in LT4-treated patients | Cross-sectional survey |
Spain (1) | Patients with adequately treated primary hypothyroidism of any cause (n = 218) |
ThyPRO (primary outcome) | ↑ for lower TSH levels |
LT4: levothyroxine; SCH: subclinical hypothyroidism; LT3: L-tri-iodothyronine; HRQL: Hypothyroid-specific health-related quality of life questionnaire; SF-36: Short Form (36) Health Survey; QoL: quality of life; RAND: RAND Corporation; PCS: physical composite score; ThyDQoL: Thyroid-Dependent Quality of Life Questionnaire; MCS: mental composite score; FT3: free tri-iodothyronine; FT4: free thyroxine; DIO: deiodinase; TSH: thyroid-stimulating hormone; TPO-Ab: antibodies against thyroid peroxidase; DTE: dried thyroid extract; ThyPRO: Thyroid-Specific Patient-Reported Outcome Measure; ADR: adverse drug reaction; TG-Ab: antibodies against thyroglobulin; PedsQL, Pediatric Quality of Life Inventory; ThyTSQ: Underactive Thyroid Treatment Satisfaction Questionnaire. * We considered that QoL was the study’s primary outcome when it was stated as such in the publication or, in the absence of such a statement, when it was the first-mentioned outcome in a list or was most the comprehensively reported outcome. ↑ significantly better QoL or a significant improvement in QoL; ⇔ no significant difference or change in QoL; ↓ significantly worse QoL or a significant decrease in QoL.