Table 2.
Reviewed randomized 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 |
|---|---|---|---|---|---|---|---|
| Pollock [46] | BMJ 2001 | LT4 vs. placebo in SCH | Double-blind randomized crossover trial | UK (1) | Patients with symptoms of hypothyroidism (n = 22) |
SF-36 (secondary outcome) |
⇔ for LT4 vs. placebo |
| Clyde [25] | JAMA 2003 | LT4 vs. combination therapy LT4 + LT3 |
Double-blind, randomized trial | USA (not reported) | Primary hypothyroidism (mostly due to autoimmune disease) (n = 44 (22 + 22)) |
HRQL (primary outcome) | ⇔ for LT4 + LT3 vs. LT4 |
| Sawka [47] | J Clin Endocrinol Metab 2003 | LT4 vs. combination therapy LT4 + LT3 |
Double-blind randomized clinical trial | USA (1) | Primary hypothyroidism treated for at least 6 months (n = 40 (20 + 20)) | MOS (secondary outcome) |
⇔ for LT4 vs. LT4 + LT3 |
| Walsh [48] | J Clin Endocrinol Metab 2003 | LT4 vs. combination therapy LT4 + LT3 |
Double-blind randomized crossover trial | Australia (1 referral center) | Primary hypothyroidism with stable LT4 treatment (n = 110 (101 completers)) | SF-36 (secondary outcome) |
⇔ for LT4 vs. LT4 + LT3 |
| Roos [49] | Arch Intern Med 2005 | LT4 dose levels Low-dose vs. normal-dose LT4 in cardiac asymptomatic hypothyroidism | Double-blind, randomized clinical trial | The Netherlands (1) | Newly diagnosed, untreated primary autoimmune hypothyroidism (n = 50 (25 on low starting dose)) |
RAND-36 (secondary outcome) |
⇔ for low LT4 starting dose vs. full LT4 starting dose |
| Escobar-Morreale [50] | Ann Intern Med 2005 | LT4 vs. combination therapy LT4 + LT3 |
Double-blind, randomized crossover trial. | Spain (1) | Women with overt primary hypothyroidism (n = 26) |
SF-36 (secondary outcome) |
⇔ for LT4 vs. LT4 + LT3 |
| Appelhof [51] | J Clin Endocrinol Metab 2005 | LT4 vs. combination therapy LT4 + LT3 |
Double-blind randomized clinical trial | The Netherlands (1) | LT4 for primary autoimmune hypothyroidism for at least 6 months (n= 130 completers (44 + 41 + 45)) |
RAND-36 (secondary outcome) |
⇔ for LT4 vs. LT4 + LT3 |
| Walsh [52] | J Clin Endocrinol Metab 2006 | LT4 dose levels | Double-blind, randomized crossover trial | Australia (1) | Primary hypothyroidism (autoimmune hypothyroidism or Graves or benign thyroid cancer) (n = 50 completers) |
SF-36 (secondary outcome) |
⇔ between LT4 dose levels |
| Razvi [53] | J Clin Endocrinol Metab 2007 | Subclinical hypothyroidism | Double-blind, randomized crossover study of LT4 vs. placebo. |
UK (27 general practices) | Stable SCH (n = 100, 99 completers) |
ThyDQoL (secondary outcome) |
⇔ for LT4 vs. placebo |
| Samuels [54] | J Clin Endocrinol Metab 2007 | SCH and QoL | Double-blind, randomized crossover study | USA (1) | 13 with autoimmune hypothyroidism and six treated for Graves’ disease (n = 19) | SF-36 (secondary outcome) |
⇔ for usual vs. lower LT4 dose |
| Samuels [55] | J Clin Endocrinol Metab 2008 | Usual LT4 dose vs. high-dose LT4 | Double-blind, randomized, cross-over study | USA (not reported) | Adult-onset primary hypothyroidism (autoimmune or Graves’ disease) (n = 33) | SF-36 (secondary outcome) |
↓ for high-dose LT4 vs. normal-dose LT4 |
| Nygaard [56] | Eur J Endocrinol 2009 | switch from LT4 to LT4 + LT3 | Double-blind, randomized cross-over study | Denmark (3) | Overt, spontaneous hypothyroid subjects on LT4 for at least 6 months (n = 59) | SF-36 (primary outcome) | ↓ with LT4 vs. LT4 + LT3 |
| Panicker [57] | J Clin Endocrinol Metab 2009 | QoL in LT4-treated patients | Cross-sectional study of a randomized trial population |
UK (28) | Patients taking at least 100 µg/day LT4 and with DNA for genotyping (n = 552) | GHQ-12 (primary outcome) |
↑ in response to LT4 + LT3 vs. LT4 (but only for some patients with a DIO2 polymorphism) |
| Bolk [58] | Arch Intern Med 2010 | Time of administration: evening or morning |
Double-blind, randomized crossover trial | The Netherlands (1) | Primary hypothyroidism (n = 90 (47 + 43)) | SF-36 (secondary outcome) |
⇔ for morning vs. evening |
| Reuters [59] | Arq Bras Endocrinol Metabol 2012 | SCH | Double-blind, randomized clinical trial | Brazil (1) | SCH (n = 35 (25 finished the study)) | SF-36 (secondary outcome) |
↑ with LT4 vs. placebo |
| Hoang [60] | J Clin Endocrinol Metab 2013 | Switch from LT4 to DTE | Double-blind randomized crossover study | USA (1) | Primary hypothyroidism and a stable dose of LT4 for at least 6 months (n = 70) |
GHQ-12 (one of several primary outcomes) | ⇔ for DTE vs. LT4 |
| Kaminski [27] | Arch Endocrinol Metab 2016 | Switch from LT4 to LT4 + LT3– primary hypothyroidism |
Double-blind, randomized crossover study. | Brazil (1) | Hypothyroidism, stable doses of LT4 during the previous six months (n = 32) |
HRQoL questionnaire (a modified version of the Chronic Thyroid Questionnaire) (secondary outcome ?) |
⇔ for LT4 vs. LT4 + LT3 |
| Stott [61] | N Engl J Med 2017 | QoL in older patients with SCH | Double-blind placebo- controlled randomized trial |
The Netherlands, UK, Eire, Switzerland (not reported) |
Adults aged 65 or over with SCH (n = 638 (318 + 320)) |
ThyPRO and EQ-5D (primary outcome) | ⇔ for LT4 vs. placebo |
| Werneck study 2 [62] | Arch Endocrinol Metab 2018 | SCH and exercise |
Randomized controlled trial | Brazil (1) | SCH (n = 20 (10 + 10)) | SF-36 (primary outcome) | ↑ with aerobic exercise training |
| Rezaei [63] | Thyroid Res 2020 | QoL in LT4-treated patients: effect of cognitive behavioral therapy |
Open-label randomized controlled trial |
Iran (1) | Women of child-bearing age with hypothyroidism (n = 86 (43 + 43)) | SF-36 (primary outcome) | ↑ with cognitive behavioral therapy |
| van der Gaag [64] | Int J Environ Res Public Health 2020 | Effect of a dietary intervention (green vegetables, beef, whole milk and butter) on QoL in SCH |
Open-label randomized controlled trial |
The Netherlands (2) | Children aged 1–12 with a pediatrician- confirmed diagnosis of SCH (n = 61 (29 + 32)) |
PedsQL (secondary outcome) |
↑ with diet improvement vs. controls |
| de Montmollin [65] | Ann Intern Med 2020 | QoL in older patients with SCH | Double-blind placebo- controlled randomized trial |
The Netherlands, UK, Eire, Switzerland (not reported) |
Adults aged 65 or over with SCH (n = 638 (66 + 66 + 252 + 254)) | ThyPRO (primary outcome) and EQ-5D (secondary outcome) |
⇔ for LT4 vs. placebo |
LT4: levothyroxine; SCH: subclinical hypothyroidism; LT3: L-tri-iodothyronine; HRQL: Hypothyroid-specific health-related quality of life questionnaire; T3: tri-iodothyronine; T4: thyroxine; SF-36: Short Form (36) Health Survey; GHQ-28: 28-item General Health Questionnaire; 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; DTE: dried thyroid extract; ThyPRO: Thyroid-Specific Patient-Reported Outcome Measure; PedsQL, Pediatric Quality of Life Inventory. * 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.