Table. Characteristics of 21 Included Randomized Clinical Trials on Thyroid Hormone Therapy for Subclinical Hypothyroidism in Adults.

Source	Country	Funding Source	Definition of Subclinical Hypothyroidism	No. of Participants	Age, Mean (SD), y	Women, No. (%)	Intervention	Control	Planned Follow-up Duration, mo	Outcomesa	Hypothyroid Symptoms at Baseline, Intervention vs Control
Stott et al,12 2017	The Netherlands, Switzerland, United Kingdom, Ireland	Nonindustry	Thyrotropin 4.6-19.99 mIU/L on 2 occasions and normal free thyroxine	737	74 (6.3)	396 (54)	Levothyroxine	Placebo	≥12b	ThyPRO,40 EQ-5D,41 Letter-Digit Coding Test,42 hand-grip strength, blood pressure, BMI, cardiovascular events, mortality, adverse effects40	ThyPRO hypothyroid symptom score: 17.5 (SD, 18.8) vs 16.9 (SD, 17.9)
Zhao et al,11 2016	China	Nonindustry	Thyrotropin 4.2-10.0 mIU/L and normal free thyroxine on 2 occasions	369	55 (7.6)	270 (73)	Levothyroxine	No intervention	15	Blood pressure, BMI	NR
Najafi et al,24 2015	Iran	Nonindustry	Thyrotropin >4.5 mIU/L, normal free thyroxine, and positive TPO-Ab	60	34 (10.0)	51 (85)	Levothyroxine	Placebo	3	BDI43	Mean number of hypothyroid symptoms per participant (range, 0-12): 4.8 vs 5.1
Ersoy et al,29 2012	Turkey	Not declared	Thyrotropin 5.0-10.0 mIU/L and normal free thyroxine	60	46 (13.1)	58 (97)	Levothyroxine	No intervention	6	Blood pressure, BMI	NR
Aghili et al,25 2012	Iran	Nonindustry	Thyrotropin >4.5 mIU/L, normal free thyroxine, and positive TPO-Ab	60	34 (10.8)	51 (85)	Levothyroxine	Placebo	3	Cognitive function (Wechsler memory scale44)	Mean number of hypothyroid symptoms per participant (range, 0-7): 3.2 vs 3.7
Reuters et al,31 2012	Brazil	Not declared	Thyrotropin >4.0 mIU/L and normal free thyroxine on 2 occasions	71	50 (10.9)	62 (87)	Levothyroxine	Placebo	6	Zulewski score,45 Short Form 36,46 BDI,43 quadriceps strength	Zulewski score (only change from baseline reported)
Cabral et al,28 2011	Brazil	Not declared	Thyrotropin >4 mIU/L and normal free thyroxine on 2 occasions	32	46 (9.0)	32 (100)	Levothyroxine	No intervention	12	BMIc	NR
Parle et al,16 2010	United Kingdom	Nonindustry	Thyrotropin >5.5 mIU/L and normal free thyroxine	94	74 (5.8)	57 (61)	Thyroxine	Placebo	12	HADS,47 cognitive function (MMSE,48 MEAMS,49 SCOLP,50 and Trail Making Test51)	NR
Nagasaki et al,36 2009	Japan	Nonindustry	Increased thyrotropin and normal free triiodothyronine/free thyroxine	95	65 (19.3)	95 (100)	Levothyroxine	Placebo	5	Blood pressure, BMI	NR
Teixeira et al,30 2008	Brazil	Industry supported	Thyrotropin >4 mIU/L and normal free thyroxine on ≥2 occasions	60	48 (10.5)	57 (95)	Levothyroxine	Placebo	12	BMI	NR
Razvi et al,32 2007	United Kingdom	Nonindustry	Thyrotropin >4 mIU/L and normal free thyroxine on ≥2 occasions	100	54 (12.6)	82 (82)	Levothyroxine	Placebo	3	ThyDQoL,52 blood pressure, BMIc	ThyDQoL (only change from baseline reported)
Jorde et al,26 2006	Norway	Nonindustry	Thyrotropin 3.5-10 mIU/L	69	62 (11.9)	32 (46)	Thyroxine	Placebo	12	GHQ-30,53 BDI,43 composite cognitive score26	Mean number of hypothyroid symptoms per participant (range, 0-19): 4.0 vs 4.0
Iqbal et al,37 2006	Norway	Nonindustry	Thyrotropin 3.5-10 mIU/L on 2 occasions and normal free triiodothyronine/free thyroxine	64	64 (12.2)	31 (48)	Thyroxine	Placebo	12	BMI	NR
Caraccio et al,38 2005	Italy	Nonindustry	Thyrotropin >3.6 mIU/L and normal free triiodothyronine	23	32 (9.6)	21 (91)	Levothyroxine	Placebo	6	BMI	NR
Yazici et al,35 2004	Turkey	Not declared	Increased thyrotropin and normal free triiodothyronine/free thyroxine	45	40 (7.9)	38 (84)	Levothyroxine	Placebo	12	Blood pressure, BMI	NR
Monzani et al,34 2004	Italy	Not declared	Thyrotropin >3.6 mIU/L	45	37 (11.0)	37 (82)	Levothyroxine	Placebo	6	Blood pressure, BMI	NR
Kong et al,27 2002	United Kingdom	Not declared	Thyrotropin 5-10 mIU/L and normal free thyroxine	40	50 (15.2)	40 (100)	Thyroxine	Placebo	6	GHQ-30,53 HADS,47 BMI	Overall, 33/40 (83%) reported fatigue and 32/40 (80%) reported weight gain
Caraccio et al,39 2002	Italy	Nonindustry	Thyrotropin >3.6 mIU/L on 2 occasions and positive TPO-Ab	49	35 (9.1)	42 (86)	Levothyroxine	Placebo	6	BMI	NR
Monzani et al,33 2001	Italy	Not declared	Thyrotropin >3.6 mIU/L for >1 y and normal free thyroxine	20	32 (12.1)	18 (90)	Levothyroxine	Placebo	6	Blood pressure, BMI	NR
Meier et al,22 2001	Switzerland	Nonindustry and industry supportedd	Thyrotropin >5 mIU/L on 2 consecutive blood tests and normal free thyroxine	66	57 (10.6)	66 (100)	Levothyroxine	Placebo	12	Billewicz score54,e	Billewicz score: −25.7 (SD, 5.2) vs −28.3 (SD, 14.1)
Cooper et al,23 1984	United States	Nonindustry	Increased thyrotropin and normal free triiodothyronine/free thyroxine	33	54 (10.1)	32 (97)	Levothyroxine	Placebo	12	BMI	Mean number of hypothyroid symptoms per participant (range, 0-6): 2.1 vs 2.4

Abbreviations: BDI, Beck Depression Inventory; BMI, body mass index; EQ-5D, Euro Quality of Life 5 Dimensions Questionnaire; GHQ-30, General Health Questionnaire (30 items); HADS, Hospital Anxiety and Depression Scale; MEAMS, Middlesex Elderly Assessment of Mental State; MMSE, Mini Mental State Examination; NR, not reported; SCOLP, Speed and Capacity of Language Processing Test; ThyDQoL, 18-Item Underactive Thyroid-Dependent Quality of Life; ThyPRO, Thyroid-Related Quality-of-Life Patient-Reported Outcome Measure (hypothyroid score: 4 items; range, 0-100; higher scores indicate more hypothyroid symptoms; tiredness score: 7 items); TPO-Ab, thyroid peroxidase antibody.

^aOnly outcomes relevant to this systematic review are listed; ie, outcomes that were included in the study protocol and published in the PROSPERO database.

^bThe Letter-Digit Coding Test outcome was available after 18 months of levothyroxine or placebo intervention; the other outcomes after 12 months.

^cData obtained through direct communication with author.

^dThis work was supported by the Swiss Research Foundation and by unconditional research grants from Henning Berlin, Sandoz Research, and Roche Research Foundations.

^eBillewicz score ranges from −47 to 67; higher scores indicate worse hypothyroid symptoms.