Table 2.

Antioxidant agents in GH and GO: clinical studies

Reference	Type of study	Compound and dosage	Patients	Main finding
Bouzas et al. [42]	Prospective non-randomized placebo-controlled, clinical trial	Allopurinol (300 mg daily orally) and nicotinamide (300 mg daily orally) vs. placebo for 3 months	22 patients with mild or moderately severe, active, newly diagnosed GO	Beneficial effect in mild and moderately severe GO: 9 (82%) of 11 patients treated with oral antioxidants showed improvement of GO vs. 3 (27%) of 11 patients in the control group (p < 0.05). Soft tissue inflammation was the component of the disease that responded more to treatment
Marcocci et al. [40]	Prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial	Sodium selenite (100 µg twice daily orally), or pentoxifylline (600 mg twice daily orally) vs. placebo (twice daily) for 6 months	159 patients with mild GO	Beneficial effect of selenium in mild GO: at the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (p < 0.001) as well as in a reduced eye involvement (p = 0.01) and slowed progression of GO (p = 0.01), as compared with placebo
Vrca et al. [43]	Prospective, randomized, placebo-controlled, clinical trial	Methimazole plus an additional capsule daily of a fixed combination of antioxidants containing β-carotene (6 mg), selenium (60 µg), vitamins C (200 mg) and E (36 mg) vs. methimazole alone	55 patients with newly detected GH	Better control of hyperthyroidism: faster normalization of thyroid hormones in patients with GH treated with methimazole plus the mixture of antioxidant agents compared with control group
Calissendorff et al. [45]	Prospective, randomized, placebo-controlled, clinical trial	“Block and replace” treatment with methimazole and levothyroxine, plus selenium (200 µg daily orally) vs. “block and replace treatment” alone for 9 months	38 patients, with newly diagnosed and untreated GH	Better control of hyperthyroidism in GH: FT4 decreased more in the selenium group at 18 weeks (14 vs. 17 pmol/L compared to the placebo group, p = 0.01) and also at 36 weeks (15 vs. 18 pmol/L, p = 0.01). TSH increased more in the selenium group at 18 weeks (0.05 vs. 0.02 mIU/L, p = 0.04)
Leo et al. [38]	Prospective, randomized, placebo-controlled, clinical trial	Methimazole plus L-selenomethionine (166 µg daily orally) vs. methimazole alone for 3 months	30 patients with untreated GH	No beneficial effect of selenium in the short-term control of GH: Administration of Methimazole was followed by a reduction of FT3 and FT4, with no difference between groups
Kahaly et al. [44]	Prospective, randomized, double-blind, placebo-controlled, clinical trial	Methimazole plus sodium selenite (300 µg daily orally) vs. methimazole alone for 6 months	61 patients with untreated GH	No beneficial effect of selenium in GH: a response was observed in 25 of 31 patients (80%) and in 27 of 33 (82%) at week 24 in the selenium (+methimazole) and placebo (+methimazole) groups, respectively. During a 12-week follow-up, 11 of 23 (48%) and 12 of 27 (44%) relapsed in the selenium and placebo groups, respectively. Serum concentrations of selenium and selenoprotein P were unrelated to response or recurrence rates