Endocrine Abstracts

Adult-onset hypothyroidism is related to anxiety, depression, and impaired neurocognition. Guidelines from all professional societies recommend levothyroxine (LT4) monotherapy as the treatment of choice. However, ~15% hypothyroid patients do not achieve a satisfactory functional level despite TSH within the reference range. The beneficial effects of combining LT4 and liothyronine (LT3) to improve neuropsychiatric functions remains unclear. Recently, 3-iodothyronamine (T1AM), a thyroid hormone derivative, demonstrated pro-learning and anti-amnestic effects in vivo. Notably, decreased T1AM tissue levels were found in pharmacological rodent model of hypothyroidism, even after adequate hormonal replacement with LT4. Here, in a mouse model of adult-onset hypothyroidism, we aimed at comparing various combinations of classical and non-classical thyroid hormones on hippocampus-dependent memory, anxiety- and depression-like behaviors. Six-week-old C57BL/6J male mice (n = 41) were given Methimazole and Potassium Perchlorate (0.20 mg/g/die and 0.30 mg/g/die) in drinking water for 49 days. As controls, n = 8 littermates received water. At day 21, mice were implanted with subcutaneous ALZET osmotic pumps delivering replacement treatments for 28 days. We had 6 experimental groups, as follows: (1) hypothyroid, n = 9; (2) LT4, n = 6; (3) LT4&LT3, n = 9; (4) LT4&T1AM, n = 8; (5) T1AM, n = 9; (6) euthyroid, n = 8. T4 and T3 serum concentrations were determined, by high performance liquid chromatography coupled with tandem mass spectroscopy (HPLC-MS/MS), and confirmed the validity of our model. Mice were exposed to: (i) Elevated Plus Maze, for the assessment of anxiety-related behaviors; (ii) Open Field Test, for locomotion; (iii) Novel Object Recognition test, for hippocampus-dependent memory; (iii) Tail Suspension Test, for depression-related behaviors. Hypothyroid mice displayed significantly impaired hippocampus-dependent memory as compared to euthyroid mice (discrimination index, DI = −0.00 ± 0.09 vs 0.28 ± 0.08, t = 2.43, P < 0.05). ANOVA detected a global significant difference in DI among the experimental groups (F (5, 43) = 4.038, P < 0.01). In detail, LT4 monotherapy almost fully restored memory (DI = 0.23 ± 0.09). A larger improvement was observed upon LT4 & T1AM replacement, while T1AM did not induce any effect per se. Memory remained disrupted under LT4 & L-T3, possibly due to thyrotoxicosis. These findings were influenced neither by locomotor activity nor by anxiety- and depression-related behaviors, which remained unchanged. In conclusion, in our pharmacological mouse model of adult-onset hypothyroidism, LT4 & T1AM combination fared better than LT4 monotherapy in ameliorating hippocampus-dependent memory, which was disrupted in hypothyroid conditions. Future studies are needed to elucidate the molecular pathways involved in the observed effects.