Rebound effect in hypothalamic-pituitary thyreotropic activity: a new model to better understand hypothyroidism and hormonal replacement therapies

Background: A debate is active on the capability to restore euthyroidism in people with hypothyroidism (hT) since symptoms and metabolic abnormalities experienced by some patients. This issue has been mainly studied by focusing on the lower stream of the Hypothalamus–Pituitary-Thyroid (HPT) axis by TSH, FT4 and FT3 levels. It would be useful to focus on the upper part of the flow of HPT axis, investigating the factors that interfere with the hypothalamic-pituitary thyrotropic activity (HPta). A model to study this aspect is provided by patients diagnosed with differentiated thyroid carcinoma (DTC) who require radioiodine (RAI). These thyroidectomized subjects, if considered otherwise healthy, are prepared for RAI administration through a one-month withdrawal of levothyroxine (LT4). Aim of the study was to investigate the factors influencing HPta during a condition of hT induced in a standardized and controlled way. Methods: The study was conducted in an endocrinology tertiary care center in Catania, Italy. In this area, adult patients diagnosed with DTC after total thyroidectomy are placed on a fixed dose of LT4 (i.e. 100 mg/day) and referred to this hospital for subsequent treatments. According to the institutional guidelines patients assessed as otherwise healthy are prepared to RAI within 6 months from thyroidectomy by a standard protocol of hT induction: 1) LT4 therapy is stopped from 28 days before the day scheduled for RAI; 2) patients assume l-triiodothyronine at fixed daily dose during the first 14 days, while they do not assume thyroid hormones during the second 14 days. We consecutively included from January 2016 to December 2019 DTC patients treated with RAI previous hT induction according to the protocol above described. Demographic and anthropometric parameters, dose of LT4 taken from thyroidectomy until withdraw for hT induction (LT4_mg/Kg/day), and the results of blood test collected the day scheduled for RAI administration (i.e., TSH (TSH_time1), Thyroglobulin, etc) were collected. Univariate regression analyses and a stepwise multivariate regression analysis were performed to evaluate which variables independently influence the TSH levels after a month of inducted hT. Results: 102 patients were included in the study. They were 78 females and 24 males with a median age of 44 years and a median BMI of 27.1 Kg/mq. Univariable linear regression analyses revealed age (P 0.005) and dose of LT4_mg/Kg/day (P 0.023) as independent factors affecting TSH levels after a month of LT4 withdrawl. Multivariable linear regression analysis included age (P 0.012), LT4_mg/Kg/day (P 0.003), and BMI (P 0.040) in the best fit model (R2 0.40) to explain hT TSH values. Conclusions: This study shows that, beyond the age, HPta in hT patients is strongly determined with a directly proportional relation, by the dose of LT4 taken from thyroidectomy to its withdrawal. These data suggest the existence of a rebound effect for HPta in the HPT axis. BMI also play a role in this phenomenon.