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Endocrine Research: Raffaele Napoli, Valentina Apuzzi, Giorgio Bosso, Carolina D'Anna, Antonietta De Sena, Concetta Pirozzi, Aldo Marano, Gelsy Arianna Lupoli, Giuseppe Cudemo, Ugo Oliviero, Margherita Matarazzo, Giovanni Lupoli, and Luigi Saccá Recombinant Human Thyrotropin Enhances Endothelial-Mediated Vasodilation of Conduit Arteries J Clin Endocrinol Metab 2009; 94: 1012-1016 [Abstract] [Full text] [PDF]

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Recombinant human TSH and endothelial function: a still unresolved issue

Fabio Monzani, Angela Dardano and Fabio Monzani   (13 July 2009)

Recombinant human TSH and endothelial function: a still unresolved issue 13 July 2009
Fabio Monzani, Professor of Internal Medicine Department of Internal Medicine, University of Pisa, via Roma 67, 56126 Pisa - Italy, Angela Dardano and Fabio Monzani Send letter to journal: Re: Recombinant human TSH and endothelial function: a still unresolved issue fmonzani{at}med.unipi.it Fabio Monzani, et al.	We read with interest the recent article by Napoli et al. describing the effect of recombinant human thyrotropin (rhTSH) on endothelial function of conduit arteries. (1). It has been proposed that TSH might directly up-regulate proinflammatory cytokines, including interleukin 6 and TNF-α that are integrated in functional networks involved in atherosclerosis (2). In this regard, we showed that an acute systemic increase of serum TSH levels by rhTSH injection induced a significant impairment of endothelium-dependent (ED) vasodilation in conduit arteries assessed by flow mediated dilation (FMD), along with a concomitant reduction of plasma antioxidant capacity and an increased production of proinflammatory cytokines (3). In contrast, in the paper by Napoli et al. (1) rhTSH administration significantly enhanced ED vasodilation without affecting serum proinflammatory cytokine levels. The degree of FMD increase was similar to that observed following the administration of major vasodilating substances and remained unchanged up to 6 days, irrespective of a concomitant huge serum TSH reduction (15 ± 2 vs 111 ± 8 mU/L). The authors conclude that rhTSH acts on the endothelial cells to initiate the vasodilatory cascade independent of any change in vascular risk biomarkers. The authors make reference to the in vitro observation showing that TSH causes a rapid response of cAMP and NO production in human aortic endothelial cells. However, NO molecule seems to play a janus-role: NO is able to reduce generation of reactive oxygen species but, when excessively produced, NO reacts with superoxides resulting in the formation of the free radical peroxynitrite (4). Moreover, a very recent paper has confirmed our previous observations, suggesting that supra-physiological concentrations of rhTSH are associated with proatherogenic activation of vascular endothelial cells and platelets as well as enhanced lipid peroxidation in patients monitored for thyroid cancer remnant (5). In conclusion, conflicting clinical and experimental data so far available are not sufficient to draw definite conclusions about the impact of rhTSH on the vascular risk profile, as assessed by either circulating biomarkers or endothelium dependent vasodilation. Further studies are therefore needed to better address this intriguing issue. References 1. Napoli R, Apuzzi V, Bosso G, D'Anna C, De Sena A, Pirozzi C, Marano A, Lupoli GA, Cudemo G, Oliviero U, Matarazzo M, Lupoli G, Saccá L 2009 Recombinant human thyrotropin enhances endothelial-mediated vasodilation of conduit arteries. J Clin Endocrinol Metab 94:1012-1016 2. Wang HC, Dragoo J, Zhou Q, Klein JR 2003 An intrinsic thyrotropin- mediated pathway of TNF-alpha production by bone marrow cells. Blood 101:119-123 3. Dardano A, Ghiadoni L, Plantinga Y, Caraccio N, Bemi A, Duranti E, Taddei S, Ferrannini E, Salvetti A, Monzani F 2006 Recombinant human thyrotropin reduces endothelium-dependent vasodilation in patients monitored for differentiated thyroid carcinoma. J Clin Endocrinol Metab 91:4175-4178 4. Pechanova O, Simko F 2007 The role of nitric oxide in the maintenance of vasoactive balance. Physiol Res 56:S7-S16 5. Desideri G, Bocale R, Milardi D, Ghiadoni L, Grassi D, Necozione S, Taddei S, di Orio F, Pontecorvi A, Ferri C 2008 Enhanced proatherogenic inflammation after recombinant human TSH administration in patients monitored for thyroid cancer remnant. Clin Endocrinol (Oxf) Dec 3. [Epub ahead of print]