Impact of Growth Hormone (GH) Deficiency and GH Replacement upon Thymus Function in Adult Patients Gabriel Morrhaye1., Hamid Kermani1., Jean-Jacques Legros1, Frederic Baron 2 , Yves Beguin2, Michel Moutschen3, Remi Cheynier4, Henri J. Martens1*, Vincent Geenen1 1 University of Liege Center of Immunology, Laboratory of Immunoendocrinology, Institute of Pathology CHU-B23, Liege-Sart Tilman, Belgium, 2 University of Liege, Division of Hematology, CHU-B35, Liege-Sart Tilman, Belgium, 3 University of Liege, Division of Immunodeficiencies and Infectious Diseases, CHU-B35, Liege-Sart Tilman, Belgium, 4 Institut Pasteur, De´partement de Virologie, Paris, France Abstract Background: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age- related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. Methodology/Principal Findings: Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/b TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p,0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p,0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/b TREC ratio (p,0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/b TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. Conclusions: In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults. Trial Registration: ClinicalTrials.gov NTC00601419 Citation: Morrhaye G, Kermani H, Legros J-J, Baron F, Beguin Y, et al. (2009) Impact of Growth Hormone (GH) Deficiency and GH Replacement upon Thymus Function in Adult Patients. PLoS ONE 4(5): e5668. doi:10.1371/journal.pone.0005668 Editor: Derya Unutmaz, New York University School of Medicine, United States of America Received February 10, 2009; Accepted April 27, 2009; Published May 22, 2009 Copyright: 2009 Morrhaye et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Walloon Region of Belgium (http://recherche-technologie.wallonie.be/fr/menu; DGTRE Reseaux2-SENEGENE nu 05/1/ 6192 and First-Spin off ThymUP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Dr. Vincent Geenen received consultant fees as clinical researcher from Pfizer, Inc. * E-mail: hmartens@ulg.ac.be . These authors contributed equally to this work. Introduction The thymus is the unique lymphoid organ responsible for the generation of self-tolerant and competent naive T cells, as well as of self antigen-specific natural regulatory T cells. The diversity of T-cell receptors for antigen (TCR) results from the random recombination of gene segments encoding the variable parts of the TCRa and b chains. Successive rearrangements in the TCR locus generate different types of TCR excision circles (TRECs), such as signal-joint (sj) TRECs and DJbTRECs [1–4]. Within some limits, quantification of sjTREC frequency is now considered to be a very valuable method to evaluate thymopoiesis, as well as the impact of the neuroendocrine system upon thymic function [5,6]. In addition, the ratio of sjTREC/DJbTREC frequencies (sj/b TREC ratio) reliably reflects the magnitude of intrathymic proliferation of precursor T cells [7–9]. For a long time, the thymus function was assumed to decrease in humans after puberty, in parallel with adipose involution. It was then thought that the peripheral T cell repertoire was mainly seeded with a complete repertoire of antigen-reactive memory T cells, with no obvious need for the maintenance of naive T cell generation. In recent years however, demonstrative evidence was provided that the adult thymus remains active until late in life and generates competent naive T cells for ensuring a diverse peripheral repertoire [1,4,10]. Growth hormone (GH) and GH receptor (GHR) are related to type I cytokines and to receptors of type I cytokines, respectively [11,12]. Already in 1930, involution of the rat thymus had been observed following hypophysectomy [13]. Thereafter, administra- PLoS ONE | www.plosone.org 1 May 2009 | Volume 4 | Issue 5 | e5668