In this report we have examined changes in cell growth parameters, cell cycle effectors and signaling pathways that accompany thyrotrope growth arrest by TH and growth resumption following its withdrawal. Flow cytometry and immunohistochemistry of proliferation markers demonstrated that TH treatment of thyrotrope tumors resulted in a reduction in the fraction of cells in S-phase which is restored upon TH withdrawal. This is accompanied by dephosphorylation and rephosphorylation of Rb protein. The expression levels of cdk2 and cyclin A, as well as cdk1 and cyclin B, were decreased by TH and following withdrawal not only did these regulators of Rb phosphorylation and mitosis increase in their expression but so too did the D1 and D3 cyclins. We also noted a rapid induction and subsequent disappearance of the type 5 receptor for the growth inhibitor, somatostatin, with TH treatment and withdrawal, respectively. Since somatostatin can arrest growth by activating MAP kinase pathways we examined these pathways in TtT-97 tumors and found that the ERK pathway and several of its upstream and downstream effectors, including CREB, were activated with TH treatment and deactivated following its withdrawal. This led to the hypothesis that TH, acting through increased sst5, could activate the ERK pathway leading to CREB-dependent decreased expression of critical cell cycle proteins, specifically cyclin A, resulting in hypophosphorylation of Rb and its subsequent arrest of S-phase progression. These processes are reversed when TH is withdrawn resulting in an increase in the fraction of S-phase cells.