Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline

"OBJECTIVE: To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults. PARTICIPANTS: The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline. EVIDENCE: The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries."

Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists.

OBJECTIVE: Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants. DESIGN: The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up. METHODS: Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment. RESULTS: Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001.Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (P<0.001). About 42% of patients in the control group required additional surgery or radiotherapy, compared with 38 and 13% subjects in the RT and PT groups, respectively (P=0.002). Outcome measures were not related to NFPA D2R abundance. CONCLUSIONS: Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.

Acromegaly: an endocrine society clinical practice guideline

OBJECTIVE: The aim was to formulate clinical practice guidelines for acromegaly. PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. CONCLUSIONS: Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.(AU)

PTTG acts as a STAT3 target gene for colorectal cancer cell growth and motility.

Pituitary tumor-transforming gene (PTTG), the index mammalian securin, is abundantly expressed in several tumors and regulates tumor growth and progression. Molecular mechanisms elucidating PTTG regulation and actions remain elusive. Here, we provide evidence that PTTG acts as a signal transducer and activator of transcription factor 3 (STAT3) target gene. Total STAT3 and Tyr705 phosphorylated STAT3 were concordantly expressed with PTTG in human colorectal tumors (n=97 and n=95, respectively, P<0.001). STAT3 specifically bound the human PTTG promoter and induced PTTG transcriptional activity (twofold) as assessed by chromatin immunoprecipitation and luciferase reporter assays. STAT3 transfection increased PTTG mRNA and protein abundance twofold in HCT116 human colon cancer cells, and induction was further enhanced (threefold) by constitutively active STAT3 (STAT3-C), whereas strongly abrogated by dominant-negative STAT3 (STAT3-DN). Attenuating PTTG expression by siRNA in STAT3 HCT116 stable transfectants suppressed cell growth and colony formation in vitro, and PTTG cell knockout also constrained activated STAT3-induced explanted murine tumor growth in vivo. STAT3 increased HCT116 cell migration and invasion up to fivefold, whereas cell mobility was abolished by STAT3-DN (>85%). Impairing PTTG expression by siRNA also strongly suppressed STAT3-faciliated cell migration and invasion by up to 90%. Knocking out PTTG in STAT3-C HCT116 stable transfectants strongly decreased tumor metastases in nude mice, indicating the requirement of PTTG for STAT3-promoted metastasis. These results elucidate a mechanism for tumor cell PTTG regulation, whereby STAT3 induces PTTG expression to facilitate tumor growth and metastasis, and further support the rationale for targeting PTTG to abrogate colorectal cancer growth.

A consensus on the diagnosis and treatment of acromegaly complications.

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.

Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression.

CONTEXT: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. OBJECTIVES: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. DESIGN: Four single-dose studies were conducted in 75 healthy volunteers. INTERVENTION: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 µg octreotide were administered. MAIN OUTCOME MEASURE: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. RESULTS: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. CONCLUSIONS: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Clinical, quality of life, and economic value of acromegaly disease control.

Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998-2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 µg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease.

Current management practices for acromegaly: an international survey.

To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.

A consensus on criteria for cure of acromegaly.

OBJECTIVE: The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. PARTICIPANTS: Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. CONCLUSIONS: Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.

Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, phase II trial.

CONTEXT: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide. OBJECTIVE: Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly. DESIGN: We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study. PATIENTS: Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 microg/liter, lack of suppression of GH to less than 1 microg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment. INTERVENTION: After treatment with octreotide 100 microg s.c. three times daily for 28 d, each patient received pasireotide 200, 400, and 600 microg s.c. twice daily in random order for 28 d. MAIN OUTCOME MEASURE: A biochemical response was defined as a reduction in GH to no more than 2.5 microg/liter and normalization of IGF-I to age- and sex-matched controls. RESULTS: After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200-600 microg s.c. bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated. CONCLUSIONS: Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.

Guidelines for acromegaly management: an update.

OBJECTIVE: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. PARTICIPANTS: The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. CONCLUSIONS: The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial.

CONTEXT: There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder. OBJECTIVE: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing's disease. DESIGN: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study. PATIENTS: Thirty-nine patients with either de novo Cushing's disease who were candidates for pituitary surgery or with persistent or recurrent Cushing's disease after surgery without having received prior pituitary irradiation. INTERVENTION: Patients self-administered sc pasireotide 600 microg twice daily for 15 d. MAIN OUTCOME MEASURE: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure. RESULTS: Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders. CONCLUSIONS: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing's disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.

Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults.

The V Consensus Group Meeting on 'Guidelines for Treatment of GH Excess and GH Deficiency in the Adult' was an international workshop held on February 20-22, 2006 in Santa Monica, California, USA. The principal aim of this meeting was to provide guidelines for the evaluation and treatment of adults with either form of abnormal GH secretion: GH excess or GH deficiency. The workshop included debates as to the choice of primary treatment, discussions of the targets for adequate treatment, and concluded with presentations on open issues germane to adult GH treatment including the role of GH in malignancies, the impact of longterm treatment on bone, and a cost-benefit analysis. The meeting was comprised of 66 delegates representing 13 different countries.

Pituitary tumor transforming gene 1 regulates Aurora kinase A activity.

Pituitary tumor transforming gene 1 (PTTG1), a transforming gene highly expressed in several cancers, is a mammalian securin protein regulating both G1/S and G2/M phases. Using protein array screening, we showed PTTG1 interacting with Aurora kinase A (Aurora-A), and confirmed the interaction using co-immunoprecipitation, His-tagged pull-down assays and intracellular immunofluorescence colocalization. PTTG1 transfection into HCT116 cells prevented Aurora-A T288 autophosphorylation, inhibited phosphorylation of the histone H3 Aurora-A substrate and resulted in abnormally condensed chromatin. PTTG1-null cell proliferation was more sensitive to Aurora-A knock down and to Aurora kinase Inhibitor III treatment. The results indicate that PTTG1 and Aurora-A interact to regulate cellular responses to anti-neoplastic drugs. PTTG1 knockdown is therefore a potential approach to improve the efficacy of tumor Aurora kinase inhibitors.

Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

Pituitary tumor transforming gene interacts with Sp1 to modulate G1/S cell phase transition.

Pituitary tumor transforming gene (PTTG1) was isolated from rat pituitary tumor cells, and subsequently identified as a securin protein as well as a transcription factor. We show here a global transcriptional effect of PTTG1 in human choriocarcinoma JEG-3 cells by simultaneously assessing 20,000 gene promoters using chromatin immunoprecipitation (ChIP)-on-Chip experiments. Seven hundred and forty-six gene promoters (P<0.001) were found enriched, with functions relating to cell cycle, metabolic control and signal transduction. Significant interaction between PTTG1 and Sp1 (P<0.000001) was found by transcriptional pattern analysis of ChIP data and further confirmed by immunoprecipitation and pull-down assays. PTTG1 acts coordinately with Sp1 to induce cyclin D3 expression approximately threefold, and promotes G1/S-phase transition independently of p21. PTTG1 deletion was also protective for anchorage-independent cell colony formation. The results show that PTTG1 exhibits properties of a global transcription factor, and specifically modulates the G1/S-phase transition by interacting with Sp1. This novel signaling pathway may be required for PTTG1 transforming activity.

Mechanisms for growth factor-induced pituitary tumor transforming gene-1 expression in pituitary folliculostellate TtT/GF cells.

PTTG1, a securin protein, also behaves as a transforming gene and is overexpressed in pituitary tumors. Because pituitary folliculostellate (FS) cells regulate pituitary tumor growth factors by paracrine mechanisms, epidermal growth factor (EGF) receptor (EGFR)-mediated PTTG1 expression and cell proliferation was tested in pituitary FS TtT/GF cells. EGFR ligands caused up to 3-fold induction of Pttg1 mRNA expression, enhanced proliferating cell nuclear antigen, and increased entry of G0/1-arrested cells into S-phase. PTTG binding factor mRNA expression was not altered. EGF-induced Pttg1 expression and cell proliferation was abolished by preincubation of TtT/GF cells with EGFR inhibitors AG1478 and gefitinib. Phosphatidylinositol 3 kinase, protein kinase C, and MAPK, but not c-Jun N-terminal kinase and Janus activating kinase signaling regulated EGF-induced Pttg1, as well as proliferating cell nuclear antigen mRNA expression and entry into S-phase. EGF-induced EGFR and ERK1/2 phosphorylation was followed by rapid MAPK kinase/ERK kinase-dependent activation of Elk-1 and c-Fos. EGF-induced Pttg1 expression peaked at the S-G2 transition and declined thereafter. Pttg1 cell cycle dependency was confirmed by suppression of EGF-induced Pttg1 mRNA by blockade of cells in early S-phase. The results show that PTTG1 and its binding protein PTTG binding factor are expressed in pituitary FS TtT/GF cells. EGFR ligands induce PTTG1 and regulate S-phase, mediated by phosphatidylinositol 3 kinase, protein kinase C, and MAPK pathways. PTTG1 is therefore a target for EGFR-mediated paracrine regulation of pituitary cell growth.