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.

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.

Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis.

Pituitary tumors are commonly encountered, and result from clonal expansion of a single mutated cell. Hypothalamic hormones, local growth factors and circulating sex steroid hormones promote pituitary tumor growth and expansion into large invasive tumors. Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion. Fibroblast growth factor-2 (bFGF) modulates angiogenesis, tumor formation and progression in many tissues, including the anterior pituitary. A pituitary tumor-derived transforming gene (PTTG) has been isolated, which is tumorigenic in vivo, regulates bFGF secretion, and inhibits chromatid separation. The human PTTG family consists of at least three homologous genes, of which PTTG1 is located on chromosome 5q33 and is expressed at low levels in most normal human tissues but is highly expressed in malignant human cell lines and in pituitary tumors. We report here that pituitary pttg is regulated in vivo and in vitro by estrogen. Maximal induction of rat pituitary pttg mRNA in vivo occurred early in pituitary transformation (normal cell to hypertrophic/hyperplastic cell), coincident with bFGF and vascular endothelial growth factor induction and pituitary angiogenesis. We also demonstrate that pttg expression is induced by bFGF, and show concordant pttg and bFGF expression in experimental and human pituitary adenomas. As bFGF and estrogen both induce pttg, and pttg expression coincides with the early lactotrophic hyperplastic response, angiogenesis and prolactinoma development, we propose a previously unknown paracrine growth factor-mediated mechanism for pituitary tumor pathogenesis and potentially other estrogen-regulated tumors.

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.

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.

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.

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 cytokine and growth factor expression and action.

The complex range of pituitary regulatory mechanisms reviewed here underlies the critical function of the pituitary in sustaining all higher life forms. Thus, the ultimate net secretion of pituitary hormones is determined by signal integration from all three tiers of pituitary control. It is clear from our current knowledge that the trophic hormone cells of the anterior pituitary are uniquely specialized to respond to these signals. Unravelling their diversity and complexity will shed light upon the normal function of the master gland. Understanding these control mechanisms will lead to novel diagnosis and therapy of disordered pituitary function (357).

Leukemia-inhibitory factor-neuroimmune modulator of endocrine function.

Leukemia-inhibitory factor (LIF) is a pleiotropic cytokine expressed by multiple tissue types. The LIF receptor shares a common gp130 receptor subunit with the IL-6 cytokine superfamily. LIF signaling is mediated mainly by JAK-STAT (janus-kinase-signal transducer and activator of transcription) pathways and is abrogated by the SOCS (suppressor-of cytokine signaling) and PIAS (protein inhibitors of activated STAT) proteins. In addition to classic hematopoietic and neuronal actions, LIF plays a critical role in several endocrine functions including the utero-placental unit, the hypothalamo-pituitary-adrenal axis, bone cell metabolism, energy homeostasis, and hormonally responsive tumors. This paper reviews recent advances in our understanding of molecular mechanisms regulating LIF expression and action and also provides a systemic overview of LIF-mediated endocrine regulation. Local and systemic LIF serve to integrate multiple developmental and functional cell signals, culminating in maintaining appropriate hormonal and metabolic homeostasis. LIF thus functions as a critical molecular interface between the neuroimmune and endocrine systems.

Pathophysiology of acromegaly.

This review discusses the pathophysiology of acromegaly. Acromegaly has been classified in this paper into distinct entities based on etiology, ultrastructural features of the pituitary, and cytogenesis. This classification has been proposed based on clinical signs, immunoperoxidase techniques, transmission electromicroscopy and immunoelectron microscopy. Pituitary causes of acromegaly include densely granulated adenomas, sparsely granulated adenomas, mixed growth hormone and prolactin cell adenomas, acidophil stem cell adenomas, mammosomatotroph cell adenomas, and pleurihormonal adenomas. GH cell hyperplasia and GH cell carcinoma are also discussed. Extrapituitary causes of acromegaly include eutopic GH cell adenoma in the sphenoid sinus or parapharyngeal region and excess GHRF secretion which may be eutopic or ectopic. The pathological, clinical, and biochemical evidence in favor of a pituitary or hypothalamic etiology of acromegaly has been reviewed. Finally, a multistage theory of GH cell tumorigenesis has been proposed as a model in an attempt to unify the genetic, environmental and biochemical factors implicated in the pathogenesis of acromegaly.

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.

Insulin suppresses growth hormone secretion by rat pituitary cells.

The effects of insulin on basal and hydrocortisone-induced growth hormone (GH) secretion were studied in rat pituitary tumor cells (GH3). Cells were grown in monolayer culture and exposed to exogenously added insulin for up to 8 d. Basal GH secretion was inhibited by insulin (0.7 nM) after a 48-h lag period by approximately 50% (P less than 0.01, vs. untreated control cells). The suppression of GH secretion was reversible, as removal of added insulin resulted in return of GH secretion to normal levels after 24 h. Maximal suppression of basal GH secretion was achieved by 0.7 nM insulin, and these effects were prevented by simultaneous exposure of the cells to guinea pig anti-insulin serum (1:2,000). No effects of insulin on cell replication were evident, and glucose concentration in the medium did not differ in control or insulin-treated wells. Insulin (7 nM) significantly suppressed the fivefold hydrocortisone-induced GH stimulation during 5 d of incubation with up to 1,000 nM of the steroid (P less than 0.001). These inhibitory effects were similarly observed in glucose- and pyruvate-free medium, and in the presence of 2-deoxyglucose. Insulin also reversed the suppression of prolactin (PRL) secretion induced by hydrocortisone (1 uM), and actually stimulated basal PRL secretion by over 50%. Insulin did not alter the inhibitory effect of hydrocortisone on GH3 cell proliferation. Although higher doses (13 nM) of insulin-like growth factor (IGF-I) also suppressed basal GH secretion, IGF-I did not alter the GH and PRL secretory changes induced by hydrocortisone. The results show that insulin exerts a direct, specific inhibitory effect on basal and hydrocortisone-induced GH secretion by GH3 cells unrelated to glucose utilization by the cells.

Insulin regulation of rat growth hormone gene transcription.

We have previously shown that insulin suppresses growth hormone (GH) messenger (m) RNA levels in rat pituitary cells. To further delineate the molecular mechanism of insulin action, the effect of insulin treatment on GH gene transcription rates was examined in GH3 pituitary cells grown in serum-free defined medium. A transcriptional run-off assay was performed when intact isolated nuclei were allowed to continue RNA synthesis in an in vitro reaction. Specific incorporation of [32P]GTP into RNA was quantified by hybridization to rat GH complementary (c) DNA. Hybridization efficiency was measured with an internal [3H]cRNA standard and ranged from 30 to 48%. Alpha-amanitin (1 microgram/ml) inhibited total transcription, and excess unlabeled rat pituitary mRNA (250 ng) competitively inhibited GH mRNA hybridization by greater than 80%. Insulin (0.7 nM) inhibited new GH mRNA synthesis, and maximal inhibition (30% of control) was observed with 7 nM insulin after 4 h treatment. The inhibitory effects of insulin on new GH mRNA synthesis were abolished by both insulin-receptor-antiserum and by guinea-pig anti-insulin serum. The results show that insulin exerts a rapid suppression of new GH mRNA synthesis. These data provide evidence for the direct transcriptional regulation of the GH gene by insulin.

Insulinlike growth factor I regulation of growth hormone gene transcription in primary rat pituitary cells.

We have previously shown that insulinlike growth factor I (IGF-I) inhibits growth hormone (GH) secretion and messenger RNA (mRNA) levels in pituitary cells. The effects of IGF-I on new GH mRNA synthesis rates in primary monolayer rat pituitary cells were therefore examined by nuclear runoff transcription assays. IGF-I (1.3 nM) treatment for 1 h inhibited GH gene transcription to 60% of controls. IGF-I (3.25 nM) maximally suppressed GH gene transcription to 30% of control values after 4 h. After 24 h treatment, GH transcription was suppressed to 48% of controls by 3.25 nM IGF-I. IGF-I (3.25 nM) also inhibited the twofold growth hormone-releasing hormone (GHRH) (10 nM)-stimulated GH gene transcription by 30% after 4 h. Transcription of the prolactin (PRL) gene was not suppressed in these cells by IGF-I. Relatively high doses of insulin (200 nM) also suppressed GH gene transcription, but epidermal growth factor and fibroblast growth factor did not change GH mRNA synthesis. The results show that IGF-I exerts a rapid and selective suppression of basal and GHRH-stimulated GH gene transcription. These data indicate a role for IGF-I in negative feedback of GH gene expression and provide evidence for the direct transcriptional regulation of the GH gene by IGF-I in primary rat anterior pituitary cells.

3,5-Dimethyl-3'-isopropyl-l-thyronine therapy in diabetic pregnancy: stimulation of rabbit fetal lung phospholipids.

Diabetes mellitus in pregnancy is associated with neonatal respiratory distress syndrome due to impaired synthesis of fetal lung surfactant. Pharmacologic agents that promote fetal lung maturity are diabetogenic and have limited use in the management of diabetic pregnancy for prevention of respiratory distress syndrome. Maternal administration of a thyroid analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) results in significant enhancement of fetal lung phospholipid synthesis and accelerated lung maturity. We therefore studied the effects of DIMIT (0.5 mg/kg per d, s.c.) administration to pregnant alloxan-diabetic rabbits on days 25 and 26 of gestation. DIMIT treatment of diabetic maternal rabbits (DD) was associated with reduction of maternal blood glucose (115 +/- 13 vs. 275 +/- 72 mg/dl, P less than 0.05) and fetal glucose (64 +/- 6 vs. 274 +/- 47 mg/dl, P less than 0.001) compared with saline-injected diabetic (D) mothers. Reduction of fetal insulin levels was also associated with maternal DIMIT therapy in diabetic rabbits (56 +/- 5 (D) vs. 24 +/- 4 microunits/ml, P less than 0.001). Maternal diabetes resulted in significant reduction of fetal lung weight (370 +/- 20 vs. 520 +/- 30 mg, P less than 0.005) and lung protein content (6.5 +/- 0.7 vs. 8.7 +/- 0.7 mg/gm, P less than 0.005), which were restored to normal in offspring of DIMIT-treated diabetic rabbits. Maternal DIMIT administration caused significant reduction in fetal lung glycogen content in control (62 +/- 5.8 vs. 25 +/- 5.9 micrograms/mg protein, P less than 0.001) and diabetic (56 +/- 7 vs. 34 +/- 5 micrograms/mg protein, P less than 0.02) offspring. Whereas maternal diabetes was associated with reduction of all major phospholipid species in fetal lung-comprising surfactant, these were restored with DIMIT therapy. The results demonstrate that short-term maternal administration of DIMIT in pregnant diabetic rabbits not only promotes fetal lung phospholipid synthesis, but also appears to ameliorate maternal hyperglycemia. Thus, DIMIT is of potential benefit in the management of diabetic pregnancy.

An insulin-induced DNA-binding protein for the human growth hormone gene.

The control of gene transcription is usually mediated by transacting transcriptional factors that bind to upstream regulatory elements. As insulin regulates transcription of the growth hormone (GH) gene, we tested nuclear extracts from unstimulated and insulin-stimulated Chinese hamster ovarian (CHO) cells for binding to four human GH (hGH) gene promoter oligonucleotide fragments identified as target-binding sequences by DNAse I footprinting. Using a mobility shift assay, an insulin-induced DNA-binding protein was identified. This protein binds to two upstream overlapping oligonucleotide sequences. Binding activity is present at low levels in unstimulated CHO cells and is stimulated by insulin treatment with a time course suggesting that protein synthesis is required. Incubation of the cells with cycloheximide and puromycin confirmed that de novo protein synthesis is necessary for the increased binding activity. Competition with excess unlabeled specific competitor oligonucleotides prevented binding, while unrelated similar-sized oligonucleotides failed to compete for binding, indicating that the observed DNA-protein complex formation is specific. A protein of approximately 70-80 kD was detected by gradient gel electrophoresis. In conclusion, insulin-mediated DNA-protein binding has been identified on the upstream hGH promoter, suggesting a trans-active role for insulin in mediating polypeptide hormone gene expression.

Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing.

Neuroendocrine ACTH secretion responds to peripheral inflammatory and stress signals. We previously demonstrated that the proinflammatory cytokine, leukemia inhibitory factor (LIF), affects the hypothalamo-pituitary-adrenal axis (HPA) by stimulating in vitro and in vivo pituitary proopiomelanocortin (POMC) gene expression and ACTH secretion and by potentiating the action of hypothalamic corticotropin releasing hormone (CRH). Whereas pathways shown thus far to regulate POMC expression exclusively involve cAMP or calcium, we here describe a direct and indirect STAT3-dependent regulation of POMC transcription by LIF. Using progressive 5'-deletions of POMC promoter, we identified a LIF-responsive -407/-301 region that contains two juxtaposed sequences within -399/-379 related to a STAT3 DNA-binding motif. Each sequence within -399/-379 separately corresponds to a low-affinity and direct binding site for STAT3, but, in combination, these sequences bind STAT3 cooperatively and with high affinity. Moreover, LIF-activated STAT3 indirectly mediates LIF corticotroph action by inducing and potentiating CRH-induced c-fos and JunB expression and binding to the POMC AP-1 element. We therefore conclude that both a direct and indirect route mediate LIF-induced STAT3 activation of POMC transcription. Demonstration of STAT3-dependent regulation of the POMC gene represents a powerful mechanism for immuno-neuroendocrine interfacing and implies a direct stimulation of ACTH secretion by inflammatory and stress-derived STAT3-inducing cytokines.