The effect of hormonal secretion on survival in adrenocortical carcinoma: A multi-center study.

BACKGROUND: Current evidence suggests that cortisol secreting adrenocortical carcinoma has worse prognosis compared to non-secreting adrenocortical carcinoma. However, the effect of other secretory subtypes is unknown. METHODS: This multicenter study within the American-Australian-Asian Adrenal Alliance included adults with adrenocortical carcinoma (1997-2020). We compared overall survival and disease-free survival among cortisol secreting, mixed cortisol/androgen secreting, androgen secreting, and non-secreting adrenocortical carcinoma. RESULTS: Of the 807 patients (mean age 50), 719 included in the secretory subtype analysis: 24.5% were cortisol secreting, 13% androgen secreting, 28% mixed cortisol/androgen, 32.5% non-secreting, and 2% were mineralocorticoid secreting. Median overall survival and disease-free survival for the entire cohort were 60 and 9 months, respectively. Median overall survival was 36 months for cortisol, 30 for mixed, 60 for androgen secreting, and 115 for non-secreting adrenocortical carcinoma, P < .01. Median disease-free survival was 7 months for cortisol, 8 for mixed, 10 for androgen, and 12 for non-secreting adrenocortical carcinoma, P = .06. On multivariable analysis of age, sex, Ki67%, secretory subtype, stage, resection, and adjuvant therapy, predictors of worse overall survival were older age, higher Ki67%, stage IV, mixed secreting, R1, and no adjuvant therapy, P < .05. On subgroup analysis of R0 resection, predictors of worse overall survival included older age and higher Ki67%. Ki67% ≥40, stage III and cortisol secretion were associated with worse disease-free survival. CONCLUSION: Mixed cortisol/androgen secreting adrenocortical carcinoma was associated with worse overall survival, while cortisol or androgen secreting alone were not. Notably, among patients after R0 resection, secretory subtype did not affect overall survival. Cortisol secreting adrenocortical carcinoma demonstrated worse disease-free survival. Ki67% remained a strong predictor of worse overall survival and disease-free survival independent of stage.

Generation of isogenic and homozygous MEN1 mutant cell lines from patient-derived iPSCs using CRISPR/Cas9.

MEN1, an autosomal dominant disorder caused by mutations in the tumor suppressor gene MEN1, manifests with co-occurrence of multiple endocrine/neuroendocrine neoplasms. An iPSC line derived from an index patient carrying the mutation c.1273C>T (p.Arg465*) was edited using a single multiplex CRISPR/Cas approach to create an isogenic control non-mutated line and a homozygous double mutant line. These cell lines will be useful for elucidating subcellular MEN1 pathophysiology and for screening to identify potential MEN1 therapeutic targets.

Exploring the role of the tumor microenvironment in refractory pituitary tumor pathogenesis.

PURPOSE: Treatment-refractory pituitary tumors demonstrate characteristics resembling those of highly aggressive tumors, in which the local tumor microenvironment (TME) plays a dominant role in promoting aggressiveness and refractoriness. However, role of the TME in pituitary tumors is not well studied. METHODS: Literature on the TME and development of refractory pituitary tumors was reviewed RESULTS: TME harbors tumorigenic immune cells, cancer-associated fibroblasts (CAF), extracellular matrix, and other factors that have been shown to affect behavior of tumor tissue. For example, tumor-associated macrophages and tumor-infiltrating lymphocytes correlate with aggressive and invasive tumor behavior in nonfunctioning and growth hormone-secreting (GH) pituitary tumors, while CAF release of TGFß, FGF2, cytokines, chemokines, and growth factors may promote treatment resistance, tumor fibrosis, and inflammation in prolactinomas and GH-secreting tumors. In turn, Wnt pathway activation can further promote cell growth in dopamine-resistant prolactinomas. Finally, proteins secreted by extracellular matrix are associated with increased angiogenesis in invasive tumors. CONCLUSION: It is likely that multiple mechanisms, including TME, contribute to the development of aggressive refractory pituitary tumors. Given the increased morbidity and mortality associated with pituitary tumor refractoriness, more research on the role of TME is warranted.

Fluid Restriction Reduces Delayed Hyponatremia and Hospital Readmissions After Transsphenoidal Surgery.

CONTEXT: Postoperative hyponatremia leads to prolonged hospital length of stay and readmission within 30 days. OBJECTIVE: To assess 3 strategies for reducing rates of postoperative hyponatremia and analyze risk factors for hyponatremia. DESIGN: Two retrospective analyses and 1 prospective study. SETTING: Tertiary referral hospital. PATIENTS: Patients undergoing transsphenoidal surgery for pituitary adenomas and other sellar and parasellar pathologies. INTERVENTION(S): Phase 1: no intervention. Phase 2: postoperative day (POD) 7 sodium testing and patient education. Phase 3: fluid restriction to 1 L/day on discharge in addition to phase 2 interventions. MAIN OUTCOME MEASURES: Rates of early and delayed hyponatremia and readmissions. Secondary outcomes were risk factors for hyponatremia and readmission costs. RESULTS: In phase 1, 296 patients underwent transsphenoidal surgery. Twenty percent developed early and 28% delayed hyponatremia. Thirty-eight percent underwent POD 7 sodium testing. Readmission rates were 15% overall and 4.3% for hyponatremia. In phase 2 (n = 316), 22% developed early and 25% delayed hyponatremia. Eighty-nine percent complied with POD 7 sodium testing. Readmissions were unchanged although severity of hyponatremia was reduced by 60%. In phase 3 (n = 110), delayed hyponatremia was reduced 2-fold [12.7%, relative risk (RR) = 0.52] and readmissions 3-fold [4.6%, RR = 0.30 (0.12-0.73)]; readmissions for hyponatremia were markedly reduced. Hyponatremia readmission increased costs by 30%. CONCLUSIONS: Restricting fluid to 1 L/day on discharge decreases rates of delayed hyponatremia and readmissions by 50%. Standardized patient education and POD 7 sodium testing decreases severity of hyponatremia but does not impact readmission rates. These protocols should be considered standard practice for patients undergoing transsphenoidal surgery.

Treatment of Cushing Disease With Pituitary-Targeting Seliciclib.

CONTEXT: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. OBJECTIVE: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). METHODS: Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥ 50% reduction in UFC from baseline to study end. RESULTS: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥ 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients who achieved ≥ 48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation. CONCLUSION: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.

Adrenal Cushing's Syndrome Treated With Preoperative Osilodrostat and Adrenalectomy.

Background/Objective: Reducing severity of Cushing's syndrome caused by an adrenal adenoma (adrenal Cushing's syndrome [ACS]) might decrease morbidity and mortality risk in adrenalectomy. We used off-label osilodrostat, approved in the United States for pituitary Cushing's disease, to reduce cortisol levels and disease severity before adrenalectomy 3 weeks later. Case Report: A 48-year-old woman with a 6-year history of obesity, depression, and anxiety and 3-year history of diabetes and hypertension was admitted with vomiting and lumbar back pain. Facial plethora and hirsutism, posterior cervicothoracic fat pad, and truncal obesity coupled with morning serum cortisol >13 µg/dL after 1 mg oral dexamethasone suppression, urinary free cortisol 1324 µg/24hr (4.0-50.0 µg/24 h), and adrenocorticotropin <5 pg/mL (6-50 pg/mL) confirmed ACS. Computed tomography with contrast revealed a 3.4-cm right adrenal mass. Osilodrostat 2 mg twice daily initiated at discharge was increased to 4 mg twice daily on day 6. Three days later, she reported nausea, vomiting, and fatigue. Despite 7.2 µg/dL morning cortisol, adrenal insufficiency was suspected; osilodrostat was reduced to 2 mg twice daily and maintenance oral hydrocortisone 20 mg daily was added with symptom resolution. Prior to adrenalectomy, morning cortisol was 5.1 µg/dL, fasting glucose was 122 mg/dL, and she self-discontinued diabetes medications. Hypertension remained unchanged (149/100 vs 151/94 mmHg). Adrenalectomy revealed a 3.4-cm focally pigmented adrenocortical adenoma. Discussion: Three-week treatment of overt ACS with off-label osilodrostat reduced cortisol and glucose levels before curative adrenalectomy. Abrupt cortisol reduction led to suspected adrenal insufficiency managed with maintenance hydrocortisone. Conclusion: Osilodrostat might help reduce ACS severity before adrenalectomy. Adrenal insufficiency is a risk but can be safely managed with hydrocortisone.

Operative approach and case volume are associated with negative resection margins for adrenocortical carcinoma.

BACKGROUND: Surgical resection with negative margins is the treatment of choice for adrenocortical carcinoma (ACC). This study was undertaken to determine factors associated with negative resection margins. METHODS: National Cancer Database was queried from 2010 to 2016 to identify patients with AJCC/ENSAT Stage I-III ACC who underwent adrenalectomy. Patient, tumor, facility, and operative characteristics were compared by margin status (positive-PM or negative-NM) and operative approach (open-OA, laparoscopic-LA, or robotic-RA). Multivariable logistic regression was used to identify factors associated with PM. RESULTS: Eight hundred and eighty-one patients were identified, of which 18.4% had PM and 81.6% had NM. Patients with advanced pathologic T stage and pathologic N1 stage were more likely to have PM (vs. NM) (T3, 49.7% vs. 24.8%, p < 0.01; T4, 26.2% vs. 10.0%, p < 0.01; N1, 6.7% vs. 3.5%, p < 0.01). Patients undergoing OA (vs. LA and RA) were more likely to have advanced clinical T stage (T4, 16.6% vs. 5.7% vs. 7.8%, p < 0.01) and larger tumors (> 6 cm, 84.6% vs. 64.1% vs. 62.3%, p < 0.01). High-volume centers (≥ 5 cases) were more likely to utilize OA. Patients undergoing LA (vs. RA) were more likely to require conversion to open (20.3% vs. 7.8%, p = 0.011). On multivariable analysis, factors associated with higher odds of PM included T3 disease (OR 7.02, 95% CI 2.66-18.55), T4 disease (OR 10.22, 95% CI 3.66-28.53), and LA (OR 1.99, 95% CI 1.28-3.09). High-volume centers were associated with lower odds of PM (OR 0.67, 95% CI 0.45-0.98). There was no significant difference in margin status between OA and RA (OR 1.44, 95% CI 0.71-2.90). CONCLUSION: Centers with higher ACC case volumes have lower odds of PM and utilize OA more often. LA is associated with higher odds of PM, whereas RA is not. These factors should be considered when planning the operative approach for ACC.

Adrenocortical Carcinoma: The Value of Lymphadenectomy.

BACKGROUND: Adrenocortical carcinoma (ACC) staging does not account for the number of positive nodes. The prognostic value of quantitative metastatic nodal burden is unknown. METHODS: The National Cancer Database was retrospectively queried from 2004-2016 to identify patients with Stage I-III ACC undergoing adrenalectomy. Patients who underwent lymphadenectomy (LAD) were further studied. Demographics, TNM staging, tumor characteristics, and surgical approach were analyzed. RESULTS: 386 LADs were identified. The median number of nodes examined was 2 (IQR 2-6), with no difference by surgical approach '[laparoscopic, 3 (1-3); robotic, 1.5 (1-4.5); open, 2 (1-7), p = 0.493]. In LADs with cN0 disease, positive nodes were seen in 17.5% of patients; an average of 6 (1-12) nodes were examined in patients who upstaged to pN1 disease compared with an average of 2 (1-6) nodes in those who remained pN0. Median survival was incrementally worse for patients with more positive nodes (62.8 vs. 21.9 vs. 13.7 vs. 11.3 vs. 10.7 months for 0, 1, 2, 3, and ≥ 4 positive nodes, respectively, p < 0.01). On multivariate analysis, significant prognostic factors for poor survival included older age, ≥ 2 comorbidities, pT3, and pT4. The strongest prognostic factor for poor survival was the number of positive nodes (1 node, hazards ratio [HR] 2.3, 95% confidence interval [CI] 1.5-3.6; 2 nodes, HR 1.3, 95% CI 0.6-3.0; 3 nodes, HR 3.0, 95% CI 1.1-8.0; ≥ 4 nodes, HR 4.0, 95% CI 2.5-6.2). Lymphadenectomy was associated with improved survival (HR 0.82, 95% CI 0.67-0.99). CONCLUSIONS: Higher quantitative metastatic nodal burden is a robust prognostic factor for worse survival in ACC.

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.

Pheochromocytoma Crisis Presenting With ARDS Successfully Treated With ECMO-Assisted Adrenalectomy.

OBJECTIVE: Pheochromocytoma (PCC) crisis caused by acute catecholamine release from an adrenal PCC or extra-adrenal paraganglioma can be difficult to diagnose and may require an unconventional management strategy to achieve good outcomes. We describe a case of PCC crisis presenting with acute respiratory distress syndrome (ARDS) that resolved with stabilization on veno-venous (VV) extracorporeal membrane oxygenation (ECMO) during adrenalectomy. CASE DESCRIPTION: A 30-year-old man with a history of severe alcohol use disorder and a prior hospital admission for alcohol withdrawal syndrome presented with sudden-onset hemoptysis, altered mental status, and severe dyspnea that rapidly deteriorated to ARDS requiring ECMO support. He demonstrated hemodynamic collapse after cannulation for VV-ECMO and stabilized after conversion to veno-arterial-ECMO, but ARDS persisted and he developed acute renal failure. Computed tomography without contrast done as part of work-up for a presumed infection revealed a 6.9 × 6.4 cm right adrenal mass suspicious for pheochromocytoma. Plasma and random urine metanephrine levels were markedly elevated. ARDS persisted despite α- and ß-adrenoreceptor blockade, and he underwent laparoscopic right adrenalectomy with VV-ECMO support. Pathology confirmed PCC with intermediate risk for malignancy. Postoperatively, he was weaned off respiratory and renal support within 10 days, showed rapid clinical improvement, and was discharged 1 month later. CONCLUSION: This case highlights diagnostic and management challenges associated with patients with PCC crisis presenting with ARDS. A multidisciplinary team approach is critical to identifying appropriate treatment strategies.

Factors Associated with Non-Operative Management of Resectable Adrenocortical Carcinoma.

INTRODUCTION: Surgery is the initial treatment of choice for patients with resectable adrenocortical carcinoma (ACC). We sought to determine factors associated with non-operative management of resectable ACC. METHODS: 2004-2016 National Cancer Database (NCDB) was queried to identify patients with AJCC/ENSAT Stage I-III ACC. Patients who underwent surgery (S) were compared to those who did not undergo surgery (NS). Multivariate logistic regression was used to identify factors associated with NS. Kaplan-Meier estimates used to assess survival. RESULTS: Two thousand-seventy patients with Stage I-III ACC were identified, of which 17.5% were NS. 85.9% of NS patients were not offered surgery; 69.9% of NS patients did not receive chemotherapy or radiation therapy. NS were older and less likely to receive care at an Academic center or high volume center (≥5 cases during the study period). NS patients were more likely to have advanced T stage and N1 disease. On multivariate regression, factors associated with lower odds of surgery include older age (OR 1.03, 95% CI 1.02-1.06), T4 disease (OR 3.34, 95% CI 1.05-10.68), and treatment at a community center (OR 2.92, 95% CI 1.58-5.40). Overall median survival was significantly poorer for NS patients (50.4 versus 78.4 months, P < 0.01). CONCLUSION: Patients with locally advanced ACC are less likely to undergo an operation, while those treated at centers with more operative experience or Academic facilities are more likely to undergo an operation. As the surgery-first approach is the current standard of care for resectable ACC, these patients may be best served at high volume Academic facilities.

Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease.

CONTEXT: Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. OBJECTIVE: We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. METHODS: We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. RESULTS: We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. CONCLUSION: We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas.

Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole-exome sequencing of 159 prospectively resected pituitary adenomas showed that somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNAs correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed that both cAMP and Fanconi anemia DNA damage repair pathways were affected by SCNAs in growth hormone-secreting (GH-secreting) somatotroph adenomas. As somatotroph differentiation and GH secretion are dependent on cAMP activation and we previously showed DNA damage, aneuploidy, and senescence in somatotroph adenomas, we studied links between cAMP signaling and DNA damage. Stimulation of cAMP in C57BL/6 mouse primary pituitary cultures using forskolin or a long-acting GH-releasing hormone (GHRH) analog increased GH production and DNA damage measured by H2AX phosphorylation and a comet assay. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. We conclude that cAMP, which induces somatotroph proliferation and GH secretion, may concomitantly induce DNA damage, potentially linking hormone hypersecretion to SCNA and genome instability. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment.

Excess growth hormone suppresses DNA damage repair in epithelial cells.

Growth hormone (GH) decreases with age, and GH therapy has been advocated by some to sustain lean muscle mass and vigor in aging patients and advocated by athletes to enhance performance. Environmental insults and aging lead to DNA damage, which - if unrepaired - results in chromosomal instability and tumorigenesis. We show that GH suppresses epithelial DNA damage repair and blocks ataxia telangiectasia mutated (ATM) kinase autophosphorylation with decreased activity. Decreased phosphorylation of ATM target proteins p53, checkpoint kinase 2 (Chk2), and histone 2A variant led to decreased DNA repair by nonhomologous end-joining. In vivo, prolonged high GH levels resulted in a 60% increase in unrepaired colon epithelial DNA damage. GH suppression of ATM was mediated by induced tripartite motif containing protein 29 (TRIM29) and attenuated tat interacting protein 60 kDa (Tip60). By contrast, DNA repair was increased in human nontumorous colon cells (hNCC) where GH receptor (GHR) was stably suppressed and in colon tissue derived from GHR-/- mice. hNCC treated with etoposide and GH showed enhanced transformation, as evidenced by increased growth in soft agar. In mice bearing human colon GH-secreting xenografts, metastatic lesions were increased. The results elucidate a mechanism underlying GH-activated epithelial cell transformation and highlight an adverse risk for inappropriate adult GH treatment.

Somatostatin receptor subtype 5 modifies hypothalamic-pituitary-adrenal axis stress function.

Pituitary corticotroph somatostatin receptor subtype 5 (SSTR5) signals to inhibit adrenocorticotrophin (ACTH) secretion. As ACTH deficiency results in attenuated adrenal cortisol production and an impaired stress response, we sought to clarify the role of SSTR5 in modifying the hypothalamic/pituitary/adrenal (HPA) axis. We generated Tg HP5 mice overexpressing SSTR5 in pituitary corticotrophs that produce the ACTH precursor proopiomelanocortin (POMC). Basal ACTH and corticosterone were similar in HP5 and WT mice, while HP5 mice showed attenuated ACTH and corticosterone responses to corticotrophin releasing hormone (CRH). HP5 mice exhibited attenuated corticosterone responses upon a restraint stress test and inflammatory stress following LPS injection, as well as increased anxiety-like and depressive-like behavior on open field and forced swim tests. Pituitary corticotroph CRH receptor subtype 1 (CRHR1) mRNA expression and ACTH responses to CRH were also attenuated in HP5 mice. In AtT20 cells stably overexpressing SSTR5, CRHR1 expression and cAMP response to CRH were reduced, whereas both were increased after SSTR5 KO. In elucidating mechanisms for these observations, we show that SSTR5-induced miR-449c suppresses both CRHR1 expression and function. We conclude that corticotroph SSTR5 attenuates HPA axis responses via CRHR1 downregulation, suggesting a role for SSTR5 in the pathogenesis of secondary adrenal insufficiency.

Silent corticotroph adenomas.

PURPOSE: Silent corticotroph adenomas (SCAs) present clinically as non-functioning adenomas (NFAs) but are immunopositive for adrenocorticotrophic hormone (ACTH) without biochemical and clinical manifestation of hypercortisolism. Pathologic examination of resected NFAs that demonstrate positive ACTH and/or TPIT expression confirms its corticotroph lineage. SCAs comprise up to 20% of NFAs and exhibit a higher rate of recurrence. Studies of molecular mechanisms have generated multiple hypotheses on SCA tumorigenesis, pathophysiology, and growth that as yet remain to be proven. An improved understanding of their pathologic and clinical characteristics is needed. METHODS: A literature review was performed using PubMed to identify research reports and clinical case series on SCAs. RESULTS: Up to date findings regarding epidemiology, mechanisms of pathogenesis, differentiation, progression, and growth, as well as clinical presentation, postoperative course, and treatment options for patients with SCAs are presented. Pooled results demonstrate that 25-40% of cases show cavernous sinus invasion, preoperative hypopituitarism, new-onset hypopituitarism, and recurrence. CONCLUSION: This article reviews the incidence, molecular pathology, and clinical behavior of these unique non-functioning pituitary corticotroph adenomas, and highlights the need for rigorous monitoring for recurrences and hypopituitarism in patients with SCAs.

Consensus-driven in-hospital cortisol assessment after ACTH-secreting pituitary adenoma resection.

PURPOSE: Remission from Cushing disease (CD) after pituitary adenoma resection may be predicted by a postoperative reduction in serum cortisol level. A 2008 consensus statement recommends assessing morning cortisol levels during the first postoperative week, and replacing glucocorticoid (GC) if cortisol nadir of < 2 or < 5 µg/dL is achieved. We sought to evaluate adherence to consensus recommendations following adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma resection at our tertiary medical center, and assess time to cortisol nadir to better define the window for assessment and intervention. METHODS: We retrospectively analyzed data extracted from in-hospital electronic medical records for CD surgeries between January 1991 and September 2015. We compared cortisol levels and collection times, ACTH measurement, and postoperative and discharge GC treatment before and after consensus statement publication in July 2008. RESULTS: 107 surgeries were performed in 92 patients with CD. After 2008, more surgeries had at least one cortisol value assessed (67.9% before vs. 91.3% after, p = 0.033), with median initial cortisol measurement at 14 h post-surgery. However, ACTH measurement remained unchanged (42.9% vs. 43.5%; p > 0.99). Cortisol collection during GC treatment tended to increase (32.7% vs. 57.1%; p = 0.068). Of surgeries performed without prior GC treatment, 31.7 and 55.0% had a cortisol nadir of < 2 and < 5 µg/dL, respectively, within 72 h postoperative. CONCLUSIONS: Our physicians were more diligent in measuring in-hospital postoperative cortisol levels consistent with 2008 consensus recommendations. Better management of cortisol measurements and their timing is an opportunity for improvement.

Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside.

PURPOSE OF REVIEW: Treatment of aggressive pituitary tumours often yields suboptimal control of the tumour and confers significant morbidity. Lactotroph and corticotroph-derived tumours express ErbB receptors and ligands, and mutations in ubiquitin-specific protease 8 (USP8), which alters epidermal growth factor receptor (EGFR) degradation, have been implicated in Cushing disease pathogenesis. EGFR tyrosine kinase inhibitor (TKI) therapy has emerged as a potential new therapeutic approach for patients with aggressive prolactinomas and Cushing disease. RECENT FINDINGS: Using EGFR or human epidermal growth factor receptor 2-driven prolactin (PRL) promoters, transgenic mice develop large tumours that respond to TKI inhibition. In human corticotroph primary cultures, treatment with the pan-ErbB TKI canertinib as well as the EGFR TKI gefitinib suppresses proopiomelanocortin mRNA. USP8 mutations, detected in up to two-thirds of Cushing disease, may underlie the increase in EGFR signalling in these tumours. Human prolactinomas have differential ErbB receptor expression associated with aggressive behaviour and data from an ongoing clinical trial suggest that resistant prolactinomas may respond to the EGFR TKI lapatinib. SUMMARY: Preclinical and clinical models substantiate the role of the EGFR pathway in corticotroph and lactotroph adenomas. Although further study is needed, results to date suggest that targeting the ErbB pathway may be an effective therapeutic approach for patients with aggressive pituitary tumours.