Publications by authors named "Anat Ben-Shlomo"

59 Publications

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

AACE Clin Case Rep 2021 Sep-Oct;7(5):310-314. Epub 2021 Mar 26.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

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 β-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.
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http://dx.doi.org/10.1016/j.aace.2021.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426613PMC
March 2021

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

J Surg Res 2021 Jul 14;267:651-659. Epub 2021 Jul 14.

Division of Minimally Invasive Surgery and Endocrine Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jss.2021.06.013DOI Listing
July 2021

Insulin-like Growth Factor 1 and Prolactin Levels in Chimpanzees (Pan troglodytes) Across the Lifespan.

J Endocr Soc 2021 Aug 7;5(8):bvab063. Epub 2021 Apr 7.

Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

As human and chimpanzee genomes show high homology for and , we analyzed the sera of 367 healthy chimpanzees obtained during routine physical examinations in a single colony and measured chimpanzee insulin-like growth factor (IGF)-1 and prolactin (PRL) levels across the lifespan using standard human immunoassays. Assuming chimpanzee IGF-1 levels peak during puberty as in humans, we randomly defined puberty as the age at which most IGF-1 levels were equal to or above the 90 percentile for each sex (males, ages ≥7.00 but <9.20 years; females, ≥5.00 but <8.00 years). IGF-1 levels steadily increased at a similar rate in juvenile males and females and peaked in puberty, strongly correlating with age, then slowly decreased faster in adult males than in adult females. As a group, males had a higher mean IGF-1 level than did females, but comparison by age category showed similar mean IGF-1 levels in males and females. PRL levels increased with age in females more than in males and levels were twice as high in females than in males. One pubertal male reported to have short stature had lower IGF-1 and weight compared with other males in the age group, confirming suspected growth hormone deficiency; a second male of normal height but low IGF-1 may have had delayed puberty. Overall, results show that differences in IGF-1 levels over the lifespan in this cohort of chimpanzees largely mimic those seen in humans, while patterns of PRL changes are less similar.
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http://dx.doi.org/10.1210/jendso/bvab063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256382PMC
August 2021

Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease.

J Clin Endocrinol Metab 2021 Aug;106(9):e3346-e3363

Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.

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.
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http://dx.doi.org/10.1210/clinem/dgab387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372657PMC
August 2021

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

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The 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.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Multidisciplinary management of acromegaly: A consensus.

Rev Endocr Metab Disord 2020 12 10;21(4):667-678. Epub 2020 Sep 10.

Medical Research Unit in Endcrine Diseases, Hospital de Especialidades, Centro Médico Nacional, Siglo XXI, IMSS, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.

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.
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http://dx.doi.org/10.1007/s11154-020-09588-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942783PMC
December 2020

DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas.

J Clin Invest 2020 11;130(11):5738-5755

Pituitary Center, Department of Medicine.

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.
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http://dx.doi.org/10.1172/JCI138540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598090PMC
November 2020

Excess growth hormone suppresses DNA damage repair in epithelial cells.

JCI Insight 2019 Feb 7;4(3). Epub 2019 Feb 7.

Pituitary Center.

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.
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http://dx.doi.org/10.1172/jci.insight.125762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413789PMC
February 2019

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

JCI Insight 2018 10 4;3(19). Epub 2018 Oct 4.

Pituitary Center, Department of Medicine, and.

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.
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http://dx.doi.org/10.1172/jci.insight.122932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237446PMC
October 2018

Silent corticotroph adenomas.

Pituitary 2018 Apr;21(2):183-193

Pituitary Center, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA.

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.
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http://dx.doi.org/10.1007/s11102-018-0864-8DOI Listing
April 2018

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

Pituitary 2018 Feb;21(1):41-49

Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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.
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http://dx.doi.org/10.1007/s11102-017-0845-3DOI Listing
February 2018

Vitamin D Hormone: Where Do We Stand, Where Are We Heading?

Endocrinol Metab Clin North Am 2017 12 29;46(4):xiii-xv. Epub 2017 Sep 29.

Northwest Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2017.09.002DOI Listing
December 2017

Latest Innovations in Biochemical and Imaging Diagnostics in Endocrinology.

Endocrinol Metab Clin North Am 2017 09;46(3):xiii-xv

Northwest Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, 3138 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2017.06.002DOI Listing
September 2017

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

Curr Opin Endocrinol Diabetes Obes 2017 Aug;24(4):301-305

Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.

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.
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http://dx.doi.org/10.1097/MED.0000000000000344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815830PMC
August 2017

Updates in the Genetics of Endocrine Disorders.

Endocrinol Metab Clin North Am 2017 06;46(2):xiii-xiv

Northwest Pituitary Center, Departments of Medicine (Endocrinology) and Neurological Surgery, Oregon Health & Science University, 3303 Southwest Bond Avenue, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2017.03.002DOI Listing
June 2017

Foreword.

Endocrinol Metab Clin North Am 2017 03;46(1):xiii-xv

Northwest Pituitary Center, Division of Endocrinology, Diabetes, & Clinical Nutrition, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, 3138 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2016.12.002DOI Listing
March 2017

Somatostatin and dopamine receptor regulation of pituitary somatotroph adenomas.

Pituitary 2017 Feb;20(1):93-99

Pituitary Center, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Davis Building, Room 3021, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.

Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands octreotide, lanreotide, and pasireotide, and to a lesser extent, dopamine and the dopamine analogs bromocriptine and cabergoline, suppress growth hormone (GH) secretion from a GH-secreting pituitary somatotroph adenoma. Somatostatin and dopamine receptors are G-protein coupled that inhibit adenylate cyclase activity and cAMP production and reduce intracellular calcium concentration and calcium flux oscillations. Although their main action on somatotroph cells is acute inhibition of GH secretion, they also may inhibit GH production and possibly somatotroph proliferation. These receptors have been reported to create complexes that exhibit functions distinct from that of receptor monomers. Somatostatin suppression of GH is mediated mainly by somatostatin receptor subtype 2 and to a lesser extent by SST5. Human somatostatin receptor subtype 5 has also been shown to harbor mutations associated with GH levels, somatotroph tumor behavior, and somatostatin receptor ligand (SRL) responsiveness. Reviewing current knowledge of somatostatin and dopamine receptor expression and signaling in normal and tumoral somatotroph cells offers insights into mechanisms underlying SRL and dopamine agonist effectiveness in patients with acromegaly.
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http://dx.doi.org/10.1007/s11102-016-0778-2DOI Listing
February 2017

Diabetes Mellitus.

Endocrinol Metab Clin North Am 2016 12 28;45(4):xiii-xiv. Epub 2016 Sep 28.

Northwest Pituitary Center, Division of Endocrinology, Diabetes, & Clinical Nutrition, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, 3138 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2016.09.002DOI Listing
December 2016

Upregulation of Key Molecules for Targeted Imaging and Therapy.

J Nucl Med 2016 Nov 30;57(11):1805-1810. Epub 2016 Jun 30.

Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland

Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches.

Methods: We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo.

Results: We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr-targeted imaging and radiopeptide therapy.

Conclusion: We present an approach that uses epigenetic modifiers to improve sstr targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.
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http://dx.doi.org/10.2967/jnumed.115.165092DOI Listing
November 2016

Obesity.

Endocrinol Metab Clin North Am 2016 09;45(3):xiii-xv

Northwest Pituitary Center, Division of Endocrinology, Diabetes, & Clinical Nutrition, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, 3138 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2016.06.015DOI Listing
September 2016

Enhanced cosyntropin stimulation test performance enabled by electronic medical record.

Pituitary 2016 Oct;19(5):503-6

Biostatistics Core, Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Purpose: To improve performance of the cosyntropin stimulation test (CST) used for diagnosis of adrenal-cortisol insufficiency by implementing an electronic medical record (EMR) system protocol.

Methods: We implemented a SmartForm protocol of the validated CST in our EMR system (CS-Link™, EPIC) system and compared medical staff test performance before and after protocol implementation.

Results: Correct performance of the CST improved significantly after EMR implementation. The number of correctly performed CSTs increased from 16.1 % before to 53.5 % after implementation (p < 0.0001) while those performed incorrectly and were uninterpretable decreased from 36.2 to 7.1 % (p < 0.0001). This performance improvement result in a calculated cost savings of $50,414 for every 100 tests performed.

Conclusions: The EMR system is useful for guiding medical staff to accurately perform the CST, reduce the number of wasted tests, and maximize staff time and resources.
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http://dx.doi.org/10.1007/s11102-016-0731-4DOI Listing
October 2016

Pediatric Endocrinology.

Endocrinol Metab Clin North Am 2016 06;45(2):xiii-xv

OHSU Northwest Pituitary Center, Division of Endocrinology, Diabetes, and Clinical Nutrition, Departments of Medicine and Neurological Surgery, Oregon Health and Science University, 3303 SW Bond Avenue, Code CH8N, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2016.04.002DOI Listing
June 2016

Growth hormone is permissive for neoplastic colon growth.

Proc Natl Acad Sci U S A 2016 Jun 25;113(23):E3250-9. Epub 2016 May 25.

Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048;

Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)(-/-) mice exhibited induced colon p53 levels, and cross-breeding them with Apc(min+/-) mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear β-catenin accumulation, and increased epithelial-mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the "field change" milieu permissive for neoplastic colon growth.
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http://dx.doi.org/10.1073/pnas.1600561113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988562PMC
June 2016

Cyclin E-Mediated Human Proopiomelanocortin Regulation as a Therapeutic Target for Cushing Disease.

J Clin Endocrinol Metab 2015 Jul 5;100(7):2557-64. Epub 2015 May 5.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.

Context: Cushing disease, due to pituitary corticotroph tumor ACTH hypersecretion, drives excess adrenal cortisol production with adverse morbidity and mortality. Loss of glucocorticoid negative feedback on the hypothalamic-pituitary-adrenal axis leads to autonomous transcription of the corticotroph precursor hormone proopiomelanocortin (POMC), consequent ACTH overproduction, and adrenal hypercortisolism. We previously reported that R-roscovitine (CYC202, seliciclib), a 2,6,9-trisubstituted purine analog, suppresses cyclin-dependent-kinase 2/cyclin E and inhibits ACTH in mice and zebrafish. We hypothesized that intrapituitary cyclin E signaling regulates corticotroph tumor POMC transcription independently of cell cycle progression. The aim was to investigate whether R-roscovitine inhibits human ACTH in corticotroph tumors by targeting the cyclin-dependent kinase 2/cyclin E signaling pathway.

Methods: Primary cell cultures of surgically resected human corticotroph tumors were treated with or without R-roscovitine, ACTH measured by RIA and quantitative PCR, and/or Western blot analysis performed to investigate ACTH and lineage-specific transcription factors. Cyclin E and E2F transcription factor 1 (E2F1) small interfering RNA (siRNA) transfection was performed in murine corticotroph tumor AtT20 cells to elucidate mechanisms for drug action. POMC gene promoter activity in response to R-roscovitine treatment was analyzed using luciferase reporter and chromatin immunoprecipitation assays.

Results: R-roscovitine inhibits human corticotroph tumor POMC and Tpit/Tbx19 transcription with decreased ACTH expression. Cyclin E and E2F1 exhibit reciprocal positive regulation in corticotroph tumors. R-roscovitine disrupts E2F1 binding to the POMC gene promoter and suppresses Tpit/Tbx19 and other lineage-specific POMC transcription cofactors via E2F1-dependent and -independent pathways.

Conclusion: R-roscovitine inhibits human pituitary corticotroph tumor ACTH by targeting the cyclin E/E2F1 pathway. Pituitary cyclin E/E2F1 signaling is a previously unappreciated molecular mechanism underlying neuroendocrine regulation of the hypothalamic-pituitary-adrenal axis, providing a subcellular therapeutic target for small molecule cyclin-dependent kinase 2 inhibitors of pituitary ACTH-dependent hypercortisolism, ie, Cushing disease.
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http://dx.doi.org/10.1210/jc.2015-1606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393529PMC
July 2015

Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration.

PLoS One 2015 13;10(4):e0123460. Epub 2015 Apr 13.

Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.

Background: Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury.

Methods: We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε.

Results: Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice.

Conclusions: Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but paradoxically also leads to the development of significant hypoxemia. These findings suggest that pulmonary neutrophilia is not linked to hypoxemia in ventilator-induced lung injury, and that nicotinamide exacerbates hypoxemia during VILI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395431PMC
January 2016

Updates and highlights in pituitary medicine.

Endocrinol Metab Clin North Am 2015 Mar;44(1):xxi-xxiii

Northwest Pituitary Center, Division of Endocrinology, Diabetes, & Clinical Nutrition Departments of Medicine and Neurological Surgery, Oregon Health & Science University, 3138 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2014.12.001DOI Listing
March 2015

Pharmacotherapy for acromegaly: future role for pasireotide?

Authors:
Anat Ben-Shlomo

Endocrinol Metab Clin North Am 2015 Mar 4;44(1):35-41. Epub 2014 Nov 4.

Pituitary Center, Endocrinology, Diabetes and Metabolism Division, Department of Medicine, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Davis 3066, Los Angeles, CA 90048, USA. Electronic address:

Somatostatin receptor ligands (octreotide and lanreotide) are currently first-line pharmacotherapy for patients with acromegaly in whom surgery fails to control the disease or cannot be considered. The efficacy of a new pan somatostatin receptor ligand, pasireotide, has been investigated as a potential treatment of acromegaly. Several clinical trials showed disease-remission with pasireotide in one-third of patients and some octreotide-resistant patients were responsive to pasireotide. Pasireotide can likely be used for patients with suboptimal response or resistance to treatment with the approved maximal doses of octreotide long-acting release (LAR) or lanreotide Autogel; however, the development or exacerbation of diabetes mellitus is of concern.
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http://dx.doi.org/10.1016/j.ecl.2014.10.004DOI Listing
March 2015

Somatostatin system: molecular mechanisms regulating anterior pituitary hormones.

J Mol Endocrinol 2014 Aug 29;53(1):R1-19. Epub 2014 Apr 29.

Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, Pituitary Center, Cedars Sinai Medical Center, Davis Building, Room 3066, 8700 Beverly Boulevard, Los Angeles, California 90048, USA

The somatostatin (SRIF) system, which includes the SRIF ligand and receptors, regulates anterior pituitary gland function, mainly inhibiting hormone secretion and to some extent pituitary tumor cell growth. SRIF-14 via its cognate G-protein-coupled receptors (subtypes 1-5) activates multiple cellular signaling pathways including adenylate cyclase/cAMP, MAPK, ion channel-dependent pathways, and others. In addition, recent data have suggested SRIF-independent constitutive SRIF receptor activity responsible for GH and ACTH inhibition in vitro. This review summarizes current knowledge on ligand-dependent and independent SRIF receptor molecular and functional effects on hormone-secreting cells in the anterior pituitary gland.
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http://dx.doi.org/10.1530/JME-14-0034DOI Listing
August 2014

Clinical factors associated with biochemical adrenal-cortisol insufficiency in hospitalized patients.

Am J Med 2014 Aug 13;127(8):754-762. Epub 2014 Mar 13.

Pituitary Center, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California 90048.

Background: Diagnosis of adrenal-cortisol insufficiency is often misleading in hospitalized patients, as clinical and biochemical features overlap with comorbidities. We analyzed clinical determinants associated with a biochemical diagnosis of adrenal-cortisol insufficiency in non-intensive care unit (ICU) hospitalized patients.

Methods: In a retrospective cohort study we reviewed 4668 inpatients with random morning cortisol levels ≤15 μg/dL hospitalized in our center between 2003 and 2010. Using serum cortisol threshold level of 18 μg/dL 30 or 60 minutes after Cortrosyn (250 μg; Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, Calif) injection to define biochemical adrenal-cortisol status, we characterized and compared insufficient (n = 108, serum cortisol ≤18 μg/dL) and sufficient (n = 394; serum cortisol >18 μg/dL) non-ICU hospitalized patients.

Results: Commonly reported clinical and routine biochemical adrenal-cortisol insufficiency features were similar between insufficient and sufficient inpatients. Biochemical adrenal-cortisol insufficiency was associated with increased frequency of liver disease, specifically hepatitis C (P = .01) and prior orthotopic liver transplantation (P <.001), human immunodeficiency virus (HIV; P = .005), and reported pre-existing male hypogonadism (P <.001), as compared with the biochemical adrenal-cortisol sufficiency group. Forty percent of insufficient inpatients were not treated with glucocorticoids after diagnosis. Multivariable logistic analysis demonstrated that inpatients with higher cortisol levels (P = .0001) and higher diastolic blood pressure (P = .05), and females (P = .009) were more likely not to be treated, while those with previous short-term glucocorticoid treatment (P = .002), other coexisting endocrine diseases (P = .005), or who received an in-hospital endocrinology consultation (P <.0001), were more likely to be replaced with glucocorticoids.

Conclusions: Commonly reported adrenal-cortisol insufficiency features do not reliably identify hospitalized patients biochemically confirmed to have this disorder. Comorbidities including hepatitis C, prior orthotopic liver transplantation, HIV, and reported pre-existing male hypogonadism may help identify hospitalized non-ICU patients for more rigorous adrenal insufficiency assessment.
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http://dx.doi.org/10.1016/j.amjmed.2014.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127354PMC
August 2014
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