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Dal J. Colonoscopy in acromegaly: when and why. Pituitary 2025; 28:55. [PMID: 40329062 DOI: 10.1007/s11102-025-01528-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Affiliation(s)
- Jakob Dal
- Department of Endocrinology, Aalborg University Hospital, Aalborg, 9000, Denmark.
- Steno Diabetes Center North Jutland, Aalborg, Denmark.
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Demarchis L, Chiloiro S, Giampietro A, De Marinis L, Bianchi A, Fleseriu M, Pontecorvi A. Cancer screening in patients with acromegaly: a plea for a personalized approach and international registries. Rev Endocr Metab Disord 2025:10.1007/s11154-025-09957-6. [PMID: 40088375 DOI: 10.1007/s11154-025-09957-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/25/2025] [Indexed: 03/17/2025]
Abstract
Acromegaly is a rare condition, and often diagnosis is delayed by several years, for most patients. Acromegaly is characterized by short and long-term respiratory, cardiovascular and metabolic comorbidities, with possible impact on mortality. In the last two decades, life expectancy has progressively increased in part due to a reduction in biochemically active disease, multidisciplinary treatment approaches and a reduction in complications, and the availability of new drugs. Of note, a leading cause of mortality, cardiovascular comorbidity, has been replaced by cancer(s). As such, neoplasms more frequently observed (colon, thyroid, breast, prostate, and stomach) in patients with acromegaly are receiving increased attention. Chronic exposure to increased growth hormone serum levels may contribute to an increase in the occurrence and progression of cancers. Various efforts have been made to determine the pathogenetic mechanisms involved. However, there are no clear medical-related societal agreement(s) in relation to screening methods or timing regarding neoplasm(s) diagnosis in patients with acromegaly. Additionally, independent and dependent risk factor data in patients with acromegaly is lacking. International/national registries could help lay the groundwork to better study the impact of cancer(s) in patients with acromegaly and subsequently lead to and validate the most appropriate diagnostic and therapeutic path forward.
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Affiliation(s)
- Luigi Demarchis
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Sabrina Chiloiro
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Antonella Giampietro
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura De Marinis
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Bianchi
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maria Fleseriu
- Pituitary Center, and Departments of Medicine, and Neurological Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Alfredo Pontecorvi
- Dipartimento Di Medicina Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento Di Medicina Interna, Endocrinologia E Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
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Danilowicz K, Sosa S. Acromegaly and Cancer: An Update. Arch Med Res 2023; 54:102914. [PMID: 38007382 DOI: 10.1016/j.arcmed.2023.102914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 10/03/2023] [Accepted: 11/07/2023] [Indexed: 11/27/2023]
Abstract
Acromegaly is a chronic and rare disease. The diagnosis usually takes several years. Multiple comorbidities are associated with acromegaly. Long-term exposure to growth factors may lead to complications such as the development of benign or malignant tumors. However, the association between acromegaly and cancer remains a matter of debate due to multiple limitations in epidemiological data. There is controversy between acromegaly and mortality, but evidence shows a significant improvement in mortality rates with disease control and careful management of comorbidities. Older age, increased growth hormone levels (GH) at last follow-up, higher insulin-like growth factor-1 (IGF-1) levels at diagnosis, malignancy and radiotherapy were proposed as independent predictors of mortality. In this review we summarize the current state of knowledge in this field. Incidence of different cancer types is described. Rigorous surveillance of endocrine diseases may contribute to increased tumor detection. Personalized screening should probably be recommended.
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Affiliation(s)
- Karina Danilowicz
- Division of Endocrinology, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina.
| | - Soledad Sosa
- Division of Endocrinology, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina
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Jovanović M, Kovačević S, Brkljačić J, Djordjevic A. Oxidative Stress Linking Obesity and Cancer: Is Obesity a 'Radical Trigger' to Cancer? Int J Mol Sci 2023; 24:ijms24098452. [PMID: 37176160 PMCID: PMC10179114 DOI: 10.3390/ijms24098452] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/24/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity is on the rise worldwide, and consequently, obesity-related non-communicable diseases are as well. Nutritional overload induces metabolic adaptations in an attempt to restore the disturbed balance, and the byproducts of the mechanisms at hand include an increased generation of reactive species. Obesity-related oxidative stress causes damage to vulnerable systems and ultimately contributes to neoplastic transformation. Dysfunctional obese adipose tissue releases cytokines and induces changes in the cell microenvironment, promoting cell survival and progression of the transformed cancer cells. Other than the increased risk of cancer development, obese cancer patients experience higher mortality rates and reduced therapy efficiency as well. The fact that obesity is considered the second leading preventable cause of cancer prioritizes the research on the mechanisms connecting obesity to cancerogenesis and finding the solutions to break the link. Oxidative stress is integral at different stages of cancer development and advancement in obese patients. Hypocaloric, balanced nutrition, and structured physical activity are some tools for relieving this burden. However, the sensitivity of simultaneously treating cancer and obesity poses a challenge. Further research on the obesity-cancer liaison would offer new perspectives on prevention programs and treatment development.
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Affiliation(s)
- Mirna Jovanović
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Sanja Kovačević
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Jelena Brkljačić
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Ana Djordjevic
- Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
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Abstract
Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment.
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Affiliation(s)
- Joseph C Sedlak
- The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
- Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, Massachusetts, USA
| | - Ömer H Yilmaz
- The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
- Massachusetts General Hospital, Department of Pathology, Boston, Massachusetts, USA
| | - Jatin Roper
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA;
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
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Palui R, Sridharan K, Kamalanathan S, Sahoo J, Naik D. Growth hormone and gastrointestinal malignancy: An intriguing link. World J Gastrointest Pathophysiol 2023; 14:1-11. [PMID: 36743656 PMCID: PMC9896462 DOI: 10.4291/wjgp.v14.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/25/2022] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Growth hormone (GH) excess is associated with several systemic complications, one of which is the increased risk of neoplastic processes particularly of the gastrointestinal (GI) tract. Among the GI neoplasms, the most reported association is with benign and malignant neoplasms of the colon. In the majority of published literature, an increased incidence of GI neoplasms, both colonic adenomas as well as colorectal carcinoma is reported. However, the studies on colon cancer-specific mortality rate are conflicting with recent studies reporting similar cancer-specific mortality rates in comparison to controls. Many studies have reported an association of colorectal neoplasms with GH levels. Pathogenic mechanisms put forward to explain this association of GH excess and GI neoplasms primarily involve the increased GH-insulin-like growth factor 1 (IGF-1) signaling. Both GH and IGF-1 have proliferative, anti-apoptotic, and angiogenic effects on the systemic tissues leading to cellular proliferation. Other contributing factors to the increased risk of GI neoplasms include slow intestinal transit with a redundant large bowel, altered bile acids, deranged local immune response, shared genetic susceptibility factors and hyperinsulinemia. In view of the increased risk association, most guidelines for the care of acromegaly patients recommend an initial screening colonoscopy. Recommendations for further follow-up colonoscopy differ but broadly, the guidelines agree that it depends on the findings at first colonoscopy and state of remission of GH excess. Regarding the concern about the risk of colorectal cancers in patients receiving recombinant GH therapy, most cohort studies do not show an increased risk.
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Affiliation(s)
- Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Kalyani Sridharan
- Department of Endocrinology, All India Institute of Medical Science, Rishikesh 249203, Uttarakhand, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Sulu C, Bektas AB, Guzel SS, Tay K, Sahin S, Durcan E, Ozkaya HM, Kadioglu P. Effect of metformin on thyroid cancer risk in patients with acromegaly: A preliminary observational study. Growth Horm IGF Res 2022; 66:101484. [PMID: 35870256 DOI: 10.1016/j.ghir.2022.101484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 05/01/2022] [Accepted: 06/26/2022] [Indexed: 11/04/2022]
Abstract
PURPOSE To evaluate the role of metformin on thyroid cancer risk in patients with acromegaly. METHODS Medical charts of 534 patients with acromegaly that were followed-up between 1983 and 2019 were reviewed. Patients with follow-up duration at least 6 months were included. Cohort entry was defined as first visit date. The date of each case's thyroid cancer diagnosis was defined as index date. Patients were followed until the index date, death, or last visit date, whichever came first. Nested case-control study design was selected to evaluate the association between metformin and the thyroid cancer risk in patients with acromegaly. RESULTS 291 patients with acromegaly were included into final analysis. The mean age at acromegaly diagnosis was 42.3 ± 1.3 years. The median follow-up duration was 76 [34-132] months. Among 291 patients, 13 patients (4.5%) had thyroid cancer. Thirty-one percent (n = 92) of the patients used metformin for 6 months or longer. One standard deviation (SD) increase in average growth hormone increased the odds of having thyroid cancer by 1.164 folds (p = 0.017). One SD increase of the average insulin-like growth factor 1 to upper limit of normal ratio increased the odds of having thyroid cancer by 1.201 folds (p = 0.004). If a patient used metformin for at least 6 months, the odds to have thyroid cancer was decreased, multiplied by 0.62 with a 95% confidence interval of [0.47, 0.83] (p = 0.0013). The risk of thyroid cancer decreased with increasing duration of metformin use. CONCLUSION Metformin may decrease the thyroid cancer risk in patients with acromegaly.
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Affiliation(s)
- Cem Sulu
- Division of Endocrinology, Metabolism, and Diabetes-Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
| | - Ayyuce Begum Bektas
- Graduate School of Sciences and Engineering, Koç University, Istanbul 34450, Turkey
| | - Suleyman Sami Guzel
- Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
| | - Kubilay Tay
- Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
| | - Serdar Sahin
- Division of Endocrinology, Metabolism, and Diabetes-Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
| | - Emre Durcan
- Division of Endocrinology, Metabolism, and Diabetes-Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
| | - Hande Mefkure Ozkaya
- Division of Endocrinology, Metabolism, and Diabetes-Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
| | - Pinar Kadioglu
- Division of Endocrinology, Metabolism, and Diabetes-Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey.
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Zhang X, Li Y, Zhong Y, Wang Z. Variables Associated With Body Image Concerns in Acromegaly Patients: A Cross-Sectional Study. Front Psychol 2022; 13:733864. [PMID: 35756208 PMCID: PMC9226896 DOI: 10.3389/fpsyg.2022.733864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 05/09/2022] [Indexed: 11/17/2022] Open
Abstract
Objective Acromegaly is often characterized by altered physical (including facial) appearance. However, there is little medical or psychological research on body image concerns in patients with acromegaly. The aim of this study was to identify factors influencing the body image distress in patients with acromegaly and to explore the possible effects of stigma on body image concerns. Design Cross-sectional study. Methods A total of 68 individuals with acromegaly were enrolled in the study. A total of 70 persons with nonfunctional pituitary adenomas were randomly recruited as a healthy control group. Using structured questionnaires, we explored perceived body image using the Body Image Concern Inventory. We also used the Hamilton Anxiety Scale, the Stigma Scale for Chronic Illness, the Brief Illness Perception Questionnaire, and the 36-Item Short-Form Health Survey to evaluate health-associated variables and to analyze factors that affect body image concerns in patients with acromegaly. Results Of the 68 participants, 31 were men and 37 women (mean age ± standard deviation: 46.36 ± 12.47 years). The mean body image concern score was 47.49 ± 13.81 for patients with acromegaly and 21.10 ± 7.44 for patients with nonfunctional pituitary adenoma. The difference between the two groups was statistically significant. A multiple stepwise regression analysis showed that the related factors for body image distress were gender (P = 0.001), age at diagnosis (P = 0.01), and internalized stigma (P < 0.001, Adj. R2 = 0.756). Conclusions People with acromegaly have substantial body image concerns, and these concerns are increased by the stigma associated with this disease; such concerns lead to poor quality of life (QoL). Physicians need to find better ways to control patients' hormone levels, and nurses should provide more information on how to improve body image or find ways to reduce patients' body image distress.
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Affiliation(s)
- Xiaomei Zhang
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yanqing Li
- Medical College, Nantong University, Nantong, China
| | - Yueping Zhong
- Department of Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Ziheng Wang
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China.,Medical College, Nantong University, Nantong, China
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Sulu C, Bektaş AB, Şahin S, Durcan E, Kara Z, Demir AN, Özkaya HM, Tanrıöver N, Çomunoğlu N, Kızılkılıç O, Gazioğlu N, Gönen M, Kadıoğlu P. Machine learning as a clinical decision support tool for patients with acromegaly. Pituitary 2022; 25:486-495. [PMID: 35435565 DOI: 10.1007/s11102-022-01216-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/10/2022] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To develop machine learning (ML) models that predict postoperative remission, remission at last visit, and resistance to somatostatin receptor ligands (SRL) in patients with acromegaly and to determine the clinical features associated with the prognosis. METHODS We studied outcomes using the area under the receiver operating characteristics (AUROC) values, which were reported as the performance metric. To determine the importance of each feature and easy interpretation, Shapley Additive explanations (SHAP) values, which help explain the outputs of ML models, are used. RESULTS One-hundred fifty-two patients with acromegaly were included in the final analysis. The mean AUROC values resulting from 100 independent replications were 0.728 for postoperative 3 months remission status classification, 0.879 for remission at last visit classification, and 0.753 for SRL resistance status classification. Extreme gradient boosting model demonstrated that preoperative growth hormone (GH) level, age at operation, and preoperative tumor size were the most important predictors for early remission; resistance to SRL and preoperative tumor size represented the most important predictors of remission at last visit, and postoperative 3-month insulin-like growth factor 1 (IGF1) and GH levels (random and nadir) together with the sparsely granulated somatotroph adenoma subtype served as the most important predictors of SRL resistance. CONCLUSIONS ML models may serve as valuable tools in the prediction of remission and SRL resistance.
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Affiliation(s)
- Cem Sulu
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Cerrahpasa Medical School, Istanbul University-Cerrahpaşa, Kocamustafapaşa Street No:53, 34098 Fatih, Istanbul, Turkey
| | - Ayyüce Begüm Bektaş
- Graduate School of Sciences and Engineering, Koç University, Istanbul, Turkey
| | - Serdar Şahin
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Cerrahpasa Medical School, Istanbul University-Cerrahpaşa, Kocamustafapaşa Street No:53, 34098 Fatih, Istanbul, Turkey
| | - Emre Durcan
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Cerrahpasa Medical School, Istanbul University-Cerrahpaşa, Kocamustafapaşa Street No:53, 34098 Fatih, Istanbul, Turkey
| | - Zehra Kara
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Cerrahpasa Medical School, Istanbul University-Cerrahpaşa, Kocamustafapaşa Street No:53, 34098 Fatih, Istanbul, Turkey
| | - Ahmet Numan Demir
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Cerrahpasa Medical School, Istanbul University-Cerrahpaşa, Kocamustafapaşa Street No:53, 34098 Fatih, Istanbul, Turkey
| | - Hande Mefkure Özkaya
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Cerrahpasa Medical School, Istanbul University-Cerrahpaşa, Kocamustafapaşa Street No:53, 34098 Fatih, Istanbul, Turkey
- Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Necmettin Tanrıöver
- Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey
- Department of Neurosurgery, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Nil Çomunoğlu
- Department of Medical Pathology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Osman Kızılkılıç
- Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey
- Department of Radiology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Nurperi Gazioğlu
- Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey
- Department of Neurosurgery, Istinye University, Istanbul, Turkey
| | - Mehmet Gönen
- Department of Industrial Engineering, College of Engineering, Koç University, Istanbul, Turkey
- School of Medicine, Koç University, Istanbul, Turkey
| | - Pınar Kadıoğlu
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Cerrahpasa Medical School, Istanbul University-Cerrahpaşa, Kocamustafapaşa Street No:53, 34098 Fatih, Istanbul, Turkey.
- Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey.
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Prevalence and outcome of comorbidities associated with acromegaly. Acta Neurochir (Wien) 2021; 163:3171-3180. [PMID: 33856552 DOI: 10.1007/s00701-021-04846-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/08/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Acromegaly is associated with various comorbidities, such as arterial hypertension (aHT), type 2 diabetes mellitus (DM2), obstructive sleep apnoea syndrome (OSAS), carpal tunnel syndrome (CTS) and polyposis coli. For therapeutic decisions, it is essential to know if, and to what extent, these associated morbidities are reversible or preventable. The aim of this study is to assess the prevalence and course of aHT, obesity, OSAS, CTS, DM2 and polyposis coli in acromegalic patients. METHODS The following criteria for inclusion in this database study were used: treatment for acromegaly at the authors' institutions; full endocrinological and radiological work- and follow-up; screening for aHT, DM2, CTS, OSAS, obesity and polyposis coli. All patients were followed-up for > 3 months, and treatments were indicated with the intent of biochemical remission (normal IGF-1 and random growth hormone level). RESULTS Sixty-three patients were included. Twelve (19%), 45 (71%) and 6 (10%) patients harboured micro-, macro- and giant adenomas, respectively. Nineteen tumours (30%) invaded the cavernous sinus. Mean tumour volume was 5.4 cm3. Mean follow-up time was 42 months. Sixty-one (97%) patients had transsphenoidal surgery; two patients only had drug therapy. Surgery led to remission in 31 (51%) patients. Intracavernous growth and larger tumour volume were negative predictors for cure. Drug therapy lead to remission in 22 (73%) patients within a mean follow-up of 54 months. The pretherapeutic prevalence of associated morbidities was as follows: aHT, 56%; DM2, 25%; OSAS, 29%; CTS, 29%; polyposis coli, 5%. There were neither age nor gender preferences for the respective prevalences. Surgery leads to remission of aHT and DM2 in 6% and 25%, respectively. Additional drug therapy resulted in remission of aHT, DM2 and CTS in 17%, 14% and 14%, respectively. Other associated morbidities persisted regardless of therapeutic efforts. Even if criteria for remission were not met, no new comorbidities of acromegaly developed during follow-up. CONCLUSIONS Treating acromegaly may relieve threatening associated morbidities such as aHT and DM2; nevertheless, only few comorbidities are reversible, which highlights the importance of treating acromegaly as early as possible.
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Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22126434. [PMID: 34208601 PMCID: PMC8234711 DOI: 10.3390/ijms22126434] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.
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Pituitary Adenomas: From Diagnosis to Therapeutics. Biomedicines 2021; 9:biomedicines9050494. [PMID: 33946142 PMCID: PMC8146984 DOI: 10.3390/biomedicines9050494] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
Pituitary adenomas are tumors that arise in the anterior pituitary gland. They are the third most common cause of central nervous system (CNS) tumors among adults. Most adenomas are benign and exert their effect via excess hormone secretion or mass effect. Clinical presentation of pituitary adenoma varies based on their size and hormone secreted. Here, we review some of the most common types of pituitary adenomas, their clinical presentation, and current diagnostic and therapeutic strategies.
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Battistone MF, Miragaya K, Rogozinski A, Agüero M, Alfieri A, Ballarino MC, Boero L, Danilowicz K, Diez S, Donoso M, Fainstein-Day P, Furioso A, Garcia-Basavilbaso N, Glerean M, Katz D, Loto M, Mallea-Gil S, Martinez M, Sabate MI, Servidio M, Slavinsky P, Stalldecker G, Sosa S, Szuman G, Tkatch J, Caldo I, Lubieniecki D, Guitelman M. Increased risk of preneoplastic colonic lesions and colorectal carcinoma in acromegaly: multicenter case-control study. Pituitary 2021; 24:96-103. [PMID: 33057946 DOI: 10.1007/s11102-020-01090-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/28/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Current international guidelines recommend colonoscopy in patients with acromegaly at the time of diagnosis, even though the risk of developing colorectal neoplasm is still controversial. The main objective of this Argentine multicenter study was to analyze through screening colonoscopy the presence of advanced neoplastic lesions considered as precancerous, in patients with acromegaly compared to a control group. METHODS This is a case-control retrospective study. Full length colonoscopy of 70 acromegalic patients and 128 control subjects were studied. Polyps were classified into non pre-cancerous lesions and advance neoplastic lesions which included advanced adenomas (preneoplastic) and colorectal carcinomas. RESULTS Thirty three out of 70 acromegalic patients and 32 out of 128 subjects controls presented polyps in the colonoscopy [47.1% vs 25%, p = 0.002, OR 2.68]. Non precancerous polyps were found in 11 (15.7%) and 23 (17.9%) (p = 0.690), while advanced neoplastic lesions were found in 22 (31.4%) and 9 (7.0%) (p = 0,0001 - OR: 6.06) patients and controls respectively. Advanced adenomas and colorectal carcinomas were found in 18 (27.3%) and 9 (7.0%) (p = 0,0006-OR: 4,57), and 4 (5.7%) and 0 (0.0%) p = 0.0063) of patients and controls respectively. The presence of insulin resistance was the only statistically significant associated factor among acromegalic patients with and without colonic polyps. CONCLUSIONS Our findings show an increased risk of preneoplastic colonic lesions and colorectal carcinoma in patients with chronic and sustained GH excess compared to a control group. This supports the recommendation to perform screening colonoscopy at diagnosis of acromegaly.
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Affiliation(s)
| | - Karina Miragaya
- Servicio de Endocrinología, Sanatorio Güemes, Buenos Aires, Argentina
| | - Amelia Rogozinski
- División Endocrinología, Hospital Ramos Mejía, Buenos Aires, Argentina
| | - Monica Agüero
- Grupo de trabajo Endocrinología, Hospital Tornú, Buenos Aires, Argentina
| | - Analia Alfieri
- Servicio de Endocrinología, Hospital Nacional Profesor A. Posadas, El Palomar, Buenos Aires, Argentina
| | | | - Laura Boero
- División Endocrinología, Hospital de Clínicas José de San Martin UBA, Buenos Aires, Argentina
| | - Karina Danilowicz
- División Endocrinología, Hospital de Clínicas José de San Martin UBA, Buenos Aires, Argentina
| | - Sabrina Diez
- Servicio de Endocrinología, Hospital General de Agudos Dr. Ignacio Pirovano,, Buenos Aires, Argentina
| | - Marina Donoso
- Servicio de Endocrinología, Hospital Nacional Profesor A. Posadas, El Palomar, Buenos Aires, Argentina
| | | | - Alejandra Furioso
- División Endocrinología, Hospital Ramos Mejía, Buenos Aires, Argentina
| | | | - Mariela Glerean
- Servicio de Endocrinología, Hospital Italiano, Buenos Aires, Argentina
| | - Debora Katz
- Sección Neuroendocrinología, FLENI, Buenos Aires, Argentina
| | - Monica Loto
- Servicio de Endocrinología, Hospital Británico, Buenos Aires, Argentina
| | - Susana Mallea-Gil
- Servicio de Endocrinología, Hospital Militar Central, Buenos Aires, Argentina
| | - Marcela Martinez
- Servicio de Endocrinología, Hospital C. Milstein, Buenos Aires, Argentina
| | - Maria Isabel Sabate
- Servicio de Endocrinología, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina
| | - Marisa Servidio
- Unidad de Endocrinología, Hospital Teodoro Alvarez, Buenos Aires, Argentina
| | | | - Graciela Stalldecker
- Servicio de Endocrinología, Hospital General de Agudos Dr. Ignacio Pirovano,, Buenos Aires, Argentina
| | - Soledad Sosa
- División Endocrinología, Hospital de Clínicas José de San Martin UBA, Buenos Aires, Argentina
| | - Grabriela Szuman
- Servicio de Endocrinología, Sanatorio Municipal Dr. J. Mendez, Buenos Aires, Argentina
| | - Julieta Tkatch
- División Endocrinología, Hospital Carlos G. Durand, Buenos Aires, Argentina
| | - Ignacio Caldo
- Unidad de Gastroenterología, Hospital Carlos G. Durand, Buenos Aires, Argentina
| | - Daniela Lubieniecki
- Unidad de Gastroenterología, Hospital Carlos G. Durand, Buenos Aires, Argentina
| | - Mirtha Guitelman
- División Endocrinología, Hospital Carlos G. Durand, Buenos Aires, Argentina
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Larsson SC, Carter P, Vithayathil M, Kar S, Mason AM, Burgess S. Insulin-like growth factor-1 and site-specific cancers: A Mendelian randomization study. Cancer Med 2020; 9:6836-6842. [PMID: 32717139 PMCID: PMC7520358 DOI: 10.1002/cam4.3345] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 01/02/2023] Open
Abstract
Insulin-like growth factor-1 (IGF-1) is involved in several processes relevant to carcinogenesis. We used 416 single-nucleotide polymorphisms robustly associated with serum IGF-1 levels to assess the potential causal associations between this hormone and site-specific cancers through Mendelian randomization. Summary-level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large-scale consortia including individuals of European-descent. Furthermore, we estimated genetic associations with 14 site-specific cancers in European-descent individuals in UK Biobank. Supplementary analyses were conducted for six site-specific cancers using summary-level data from the BioBank Japan Project. Genetically predicted serum IGF-1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF-1 levels was 1.11 (95% confidence interval [CI] 1.01-1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09-1.36; P = 3.9 × 10-4 ) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01-1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97-1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95-1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92-1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02-1.13; P = 4.4 × 10-3 ) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF-1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF-1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF-1 levels with prostate, breast, and other cancers.
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Affiliation(s)
- Susanna C. Larsson
- Department of Surgical SciencesUppsala UniversityUppsalaSweden
- Unit of Cardiovascular and Nutritional EpidemiologyInstitute of Environmental MedicineKarolinska InstitutetStockholmSweden
| | - Paul Carter
- Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
| | | | - Siddhartha Kar
- MRC Integrative Epidemiology UnitBristol Medical SchoolUniversity of BristolBristolUK
| | - Amy M. Mason
- British Heart Foundation Cardiovascular Epidemiology UnitDepartment of Public Health and Primary CareUniversity of CambridgeCambridgeUK
- National Institute for Health Research Cambridge Biomedical Research CentreUniversity of Cambridge and Cambridge University HospitalsCambridgeUK
| | - Stephen Burgess
- Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
- MRC Biostatistics UnitUniversity of CambridgeCambridgeUK
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Rahmani J, Kord Varkaneh H, Clark C, Zand H, Bawadi H, Ryan PM, Fatahi S, Zhang Y. The influence of fasting and energy restricting diets on IGF-1 levels in humans: A systematic review and meta-analysis. Ageing Res Rev 2019; 53:100910. [PMID: 31116995 DOI: 10.1016/j.arr.2019.100910] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 05/07/2019] [Accepted: 05/16/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Fasting and energy restricting diets have a potential means of delaying or preventing the onset of a range of age-related metabolic and neoplastic diseases. Consistently at the centre of this effect appears to be a significant reduction in circulating IGF-1 levels. The aim of the current systematic review and meta-analysis was to determine the influence of fasting and energy restriction on IGF-1 levels in human subjects. METHODS A comprehensive systematic search was conducted from onset of the database to February 2019 in Embase, MEDLINE/PubMed, and SCOPUS to identify randomized clinical trials that investigating the impact of fasting or energy restriction circulating IGF-1 levels. Effect size was reported as weighted mean difference (WMD) and 95% confidence intervals (CI) using a random-effects models. Subgroup analysis was performed to identify the probable source of heterogeneity among trials. RESULTS Total pooling of fasting and energy restriction randomised controlled trials in WMD analysis revealed no significant effect on circulating IGF-1 levels (WMD: -16.41 ng/ml, 95% CI: -35.88, 3.07). Sub grouped analysis fasting regimens appeared to substantially reduce IGF-1 (WMD: -28.87 ng/ml, 95% CI: -43.69, -14.05, I2 = 00%), energy restricting regimens failed to do the same (WMD: -10.98 ng/ml, 95% CI: -33.08, 11.11, I2 = 90%). Within this final subgrouping, it was observed that only energy restriction regimens of 50% or greater of normal daily energy intake were capable of significantly reducing IGF-1 levels (WMD: -36.57 ng/ml, 95% CI: -59.19, -13.95, I2 = 00%). Finally, a meta regression were noted in which the percentage restriction of daily energy intake inversely correlated with plasma IGF-1 levels (p = 0.04). CONCLUSION This study uncovered that fasting significantly reduced levels of IGF-1, while energy restriction diets were successful only when intake was reduced by 50% or more.
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Gupta A, Xu Z, Kano H, Sisterson N, Su YH, Krsek M, Nabeel AM, El-Shehaby A, Karim KA, Martínez-Moreno N, Mathieu D, McShane BJ, Martínez-Álvarez R, Reda WA, Liscak R, Lee CC, Lunsford LD, Sheehan JP. Upfront Gamma Knife radiosurgery for Cushing's disease and acromegaly: a multicenter, international study. J Neurosurg 2019; 131:532-538. [PMID: 30117768 DOI: 10.3171/2018.3.jns18110] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 03/21/2018] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Gamma Knife radiosurgery (GKS) is typically used after failed resection in patients with Cushing's disease (CD) and acromegaly. Little is known about the upfront role of GKS for patients with CD and acromegaly. In this study, the authors examine the outcome of upfront GKS for patients with these functioning adenomas. METHODS An international group of 7 Gamma Knife centers sent pooled data from 46 patients (21 with CD and 25 with acromegaly) undergoing upfront GKS to the coordinating center of the study for analysis. Diagnosis was established on the basis of clinical, endocrine, and radiological studies. All patients were treated on a common radiosurgical platform and longitudinally followed for tumor control, endocrine remission, and hypopituitarism. Patients received a tumor median margin dose of 25 Gy (range 12-40.0 Gy) at a median isodose of 50%. RESULTS The median endocrine follow-up was 69.5 months (range 9-246 months). Endocrine remission was achieved in 51% of the entire cohort, with 28% remission in acromegaly and 81% remission for those with CD at the 5-year interval. Patients with CD achieved remission earlier as compared to those with acromegaly (p = 0.0005). In patients post-GKS, the pituitary adenoma remained stable (39%) or reduced (61%) in size. Hypopituitarism occurred in 9 patients (19.6%), and 1 (2.2%) developed third cranial nerve (CN III) palsy. Eight patients needed further intervention, including repeat GKS in 6 and transsphenoidal surgery in 2. CONCLUSIONS Upfront GKS resulted in good tumor control as well as a low rate of adverse radiation effects in the whole group. Patients with CD achieved a faster and far better remission rate after upfront GKS in comparison to patients with acromegaly. GKS can be considered as an upfront treatment in carefully selected patients with CD who are unwilling or unable to undergo resection, but it has a more limited role in acromegaly.
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Affiliation(s)
- Amitabh Gupta
- 1Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Zhiyuan Xu
- 1Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Hideyuki Kano
- 2Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Nathaniel Sisterson
- 2Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Yan-Hua Su
- 3Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
| | - Michal Krsek
- 4Second Department of Medicine, Third Faculty of Medicine of the Charles University, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Ahmed M Nabeel
- 5Gamma Knife Center Cairo-Nasser Institute, Neurosurgery Department, Benha University, Benha, Egypt
| | - Amr El-Shehaby
- 6Gamma Knife Center Cairo-Nasser Institute, Neurosurgery Department, Ain Shams University, Cairo, Egypt
| | - Khaled A Karim
- 7Gamma Knife Center Cairo-Nasser Institute, Clinical Oncology Department, Ain Shams University, Cairo, Egypt
| | - Nuria Martínez-Moreno
- 8Department of Functional Neurosurgery and Radiosurgery, Ruber International Hospital, Madrid, Spain
| | - David Mathieu
- 9Division of Neurosurgery, Université de Sherbrooke, Centre de Recherche du CHUS, Sherbrooke, Québec, Canada; and
| | - Brendan J McShane
- 10Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic
| | - Roberto Martínez-Álvarez
- 8Department of Functional Neurosurgery and Radiosurgery, Ruber International Hospital, Madrid, Spain
| | - Wael A Reda
- 6Gamma Knife Center Cairo-Nasser Institute, Neurosurgery Department, Ain Shams University, Cairo, Egypt
| | - Roman Liscak
- 10Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic
| | - Cheng-Chia Lee
- 3Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
| | - L Dade Lunsford
- 2Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Jason P Sheehan
- 1Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
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17
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Malcomson FC. Mechanisms underlying the effects of nutrition, adiposity and physical activity on colorectal cancer risk. NUTR BULL 2018. [DOI: 10.1111/nbu.12359] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Usman M, Volpi EV. DNA damage in obesity: Initiator, promoter and predictor of cancer. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 778:23-37. [PMID: 30454680 DOI: 10.1016/j.mrrev.2018.08.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 07/29/2018] [Accepted: 08/15/2018] [Indexed: 12/13/2022]
Abstract
Epidemiological evidence linking obesity with increased risk of cancer is steadily growing, although the causative aspects underpinning this association are only partially understood. Obesity leads to a physiological imbalance in the regulation of adipose tissue and its normal functioning, resulting in hyperglycaemia, dyslipidaemia and inflammation. These states promote the generation of oxidative stress, which is exacerbated in obesity by a decline in anti-oxidant defence systems. Oxidative stress can have a marked impact on DNA, producing mutagenic lesions that could prove carcinogenic. Here we review the current evidence for genomic instability, sustained DNA damage and accelerated genome ageing in obesity. We explore the notion of genotoxicity, ensuing from systemic oxidative stress, as a key oncogenic factor in obesity. Finally, we advocate for early, pre-malignant assessment of genome integrity and stability to inform surveillance strategies and interventions.
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Affiliation(s)
- Moonisah Usman
- Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK
| | - Emanuela V Volpi
- Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK.
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Woodmansee WW, Gordon MB, Molitch ME, Ioachimescu AG, Carver DW, Mirakhur B, Cox D, Salvatori R. Screening for comorbid conditions in patients enrolled in the SODA registry: a 2-year observational analysis. Endocrine 2018; 61:105-117. [PMID: 29767287 PMCID: PMC5997114 DOI: 10.1007/s12020-018-1615-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 04/21/2018] [Indexed: 11/28/2022]
Abstract
PURPOSE This 2-year analysis assessed frequency of comorbidities and comorbidity screening in the Somatuline® (lanreotide, LAN) Depot for Acromegaly (SODA) registry. METHODS Patient data collected included pituitary hormone deficiencies, sleep studies, echocardiograms, gallbladder sonographies, colonoscopies, and glycated hemoglobin (HbA1c) levels. Insulin-like growth factor-1 (IGF-1) and growth hormone levels in patients with (DM) and without (non-DM) diabetes mellitus were analyzed. RESULTS There were 241 patients enrolled. Pituitary hormone deficiencies were reported more frequently at enrollment in male (56.9%) vs female patients (32.0%; p < 0.001). TSH deficiency was the most common endocrine deficiency (69.8%), followed by gonadotropin deficiency (62.3%). Screening tests reported at enrollment: sleep studies in 29.9% (79.2% had sleep apnea), echocardiogram in 46.1% (46.8% abnormal), gallbladder sonography in 18.7% (17.8% had gallstones), and colonoscopy in 48.1% (35.3% had polyps). Follow-up studies were reported less frequently at 1 and 2 years. HbA1c data were reported in 30.8% and 41.2% after 1 and 2 years. HbA1c levels were similar at 1 and 2 years of LAN therapy among DM and non-DM patients with available data. Fewer DM vs non-DM patients achieved IGF-1 below upper limit of normal at Month 24 (58.3% vs 80.6%; p = 0.033). CONCLUSIONS Fewer than half of patients in SODA had screening results reported at enrollment for sleep apnea, cardiomyopathy, and colon polyps. Gallbladder imaging was reported in a minority of patients. Lower IGF-1 control rates were observed in DM vs non-DM patients at Month 24. These data suggest a need for better monitoring of comorbidities in US acromegaly patients.
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Affiliation(s)
- Whitney W Woodmansee
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA.
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital/Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.
| | - Murray B Gordon
- Allegheny Neuroendocrinology Center, Division of Endocrinology, Allegheny General Hospital, 420 E North Ave, Suite 205, Pittsburgh, PA, 15212, USA
| | - Mark E Molitch
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 645 N. Michigan Avenue, Suite 530, Chicago, IL, 60611, USA
| | - Adriana G Ioachimescu
- Department of Medicine, Division of Endocrinology, Metabolism and Lipids, and Department of Neurosurgery, Emory University School of Medicine, 1365 B Clifton Rd, NE, B6209, Atlanta, GA, 30322, USA
| | - Don W Carver
- Ipsen Biopharmaceuticals statistician consultant, 106 Allen Road, Basking Ridge, NJ, 07920, USA
| | - Beloo Mirakhur
- Medical Affairs, Ipsen Biopharmaceuticals, Inc., 106 Allen Road, Basking Ridge, NJ, 07920, USA
| | - David Cox
- Medical Affairs, Ipsen Biopharmaceuticals, Inc., 106 Allen Road, Basking Ridge, NJ, 07920, USA
| | - Roberto Salvatori
- Division of Endocrinology, Diabetes and Metabolism and Pituitary Center, Johns Hopkins University, 1830 East Monument Street #333, Baltimore, MD, 21287, USA
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Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. Front Endocrinol (Lausanne) 2018; 9:35. [PMID: 29487568 PMCID: PMC5816795 DOI: 10.3389/fendo.2018.00035] [Citation(s) in RCA: 167] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 01/29/2018] [Indexed: 01/02/2023] Open
Abstract
The growth hormone receptor (GHR), although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK-STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2. This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling.
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Affiliation(s)
- Farhad Dehkhoda
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Christine M. M. Lee
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Johan Medina
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Andrew J. Brooks
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
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Regulation of insulin-like growth factor receptors by Ubiquilin1. Biochem J 2017; 474:4105-4118. [PMID: 29054976 DOI: 10.1042/bcj20170620] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 10/03/2017] [Accepted: 10/19/2017] [Indexed: 12/18/2022]
Abstract
Insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase that mediates growth, proliferation and survival. Dysregulation of IGF pathway contributes to the initiation, progression and metastasis of cancer and is also involved in diseases of glucose metabolism, such as diabetes. We have identified Ubiquilin1 (UBQLN1) as a novel interaction partner of IGF1R, IGF2R and insulin receptor (INSR). UBQLN family of proteins have been studied primarily in the context of protein quality control and in the field of neurodegenerative disorders. Our laboratory discovered a link between UBQLN1 function and tumorigenesis, such that UBQLN1 is lost and underexpressed in 50% of human lung adenocarcinoma cases. We demonstrate here that UBQLN1 regulates the expression and activity of IGF1R. Following loss of UBQLN1 in lung adenocarcinoma cells, there is accelerated loss of IGF1R. Despite decreased levels of total receptors, the ratio of active : total receptors is higher in cells that lack UBQLN1. UBQLN1 also regulates INSR and IGF2R post-stimulation with ligand. We conclude that UBQLN1 is essential for normal regulation of IGF receptors. UBQLN-1-deficient cells demonstrate increased cell viability compared with control when serum-starved and stimulation of IGF pathway in these cells increased their migratory potential by 3-fold. As the IGF pathway is involved in processes of normal growth, development, metabolism and cancer progression, understanding its regulation by Ubiquilin1 can be of tremendous value to many disciplines.
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Abstract
BACKGROUND Acromegaly is a rare and underdiagnosed disorder caused, in more than 95% of cases, by a growth hormone (GH)-secreting pituitary adenoma. The GH hypersecretion leads to overproduction of insulin-like growth factor 1 (IGF-1) which results in a multisystem disease characterized by somatic overgrowth, multiple comorbidities, physical disfigurement, and increased mortality. OBJECTIVE This article aims to review the clinical features of acromegaly at diagnosis. DISCUSSION/CONCLUSION Acromegaly affects both males and females equally and the average age at diagnosis ranges from 40 to 50 years (up to 5% of cases < the age 20). Due to insidious onset and slow progression, acromegaly is often diagnosed five to more than ten years after its onset. The typical coarsening of facial features include furrowing of fronthead, pronounced brow protrusion, enlargement of the nose and the ears, thickening of the lips, skin wrinkles and nasolabial folds, as well as mandibular prognathism that leads to dental malocclusion and increased interdental spacing. Excessive growth of hands and feet (predominantly due to soft tissue swelling) is present in the vast majority of acromegalic patients. Gigantism accounts for up to 5% of cases and occurs when the excess of GH becomes manifest in the young, before the epiphyseal fusion. The disease also has rheumatologic, cardiovascular, respiratory, neoplastic, neurological, and metabolic manifestations which negatively impact its prognosis and patients quality of life. Less than 15% of acromegalic patients actively seek medical attention for change in appearance or enlargement of the extremities. The presentation of acromegaly is more often related to its systemic comorbidities or to local tumor effects.
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Affiliation(s)
- Lucio Vilar
- Division of Endocrinology, Hospital das Clínicas, Federal University of Pernambuco, Rua Heitor Maia Filho, 100/502, Madalena, Recife, CEP 50.720-525, Brazil.
| | | | - Ruy Lyra
- Division of Endocrinology, Hospital das Clínicas, Federal University of Pernambuco, Rua Heitor Maia Filho, 100/502, Madalena, Recife, CEP 50.720-525, Brazil
| | - Raissa Lyra
- Endocrine Research Center of Pernambuco, Recife, Brazil
| | - Luciana A Naves
- Division of Endocrinology, Brasilia University Hospital, Brasilia, Brazil
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Calderón MDR, Delgado E, García Campos F. Acromegaly and associated tumours: what should gastroenterologists know? GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 40:41-47. [PMID: 26966026 DOI: 10.1016/j.gastrohep.2015.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 11/21/2015] [Accepted: 12/04/2015] [Indexed: 06/05/2023]
Abstract
Acromegaly is a clinical syndrome caused by the excessive production of growth hormone. It is associated with high morbidity and significantly increased mortality, mainly due to cardiovascular and respiratory complications, and cancer. Mortality is reduced to that of the general population following successful treatment, in other words, when insulin-like growth factor (IGF-I) and growth hormone values return to normal levels. Not all tumours associated with this syndrome benefit from cost-effective early diagnosis programmes. An in-depth knowledge on the part of clinicians of the morbidity and mortality associated with acromegaly, allowing them in many cases to anticipate the expected clinical course of the disease, is the best therapeutic and follow-up strategy in these patients.
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The risks of overlooking the diagnosis of secreting pituitary adenomas. Orphanet J Rare Dis 2016; 11:135. [PMID: 27716353 PMCID: PMC5052978 DOI: 10.1186/s13023-016-0516-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 09/16/2016] [Indexed: 01/06/2023] Open
Abstract
Secreting pituitary adenomas that cause acromegaly and Cushing’s disease, as well as prolactinomas and thyrotroph adenomas, are uncommon, usually benign, slow-growing tumours. The rarity of these conditions means that their diagnosis is not familiar to most non-specialist physicians. Consequently, pituitary adenomas may be overlooked and remain untreated, and affected individuals may develop serious comorbidities that reduce their quality of life and life expectancy. Because many signs and symptoms of pituitary adenomas overlap with those of other, more common disorders, general practitioners and non-endocrinology specialists need to be aware of the “red flags” suggestive of these conditions. A long duration of active disease in patients with secreting pituitary adenomas is associated with an increased risk of comorbidities and reduced quality of life. Appropriate treatment can lead to disease remission, and, although some symptoms may persist in some patients, treatment usually reduces the incidence and severity of comorbidities and improves quality of life. Therefore, correct, early diagnosis and characterization of a pituitary adenoma is crucial for patients, to trigger timely, appropriate treatment and to optimize outcome. This article provides an overview of the epidemiology of hormonal syndromes associated with pituitary adenomas, discusses the difficulties of and considerations for their diagnosis, and reviews the comorbidities that may develop, but can be prevented, by accurate diagnosis and appropriate treatment. We hope this review will help general practitioners and non-endocrinology specialists to suspect secreting pituitary adenomas and refer patients to an endocrinologist for confirmation of the diagnosis and treatment.
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Abreu A, Tovar AP, Castellanos R, Valenzuela A, Giraldo CMG, Pinedo AC, Guerrero DP, Barrera CAB, Franco HI, Ribeiro-Oliveira A, Vilar L, Jallad RS, Duarte FG, Gadelha M, Boguszewski CL, Abucham J, Naves LA, Musolino NRC, de Faria MEJ, Rossato C, Bronstein MD. Challenges in the diagnosis and management of acromegaly: a focus on comorbidities. Pituitary 2016; 19:448-57. [PMID: 27279011 PMCID: PMC4935749 DOI: 10.1007/s11102-016-0725-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life. METHODS We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment. FINDINGS AND CONCLUSIONS Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.
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Affiliation(s)
- Alin Abreu
- Endocrinology Unit, Centro Médico Imbanaco Cali, Cali, Colombia
| | - Alejandro Pinzón Tovar
- Internal Medicine Department, Hospital of Neiva, University Surcolombiana, Neiva, Colombia
| | - Rafael Castellanos
- Internal Medicine Department, University Industrial of Santander, Bucaramanga, Colombia
| | - Alex Valenzuela
- Department of Internal Medicine, Endocrinology Fundación Cardio-Infantil, Instituto de Cardiología, Universidad del Rosario, Bogotá, Colombia
| | | | | | - Doly Pantoja Guerrero
- Endocrinology Unit, Hospital Universitario Departamental de Nariño, CENTRO de Endocrinologia CENDOO, Universidad Nacional de Colombia, Pasto, Colombia
| | - Carlos Alfonso Builes Barrera
- Endocrinology Department, Hospital Universitario San Vicente Fundación, Universidad de Antioquia, Medellín, Colombia
| | | | | | - Lucio Vilar
- Endocrinology and Chair, Division of Endocrinology, Hospital das Clínicas, Pernambuco Federal University Medical School, Recife, Brazil
| | - Raquel S Jallad
- Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clínicas, University of São Paulo Medical School, Av. Dr. Eneas de Carvalho, 255, 7ºandar, sala 7037, São Carlos, SP, CEP 05403-000, Brazil
| | - Felipe Gaia Duarte
- Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clínicas, University of São Paulo Medical School, Av. Dr. Eneas de Carvalho, 255, 7ºandar, sala 7037, São Carlos, SP, CEP 05403-000, Brazil
| | - Mônica Gadelha
- Endocrine Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cesar Luiz Boguszewski
- Department of Internal Medicine, Endocrine Division (SEMPR), Federal University of Paraná, Curitiba, Brazil
| | - Julio Abucham
- Neuroendocrine Unit, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Luciana A Naves
- Department of Endocrinology, Faculty of Medicine, University of Brasilia, Brasília, Brazil
| | - Nina Rosa C Musolino
- Neuroendocrine Unit, Division of Neurosurgery, Hospital das Clínicas, University of Sao Paulo School of Medicine, São Paulo, SP, Brazil
| | - Maria Estela Justamante de Faria
- Department of Odontology, Central Unit, Hospital das Clínicas, University of Sao Paulo School of Medicine, São Paulo, SP, Brazil
| | - Ciliana Rossato
- Department of Odontology, Central Unit, Hospital das Clínicas, University of Sao Paulo School of Medicine, São Paulo, SP, Brazil
| | - Marcello D Bronstein
- Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clínicas, University of São Paulo Medical School, Av. Dr. Eneas de Carvalho, 255, 7ºandar, sala 7037, São Carlos, SP, CEP 05403-000, Brazil.
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Yuen KCJ, Heaney AP, Popovic V. Considering GH replacement for GH-deficient adults with a previous history of cancer: a conundrum for the clinician. Endocrine 2016; 52:194-205. [PMID: 26732039 DOI: 10.1007/s12020-015-0840-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 12/18/2015] [Indexed: 11/30/2022]
Abstract
Previous studies have shown that GH and IGF-I may enhance tumorigenesis, metastasis, and cell proliferation in humans and animals. Evidence supporting this notion is derived from animal model studies, epidemiological studies, experience from patients with acromegaly, molecular therapeutic manipulation of GH and IGF-I actions, and individuals with GH receptor and congenital IGF-I deficiencies. Prior exposure to radiation therapy, aging, family history of cancer, and individual susceptibility may also contribute to increase this risk. Therefore, the use of GH replacement in patients with a history of cancer raises hypothetical safety concerns for patients, caregivers, and providers. Studies of GH therapy in GH-deficient adults with hypopituitarism and childhood cancer survivors have not convincingly demonstrated an increased cancer risk. Conversely, the risk of occurrence of a second neoplasm (SN) in childhood cancer survivors may be increased, with meningiomas being the most common tumor; however, this risk appears to decline over time. In light of these findings, if GH replacement is to be considered in patients with a previous history of cancer, we propose this consideration to be based on each individual circumstance and that such therapy should only be initiated at least 2 years after cancer remission is achieved with the understanding that in some patients (particularly those with childhood cancers), GH may potentially increase the risk of SNs. In addition, close surveillance should be undertaken working closely with the patient's oncologist. More long-term data are thus needed to determine if GH replacement in GH-deficient adults with a history of cancer is associated with the development of de novo tumors and tumor recurrence.
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Affiliation(s)
- Kevin C J Yuen
- Department of Neurosurgery and Neurology, Swedish Pituitary Center, Swedish Neuroscience Institute, Seattle, WA, 98122, USA.
| | - Anthony P Heaney
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90073, USA
| | - Vera Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disease, University Clinical Center Belgrade, Faculty of Medicine, University of Belgrade, Dr Subotica 13, 11000, Belgrade, Serbia
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Fontana L, Villareal DT, Das SK, Smith SR, Meydani SN, Pittas AG, Klein S, Bhapkar M, Rochon J, Ravussin E, Holloszy JO. Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: a randomized clinical trial. Aging Cell 2016; 15:22-7. [PMID: 26443692 PMCID: PMC4717266 DOI: 10.1111/acel.12400] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2015] [Indexed: 12/28/2022] Open
Abstract
Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anticancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and cortisol in humans. To test the sustained effects of CR on these key hormonal adaptations, we performed a multicenter randomized trial of a 2-year 25% CR intervention in 218 nonobese (body mass index between 22 and 27.8 kg m(-2) ) young and middle-aged (20-50 years age range) men and women. Average CR during the first 6 months was 19.5 ± 0.8% and 9.1 ± 0.7% over the next 18 months of the study. Weight loss averaged 7.6 ± 0.3 kg over the 2-years period of which 71% was fat mass loss (P < 0.0001). Average CR during the CR caused a significant 21% increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2 years (P < 0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum cortisol concentrations were slightly but significantly increased by CR at 1 year only (P = 0.003). Calorie restriction had no effect on serum concentrations of PDGF-AB and TGFβ-1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF-1 concentration or with a sustained and biological relevant increase in serum cortisol. However, long-term CR in humans significantly and persistently increases serum IGFBP-1 concentration.
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Affiliation(s)
- Luigi Fontana
- Department of Medicine Washington University School of Medicine St Louis MO USA
- Department of Clinical and Experimental Sciences University of Brescia Medical School Brescia Italy
- CEINGE Biotecnologie Avanzate Napoli Italy
| | - Dennis T. Villareal
- Department of Medicine Washington University School of Medicine St Louis MO USA
- Center for Translational Research on Inflammatory Diseases (CTRID) Baylor College of Medicine Michael E DeBakey VA Medical Center Houston TX USA
| | - Sai K. Das
- Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA
| | - Steven R. Smith
- Pennington Biomedical Research Center Baton Rouge LA USA
- Translational Research Institute for Metabolism and Diabetes Florida Hospital Sanford Burnham Medical Research Institute Orlando FL USA
| | - Simin N. Meydani
- Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA
| | - Anastassios G. Pittas
- Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA
| | - Samuel Klein
- Department of Medicine Washington University School of Medicine St Louis MO USA
| | | | - James Rochon
- Duke Clinical Research Institute Durham NC USA
- Rho Federal Systems Chapel Hill NC USA
| | - Eric Ravussin
- Pennington Biomedical Research Center Baton Rouge LA USA
| | - John O. Holloszy
- Department of Medicine Washington University School of Medicine St Louis MO USA
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Abstract
There is strong evidence that modifiable lifestyle factors such as obesity play a key role in colorectal carcinogenesis. Epidemiologic data have consistently reported a positive association between obesity and colorectal cancer. The relative risk associated with general obesity (as assessed by BMI) is higher in men than in women and for cancer of the colon than for cancer of the rectum. Abdominal obesity (as assessed by waist circumference (WC) or waist-to-hip ratio) is associated with an increased risk of colorectal cancer in both sexes, with stronger associations for cancer of the colon than for cancer of the rectum. Plausible biological mechanisms include insulin resistance, hyperinsulinemia, chronic inflammation, altered levels of growth factors, adipocytokines and steroid hormones. In addition to its effect on colorectal cancer incidence, obesity may play a role in colorectal cancer recurrence, treatment outcomes and survival. Understanding the effects of childhood and adolescent obesity and weight change over the life course in relation to future risk of colorectal cancer is incomplete but essential for targeted preventive recommendations. This chapter summarizes the current evidence on the relationship between obesity and colorectal cancer and colorectal adenoma, a common precursor lesion.
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Affiliation(s)
- Carmen Jochem
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Michael Leitzmann
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
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Abstract
Acromegaly (ACM) is a chronic, progressive disorder caused by the persistent hypersecretion of GH, in the vast majority of cases secreted by a pituitary adenoma. The consequent increase in IGF1 (a GH-induced liver protein) is responsible for most clinical features and for the systemic complications associated with increased mortality. The clinical diagnosis, based on symptoms related to GH excess or the presence of a pituitary mass, is often delayed many years because of the slow progression of the disease. Initial testing relies on measuring the serum IGF1 concentration. The oral glucose tolerance test with concomitant GH measurement is the gold-standard diagnostic test. The therapeutic options for ACM are surgery, medical treatment, and radiotherapy (RT). The outcome of surgery is very good for microadenomas (80-90% cure rate), but at least half of the macroadenomas (most frequently encountered in ACM patients) are not cured surgically. Somatostatin analogs are mainly indicated after surgical failure. Currently their routine use as primary therapy is not recommended. Dopamine agonists are useful in a minority of cases. Pegvisomant is indicated for patients refractory to surgery and other medical treatments. RT is employed sparingly, in cases of persistent disease activity despite other treatments, due to its long-term side effects. With complex, combined treatment, at least three-quarters of the cases are controlled according to current criteria. With proper control of the disease, the specific complications are partially improved and the mortality rate is close to that of the background population.
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Affiliation(s)
- Cristina Capatina
- Department of EndocrinologyCarol Davila University of Medicine and Pharmacy, Bucharest, RomaniaCI Parhon National Institute of EndocrinologyBucharest, RomaniaDepartment of EndocrinologyOxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK Department of EndocrinologyCarol Davila University of Medicine and Pharmacy, Bucharest, RomaniaCI Parhon National Institute of EndocrinologyBucharest, RomaniaDepartment of EndocrinologyOxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK
| | - John A H Wass
- Department of EndocrinologyCarol Davila University of Medicine and Pharmacy, Bucharest, RomaniaCI Parhon National Institute of EndocrinologyBucharest, RomaniaDepartment of EndocrinologyOxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK
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Wu XY, Wu ZF, Cao QH, Chen C, Chen ZW, Xu Z, Li WS, Liu FK, Yao XQ, Li G. Insulin-like growth factor receptor-1 overexpression is associated with poor response of rectal cancers to radiotherapy. World J Gastroenterol 2014; 20:16268-16274. [PMID: 25473182 PMCID: PMC4239516 DOI: 10.3748/wjg.v20.i43.16268] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 05/02/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the potential correlation between insulin-like growth factor receptor-1 (IGF-1R) expression and rectal cancer radiosensitivity.
METHODS: Eighty-seven rectal cancer patients (cTNM I-III) treated in our department between January 2011 and December 2012 were enrolled. All subjects were treated with preoperative radiotherapy and radical resection of rectal carcinoma. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were performed to detect IGF-1R expression in pre-treatment and postoperative colorectal cancer specimens. Radiosensitivity for rectal cancer specimens was evaluated by observing rectal carcinoma mass regression combined with fibrosis on HE staining, degree of necrosis and quantity of remaining tumor cells. The relative IGF-1R expression was evaluated for association with tumor radiosensitivity.
RESULTS: Immunohistochemistry showed diffuse IGF-1R staining on rectal cancer cells with various degrees of signal density. IGF-1R expression was significantly correlated with cTNM staging (P = 0.012) while no significant association was observed with age, sex, tumor size and degree of differentiation (P = 0.424, 0.969, 0.604, 0.642). According to the Rectal Cancer Regression Grades (RCRG), there were 31 cases of RCRG1 (radiation sensitive), 28 cases of RCRG2 and 28 cases of RCRG3 (radiation resistance) in 87 rectal cancer subjects. IGF-1R protein hyper-expression was significantly correlated with a poor response to radiotherapy (P < 0.001, r = 0.401). RT-PCR results from pre-radiation biopsy specimens also showed that IGF-1R mRNA negative group exhibited a higher radiation sensitivity (P < 0.001, r = 0.497). Compared with the pre-radiation biopsy specimens, the paired post-operative specimens showed a significantly increased IGF-1R protein and mRNA expression in the residual cancer cells (P < 0.001, respectively).
CONCLUSION: IGF-1R expression level may serve as a predictive biomarker for radiosensitivity of rectal cancer before preoperative radiotherapy.
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Abstract
It has been difficult to identify factors that affect the risk of cancer, but we know that people are at higher risk as they get older, or if they have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Early population-based and case-control studies suggested that higher serum levels of IGF1 could be associated with increased cancer risk. Since GH therapy increases IGF1 levels, concern has been raised regarding its potential role as a cancer initiation factor. Experimental evidence and some clinical studies showed that when GH/IGF1 secretion or action was inhibited, a decreased incidence and rate of progression of cancers occurred. However, human populations comprise a garden variety of genotypes that respond differently to the same kind of exposures. Human population studies frequently reveal only very small effects to these exposures. So, are GH and cancer guilty by association? After more than 20 years, leukemia, a major safety issue initially believed associated with GH treatment in children with GH deficiency (GHD), has not been confirmed but the risk of second malignancies in patients previously treated with irradiation has been detected or confirmed through the National Cooperative Growth Study. Overall, this large study confirmed the favorable overall safety profile of GH therapy in children with GHD, and also highlighted specific populations at potential risk. The risk of secondary malignancy following radiotherapy is surely related to radiotherapy more than GH therapy that may increase growth but is less likely to start the oncogenic process. In GH-deficient adults treated with GH, observational studies (KIMS, HypoCCS) have shown that when IGF1 levels were targeted within normal age-related reference ranges, the occurrence of malignancies was not higher than in the general population.
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Affiliation(s)
- Sandra Pekic
- Faculty of Medicine, University of Belgrade and Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Belgrade,
Dr Subotica 13, 11000 Belgrade, Serbia
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Acromegaly: a single centre's experience of stereotactic radiosurgery and radiotherapy for growth hormone secreting pituitary tumours with the linear accelerator. J Clin Neurosci 2013; 20:1506-13. [PMID: 23911106 DOI: 10.1016/j.jocn.2012.11.026] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 11/07/2012] [Accepted: 11/17/2012] [Indexed: 01/05/2023]
Abstract
Primary treatment for growth-hormone secreting pituitary adenomas usually involves surgery, with treatment options for recurrent and persistent disease including repeat surgery, medication and radiation therapy. The majority of previously published series for radiation therapy in acromegaly in the past 20 years have been based on Gamma-Knife (Elekta, Stockholm, Sweden) surgery. To our knowledge, we present the largest series of linear accelerator-based treatment for this disease, with a review of 121 patients treated at our institution; since 1990, 86 patients underwent stereotactic radiosurgery (SRS), 10 patients underwent fractionated stereotactic radiotherapy (FSRT), and for the purposes of comparison we also reviewed 25 patients who underwent conventional radiotherapy prior to 1990. Tumour volume control in all three groups was excellent and consistent with previously reported literature - only three of 86 (4%) patients undergoing SRS had a documented increase in tumour size, and none of the patients undergoing FSRT had a documented increase in size following a median follow-up of 5.5 and 5.1 years for SRS and FSRT, respectively. Target growth hormone levels of <2.5 ng/mL were met by 12 of 86 (14%) of the SRS group, and by two of 10 (20%) in the FSRT group. Target insulin-like growth factor-1 levels of age and sex matched controls were achieved in 16 of 86 patients (18.6%) post-SRS and five of 10 patients (50%) post-FSRT. New hormonal deficits requiring replacement therapy were identified in 17 of 86 (19.8%) patients post-SRS which is consistent with previously published radiosurgical series. Identified non-hormonal morbidity was low (<5%).
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Hamurcu Z, Cakir I, Donmez-Altuntas H, Bitgen N, Karaca Z, Elbuken G, Bayram F. Micronucleus evaluation in mitogen-stimulated lymphocytes of patients with acromegaly. Metabolism 2011; 60:1620-6. [PMID: 21550080 DOI: 10.1016/j.metabol.2011.03.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Revised: 03/17/2011] [Accepted: 03/18/2011] [Indexed: 01/11/2023]
Abstract
Acromegaly is a syndrome characterized by a sustained elevation of circulating growth hormone and insulin-like growth factor-1 (IGF-1). Insulin-like growth factor-1 is a potent mitogen and has a role in the transformation of normal cells to malignant cells. This study aims to evaluate the spontaneous micronucleus (MN) frequency by using the cytokinesis-block MN assay to determine genetic damage in the lymphocytes of patients with acromegaly. The study was carried out in 20 patients who had active acromegaly and in 20 age- and sex-matched healthy controls. The MN values were measured in binucleated cells obtained from mitogen-stimulated lymphocytes of patients and control subjects. The distribution of binucleated cells with 1, 2, 3, or more MNs was also measured. We found significantly higher MN frequency values in the lymphocytes of acromegalic patients than in those of the control subjects (2.23 ± 0.68 vs 1.03 ± 0.54, P = .001). The MN frequency increased with increasing IGF-1 levels of acromegalic patients (P = .036, R = 0.47). We observed that the number of binucleated cells with 2 MNs was higher for the majority of patients with acromegaly than for control subjects. Furthermore, the receiver operating characteristic curve (area under the curve = 0.914, P < .0001) was calculated to assess the discriminative power of the MN frequency. Our results indicate that increased MN frequency in the lymphocytes of patients with acromegaly may reflect genomic instability and this increased MN frequency may be associated with elevated levels of circulating growth hormone and IGF-1.
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Affiliation(s)
- Zuhal Hamurcu
- Department of Medical Biology, Medical Faculty, Erciyes University, Kayseri, Turkey.
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Clayton PE, Banerjee I, Murray PG, Renehan AG. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 2011; 7:11-24. [PMID: 20956999 DOI: 10.1038/nrendo.2010.171] [Citation(s) in RCA: 249] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH-IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.
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Affiliation(s)
- Peter E Clayton
- Manchester Academic Health Sciences Centre, University of Manchester, Paediatric Endocrinology, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.
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Wernli KJ, Newcomb PA, Wang Y, Makar KW, Shadman M, Chia VM, Burnett-Hartman A, Wurscher MA, Zheng Y, Mandelson MT. Body size, IGF and growth hormone polymorphisms, and colorectal adenomas and hyperplastic polyps. Growth Horm IGF Res 2010; 20:305-309. [PMID: 20580999 PMCID: PMC2918710 DOI: 10.1016/j.ghir.2010.04.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Revised: 03/22/2010] [Accepted: 04/23/2010] [Indexed: 12/31/2022]
Abstract
OBJECTIVE We examined the risk of colorectal polyps in relation to body size factors and candidate polymorphisms in selected genes of insulin-like growth factor (IGF1) (rs5742612), IGF1 receptor (IGF1R) (rs2229765), IGF binding protein 3 (IGFBP3) (rs2854746) and growth hormone (GH1) (rs2665802). DESIGN Cases with colorectal adenomas (n=519), hyperplastic polyps (n=691), or both lesions (n=227), and controls (n=772), aged 20-74 years, were recruited from patients who underwent colonoscopy between December 2004 and September 2007 at a large integrated-health plan in Washington state. Subjects participated in a 45-minute telephone interview to ascertain body size and physical activity, and provided a buccal DNA sample for genetic analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable polytomous regression. RESULTS Compared to those of normal weight, higher body mass index (BMI) was associated with elevated risk of colorectal adenomas (OR=1.65, 95% CI 1.22-2.25 BMI>or=30 kg/m(2), p-trend=0.002) and both lesions (OR=2.15, 95% CI 1.43-3.22 BMI>or=30 kg/m(2), p-trend=0.003), but there was no relationship with hyperplastic polyps. Obesity at age 18 and a weight gain of >or=21 kg since age 18 were also significantly associated with an increased risk of colorectal adenomas and both lesions, but not hyperplastic polyps. There was a reduced risk of colorectal adenomas (OR=0.63, 95% CI 0.42-0.94) and hyperplastic polyps (OR=0.7, 95% CI 0.5-0.9) associated with the homozygous variant genotype for GH1. Few meaningful results were evident for the other polymorphisms. CONCLUSIONS There is an increased risk of colorectal adenomas and presence of both adenomas and hyperplastic polyps in relation to increasing body size. Some genetic variation in GH1 might contribute to a reduced risk of colorectal adenomas and hyperplastic polyps.
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Affiliation(s)
- Karen J Wernli
- Program in Cancer Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Sherlock M, Ayuk J, Tomlinson JW, Toogood AA, Aragon-Alonso A, Sheppard MC, Bates AS, Stewart PM. Mortality in patients with pituitary disease. Endocr Rev 2010; 31:301-42. [PMID: 20086217 DOI: 10.1210/er.2009-0033] [Citation(s) in RCA: 265] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Pituitary disease is associated with increased mortality predominantly due to vascular disease. Control of cortisol secretion and GH hypersecretion (and cardiovascular risk factor reduction) is key in the reduction of mortality in patients with Cushing's disease and acromegaly, retrospectively. For patients with acromegaly, the role of IGF-I is less clear-cut. Confounding pituitary hormone deficiencies such as gonadotropins and particularly ACTH deficiency (with higher doses of hydrocortisone replacement) may have a detrimental effect on outcome in patients with pituitary disease. Pituitary radiotherapy is a further factor that has been associated with increased mortality (particularly cerebrovascular). Although standardized mortality ratios in pituitary disease are falling due to improved treatment, mortality for many conditions are still elevated above that of the general population, and therefore further measures are needed. Craniopharyngioma patients have a particularly increased risk of mortality as a result of the tumor itself and treatment to control tumor growth; this is a key area for future research in order to optimize the outcome for these patients.
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Affiliation(s)
- Mark Sherlock
- Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, United Kingdom
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Jain R, L. Thiele D. Gastrointestinal and Hepatic Manifestations of Systemic Diseases. SLEISENGER AND FORDTRAN'S GASTROINTESTINAL AND LIVER DISEASE 2010:557-592.e11. [DOI: 10.1016/b978-1-4160-6189-2.00035-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ramos O, Boguszewski CL, Teixeira S, De Bem R, Parolim B, Prolla JC. Performance of computed tomographic colonography for the screening of colorectal polyp in acromegalic patients: a prospective study. ARQUIVOS DE GASTROENTEROLOGIA 2009; 46:90-6. [PMID: 19578607 DOI: 10.1590/s0004-28032009000200003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2008] [Accepted: 03/19/2009] [Indexed: 01/11/2023]
Abstract
CONTEXT Acromegalic patients have better chances to develop colorectal polyps and cancer and, considered a high-risk group, need to undergo frequent screening examinations. Moreover, in acromegalia, the increased bowel length and the intestinal loop complexity can lead to higher levels of technical difficulties and increase the risks of complications at conventional colonoscopy. Computed tomographic colonography, also known as virtual colonoscopy, is an innovative and secure technology which is revolutionizing the diagnosis of colon and rectum neoplasias. OBJECTIVE To analyze computed tomographic colonography performance for the screening of colorectal polyps in acromegalic patients. METHODS A prospective study of 21 asymptomatic acromegalic patients, 12 male and 9 female, average age 49, who underwent computed tomographic colonography and conventional colonoscopy. Computed tomographic colonography was performed with a GE Helical Multislice Computed Tomography Apparatus. Conventional colonoscopy was performed in the same day, without previous knowledge of the computed tomographic colonography diagnostics. The study evaluated the capacity of computed tomographic colonography to detect patients with colorectal polyps and identify each colorectal lesion described by the colonoscopy. RESULTS In two patients (2/21), conventional colonoscopy was incomplete. However, in all patients computed tomographic colonography was complete. In Phase I ('per patient'), computed tomographic colonography diagnosed eight of the nine patients with colorectal polyps and showed 88% sensitivity, 75% specificity and 81% accuracy. In Phase II ('per polyp'), out of the 21 acromegalic patients included in this study, 12 presented normal findings at conventional colonoscopy. A total of 19 polyps were identified in 9 patients. Ten of the 19 polyps were smaller than 10 mm, and 9 were equal to or larger than 10 mm. Computed tomographic colonography identified 7 of the 9 polyps >10 mm described by conventional colonoscopy and only 6 of the 10 small polyps identified at conventional colonoscopy were detected by computed tomographic colonography. The histological analysis of resected lesions revealed 12 tubular adenomas, 6 hyperplastic polyps and 1 colonic tubulo-villous adenoma with an adenocarcinoma focus. CONCLUSION The authors present the first reports of computed tomographic colonography in the screening of colorectal polyps in acromegalic patients. In this study, computed tomographic colonography was performed without complications and a complete and safe colorectal evaluation was possible in all acromegalic patients. Moreover, computed tomographic colonography presented good sensitivity, specificity and accuracy for the identification of acromegalic patients with polyps of any size and better results in the diagnosis of large polyps, when they were compared to small polypoid lesions.
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Affiliation(s)
- Odery Ramos
- Department of Gastroenterology, Faculdade de Medicina, Universidade Federal do Paraná, Curitiba, PR, Brazil.
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Abstract
Excessive production of the growth hormone (GH) is responsible for acromegaly. It is related to a pituitary GH-secreting adenoma in most cases. Prevalence is estimated 40-130 per million inhabitants. It is characterised by slowly progressive acquired somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The rheumatologic, cardiovascular, respiratory and metabolic consequences determine its prognosis. The diagnosis is confirmed by an increased serum GH concentration, unsuppressible by an oral glucose load and by detection of increased levels of insulin-like growth factor-I (IGF-I). Treatment is aimed at correcting (or preventing) tumour compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. When surgery, the usual first-line treatment, fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogues and/or radiotherapy can be used. The GH-receptor antagonist (pegvisomant) is helpful in patients who are resistant to somatostatin analogues. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most cases, allowing a normal life expectancy.
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Affiliation(s)
- Philippe Chanson
- Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Université Paris-Sud 11, INSERM U693, Le Kremlin-Bicêtre, France.
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Bogazzi F, Ultimieri F, Raggi F, Russo D, Lombardi M, Cosci C, Brogioni S, Gasperi M, Bartalena L, Martino E. Reduced colonic apoptosis in mice overexpressing bovine growth hormone occurs through changes in several kinase pathways. Growth Horm IGF Res 2009; 19:432-441. [PMID: 19230732 DOI: 10.1016/j.ghir.2009.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Revised: 12/03/2008] [Accepted: 01/16/2009] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Growth hormone (GH) has antiapoptotic effects in several cell lines, including human colonic adenocarcinoma cells. In addition, it has been reported that patients with acromegaly have reduced apoptosis in colonic mucosa. The aim of the study was to investigate colonic apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH (Acro) aged 3 months (young) or 9 months (elder). DESIGN AND METHODS Apoptosis in colonic epithelial cells was evaluated by TUNEL and Annexin V; expression of pro- and anti-apoptotic proteins was assessed by Western blot. GH action was blocked treating Acro with a selective GH receptor antagonist. RESULTS Young and elder Acro had lower colonic apoptosis [driven by GH through p38, p44/42 and PI3 kinase pathways], than littermate controls; changes were abolished by treating Acro with a selective GH receptor antagonist. The effects of GH were consistent with an anti-apoptotic phenotype (reduced cytosolic cytochrome-c, Bad and Bax and increased Bcl-2, and Bcl-XL level) leading to lower activation of caspase-9 and caspase-3. Changes in apoptotic proteins reversed after treatment with a GH receptor antagonist, suggesting a direct effect of GH. In addition, antiapoptotic phenotype of Acro had a protective role against doxorubicin-induced apoptosis. CONCLUSIONS Our results suggest that GH leads to increased and reduced levels of anti- and pro-apoptotic proteins, respectively, lowering apoptosis in either young or elder transgenic animals through activation of several kinase pathways.
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Affiliation(s)
- Fausto Bogazzi
- Department of Endocrinology and Metabolism, University of Pisa, Ospedale Cisanello, Pisa, Italy.
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Ronchi CL, Coletti F, Fesce E, Montefusco L, Ogliari C, Verrua E, Epaminonda P, Ferrante E, Malchiodi E, Morelli V, Beck-Peccoz P, Arosio M. Detection of small bowel tumors by videocapsule endoscopy in patients with acromegaly. J Endocrinol Invest 2009; 32:495-500. [PMID: 19494714 DOI: 10.1007/bf03346495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The prevalence of colon polyposis andmalignancies is increased in acromegalic patients as compared to the general population. An epidemiological study suggests a high prevalence also of small bowel (SB) tumors that nowadays may be detected by videocapsule endoscopy (VCE). The aim of the study was to assess the prevalence of SB neoplasms using VCE in acromegalic patients in comparison to control subjects and to correlate it with cancer risk factors and acromegaly-related parameters. Eighteen acromegalic patients (6 males and 12 females, age+/-SD: 54+/-10 yr), 5 cured after surgery (followed by radiotherapy in 3 cases) and 13 on pharmacological treatment were enrolled, and 36 sex- and age-matched non-acromegalic subjects served as a control group. Cancer risk factors, duration of acromegaly, GH and IGF-I levels, IGF binding protein 3 and IGF-II concentrations, metabolic parameters, tumor markers, colonic lesions by total colonoscopy, and SB lesions by VCE were investigated. VCE images suggestive of SB lesions were detected in 5/36 controls [14%, 4 described as gastrointestinal stromal nodular tumors (GIST), and 1 as polyp] and in 5/18 acromegalic patients [28%, 2 GIST and 3 polyps]. In acromegaly, the calculated relative risk for all SB lesions was 1.69 [95%confidence interval (CI): 0.78-3.65], while the relative risk for SB polyps was 2.50 (95% CI: 1.23-5.07). The effective duration of active disease was longer in patients with positive than in those with negative VCE (112+/-89 vs 49+/-40 months, p=0.06). In conclusion, these preliminary results suggest that acromegalic patients might have a high risk of SB polyp development. VCE might be a useful adjunctive diagnostic tool in acromegaly.
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Affiliation(s)
- C L Ronchi
- Department of Medical Sciences, University of Milan, Milan, Italy
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Abstract
The type 1 IGF receptor (IGF-IR) is activated by two ligands, IGF-1 and IGF-2, and by insulin at supraphysiological concentrations. It plays a significant role in the growth of normal and abnormal cells, and antibodies against the IGF-IR are now in clinical trials. Targeting of the IGF-IR in cancer cells (by antibodies or other means) can be improved by the appropriate selection of responsive tumors. This review focuses on the optimization of IGF-IR targeting in human cancer.
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Affiliation(s)
- Renato Baserga
- Thomas Jefferson University, Kimmel Cancer Center, Bluemle Life Sciences Center, Philadelphia, PA 1910, USA.
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Chanson P, Bertherat J, Beckers A, Bihan H, Brue T, Caron P, Chabre O, Cogne M, Cortet-Rudelli C, Delemer B, Dufour H, Gaillard R, Gueydan M, Morange I, Souberbielle JC, Tabarin A. French consensus on the management of acromegaly. ANNALES D'ENDOCRINOLOGIE 2009; 70:92-106. [DOI: 10.1016/j.ando.2008.12.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2008] [Accepted: 12/04/2008] [Indexed: 01/05/2023]
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Chanson P, Bertherat J, Beckers A, Bihan H, Brue T, Caron P, Chabre O, Cogne M, Cortet-Rudelli C, Delemer B, Dufour H, Gaillard R, Gueydan M, Morange I, Souberbielle JC, Tabarin A. Consensus français sur la prise en charge de l’acromégalie. ANNALES D'ENDOCRINOLOGIE 2009. [DOI: 10.1016/j.ando.2008.12.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Function of CSE1L/CAS in the secretion of HT-29 human colorectal cells and its expression in human colon. Mol Cell Biochem 2009; 327:163-70. [PMID: 19224336 DOI: 10.1007/s11010-009-0054-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2008] [Accepted: 02/04/2009] [Indexed: 01/10/2023]
Abstract
The secretion of colorectal epithelium is important for maintaining the physiological function of colorectal organ. Herein, we report that cellular apoptosis susceptibility (CAS) (or CSE1L) protein regulates the secretion of HT-29 human colorectal cells. Polarity is essential for directed secretion of substances produced by epithelial cells to the external (luminal) compartment; CAS overexpression induced polarization of HT-29 cells. CAS was punctate stained in the cytoplasm of HT-29 cells, and CAS overexpression increased the translocation of CAS-stained vesicles to the cytoplasm near cell membrane and cell protrusions. CAS overexpression increased the secretion of carcinoembryonic antigen (CEA) and cathepsin D. Immunohistochemistry showed CAS was positively stained in the goblet cells of colon mucosa and cells in the crypts of Lieberkühn of human colon as well as the glands in metastatic colorectal cancer tissue. Our results suggest that CAS regulates the secretion of colorectal cells and may regulate the metastasis of colorectal cancer.
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Khoury-Shakour S, Gruber SB, Lejbkowicz F, Rennert HS, Raskin L, Pinchev M, Rennert G. Recreational physical activity modifies the association between a common GH1 polymorphism and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2009; 17:3314-8. [PMID: 19064544 DOI: 10.1158/1055-9965.epi-08-0062] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
UNLABELLED Growth hormone may be associated with the development of colorectal cancer directly and/or indirectly via increased serum level of insulin-like growth factor (IGF-I). Regular physical activity can decrease insulin resistance and modulates IGF-I production. A common polymorphism in the GH1 gene, rs2665802, was previously shown to be associated with lower IGF-I levels and decreased colorectal cancer (CRC) risk. We investigated the association of this polymorphism and physical activity with colorectal cancer risk in a case-control study. METHODS The analysis includes 3,041 (1,402 cases and 1,639 controls) participants in the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study in Northern Israel. Analysis was carried out separately in two sets. The first set included 1,248 subjects (625 cases, 623 controls), and the second validation set consisted of 1,793 subjects (777 cases, 1,016 controls). RESULTS No association was found between the studied polymorphism and CRC risk. However, evaluation of gene environment interactions revealed an interaction between leisure time physical activity and the GH1 polymorphism, which was consistent in both sets (P(interaction) = 0.005). The genotype AA was associated with decreased risk of CRC among individuals who did not engage in any such activity (odds ratio, 0.76; 95% confidence interval, 0.52-0.98), whereas the same genotype was marginally associated with increased risk among individuals who reported physical activity (odds ratio, 1.38; 95% confidence interval, 0.98-1.94). CONCLUSIONS We found that the A allele of the rs2665802 polymorphism is associated with reduced risk of CRC only among physically inactive individuals, indicating an interaction between physical activity and the growth hormone/IGF-I system. A replication of the observed findings and further investigation of the underlying mechanism is warranted.
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Affiliation(s)
- Sana Khoury-Shakour
- Clalit Health Services National Cancer Control Center, at Carmel Medical Center, Haifa 34362, Israel.
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Resmini E, Tagliafico A, Bacigalupo L, Giordano G, Melani E, Rebora A, Minuto F, Rollandi GA, Ferone D. Computed tomography colonography in acromegaly. J Clin Endocrinol Metab 2009; 94:218-222. [PMID: 18957501 DOI: 10.1210/jc.2008-1479] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION AND AIM Acromegalic patients have an increased risk for the development of colorectal cancer. For this reason, since 1996, screening colonoscopy has been recommended in all patients with acromegaly. The aim of our study was to assess the feasibility and to evaluate the results of computed tomography (CT)-colonography in acromegaly. PATIENTS AND METHODS We examined 23 acromegalic patients with no history of colorectal cancer (11 females and 12 males; age range 18-79 yr; disease duration range 1-15 yr) with CT-colonography. Twenty of them underwent traditional colonoscopy after the CT-colonography. RESULTS CT-colonography examination results were adequate in 17 of 23 cases (73%). CT-colonography found 12 polyps in eight patients, 95% confirmed by traditional colonoscopy. One polyp was a sigmoid cancer, and the diagnosis was confirmed at surgery. There were no polyps found by traditional colonoscopy that CT-colonography was not able to identify. The lesions were located in right colon (two), transversum (three), left colon (five), and sigmoid colon (two). Patient acceptance of the technique was good in 65%, medium in 20%, and poor in 15%. CONCLUSION For the first time we have demonstrated that CT-colonography has the potential ability to replace traditional colonoscopy in acromegalic patients. CT-colonography could be used as a screening modality for colon cancer in acromegaly.
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Affiliation(s)
- Eugenia Resmini
- Department of Endocrine and Medical Sciences, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy
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Higham CE, Trainer PJ. Growth hormone excess and the development of growth hormone receptor antagonists. Exp Physiol 2008; 93:1157-69. [PMID: 18617577 DOI: 10.1113/expphysiol.2008.042515] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH-GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor-GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH-IGF-I axis.
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Affiliation(s)
- C E Higham
- Department of Endocrinology, Christie Hospital, Manchester M20 4BX, UK
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