Endocrinology and Metabolism

Original Article

⁶⁸Ga-DOTATOC PET/CT in the Localization of Pituitary Tumors in Cushing’s Disease: Kyungwon Kim, Dongwoo Kim, Min-Ho Lee, Yae Won Park, Sung Soo Ahn, Ju Hyung Moon, Eui Hyun Kim, Sun Ho Kim, Cheol Ryong Ku, Eun Jig Lee; Received November 20, 2024 Accepted January 21, 2025 Published online March 18, 2025; DOI: https://doi.org/10.3803/EnM.2024.2249 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
This study aimed to determine the value of ⁶⁸Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) in localizing adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas.
Methods
In this retrospective cohort study, we enrolled 30 patients with Cushing’s disease and positive ACTH immunoreactivity. All patients underwent ⁶⁸Ga-DOTATOC PET/CT and pituitary magnetic resonance imaging (MRI) before transsphenoidal adenomectomy.
Results
Twenty-five patients showed ⁶⁸Ga-DOTATOC uptake in their pituitary glands on PET/CT. Median age, pre-operative ACTH levels, pre-operative cortisol, and tumor size on MRI were comparable irrespective of DOTATOC uptake. ⁶⁸Ga-DOTATOC PET/CT showed a 77% success rate for localizing adenomas, which was not statistically different from that of MRI. The ACTH level in the successful localization group was significantly higher than that in the failed group (84.41 pg/mL vs. 37.26 pg/mL, P=0.001). The ACTH level was statistically significant predictor of successful localization using ⁶⁸Ga-DOTATOC PET/CT (P=0.013). The area under the curve was 0.932 with a cutoff of 53.86 pg/mL for ACTH levels to determine successful localization. Pre-operative ACTH levels above 53.86 pg/mL showed the best diagnostic accuracy in predicting the success of localizing adenomas (sensitivity, 91.3%; specificity, 85.7%). Mean and maximum standardized uptake value of adenoma negatively correlated to pre-operative ACTH level.
Conclusion
Plasma ACTH level is a favorable predictor for the successful localization and negative correlation with ⁶⁸Ga-DOTATOC uptake of corticotroph adenomas in ⁶⁸Ga-DOTATOC PET/CT. ⁶⁸Ga-DOTATOC PET/CT did not improve tumor localization for Cushing’s disease compared with MRI alone.

Review Article

Hypothalamus and pituitary gland
Elucidating Clinical Queries for Tailored Therapy in Patients with Prolactinoma: Min-Ho Lee, Jae Won Hong, Kyungwon Kim, Cheol Ryong Ku, Eun Jig Lee; Endocrinol Metab. 2024;39(6):819-826. Published online October 14, 2024; DOI: https://doi.org/10.3803/EnM.2024.2057

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Prolactinomas are the most prevalent type of pituitary neuroendocrine adenomas, primarily affecting women of reproductive age. Unlike other pituitary tumors, the first-line management has traditionally been pharmacological rather than surgical. This preference is due to the effectiveness of dopamine agonists (DAs), which typically reduce tumor size and normalize prolactin levels in most patients. However, this does not imply that there is no room for improvement; the duration of treatment and medication side effects often lead to compliance issues among patients. Recent advances in surgical techniques and molecular biology have paved the way for the development of precision medicine, allowing for more flexible and personalized treatment strategies for prolactinomas. This review aims to enhance clinical decision-making and patient care for endocrinologists by focusing on several key factors: predictive markers of DA sensitivity, clinical characteristics and suitability for transsphenoidal adenomectomy as a potential first-line treatment, factors determining the successful withdrawal of DAs after prolonged use, safety concerns during pre/post-pregnancy and breastfeeding, and determinants of tumor aggressiveness. Through tailored therapy—a patient-focused, multidisciplinary approach— we aim to improve the management of prolactinoma patients.

Citations

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When to embark on surgery for prolactin-secreting pituitary adenoma?
Nazmin Ahmed, Subodh Gautam, Bipin Chaurasia
Annals of Medicine & Surgery.2025; 87(4): 1798. CrossRef

Original Article

Mineral, Bone & Muscle Big Data Articles (National Health Insurance Service Database)
Increased Risk of Hip Fracture in Patients with Acromegaly: A Nationwide Cohort Study in Korea: Jiwon Kim, Namki Hong, Jimi Choi, Ju Hyung Moon, Eui Hyun Kim, Eun Jig Lee, Sin Gon Kim, Cheol Ryong Ku; Endocrinol Metab. 2023;38(6):690-700. Published online October 30, 2023; DOI: https://doi.org/10.3803/EnM.2023.1782

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Background
Acromegaly leads to various skeletal complications, and fragility fractures are emerging as a new concern in patients with acromegaly. Therefore, this study investigated the risk of fractures in Korean patients with acromegaly.
Methods
We used the Korean nationwide claims database from 2009 to 2019. A total of 931 patients with acromegaly who had never used an osteoporosis drug before and were treated with surgery alone were selected as study participants, and a 1:29 ratio of 26,999 age- and sex-matched osteoporosis drug-naïve controls without acromegaly were randomly selected from the database.
Results
The mean age was 46.2 years, and 50.0% were male. During a median follow-up of 54.1 months, there was no difference in the risks of all, vertebral, and non-vertebral fractures between the acromegaly and control groups. However, hip fracture risk was significantly higher (hazard ratio [HR], 2.73; 95% confidence interval [CI], 1.32 to 5.65), and non-hip and non-vertebral fractures risk was significantly lower (HR, 0.40; 95% CI, 0.17 to 0.98) in patients with acromegaly than in controls; these results remained robust even after adjustment for socioeconomic status and baseline comorbidities. Age, type 2 diabetes mellitus, cardio-cerebrovascular disease, fracture history, recent use of acid-suppressant medication, psychotropic medication, and opioids were risk factors for all fractures in patients with acromegaly (all P<0.05).
Conclusion
Compared with controls, patients surgically treated for acromegaly had a higher risk of hip fractures. The risk factors for fracture in patients with acromegaly were consistent with widely accepted risk factors in the general population.

Citations

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Long-Term Prognosis and Systemic Impact of Acromegaly: Analyses Utilizing Korean National Health Insurance Data
Sangmo Hong, Kyungdo Han, Cheol-Young Park
Endocrinology and Metabolism.2025; 40(1): 1. CrossRef
Musculoskeletal disease in acromegaly—a population-based registry study
Christian Rosendal, Mai Christiansen Arlien-Søborg, Eigil Husted Nielsen, Claus Larsen Feltoft, Åse Krogh Rasmussen, Marianne Skovsager Andersen, Jens Otto Lunde Jørgensen, Jakob Dal
European Journal of Endocrinology.2025; 192(3): 308. CrossRef
Novel approach to bone comorbidity in resistant acromegaly
Stefano Frara, Matteo Acanfora, Vincenzo Franzese, Maria Luisa Brandi, Marco Losa, Andrea Giustina
Pituitary.2024; 27(6): 813. CrossRef

Songwon Lecture 2022

Hypothalamus and pituitary gland
Multiomics Approach to Acromegaly: Unveiling Translational Insights for Precision Medicine: Kyungwon Kim, Cheol Ryong Ku, Eun Jig Lee; Endocrinol Metab. 2023;38(5):463-471. Published online October 13, 2023; DOI: https://doi.org/10.3803/EnM.2023.1820

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The clinical characteristics and prognoses of acromegaly vary among patients. Assessment of current and novel predictors can lead to multilevel categorization of patients, allowing integration into new clinical guidelines and a reduction in the increased morbidity and mortality associated with acromegaly. Despite advances in the diagnosis and treatment of acromegaly, its pathophysiology remains unclear. Recent advancements in multiomics technologies, including genomics, transcriptomics, proteomics, metabolomics, and radiomics, have offered new opportunities to unravel the complex pathophysiology of acromegaly. This review comprehensively explores the emerging role of multiomics approaches in elucidating the molecular landscape of acromegaly. We discuss the potential implications of multiomics data integration in the development of novel diagnostic tools, identification of therapeutic targets, and the prospects of precision medicine in acromegaly management. By integrating diverse omics datasets, these approaches can provide valuable insights into disease mechanisms, facilitate the identification of diagnostic biomarkers, and identify potential therapeutic targets for precision medicine in the management of acromegaly.

Citations

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“Micromegaly”: Acromegaly with apparently normal GH, an entity on its own?
Lucio Vilar, Luciana Ansaneli Naves, Manoel Ricardo Alves Martins, Antônio Ribeiro-Oliveira Jr
Best Practice & Research Clinical Endocrinology & Metabolism.2024; 38(3): 101878. CrossRef

Special Articles

Miscellaneous
Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society: Hyemi Kwon, Eun Roh, Chang Ho Ahn, Hee Kyung Kim, Cheol Ryong Ku, Kyong Yeun Jung, Ju Hee Lee, Eun Heui Kim, Sunghwan Suh, Sangmo Hong, Jeonghoon Ha, Jun Sung Moon, Jin Hwa Kim, Mi-kyung Kim, The Committee of Clinical Practice Guideline of the Korean Endocrine Society; Endocrinol Metab. 2022;37(6):839-850. Published online December 26, 2022; DOI: https://doi.org/10.3803/EnM.2022.1627

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Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

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Miscellaneous
COVID-19 Vaccination for Endocrine Patients: A Position Statement from the Korean Endocrine Society: Cheol Ryong Ku, Kyong Yeun Jung, Chang Ho Ahn, Jun Sung Moon, Ju Hee Lee, Eun Heui Kim, Hyemi Kwon, Hee Kyung Kim, Sunghwan Suh, Sangmo Hong, Jeonghoon Ha, Eun Roh, Jin Hwa Kim, Mi-kyung Kim, the Committee of Clinical Practice Guideline of the Korean Endocrine Society; Endocrinol Metab. 2021;36(4):757-765. Published online August 17, 2021; DOI: https://doi.org/10.3803/EnM.2021.404

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Since the first outbreak of coronavirus disease 2019 (COVID-19), ongoing efforts have been made to discover an efficacious vaccine against COVID-19 to combat the pandemic. In most countries, both mRNA and DNA vaccines have been administered, and their side effects have also been reported. The clinical course of COVID-19 and the effects of vaccination against COVID-19 are both influenced by patients’ health status and involve a systemic physiological response. In view of the systemic function of endocrine hormones, endocrine disorders themselves and the therapeutics used to treat them can influence the outcomes of vaccination for COVID-19. However, there are very limited data to support the development of clinical guidelines for patients with specific medical backgrounds based on large clinical trials. In the current severe circumstances of the COVID-19 pandemic, position statements made by clinical specialists are essential to provide appropriate recommendations based on both medical evidence and clinical experiences. As endocrinologists, we would like to present the medical background of COVID-19 vaccination, as well as precautions to prevent the side effects of COVID-19 vaccination in patients with specific endocrine disorders, including adrenal insufficiency, diabetes mellitus, osteoporosis, autoimmune thyroid disease, hypogonadism, and pituitary disorders.

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Original Articles

Clinical Study
Associations of GNAS Mutations with Surgical Outcomes in Patients with Growth Hormone-Secreting Pituitary Adenoma: Hyein Jung, Kyungwon Kim, Daham Kim, Ju Hyung Moon, Eui Hyun Kim, Se Hoon Kim, Cheol Ryong Ku, Eun Jig Lee; Endocrinol Metab. 2021;36(2):342-350. Published online March 23, 2021; DOI: https://doi.org/10.3803/EnM.2020.875

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Background
The guanine nucleotide-binding protein, alpha stimulating (GNAS) gene has been associated with growth hormone (GH)-secreting pituitary adenoma. We investigated the prevalence of GNAS mutations in Korean patients with acromegaly and assessed whether mutation status correlated with biochemical or clinical characteristics.
Methods
We studied 126 patients with acromegaly who underwent surgery between 2005 and 2014 at Severance Hospital. We performed GNAS gene analysis and evaluated age, sex, hormone levels, postoperative biochemical remission, and immunohistochemical staining results of the tumor.
Results
GNAS mutations were present in 75 patients (59.5%). Patients with and without GNAS mutations showed similar age distribution and Knosp classification. The proportion of female patients was 76.5% and 48.0% in the GNAS-negative and GNAS-mutation groups, respectively (P=0.006). In immunohistochemical staining, the GNAS-mutation group showed higher GH expression in pituitary tumor tissues than the mutation-negative group (98.7% vs. 92.2%, P=0.015). Patients with GNAS mutations had higher preoperative insulin-like growth factor-1 levels (791.3 ng/mL vs. 697.0 ng/mL, P=0.045) and lower immediate postoperative basal (0.9 ng/mL vs. 1.0 ng/mL, P=0.191) and nadir GH levels (0.3 ng/mL vs. 0.6 ng/mL, P=0.012) in oral glucose tolerance tests. Finally, the GNAS-mutation group showed significantly higher surgical remission rates than the mutation-negative group, both at 1 week and 6 months after surgical resection (70.7% vs. 54.9%, P=0.011; 85.3% vs. 82.4%, P=0.007, respectively).
Conclusion
GNAS mutations in GH-secreting pituitary tumors are associated with higher preoperative insulin-like growth factor-1 levels and surgical remission rates and lower immediate postoperative nadir GH levels. Thus, GNAS mutation status can predict surgical responsiveness in patients with acromegaly.

Citations

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Contract to kill: GNAS mutation
Pratima Raut, Poompozhil Mathivanan, Surinder K. Batra, Moorthy P. Ponnusamy
Molecular Cancer.2025;[Epub] CrossRef
Genetic diagnosis in acromegaly and gigantism: From research to clinical practice
Claudia Ramírez-Rentería, Laura C. Hernández-Ramírez
Best Practice & Research Clinical Endocrinology & Metabolism.2024; 38(3): 101892. CrossRef
Unlocking the Genetic Secrets of Acromegaly: Exploring the Role of Genetics in a Rare Disorder
Ioana Balinisteanu, Lavinia Caba, Andreea Florea, Roxana Popescu, Laura Florea, Maria-Christina Ungureanu, Letitia Leustean, Eusebiu Vlad Gorduza, Cristina Preda
Current Issues in Molecular Biology.2024; 46(8): 9093. CrossRef
Advancements in Molecular Diagnosis and Pharmacotherapeutic Strategies for Invasive Pituitary Adenomas
Dingkai Xu, Ling Wang, Maohua Zheng
Immunity, Inflammation and Disease.2024;[Epub] CrossRef
GNAS mutations suppress cell invasion by activating MEG3 in growth hormone–secreting pituitary adenoma
CHAO TANG, CHUNYU ZHONG, JUNHAO ZHU, FENG YUAN, JIN YANG, YONG XU, CHIYUAN MA
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Haruto Nishida, Yoshihiko Kondo, Takahiro Kusaba, Kazuhiro Kawamura, Yuzo Oyama, Tsutomu Daa, Avaniyapuram Kannan Murugan
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Xiya Ma, Kun Zhang, Jing Xu, Hongjun Gao, Shaoxing Yang, Haifeng Qin, Hong Wang, Fang Gao, Xiaoqing Liu
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Multiomics Approach to Acromegaly: Unveiling Translational Insights for Precision Medicine
Kyungwon Kim, Cheol Ryong Ku, Eun Jig Lee
Endocrinology and Metabolism.2023; 38(5): 463. CrossRef
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Mariana Torres-Morán, Alexa L. Franco-Álvarez, Rosa G. Rebollar-Vega, Laura C. Hernández-Ramírez
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Endocrine Research
Danshen Extracts Prevents Obesity and Activates Mitochondrial Function in Brown Adipose Tissue: Yoon Hee Cho, Cheol Ryong Ku, Young-Suk Choi, Hyeon Jeong Lee, Eun Jig Lee; Endocrinol Metab. 2021;36(1):185-195. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.835

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Background
Danshen has been widely used in oriental medicine to improve body function. The purpose of this study is to investigate the effect of water-soluble Danshen extract (DE) on weight loss and on activation proteins involved in mitochondrial biogenesis in brown adipose tissue (BAT) in obese mice.
Methods
BAT was isolated from 7-week-old male Sprague-Dawley rats, and expression of proteins related to mitochondrial biogenesis was confirmed in both brown preadipocytes and mature brown adipocytes treated with DE. For the in vivo study, low-density lipoprotein receptor knock out mice were divided into three groups and treated for 17 weeks with: standard diet; high fat diet (HFD); HFD+DE. Body weight was measured every week, and oral glucose tolerance test was performed after DE treatment in streptozotocin-induced diabetic mice. To observe the changes in markers related to thermogenesis and adipogenesis in the BAT, white adipose tissue (WAT) and liver of experimental animals, tissues were removed and immediately frozen in liquid nitrogen.
Results
DE increased the expression of uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in brown preadipocytes, and also promoted the brown adipocyte differentiation and mitochondrial function in the mature brown adipocytes. Reactive oxygen species production in brown preadipocytes was increased depending on the concentration of DE. DE activates thermogenesis in BAT and normalizes increased body weight and adipogenesis in the liver due to HFD. Browning of WAT was increased in WAT of DE treatment group.
Conclusion
DE protects against obesity and activates mitochondrial function in BAT.

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Brief Report

Hypothalamus and Pituitary gland
Establishment of Reference Intervals for Serum Insulin-Like Growth Factor I in Korean Adult Population: Boyeon Kim, Yonggeun Cho, Cheol Ryong Ku, Sang-Guk Lee, Kyung-A Lee, Jeong-Ho Kim; Endocrinol Metab. 2020;35(4):960-964. Published online November 20, 2020; DOI: https://doi.org/10.3803/EnM.2020.732

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Appropriate reference intervals of serum insulin-like growth factor I (IGF-I) is important for diagnosing and monitoring patients with growth hormone-related diseases. To establish reference intervals, adult individuals (n=1,334, 680 men and 654 women) were divided into six age groups (20–29, 30–39, 40–49, 50–59, 60–69, ≥70). Serum IGF-I was measured by chemiluminescence immunoassay (Liaison). Concordance of patient classification based on reference intervals, manufacturer’s intervals, and standard deviation score (SDS) was evaluated. New reference intervals had higher upper and lower limits than those specified by the manufacturer. The agreement between classification using new reference interval and the manufacturer’s reference interval, and that using new reference interval and SDS was 75.0% (weighted kappa, 0.17), 91.9% (weighted kappa, 0.51) in men and 91.0% (weighted kappa, 0.41), 92.5% (weighted kappa, 0.53) in women, respectively. Reference intervals should be established not only based on age and sex, but also on ethnicity and assay method.

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Special Article

Miscellaneous
Diagnosis and Treatment of Growth Hormone Deficiency: A Position Statement from Korean Endocrine Society and Korean Society of Pediatric Endocrinology: Jung Hee Kim, Hyun Wook Chae, Sang Ouk Chin, Cheol Ryong Ku, Kyeong Hye Park, Dong Jun Lim, Kwang Joon Kim, Jung Soo Lim, Gyuri Kim, Yun Mi Choi, Seong Hee Ahn, Min Ji Jeon, Yul Hwangbo, Ju Hee Lee, Bu Kyung Kim, Yong Jun Choi, Kyung Ae Lee, Seong-Su Moon, Hwa Young Ahn, Hoon Sung Choi, Sang Mo Hong, Dong Yeob Shin, Ji A Seo, Se Hwa Kim, Seungjoon Oh, Sung Hoon Yu, Byung Joon Kim, Choong Ho Shin, Sung-Woon Kim, Chong Hwa Kim, Eun Jig Lee; Endocrinol Metab. 2020;35(2):272-287. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.272

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Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.

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Review Article

Hypothalamus and Pituitary gland
Precision Therapy in Acromegaly Caused by Pituitary Tumors: How Close Is It to Reality?: Cheol Ryong Ku, Vladimir Melnikov, Zhaoyun Zhang, Eun Jig Lee; Endocrinol Metab. 2020;35(2):206-216. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.206

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Acromegaly presents with an enigmatic range of symptoms and comorbidities caused by chronic and progressive growth hormone elevations, commonly due to endocrinologic hypersecretion from a pituitary gland tumor. Comprehensive national acromegaly databases have been appearing over the years, allowing for international comparisons of data, although still presenting varying prevalence and incidence rates. Lack of large-scale analysis in geographical and ethnic differences in clinical presentation and management requires further research. Assessment of current and novel predictors of responsiveness to distinct therapy can lead to multilevel categorization of patients, allowing integration into new clinical guidelines and reduction of increased morbidity and mortality associated with acromegaly. This review compares current data from epidemiological studies and assesses the present-day application of prognostic factors in medical practice, the reality of precision therapy, as well as its future prospects in acromegaly, with a special focus on its relevance to the South Korean population.

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Predictors of morphofunctional features of somatotrophic tumors and of the effectiveness of treatment with first-generation somatostatin receptor ligands
E. V. Pronin, V. S. Pronin, M. B. Antsiferov, A. V. Petryaykin, T. M. Alexeeva, A. M. Lapshina, L. S. Urusova, A. N. Khoruzhaya, S. M. Tamaeva
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Elucidating Clinical Queries for Tailored Therapy in Patients with Prolactinoma
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Risk of depression in patients with acromegaly in Korea (2006-2016): a nationwide population-based study
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The Future of Somatostatin Receptor Ligands in Acromegaly
Monica R Gadelha, Luiz Eduardo Wildemberg, Leandro Kasuki
The Journal of Clinical Endocrinology & Metabolism.2022; 107(2): 297. CrossRef
Innovative therapeutics in acromegaly
Leandro Kasuki, Mônica R. Gadelha
Best Practice & Research Clinical Endocrinology & Metabolism.2022; 36(6): 101679. CrossRef
Risk of Neurodegenerative Diseases in Patients With Acromegaly
Sangmo Hong, Kyungdo Han, Kyung-Soo Kim, Cheol-Young Park
Neurology.2022;[Epub] CrossRef
Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands
Luiz Eduardo Wildemberg, Aline Helen da Silva Camacho, Renan Lyra Miranda, Paula C L Elias, Nina R de Castro Musolino, Debora Nazato, Raquel Jallad, Martha K P Huayllas, Jose Italo S Mota, Tobias Almeida, Evandro Portes, Antonio Ribeiro-Oliveira, Lucio Vi
The Journal of Clinical Endocrinology & Metabolism.2021; 106(7): 2047. CrossRef
Skin anomalies in acromegalic patients (Review of the practical aspects)
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Original Article

Endocrine Research
Therapeutic Effect of a Novel Chimeric Molecule Targeting Both Somatostatin and Dopamine Receptors on Growth Hormone-Secreting Pituitary Adenomas: Jean Kim, Ju Hun Oh, Heather Harlem, Michael D. Culler, Cheol Ryong Ku, Eun Jig Lee; Endocrinol Metab. 2020;35(1):177-187. Published online March 19, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.1.177

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Background

Acromegaly is a rare disease primarily caused by growth hormone (GH)-secreting pituitary adenomas, and its treatment is costly. Moreover, some patients are unresponsive to treatment. Hence, there are increasing efforts to develop new drugs with improved effectiveness for this disease. BIM23B065 is a novel chimeric molecule that acts on both somatostatin and dopamine receptors. This study aimed to investigate the effects of BIM23B065 compared with those of a somatostatin receptor analog and a dopamine agonist.

Methods

The effects of BIM23B065 on the proliferation, GH and insulin-like growth factor-1 (IGF-1) levels, and extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element binding (CREB) phosphorylation of GH3 cells were investigated with MTS assay, enzyme-linked immunosorbent assay, and Western blotting, respectively. The dosage and treatment duration of BIM23B065 were tested in animal models of GH-secreting pituitary adenoma. The effect of BIM23B065 (3 mg/kg/day) on changes in IGF-1 levels before and after treatment was further investigated.

Results

In vitro, BIM23B065 treatment decreased GH release in the culture media and downregulated ERK 1/2 and CREB phosphorylation to 22% and 26%, respectively. In vivo, IGF-1 expression decreased to 50 % after 4 weeks of treatment with BIM23B065 using an osmotic pump implant. Moreover, magnetic resonance imaging results showed that the tumor size decreased significantly following treatment with BIM23B065 for 4 weeks.

Conclusion

The novel chimeric molecule was effective in decreasing IGF-1 and GH levels and may serve as an effective therapeutic agent for acromegaly.

Citations

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Pituitary Tumorigenesis—Implications for Management
Rodanthi Vamvoukaki, Maria Chrysoulaki, Grigoria Betsi, Paraskevi Xekouki
Medicina.2023; 59(4): 812. CrossRef
Current and Emerging Medical Therapies in Pituitary Tumors
Nicolas Sahakian, Frédéric Castinetti, Thierry Brue, Thomas Cuny
Journal of Clinical Medicine.2022; 11(4): 955. CrossRef
Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells
Thomas Cuny, Thomas Graillon, Célines Defilles, Rakesh Datta, Shengwen Zhang, Dominique Figarella-Branger, Henry Dufour, Grégory Mougel, Thierry Brue, Tanya Landsman, Heather A. Halem, Michael D. Culler, Anne Barlier, Alexandru Saveanu
Pituitary.2021; 24(3): 351. CrossRef
Efficacy of a Novel Second-Generation Somatostatin-Dopamine Chimera (TBR-065) in Human Medullary Thyroid Cancer: A Preclinical Study
Alessandra Dicitore, Maria Celeste Cantone, Germano Gaudenzi, Davide Saronni, Silvia Carra, Maria Orietta Borghi, Manuela Albertelli, Diego Ferone, Leo J. Hofland, Luca Persani, Giovanni Vitale
Neuroendocrinology.2021; 111(10): 937. CrossRef
Emerging drugs for the treatment of acromegaly
Claudia Campana, Giuliana Corica, Federica Nista, Francesco Cocchiara, Giulia Graziani, Keyvan Khorrami, Marta Franco, Mara Boschetti, Diego Ferone, Federico Gatto
Expert Opinion on Emerging Drugs.2020; 25(4): 409. CrossRef

Special Article

Hypothalamus and Pituitary gland
Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement: Sang Ouk Chin, Cheol Ryong Ku, Byung Joon Kim, Sung-Woon Kim, Kyeong Hye Park, Kee Ho Song, Seungjoon Oh, Hyun Koo Yoon, Eun Jig Lee, Jung Min Lee, Jung Soo Lim, Jung Hee Kim, Kwang Joon Kim, Heung Yong Jin, Dae Jung Kim, Kyung Ae Lee, Seong-Su Moon, Dong Jun Lim, Dong Yeob Shin, Se Hwa Kim, Min Jeong Kwon, Ha Young Kim, Jin Hwa Kim, Dong Sun Kim, Chong Hwa Kim; Endocrinol Metab. 2019;34(1):53-62. Published online March 21, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.1.53

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The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

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Hydrogel-fiber-mesh-based 3D cell cultures: A new method for studying pituitary tumors
Wooju Jeong, Sungrok Wang, Yumin Kim, Soohyun Lee, Minhu Huang, Jaeil Park, Myung-Han Yoon, Chang-Myung Oh, Cheol Ryong Ku
Smart Materials in Medicine.2024; 5(2): 281. CrossRef
Differential gene expression and pathway analysis in growth hormone-secreting pituitary tumors according to granulation pattern
Kyungwon Kim, Yeongmin Kim, Se Hoon Kim, Ju Hyung Moon, Eui Hyun Kim, Eun Jig Lee, Chang-Myung Oh, Cheol Ryong Ku
Frontiers in Oncology.2024;[Epub] CrossRef
Agonists, Antagonists and Receptors of Somatostatin: Pathophysiological and Therapeutical Implications in Neoplasias
Argyrios Periferakis, Georgios Tsigas, Aristodemos-Theodoros Periferakis, Carla Mihaela Tone, Daria Alexandra Hemes, Konstantinos Periferakis, Lamprini Troumpata, Ioana Anca Badarau, Cristian Scheau, Ana Caruntu, Ilinca Savulescu-Fiedler, Constantin Carun
Current Issues in Molecular Biology.2024; 46(9): 9721. CrossRef
Insulin-Like Growth Factor 1 as a Pillar in Acromegaly: From Diagnosis to Long-Term Management
Mi Kyung Kim
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Diagnosis and Management of Acromegaly: A Consensus Statement of the Pituitary Study Group of the Portuguese Society of Endocrinology, Diabetes and Metabolism
Luís Miguel Cardoso, Pedro Marques, Maria Teresa Pereira, Ana Agapito, Rui Almeida, Sara Amaral, Maria João Bugalho, Maria Begoña Cattoni, Luísa Cortez, Diana Borges Duarte, João Sequeira Duarte, Fernando Fonseca, Leonor Gomes, Inês Manique, Olinda
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Suneela Dhaneshwar, Shrishti Shandily, Vatsalya Tiwari
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Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly
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International Journal of Thyroidology.2022; 15(1): 1. CrossRef
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I. A. Ilovayskaya
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Alexandru Dan Popescu, Mara Carsote, Ana Valea, Andreea Gabriela Nicola, Ionela Teodora Dascălu, Tiberiu Tircă, Jaqueline Abdul-Razzak, Mihaela Jana Țuculină
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Severe respiratory failure in a patient with COVID-19 and acromegaly: rapid improvement after adding octreotide
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Precision Therapy in Acromegaly Caused by Pituitary Tumors: How Close Is It to Reality?
Cheol Ryong Ku, Vladimir Melnikov, Zhaoyun Zhang, Eun Jig Lee
Endocrinology and Metabolism.2020; 35(2): 206. CrossRef
Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement
Sang Ouk Chin, Cheol Ryong Ku, Byung Joon Kim, Sung-Woon Kim, Kyeong Hye Park, Kee Ho Song, Seungjoon Oh, Hyun Koo Yoon, Eun Jig Lee, Jung Min Lee, Jung Soo Lim, Jung Hee Kim, Kwang Joon Kim, Heung Yong Jin, Dae Jung Kim, Kyung Ae Lee, Seong-Su Moon, Dong
The Korean Journal of Medicine.2019; 94(6): 485. CrossRef

Response

Obesity and Metabolism
Response: The Effects of High Fat Diet and Resveratrol on Mitochondrial Activity of Brown Adipocytes (Endocrinol Metab 2016;31:328-35, Cheol Ryong Ku et al.): Cheol Ryong Ku, Eun Jig Lee; Endocrinol Metab. 2016;31(3):482-483. Published online September 26, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.3.482

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Citations

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Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor
Clara Lefranc, Malou Friederich-Persson, Roberto Palacios-Ramirez, Aurelie Nguyen Dinh Cat
Journal of Endocrinology.2018; 238(3): R143. CrossRef

Original Article

Endocrine Research
The Effects of High Fat Diet and Resveratrol on Mitochondrial Activity of Brown Adipocytes: Cheol Ryong Ku, Yoon Hee Cho, Zhen-Yu Hong, Ha Lee, Sue Ji Lee, Seung-soo Hong, Eun Jig Lee; Endocrinol Metab. 2016;31(2):328-335. Published online April 8, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.2.328

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Background

Resveratrol (RSV) is a polyphenolic phytoalexin that has many effects on metabolic diseases such as diabetes and obesity. Given the importance of brown adipose tissue (BAT) for energy expenditure, we investigated the effects of RSV on brown adipocytes.

Methods

For the in vitro study, interscapular BAT was isolated from 7-week-old male Sprague Dawley rats. For the in vivo study, 7-week-old male Otsuka Long Evans Tokushima Fatty (OLETF) rats were divided into four groups and treated for 27 weeks with: standard diet (SD); SD+RSV (10 mg/kg body weight, daily); high fat diet (HFD); HFD+RSV. RSV was provided via oral gavage once daily during the in vivo experiments.

Results

RSV treatment of primary cultured brown preadipocytes promoted mitochondrial activity, along with over-expression of estrogen receptor α (ER-α). In OLETF rats, both HFD and RSV treatment increased the weight of BAT and the differentiation of BAT. However, only RSV increased the mitochondrial activity and ER-α expression of BAT in the HFD-fed group. Finally, RSV improved the insulin sensitivity of OLETF rats by increasing the mitochondrial activity of BAT, despite having no effects on white adipocytes and muscles in either diet group.

Conclusion

RSV could improve insulin resistance, which might be associated with mitochondrial activity of brown adipocyte. Further studies evaluating the activity of RSV for both the differentiation and mitochondrial activity of BAT could be helpful in investigating the effects of RSV on metabolic parameters.

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