Endocrinology and Metabolism

Review Article

Adrenal gland
A Contemporary Approach to the Diagnosis and Management of Adrenal Insufficiency: Suranut Charoensri, Richard J. Auchus; Endocrinol Metab. 2024;39(1):73-82. Published online January 22, 2024; DOI: https://doi.org/10.3803/EnM.2024.1894

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Adrenal insufficiency (AI) can be classified into three distinct categories based on its underlying causes: primary adrenal disorders, secondary deficiencies in adrenocorticotropin, or hypothalamic suppression from external factors, most commonly glucocorticoid medications used for anti-inflammatory therapy. The hallmark clinical features of AI include fatigue, appetite loss, unintentional weight loss, low blood pressure, and hyponatremia. Individuals with primary AI additionally manifest skin hyperpigmentation, hyperkalemia, and salt craving. The diagnosis of AI is frequently delayed due to the non-specific symptoms and signs early in the disease course, which poses a significant challenge to its early detection prior to an adrenal crisis. Despite the widespread availability of lifesaving glucocorticoid medications for decades, notable challenges persist, particularly in the domains of timely diagnosis while simultaneously avoiding misdiagnosis, patient education for averting adrenal crises, and the determination of optimal replacement therapies. This article reviews recent advancements in the contemporary diagnostic strategy and approaches to optimal treatment for AI.

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Post-Traumatic Hypopituitarism
Nissa Blocher
Current Physical Medicine and Rehabilitation Reports.2024;[Epub] CrossRef
Severe Fatigue in Uncontrolled Asthma: Contributing Factors and Impact of Rehabilitation
Karin B. Fieten, Lianne ten Have, Linde N. Nijhof, Lucia Rijssenbeek-Nouwens, Anneke ten Brinke
The Journal of Allergy and Clinical Immunology: In Practice.2024;[Epub] CrossRef
Adrenal Insufficiency in Patients with Beta Thalassemia: A Meta-Analysis
Christos Savvidis, Dimitra Ragia, Sophia Delicou, Aikaterini Xydaki, Manfredi Rizzo, Ioannis Ilias
Medicina.2024; 60(10): 1571. CrossRef

Original Article

Miscellaneous
Incidence of Endocrine-Related Dysfunction in Patients Treated with New Immune Checkpoint Inhibitors: A Meta-Analysis and Comprehensive Review: Won Sang Yoo, Eu Jeong Ku, Eun Kyung Lee, Hwa Young Ahn; Endocrinol Metab. 2023;38(6):750-759. Published online November 13, 2023; DOI: https://doi.org/10.3803/EnM.2023.1785

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Background
This study investigated the incidence of endocrine immune-related adverse events (irAEs) for recently developed immune checkpoint inhibitor (ICI) drugs.
Methods
We collected studies on newly developed ICI drugs using PubMed/Medline, Embase, and Cochrane Library from inception through January 31, 2023. Among ICI drugs, nivolumab, pembrolizumab, and ipilimumab were excluded from the new ICI drugs because many papers on endocrine-related side effects have already been published.
Results
A total of 44,595 patients from 177 studies were included in this analysis. The incidence of hypothyroidism was 10.1% (95% confidence interval [CI], 8.9% to 11.4%), thyrotoxicosis was 4.6% (95% CI, 3.8% to 5.7%), hypophysitis was 0.8% (95% CI, 0.5% to 1.1%), adrenal insufficiency was 0.9% (95% CI, 0.7% to 1.1%), and hyperglycemia was 2.3% (95% CI, 1.6% to 3.4%). Hypothyroidism and thyrotoxicosis occurred most frequently with programmed cell death protein-1 (PD-1) inhibitors (13.7% and 7.5%, respectively). The rate of endocrine side effects for the combination of a programmed death-ligand 1 inhibitor (durvalumab) and cytotoxic T lymphocyte-associated antigen 4 inhibitor (tremelimumab) was higher than that of monotherapy. In a meta-analysis, the combination of tremelimumab and durvalumab had a 9- to 10-fold higher risk of pituitary and adrenal-related side effects than durvalumab alone.
Conclusion
Newly developed PD-1 inhibitors had a high incidence of thyroid-related irAEs, and combined treatment with durvalumab and tremelimumab increased the risk of pituitary- and adrenal-related irAEs. Based on these facts, it is necessary to predict the endocrine side effects corresponding to each ICI drug, diagnose and treat them appropriately, and try to reduce the morbidity and mortality of patients.

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Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease
Saedis Saevarsdottir, Kristbjörg Bjarnadottir, Thorsteinn Markusson, Jonas Berglund, Thorunn A. Olafsdottir, Gisli H. Halldorsson, Gudrun Rutsdottir, Kristbjorg Gunnarsdottir, Asgeir Orn Arnthorsson, Sigrun H. Lund, Lilja Stefansdottir, Julius Gudmundsson
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Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study
Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Tetsushi Izuchi, Koji Suzuki, Koki Otake, Yoshinori Yasuda, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Naoki Nishio, Shoi
Cancer Immunology, Immunotherapy.2024;[Epub] CrossRef
Pituitary Complications of Checkpoint Inhibitor Use
Natalia Chamorro-Pareja, Alexander T Faje, Karen K Miller
Endocrinology.2024;[Epub] CrossRef

Review Article

Adrenal Gland
Clinical and Technical Aspects in Free Cortisol Measurement: Man Ho Choi; Endocrinol Metab. 2022;37(4):599-607. Published online August 19, 2022; DOI: https://doi.org/10.3803/EnM.2022.1549

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Accurate measurement of cortisol is critical in adrenal insufficiency as it reduces the risk associated with misdiagnosis and supports the optimization of stress dose. Comprehensive assays have been developed to determine the levels of bioactive free cortisol and their clinical and analytical efficacies have been extensively discussed because the level of total cortisol is affected by changes in the structure or circulating levels of corticoid-binding globulin and albumin, which are the main reservoirs of cortisol in the human body. Antibody-based immunoassays are routinely used in clinical laboratories; however, the lack of molecular specificity in cortisol assessment limits their applicability to characterize adrenocortical function. Improved specificity and sensitivity can be achieved by mass spectrometry coupled with chromatographic separation methods, which is a cutting-edge technology to measure individual as well as a panel of steroids in a single analytical run. The purpose of this review is to introduce recent advances in free cortisol measurement from the perspectives of clinical specimens and issues associated with prospective analytical technologies.

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Comparative analysis of salivary cortisol measurements using different assay methods in relation to serum-free cortisol measurement
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Daniela Bartolovic, Snezana Jovicic, Branka Terzic
Vojnosanitetski pregled.2024; 81(5): 318. CrossRef
Current Challenges and Future Directions in the Assessment of Glucocorticoid Status
Sophie A Clarke, Pei Chia Eng, Alexander N Comninos, Katharine Lazarus, Sirazum Choudhury, Christie Tsang, Karim Meeran, Tricia M Tan, Waljit S Dhillo, Ali Abbara
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Run Yu
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Kwuntida Uthaisar Kotepui, Frederick Ramirez Masangkay, Kinley Wangdi, Aongart Mahittikorn, Hideyuki J. Majima, Manas Kotepui
Scientific Reports.2024;[Epub] CrossRef
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Stephanie Lawrence, R. Hal Scofield
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Aleksandar Sic, Kiana Cvetkovic, Eshanika Manchanda, Nebojsa Nick Knezevic
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Kade C. Flowers, Kate E. Shipman
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Electrochemical sensors for cortisol detection: Principles, designs, fabrication, and characterisation
Gopi Karuppaiah, Min-Ho Lee, Shekhar Bhansali, Pandiaraj Manickam
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Critical Care.2022;[Epub] CrossRef

Special Article

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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Review Article

Miscellaneous
Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors: Shintaro Iwama, Tomoko Kobayashi, Hiroshi Arima; Endocrinol Metab. 2021;36(2):312-321. Published online April 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1007

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Immune-related adverse events (irAEs) affecting the endocrine glands are among the most frequent irAEs induced by immune checkpoint inhibitors (ICIs) and include hypopituitarism, primary adrenal insufficiency, thyrotoxicosis, hypothyroidism, hypoparathyroidism, and type 1 diabetes mellitus. Since the incidence and clinical features of endocrine irAEs vary according to the ICI used, it is important to understand the characteristics of these irAEs and to manage each one appropriately. Since some endocrine irAEs, including adrenal crisis and diabetic ketoacidosis, are potentially life-threatening, predicting the risk of endocrine irAEs before their onset is critical. Several autoantibodies have been detected in patients who develop endocrine irAEs, among which anti-thyroid antibodies may be predictive biomarkers of thyroid dysfunction. In this review, we describe the clinical features of each endocrine irAE induced by ICIs and discuss their potential biomarkers, including autoantibodies.

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Clinical characteristics and potential biomarkers of thyroid and pituitary immune-related adverse events
Tomoko Kobayashi, Shintaro Iwama, Hiroshi Arima
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A case of rapidly progressive insulin-dependent diabetes mellitus without islet autoantibodies developed over two years after the first dose of nivolumab
Kota Nishihama, Yuko Okano, Chisa Inoue, Kanako Maki, Kazuhito Eguchi, Soichiro Tanaka, Atsuro Takeshita, Mei Uemura, Taro Yasuma, Toshinari Suzuki, Esteban C. Gabazza, Yutaka Yano
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Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study
Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Tetsushi Izuchi, Koji Suzuki, Koki Otake, Yoshinori Yasuda, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Naoki Nishio, Shoi
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Adrenal Insufficiency and Thyrotoxicosis Following Combined Immune Checkpoint Inhibitor Use: A Case Report and Literature Review
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Changes in TgAb and TPOAb titers are greater in thyrotoxicosis than isolated hypothyroidism induced by PD-1 blockade
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Elevated TSH Level, TgAb, and Prior Use of Ramucirumab or TKIs as Risk Factors for Thyroid Dysfunction in PD-L1 Blockade
Tomoko Kobayashi, Shintaro Iwama, Ayana Yamagami, Yoshinori Yasuda, Takayuki Okuji, Masaaki Ito, Xin Zhou, Masahiko Ando, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Taka
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Fabiana Pani, Yoshinori Yasuda, Sylvie T Rousseau, Kevin C Bermea, Solmaz Roshanmehr, Rulin Wang, Srinivasan Yegnasubramanian, Patrizio Caturegli, Luigi Adamo
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Original Article

Clinical Study
Stimulated Salivary Cortisol as a Noninvasive Diagnostic Tool for Adrenal Insufficiency: Yoon Ji Kim, Jung Hee Kim, A Ram Hong, Kyeong Seon Park, Sang Wan Kim, Chan Soo Shin, Seong Yeon Kim; Endocrinol Metab. 2020;35(3):628-635. Published online September 22, 2020; DOI: https://doi.org/10.3803/EnM.2020.707

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Background
Salivary cortisol is routinely used as a diagnostic test for Cushing syndrome. The diagnostic use of salivary cortisol for adrenal insufficiency (AI), however, is less established. We aimed to investigate the utility of morning basal and adrenocorticotropic hormone-stimulated salivary cortisol in diagnosing AI in Korean adults.
Methods
We prospectively included 120 subjects (female, n=70) from Seoul National University Hospital. AI was defined as a stimulated serum cortisol level of <496.8 nmol/L during the short Synacthen test (SST). Serum and saliva samples were drawn between 8:00 AM and 10:00 AM. Salivary cortisol levels were measured using an enzyme immunoassay kit.
Results
Thirty-four patients were diagnosed with AI according to the SST results. Age, sex, body mass index, serum albumin levels, and serum creatinine levels did not significantly differ between the normal and AI groups. Basal and stimulated salivary cortisol levels were positively correlated with basal (r=0.538) and stimulated serum cortisol levels (r=0.750), respectively (all P<0.001). Receiver operating characteristic curve analysis yielded a cutoff level of morning basal salivary cortisol of 3.2 nmol/L (sensitivity, 84.9%; specificity, 73.5%; area under the curve [AUC]=0.822). The optimal cutoff value of stimulated salivary cortisol was 13.2 nmol/L (sensitivity, 90.7%; specificity, 94.1%; AUC=0.959). Subjects with a stimulated salivary cortisol level above 13.2 nmol/L but a stimulated serum cortisol level below 496.8 nmol/L (n=2) had lower serum albumin levels than those showing a concordant response.
Conclusion
The diagnostic performance of stimulated salivary cortisol measurements after the SST was comparable to serum cortisol measurements for diagnosing AI.

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Eva A. van Aalen, Joep J. J. Lurvink, Leandra Vermeulen, Benice van Gerven, Yan Ni, Remco Arts, Maarten Merkx
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A Contemporary Approach to the Diagnosis and Management of Adrenal Insufficiency
Suranut Charoensri, Richard J. Auchus
Endocrinology and Metabolism.2024; 39(1): 73. CrossRef
Insuficiencia suprarrenal
A.E. Ortiz-Flores, M. Araujo-Castro, E. Pascual-Corrales, H.F. Escobar-Morreale
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Utility of Salivary Cortisol and Cortisone in the Diagnostics of Adrenal Insufficiency
Kåre Kvam Hellan, Martin Lyngstad, Paal Methlie, Kristian Løvås, Eystein Sverre Husebye, Grethe Åstrøm Ueland
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Nissa Blocher
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The Reliability of Salivary Cortisol Compared to Serum Cortisol for Diagnosing Adrenal Insufficiency with the Gold Standard ACTH Stimulation Test in Children
Silvia Ciancia, Sjoerd A. A. van den Berg, Erica L. T. van den Akker
Children.2023; 10(9): 1569. CrossRef
РІВЕНЬ СТРЕСУ В ДІТЕЙ ШКІЛЬНОГО ВІКУ З COVID-19
Г. А. Павлишин, О. І. Панченко
Здобутки клінічної і експериментальної медицини.2023; (4): 119. CrossRef
Secondary adrenal suppression related to high doses of inhaled corticosteroids in patients with severe asthma
Mariana Lobato, João Gaspar-Marques, Pedro Carreiro-Martins, Paula Leiria-Pinto
Annals of Allergy, Asthma & Immunology.2022; 128(4): 464. CrossRef
Clinical and Technical Aspects in Free Cortisol Measurement
Man Ho Choi
Endocrinology and Metabolism.2022; 37(4): 599. CrossRef
Continuous biomarker monitoring with single molecule resolution by measuring free particle motion
Alissa D. Buskermolen, Yu-Ting Lin, Laura van Smeden, Rik B. van Haaften, Junhong Yan, Khulan Sergelen, Arthur M. de Jong, Menno W. J. Prins
Nature Communications.2022;[Epub] CrossRef
Reversible Immunosensor for the Continuous Monitoring of Cortisol in Blood Plasma Sampled with Microdialysis
Laura van Smeden, Annet Saris, Khulan Sergelen, Arthur M. de Jong, Junhong Yan, Menno W. J. Prins
ACS Sensors.2022; 7(10): 3041. CrossRef
Adrenal insufficiency in HIV/AIDS: a review
Simon Mifsud, Zachary Gauci, Mark Gruppetta, Charles Mallia Azzopardi, Stephen Fava
Expert Review of Endocrinology & Metabolism.2021; 16(6): 351. CrossRef

Review Article

Miscellaneous
Encountering COVID-19 as Endocrinologists: Eun-Jung Rhee, Jung Hee Kim, Sun Joon Moon, Won-Young Lee; Endocrinol Metab. 2020;35(2):197-205. Published online June 23, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.197

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The world is entering an era of disaster and chaos due to coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2. Since its first emergence in December 2019 in Wuhan, China, COVID-19 has swept through Asia and propagated throughout the world to Europe and North America. As of April 13, 1,773,084 people were infected and 111,652 people had died from COVID-19 globally, and new record levels of infection are being reported every day. Based on the data that have been amassed so far, the primary risk factors for a severe disease course or even mortality from COVID-19 are underlying diseases such as diabetes and hypertension. As the global prevalence of diabetes continues to increase, patients with endocrine diseases such as diabetes mellitus and those who are on long-term corticosteroid therapy due to adrenal insufficiency or hypopituitarism are at risk for a poor prognosis of COVID-19. As endocrinologists, we would like to briefly review the current knowledge about the relationship between COVID-19 and endocrine diseases and to discuss what we can do for the safety and health of our patients with endocrine diseases in this globally threatening situation.

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International Journal of Molecular Sciences.2022; 23(13): 7326. CrossRef
WhatsApp-Based Virtual Consultation in Clinical Practice during COVID Times
Ramakanth Bhargav Panchangam, Pradeep Puthenveetil, Sunil Kumar Kota, Sabaretnam Mayilvaganan
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Thyroid and COVID-19: a review on pathophysiological, clinical and organizational aspects
G. Lisco, A. De Tullio, E. Jirillo, V. A. Giagulli, G. De Pergola, E. Guastamacchia, V. Triggiani
Journal of Endocrinological Investigation.2021; 44(9): 1801. CrossRef
Effects of a DPP-4 Inhibitor and RAS Blockade on Clinical Outcomes of Patients with Diabetes and COVID-19
Sang Youl Rhee, Jeongwoo Lee, Hyewon Nam, Dae-Sung Kyoung, Dong Wook Shin, Dae Jung Kim
Diabetes & Metabolism Journal.2021; 45(2): 251. CrossRef
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
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Diabetes & Metabolism Journal.2020; 44(5): 737. CrossRef
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Michelle D Lundholm, Caroline Poku, Nicholas Emanuele, Mary Ann Emanuele, Norma Lopez
Journal of the Endocrine Society.2020;[Epub] CrossRef

Original Articles

Clinical Characteristics of Patients with Adrenal Insufficiency in a General Hospital: Ye Yeon Lee, Nan Hee Cho, Jong Won Lee, Nam Kyung Kim, Hye Soon Kim, Mi-Kyung Kim; Endocrinol Metab. 2017;32(1):83-89. Published online February 28, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.1.83

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Background

Adrenal insufficiency (AI) is a life-threatening disorder caused by the deficiency of adrenal steroid hormones. This retrospective cross-sectional study investigated the characteristics of patients with AI in Korea.

Methods

All consecutive patients with suspected AI who received care at a tertiary referral center in Korea in 2014 and underwent adrenocorticotropic hormone stimulation or insulin-tolerance testing were identified through a review of medical charts. Patients diagnosed with AI were enrolled. Their demographic, clinical, and treatment details were extracted.

Results

Of 771 patients with suspected AI, 183 (23.7%) received a definitive diagnosis. The most common reason for testing was the presence of suspicious AI-related symptoms (30.0%), followed by a history of steroid medications (23.5%). Their mean age was 66.7 years, and females predominated (67.8%). The most common symptoms were general weakness, anorexia, arthralgia, and fever. Approximately half (53.6%) had a history of steroid use. Hydrocortisone was the most common treatment (71.6%), with most patients taking a 30 mg dose (44.2%). The most common dose frequency was twice a day (78.6%). Fourteen patients were treated for adrenal crisis (n=10, 5.5%) or an intercurrent illness (n=4, 2.2%).

Conclusion

AI may have been caused by steroid medication use in many of the patients included in this study. The detection of AI can be improved by careful history-taking and being alert to the possibility that a patient has used steroids.

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Risk of Mental Illnesses in Patients With Hypopituitarism: A Nationwide Population-Based Cohort Study
I-Hua Wei, Chih-Chia Huang
Psychiatry Investigation.2022; 19(6): 418. CrossRef
The Role of the Pharmacist in Optimizing Cancer Immunotherapy: A Retrospective Study of Nivolumab Adverse Events
Bradley D. Menz, Jacinta L. Johnson, Davina F. Gillard, William Chong, Michael B. Ward
Journal of Pharmacy Practice.2021; 34(3): 386. CrossRef
Clinical and biochemical factors to predict biochemical adrenal insufficiency in hospitalized patients with indeterminate cortisol levels: a retrospective study
Worapaka Manosroi, Natapong Kosachunhanan, Pichitchai Atthakomol
BMC Endocrine Disorders.2020;[Epub] CrossRef
Possible adrenal insufficiency among fatigue patients in a psychosomatic medical clinic
Sunao Matsubayashi, Nobuhiro Nakatake, Takeshi Hara
Endocrine Journal.2020; 67(1): 53. CrossRef
Encountering COVID-19 as Endocrinologists
Eun-Jung Rhee, Jung Hee Kim, Sun Joon Moon, Won-Young Lee
Endocrinology and Metabolism.2020; 35(2): 197. CrossRef
Glucocorticoid management of adrenal insufficiency in the United Kingdom: assessment using real-world data
Kamran Iqbal, Kate Halsby, Robert D Murray, Paul V Carroll, Robert Petermann
Endocrine Connections.2019; 8(1): 20. CrossRef

Clinical Study
Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary Adrenal Insufficiency: Jong Ha Baek, Soo Kyoung Kim, Jung Hwa Jung, Jong Ryeal Hahm, Jaehoon Jung; Endocrinol Metab. 2016;31(1):153-160. Published online March 16, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.1.153

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Background

The chronic use of glucocorticoids (GC) suppresses function of the hypothalamic-pituitary-adrenal axis and often results in secondary adrenal insufficiency (AI). The present study aimed to determine the recovery rate of adrenal function in patients with secondary AI within 1 to 2 years and to assess the factors predictive of adrenal function recovery.

Methods

This was a retrospective observational study that enrolled patients diagnosed with GC-induced secondary AI between 2007 and 2013. AI was defined by peak serum cortisol levels <18 µg/dL during a standard-dose short synacthen test (SST). A follow-up SST was performed after 1 to 2 years, and responders were defined as those with adrenocorticotropic hormone (ACTH)-stimulated peak serum cortisol levels ≥18 µg/dL.

Results

Of the total 34 patients diagnosed with GC-induced secondary AI at first, 20 patients (58.8%) recovered normal adrenal function by the time of the follow-up SST (median follow-up period, 16.5 months). Although the baseline serum ACTH and cortisol levels at the first SST did not differ between responders and non-responders, the incremental cortisol response during the first SST was higher in responders than that of non-responders (7.88 vs. 3.56, P<0.01). Additionally, higher cortisol increments during the first SST were an independent predictive factor of the adrenal function recovery (odds ratio, 1.58; 95% confidence interval, 1.02 to 2.46; P<0.05).

Conclusion

In the present study, adrenal function recovery was achieved frequently in patients with GC-induced secondary AI within 1 to 2 years. Additionally, an incremental cortisol response at the first SST may be an important predictive factor of adrenal function recovery.

Citations

Citations to this article as recorded by

European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency
Felix Beuschlein, Tobias Else, Irina Bancos, Stefanie Hahner, Oksana Hamidi, Leonie van Hulsteijn, Eystein S Husebye, Niki Karavitaki, Alessandro Prete, Anand Vaidya, Christine Yedinak, Olaf M Dekkers
European Journal of Endocrinology.2024; 190(5): G25. CrossRef
European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency
Felix Beuschlein, Tobias Else, Irina Bancos, Stefanie Hahner, Oksana Hamidi, Leonie van Hulsteijn, Eystein S Husebye, Niki Karavitaki, Alessandro Prete, Anand Vaidya, Christine Yedinak, Olaf M Dekkers
The Journal of Clinical Endocrinology & Metabolism.2024; 109(7): 1657. CrossRef
Safely Withdrawing Glucocorticoid Therapy: A Case-Based Approach
Mohammed Alenazi, Khaled Aldahmani, Syed Ali Imran
Journal of Diabetes and Endocrine Practice.2024; 07(03): 129. CrossRef
Secondary Adrenal Insufficiency: Recent Updates and New Directions for Diagnosis and Management
Lucinda M. Gruber, Irina Bancos
Endocrine Practice.2022; 28(1): 110. CrossRef
Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study
Andrew Menzies-Gow, Mark Gurnell, Liam G Heaney, Jonathan Corren, Elisabeth H Bel, Jorge Maspero, Timothy Harrison, David J Jackson, David Price, Njira Lugogo, James Kreindler, Annie Burden, Alex de Giorgio-Miller, Kelly Padilla, Ubaldo J Martin, Esther G
The Lancet Respiratory Medicine.2022; 10(1): 47. CrossRef
Development and Resolution of Secondary Adrenal Insufficiency after an Intra-Articular Steroid Injection
Jia Wei Tan, Sachin K. Majumdar, Osamu Isozaki
Case Reports in Endocrinology.2022; 2022: 1. CrossRef
Long‐term corticosteroid use, adrenal insufficiency and the need for steroid‐sparing treatment in adult severe asthma
M. Gurnell, L. G. Heaney, D. Price, A. Menzies‐Gow
Journal of Internal Medicine.2021; 290(2): 240. CrossRef
Glucocorticoid Withdrawal—An Overview on When and How to Diagnose Adrenal Insufficiency in Clinical Practice
Katarzyna Pelewicz, Piotr Miśkiewicz
Diagnostics.2021; 11(4): 728. CrossRef
Morning Serum Cortisol as a Predictor for the HPA Axis Recovery in Cushing’s Disease
Q. Cui, D. Liu, B. Xiang, Q. Sun, L. Fan, M. He, Y. Wang, X. Zhu, H. Ye, Giorgio Borretta
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Dexamethasone-related adrenal insufficiency in patients with brain and skull base tumours
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Articles inEndocrinology and Metabolismin 2016
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The unresolved riddle of glucocorticoid withdrawal
F. Guerrero Pérez, A. P. Marengo, C. Villabona Artero
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Lessons from iatrogenic Cushing syndrome in children
Betty P Messazos, Margaret R Zacharin
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Case Reports

Adrenal gland
Allgrove (Triple A) Syndrome: A Case Report from the Kashmir Valley: Raiz Ahmad Misgar, Nazir Ahmad Pala, Mahroosa Ramzan, Arshad Iqbal Wani, Mir Iftikhar Bashir, Bashir Ahmad Laway; Endocrinol Metab. 2015;30(4):604-606. Published online December 31, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.4.604

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Allgrove (Triple A) syndrome is a rare autosomal recessive disorder characterized by cardinal features of adrenal insufficiency due to adrenocorticotropic hormone (ACTH) resistance, achalasia, and alacrimia. It is frequently associated with neurological manifestations like polyneuropathy. Since its first description by Allgrove in 1978, approximately 100 cases have been reported in the literature. Here we report an 18-year-old boy diagnosed as having Allgrove syndrome, with ACTH resistant adrenal insufficiency, achalasia, alacrimia, and severe motor polyneuropathy. Alacrimia was the earliest feature evident at the age of 8 years. He presented with achalasia and adrenal insufficiency at 12 and 18 years respectively and developed neurological symptoms in the form of severe muscle wasting at the age of 15 years. Patients with Allgrove syndrome usually manifest adrenal insufficiency and achalasia during first decade of life. Our patient manifested adrenal insufficiency and achalasia in the second decade and manifested neurological dysfunction before adrenal dysfunction.

Citations

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Child Neurology: Allgrove Syndrome
Juhi Gupta, Sayoni Roy Chowdhury, Prashant Jauhari, Kaushik Ragunathan, Biswaroop Chakrabarty, Vandana Jain, Sheffali Gulati
Neurology.2024;[Epub] CrossRef
Don’t forget Allgrove syndrome in adult patients as a bulbar-ALS mimicker
Martina Vigano’, Vittorio Mantero, Paola Basilico, Fiammetta Pirro, Dario Ronchi, Alessio Di Fonzo, Andrea Salmaggi
Neurological Sciences.2023; 44(10): 3703. CrossRef
Triple A (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy
Satyam Singh Jayant, Rahul Gupta, Kanhaiya Agrawal, Liza Das, Pinaki Dutta, Anil Bhansali
Hormones.2021; 20(1): 197. CrossRef
Allgrove syndrome with amyotrophy
Míriam Carvalho Soares, Otávio Gomes Lins, José Ronaldo Lima de Carvalho, Cláudia Cristina de Sá, Vanessa Van der Linden, Anna Paula Paranhos Miranda Covaleski
Practical Neurology.2021; : practneurol-2021-003192. CrossRef
Triple A syndrome (Allgrove syndrome) – A journey from clinical symptoms to a syndrome
Prakarti Yadav, Deepak Kumar, GopalK Bohra, MahendraK Garg
Journal of Family Medicine and Primary Care.2020; 9(5): 2531. CrossRef
Case report of a familial triple: a syndrome and review of the literature
Federica Gaiani, Pierpacifico Gismondi, Roberta Minelli, Giovanni Casadio, Nicola de’Angelis, Fabiola Fornaroli, Gian Luigi de’Angelis, Marco Manfredi
Medicine.2020; 99(22): e20474. CrossRef
Clinical and genetic characterisation of a series of patients with triple A syndrome
Erdal Kurnaz, Paolo Duminuco, Zehra Aycan, Şenay Savaş-Erdeve, Nursel Muratoğlu Şahin, Melişah Keskin, Elvan Bayramoğlu, Marco Bonomi, Semra Çetinkaya
European Journal of Pediatrics.2018; 177(3): 363. CrossRef
Clinical heterogeneity and molecular profile of triple A syndrome: a study of seven cases
Kanika Singh, Ratna Dua Puri, Pratibha Bhai, Archana Dayal Arya, Garima Chawla, Renu Saxena, Ishwar C. Verma
Journal of Pediatric Endocrinology and Metabolism.2018; 31(7): 799. CrossRef
Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove syndrome: a case report
H. Berrani, T. Meskini, M. Zerkaoui, H. Merhni, S. Ettair, A. Sefiani, N. Mouane
BMC Pediatrics.2018;[Epub] CrossRef

A Case of Primary Adrenal Insufficiency in a Patient with Acquired Immunodeficiency Syndrome.: Jae Ho Choi, Suk Chon, Yu Chul Hwang, Jun Seong Son, Seung Joon Oh, Kyu Jeung Ahn, Ho Yeon Chung, Jeong Taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, In Kyung Jeong; Endocrinol Metab. 2011;26(3):253-257. Published online September 1, 2011; DOI: https://doi.org/10.3803/EnM.2011.26.3.253

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Abstract PDF

The adrenal gland is the most commonly involved endocrine organ in patients infected with the human immunodeficiency virus (HIV). Adrenal function abnormality is more common in HIV patients than in the general population. It is important to recognize the condition of adrenal insufficiency, as this adrenal disorder may prove fatal if left untreated. Herein, we report a case of primary adrenal insufficiency in a 37-year-old male patient with acquired immunodeficiency syndrome. The patient complained of fever, general weakness, and fatigue. Impaired adrenal function was noted in the rapid ACTH stimulation test. After steroid supplementation, the patient's symptoms were improved. Therefore, HIV care physicians should ascertain adrenal dysfunction in HIV patients when they complain of fever and general weakness.

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A Case Report of Adrenal Insufficiency Treated with Korean Medicine
Young-ji Kim, Jung-yeon Kwon, Ho-yeon Go, Kyung-hwan Kong
The Journal of Internal Korean Medicine.2017; 38(5): 583. CrossRef

A Case Report of Bilateral Adrenocortical Carcinoma Complicated by Adrenal Insufficiency.: Min Joo Kim, Jung Hee Kim, Tae Young Kim, Sang Wan Kim; Endocrinol Metab. 2011;26(3):243-247. Published online September 1, 2011; DOI: https://doi.org/10.3803/EnM.2011.26.3.243

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Abstract PDF

Adrenocortical carcinoma is often functional and presents with signs and symptoms of adrenal steroid hormone excess. Adrenal insufficiency secondary to bilateral adrenocortical carcinoma is a particularly rare complication. We recently encountered a case of bilateral adrenocortical carcinoma complicated by adrenal insufficiency. A 52-year-old male was transferred to this hospital complaining of general weakness and weight loss. A bilateral adrenal mass was detected on abdomen CT. Plasma cortisol and aldosterone failed to rise during the rapid ACTH stimulation test. The CT-guided adrenal biopsy revealed findings consistent with adrenocortical carcinoma. Left hemiparesis was developed and brain metastasis was detected via brain MRI. Despite the application of gamma knife surgery and chemotherapy, the disease progressed and the patient died.

Citations

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Bilateral Adrenocortical Carcinoma Presenting as Acute Adrenal Insufficiency
Anshita Aggarwal, Aprajita Verma, Aparajita Roy, Bindu Kulshreshtha
European Endocrinology.2020; 16(2): 172. CrossRef
A Case of Bilateral ACTH-independent Adrenal Adenomas with Cushing's Syndrome Treated by Ipsilateral Total and Contralateral Partial Laparoscopic Adrenalectomy
Seung Ah Park, Dong min Jung, Soon young Kim, Nan Young Choi, Tae-jun Kim, Yong kyun Kim, Seong kyun Na, Chul Sik Kim, Seong Jin Lee, Sung-Hee Ihm, Jun Goo Kang
The Korean Journal of Obesity.2013; 22(4): 254. CrossRef

Original Article

No Significance of the Free Cortisol Index Compared to Total Cortisol in Critically Ill Patients.: Kyung Won Kim, Sang Wan Kim, Hee Joung Kim, Chan Soo Shin, Sung Jae Park, Gil Joon Suh, Seong Yeon Kim; Endocrinol Metab. 2011;26(2):120-125. Published online June 1, 2011; DOI: https://doi.org/10.3803/EnM.2011.26.2.120

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Abstract PDF

BACKGROUND
Some patients exhibit an inadequate response of cortisol to stressful conditions; this state is known as critical illness-related corticosteroid insufficiency. These patients have low serum binding protein concentrations, thereby suggesting that total serum cortisol may not be reflective of circulating cortisol activity. As the free cortisol index (FCI = total cortisol/corticosteroid-binding globulin) has been correlated with serum free cortisol, we measured FCI in Korean patients for the first time. In this study, we attempted to determine whether FCI was superior to total cortisol in predicting 30-day mortality. METHODS: We recruited 65 critically ill patients with relatively high Acute Physiology, Age and Chronic Health Evaluation (APACHE III) scores. Fourteen patients with pituitary disease but normal pituitary function were recruited from outpatient clinics. Total cortisol and corticosteroid-binding globulin were measured in patients and controls during the short Synacthen test. RESULTS: The basal cortisol level and basal FCI level were higher in patients (n = 65) than in healthy controls (P < 0.001, respectively). We found that total cortisol was strongly correlated with FCI (P < 0.001) in critically ill patients; however, neither total cortisol nor FCI were associated with 30-day mortality among patients. Only severe clinical criteria (such as APACHE-III scores and low albumin) were associated with 30-day mortality. CONCLUSION: Our results do not suggest that FCI is more accurate than total cortisol in predicting clinical outcomes in critically ill patients.

Citations

Citations to this article as recorded by

No Significance of the Free Cortisol Index Compared to Total Cortisol in Critically Ill Patients
Doo-Man Kim
Endocrinology and Metabolism.2011; 26(2): 118. CrossRef

Case Reports

Primary Bilateral Adrenal Non-Hodgkin's Lymphoma Presented with Adrenal Insufficiency: A Case Report.: Eun Young Lee, Kyoung Min Kim, Kwang Joon Kim, Songmi Noh, Jin Seok Kim, Woo Ik Yang, Sung Kil Lim; Endocrinol Metab. 2011;26(1):101-105. Published online March 1, 2011; DOI: https://doi.org/10.3803/EnM.2011.26.1.101

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Primary adrenal lymphoma is a very rare disease and it is known to have a poor prognosis. We report here on a case of primary adrenal insufficiency that was secondary to primary bilateral adrenal lymphoma. A 54-year old man was hospitalized because of easy fatigability, weight loss and consistent malaise for 6 months. The physical examination revealed hyperpigmentation on the anterior chest and hypotension. According these findings and symptoms, we did a rapid ACTH stimulation test with a clinical suspicion of adrenal insufficiency. He showed an inadequate adrenal response and so he was diagnosed with adrenal insufficiency. The abdominal CT images showed bilateral huge adrenal masses and increased uptake of the adrenal glands on PET. The pathologic diagnosis by ultrasound-guided gun biopsy of the right adrenal gland was diffuse large B cell lymphoma. The patient was administered combination chemotherapy with the R-CHOP regimen, and after 8-cycles of chemotherapy, he achieved complete remission of tumor according to the image studies and he recovered his adrenal function. Primary adrenal lymphoma, although a rare disease, should be considered in patients with bilateral enlargement of the adrenal glands and when the adrenal glands show increased uptake on a PET scan, and especially there is adrenal insufficiency.

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Systemic vs. intrathecal central nervous system prophylaxis in primary adrenal/renal diffuse large b-cell Lymphoma: A multi-institution retrospective analysis and systematic review
John Xie, Albert Jang, Motohide Uemura, Shigeaki Nakazawa, Teresa Calimeri, Andres JM Ferreri, Shuang R. Chen, Janet L. Schmid, Theresa C. Brown, Francisco Socola, Hana Safah, Nakhle S. Saba
Leukemia Research Reports.2021; 16: 100263. CrossRef

A Case of Pituitary Macroadenoma Accompanied with CRH Deficiency.: Yoo Jung Nahm, Jin Soo Kim, Keun Jong Cho, Uk Hyun Kil, Sung Yong Woo, Sung Rae Kim, Soon Jib Yoo, Sung Koo Kang, Ho Young Son; J Korean Endocr Soc. 2006;21(2):153-157. Published online April 1, 2006; DOI: https://doi.org/10.3803/jkes.2006.21.2.153

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Abstract PDF: Pituitary tumor can be accompanied with various pituitary hormone abnormalities. Pituitary tumors can be divided into functioning or nonfunctioning tumors. A functioning pituitary tumor, via the oversecretion of pituitary hormones, causes diverse clinical features. A nonfunctioning pituitary tumor can be accompanied with pituitary dysfunction and this may be due to compression or destruction of normal pituitary tissue, suppression of the pituitary portal system or direct damage to the hypothalamus. Corticotropin-releasing hormone (CRH) deficiency, which is caused by defects in the synthesis or release of CRH, is a cause of secondary adrenocortical insufficiency. The clinical presentations are hypoglycemia, weight loss, anemia, weakness, nausea, vomiting and hyponatremia. Acquired CRH deficiency has also been suggested to occur based on a lack of adrenocorticotropic hormone (ACTH) response to insulin-induced hypoglycemia, but there is a normal ACTH response to exogenous CRH. We experienced a case of a woman with pituitary macroadenoma accompanied with CRH deficiency. We report here on this case with the review of the literature.

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