{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:17:55Z","timestamp":1784557075095,"version":"3.55.0"},"reference-count":15,"publisher":"Bioscientifica","issue":"1","license":[{"start":{"date-parts":[[2023,1,1]],"date-time":"2023-01-01T00:00:00Z","timestamp":1672531200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["edm.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,1,1]]},"abstract":"<jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>Hypercalcaemia is a common complication seen in malignancy, frequently due to paraneoplastic parathyroid hormone-related peptide production or osteolytic bony metastases. We present a 58-year-old female with immunotherapy-mediated hypophysitis causing secondary cortisol deficiency resulting in severe glucocorticoid-responsive hypercalcaemia. Whilst hypophysitis is a well recognised adverse event in those receiving immunotherapy for advanced malignancy, it does not typically present with hypercalcaemia. The mechanism responsible for hypercalcaemia due to hypocortisolaemia has not been fully elucidated although hypotheses include the effects of volume depletion and thyroxine\u2019s action on bone. Prompt treatment with glucocorticoids caused an improvement in the patient\u2019s symptoms and corrected her hypercalcaemia which later returned after an attempted glucocorticoid wean. With the increasing uptake of immunotherapy, clinicians should be aware of this unusual presentation of immunotherapy-related hypophysitis and secondary hypocortisolaemia which can be life-threatening if the diagnosis is delayed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Learning points<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Immunotherapy can cause inflammation of the pituitary gland resulting in secondary hypocortisolaemia, which can, though rarely, present as hypercalcaemia.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Secondary hypocortisolaemia requires prompt recognition and treatment with glucocorticoids. Glucocorticoid replacement leads to rapid clinical and biochemical improvement in these patients.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The differential diagnosis for glucocorticoid-responsive hypercalcaemia extends beyond granulomatous disorders (e.g. sarcoidosis, tuberculosis) to adrenocorticotrophic hormone and cortisol deficiency, particularly in patients receiving immunotherapy.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Hypocortisolaemia can lead to hypercalcaemia through various proposed mechanisms. Low serum glucocorticoids are associated with reduced blood volume, thus reducing renal calcium excretion. In addition, without glucocorticoid\u2019s inhibitory action, thyroxine appears to drive calcium mobilisation from bone.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>","DOI":"10.1530\/edm-22-0375","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T09:55:38Z","timestamp":1673949338000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-2","source":"Crossref","is-referenced-by-count":3,"title":["Hypercalcaemia secondary to hypophysitis and cortisol deficiency: another immunotherapy-related adverse event"],"prefix":"10.1530","volume":"2023","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6013-5471","authenticated-orcid":true,"given":"Samuel R","family":"Miller","sequence":"first","affiliation":[{"name":"Medical Oncology, Royal North Shore Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1242-2476","authenticated-orcid":true,"given":"Shejil","family":"Kumar","sequence":"additional","affiliation":[{"name":"Endocrinology, Royal North Shore Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Yuile","sequence":"additional","affiliation":[{"name":"Medical Oncology, Royal North Shore Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M","family":"Menzies","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia; The University of Sydney; Faculty of Medicine and Health; The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Experimental and Molecular Medicine","first-page":"1","article-title":"Immune checkpoint inhibitors: recent progress and potential biomarkers","volume":"50","author":"Darvin","year":"2018","unstructured":"Darvin P\n\n\nToor SM\n\n\nSasidharan Nair V\n\n\nElkord E\n\n. Immune checkpoint inhibitors: recent progress and potential biomarkers. Experimental and Molecular Medicine\n2018\n50\n1\u201311. (https:\/\/doi.org\/10.1038\/s12276-018-0191-1)"},{"key":"bib2","series-title":"JAMA Oncology","first-page":"173","article-title":"Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis","volume":"4","author":"Barroso-Sousa","year":"2018","unstructured":"Barroso-Sousa R\n\n\nBarry WT\n\n\nGarrido-Castro AC\n\n\nHodi FS\n\n\nMin L\n\n\nKrop IE\n\n\nTolaney SM\n\n. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncology\n2018\n4\n173\u2013182. (https:\/\/doi.org\/10.1001\/jamaoncol.2017.3064)"},{"key":"bib3","series-title":"Cureus","article-title":"Pembrolizumab-induced hypophysitis with isolated adrenocorticotropic hormone (ACTH) deficiency: a rare immune-mediated adverse event","volume":"13","author":"Doodnauth","year":"2021","unstructured":"Doodnauth AV\n\n\nKlar M\n\n\nMulatu YS\n\n\nMalik ZR\n\n\nPatel KH\n\n\nMcFarlane SI\n\n. Pembrolizumab-induced hypophysitis with isolated adrenocorticotropic hormone (ACTH) deficiency: a rare immune-mediated adverse event. Cureus\n2021\n13 e15465. (https:\/\/doi.org\/10.7759\/cureus.15465)"},{"key":"bib4","series-title":"BMJ Case Reports","article-title":"Hypercalcaemia, adrenal insufficiency and bilateral adrenal histoplasmosis in a middle-aged man: a diagnostic dilemma","volume":"12","author":"Agrawal","year":"2019","unstructured":"Agrawal S\n\n\nGoyal A\n\n\nAgarwal S\n\n\nKhadgawat R\n\n. Hypercalcaemia, adrenal insufficiency and bilateral adrenal histoplasmosis in a middle-aged man: a diagnostic dilemma. BMJ Case Reports\n2019\n12 e231142. (https:\/\/doi.org\/10.1136\/bcr-2019-231142)"},{"key":"bib5","series-title":"BMJ Case Reports","first-page":"bcr0320125983","article-title":"Adrenal insufficiency secondary to inappropriate oral administration of topical exogenous steroids presenting with hypercalcaemia","volume":"2012","author":"Bhatti","year":"2012","unstructured":"Bhatti RS\n\n\nFlynn MD\n\n. Adrenal insufficiency secondary to inappropriate oral administration of topical exogenous steroids presenting with hypercalcaemia. BMJ Case Reports\n2012\n2012\nbcr0320125983. (https:\/\/doi.org\/10.1136\/bcr.03.2012.5983)"},{"key":"bib6","series-title":"Clinical Endocrinology","first-page":"261","article-title":"Secondary hypoadrenalism presenting with hypercalcaemia","volume":"41","author":"Vasikaran","year":"1994","unstructured":"Vasikaran SD\n\n\nTallis GA\n\n\nBraund WJ\n\n. Secondary hypoadrenalism presenting with hypercalcaemia. Clinical Endocrinology\n1994\n41\n261\u2013264. (https:\/\/doi.org\/10.1111\/j.1365-2265.1994.tb02540.x)"},{"key":"bib7","series-title":"Journal of Oncology Practice","first-page":"426","article-title":"Cancer-related hypercalcemia","volume":"12","author":"Goldner","year":"2016","unstructured":"Goldner W\n\n\nCancer-related hypercalcemia. Journal of Oncology Practice\n2016\n12\n426\u2013432. (https:\/\/doi.org\/10.1200\/JOP.2016.011155)"},{"key":"bib8","series-title":"Mental Health Clinician","first-page":"318","article-title":"Lithium-induced hypercalcemia with normal parathyroid hormone: a case report","volume":"9","author":"Dorflinger","year":"2019","unstructured":"Dorflinger C\n\n\nFuller M\n\n. Lithium-induced hypercalcemia with normal parathyroid hormone: a case report. Mental Health Clinician\n2019\n9\n318\u2013321. (https:\/\/doi.org\/10.9740\/mhc.2019.09.318)"},{"key":"bib9","series-title":"Journal of Clinical Endocrinology and Metabolism","first-page":"6316","article-title":"Clinical review: rare causes of hypercalcemia","volume":"90","author":"Jacobs","year":"2005","unstructured":"Jacobs TP\n\n\nBilezikian JP\n\n. Clinical review: rare causes of hypercalcemia. Journal of Clinical Endocrinology and Metabolism\n2005\n90\n6316\u20136322. (https:\/\/doi.org\/10.1210\/jc.2005-0675)"},{"key":"bib10","series-title":"Endocrine Connections","first-page":"G1","article-title":"Society for Endocrinology endocrine emergency guidance: emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients","volume":"5","author":"Arlt","year":"2016","unstructured":"Arlt W\n\n\nSociety for Endocrinology Clinical Committee. Society for Endocrinology endocrine emergency guidance: emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocrine Connections\n2016\n5\nG1\u2013G3. (https:\/\/doi.org\/10.1530\/EC-16-0054)"},{"key":"bib11","series-title":"Journal of Internal Medicine","first-page":"535","article-title":"Hypercalcaemia in Addison\u2019s disease: calciotropic hormone profile and bone histology","volume":"232","author":"Montoli","year":"1992","unstructured":"Montoli A\n\n\nColussi G\n\n\nMinetti L\n\n. Hypercalcaemia in Addison\u2019s disease: calciotropic hormone profile and bone histology. Journal of Internal Medicine\n1992\n232\n535\u2013540. (https:\/\/doi.org\/10.1111\/j.1365-2796.1992.tb00636.x)"},{"key":"bib12","series-title":"Nature","first-page":"1277","article-title":"Normocalcaemia in relation to cortisone Secretion","volume":"217","author":"Jowsey","year":"1968","unstructured":"Jowsey J\n\n\nSimons GW\n\n. Normocalcaemia in relation to cortisone Secretion. Nature\n1968\n217\n1277\u20131279. (https:\/\/doi.org\/10.1038\/2171277a0)"},{"key":"bib13","series-title":"APMIS","first-page":"367","article-title":"Expression of stanniocalcin in zona glomerulosa and medulla of normal human adrenal glands, and some adrenal tumors and cell lines","volume":"108","author":"Miura","year":"2000","unstructured":"Miura W\n\n\nMizunashi K\n\n\nKimura N\n\n\nKoide Y\n\n\nNoshiro T\n\n\nMiura Y\n\n\nFurukawa Y\n\n\nNagura H\n\n. Expression of stanniocalcin in zona glomerulosa and medulla of normal human adrenal glands, and some adrenal tumors and cell lines. APMIS\n2000\n108\n367\u2013372. (https:\/\/doi.org\/10.1034\/j.1600-0463.2000.d01-70.x)"},{"key":"bib14","series-title":"Frontiers in Endocrinology","first-page":"172","article-title":"New insights into physiological and pathophysiological functions of Stanniocalcin 2","volume":"11","author":"Joshi","year":"2020","unstructured":"Joshi AD\n\n\nNew insights into physiological and pathophysiological functions of Stanniocalcin 2. Frontiers in Endocrinology\n2020\n11\n172. (https:\/\/doi.org\/10.3389\/fendo.2020.00172)"},{"key":"bib15","series-title":"Endocrinology, Diabetes and Metabolism Case Reports","first-page":"21","article-title":"Glucocorticoid-induced adrenal insufficiency: an uncommon cause of hypercalcaemia","volume":"2022","author":"De Silva","year":"2022","unstructured":"De Silva SDN\n\n\nAravinthan M\n\n\nKatulanda P\n\n. Glucocorticoid-induced adrenal insufficiency: an uncommon cause of hypercalcaemia. Endocrinology, Diabetes and Metabolism Case Reports\n2022\n2022\n21\u20130177. (https:\/\/doi.org\/10.1530\/EDM-21-0177)"}],"container-title":["Endocrinology, Diabetes &amp; Metabolism Case Reports"],"original-title":[],"link":[{"URL":"https:\/\/edm.bioscientifica.com\/view\/journals\/edm\/2023\/1\/EDM22-0375.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/edm.bioscientifica.com\/view\/journals\/edm\/2023\/1\/EDM22-0375.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/edm.bioscientifica.com\/view\/journals\/edm\/2023\/1\/EDM22-0375.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:48:06Z","timestamp":1784555286000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/edm\/article\/3191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,1]]},"references-count":15,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.1530\/edm-22-0375","relation":{},"ISSN":["2052-0573"],"issn-type":[{"value":"2052-0573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,1]]}}}