{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T17:48:22Z","timestamp":1766512102432,"version":"3.48.0"},"reference-count":20,"publisher":"Bioscientifica","issue":"4","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["edm.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"\n Summary<\/jats:title>\n We describe two rare cases of primary bilateral macronodular adrenal hyperplasia (PBMAH) with mild autonomous cortisol secretion (MACS), incidentally discovered and further evaluated for aberrant cortisol responses to various stimuli. In both patients, morning serum cortisol levels remained elevated following 1 mg dexamethasone suppression test (DST) and 4 mg intravenous DST, while basal adrenocorticotropic hormone (ACTH) levels were suppressed. However, 24 h urinary free cortisol and nocturnal salivary cortisol levels were within normal limits. The first case involved a 69-year-old woman who exhibited significant increases in cortisol in response to luteinizing hormone-releasing hormone (LHRH; +142%), vasopressin (+66%) and metoclopramide (+98%). Treatment with the long-acting GnRH agonist leuprolide acetate led to decreased cortisol production and normalization of ACTH levels. The second case, a 54-year-old woman, showed cortisol increases following stimulation with LHRH (+58%), cosyntropin (+1,016%) and vasopressin (+46%). However, leuprolide acetate treatment did not successfully control her hypercortisolism. These cases highlight the clinical relevance of identifying aberrant cortisol responses to specific stimuli in patients with PBMAH and MACS. Such findings may inform the use of targeted medical therapies as alternatives to unilateral or bilateral adrenalectomy. In addition, a more pronounced cortisol response to LHRH compared to other stimuli may predict a favorable response to GnRH agonist therapy.<\/jats:p>\n <\/jats:sec>\n \n Learning points<\/jats:title>\n \n \n Systematic dynamic stimulation testing to assess cortisol response to a variety of stimuli should be offered to all patients with primary bilateral adrenal hyperplasia (PBMAH) with indication for treatment.<\/jats:p>\n <\/jats:list-item>\n \n \n Identification of an aberrant response suggesting potential overexpression of\n \u03b2<\/jats:italic>\n -adrenergic or luteinizing hormone\/chorionic gonadotropin receptors (LHCGRs) may allow the use of targeted medical therapies, instead of unilateral or bilateral adrenalectomy, to control the cortisol excess in a subset of patients.\n <\/jats:p>\n <\/jats:list-item>\n \n In patients with MACS who have an aberrant cortisol response following LHRH stimulation, the long-acting GnRH agonist leuprolide acetate can be used to suppress endogenous LH production and improve hypercortisolism.<\/jats:p>\n <\/jats:list-item>\n \n A greater increase in cortisol secretion following LHRH stimulation and small response to the other stimuli could potentially be predictive of a better response to treatment with leuprolide acetate.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>","DOI":"10.1530\/edm-24-0074","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T17:48:39Z","timestamp":1762451319000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-2","source":"Crossref","is-referenced-by-count":0,"title":["Two cases of MACS due to PBMAH associated with an in vivo aberrant response to LHRH treated with leuprolide acetate"],"prefix":"10.1530","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8051-4608","authenticated-orcid":true,"given":"Laurie","family":"Branchaud-Croiseti\u00e8re","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Research Center, Centre Hospitalier de l\u2019Universit\u00e9 de Sherbrooke (CRCHUS), Sherbrooke, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Maillet","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Research Center, Centre Hospitalier de l\u2019Universit\u00e9 de Sherbrooke (CRCHUS), Sherbrooke, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9791-2118","authenticated-orcid":true,"given":"Matthieu","family":"St-Jean","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Research Center, Centre Hospitalier de l\u2019Universit\u00e9 de Sherbrooke (CRCHUS), Sherbrooke, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"416","reference":[{"key":"bib1","series-title":"J Clin Endocrinol Metab","first-page":"3331","article-title":"Approach to the patient with adrenal incidentaloma","volume":"106","author":"Bancos I","year":"2021","unstructured":"Bancos I\n & \nPrete A\n\n. Approach to the patient with adrenal incidentaloma. J Clin Endocrinol Metab 2021 106 3331\u20133353. (https:\/\/doi.org\/10.1210\/clinem\/dgab512)"},{"key":"bib2","series-title":"Eur J Endocrinol","first-page":"G1","article-title":"European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors","volume":"189","author":"Fassnacht M","year":"2023","unstructured":"Fassnacht M\n, \nTsagarakis S\n, \nTerzolo M\n, et al.\n European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2023 189 G1\u2013G42. (https:\/\/doi.org\/10.1093\/ejendo\/lvad066)"},{"key":"bib3","series-title":"J Endocr Soc","article-title":"An overview of the heterogeneous causes of cushing syndrome resulting from primary macronodular adrenal hyperplasia (PMAH)","volume":"6","author":"Charchar HLS","year":"2022","unstructured":"Charchar HLS\n & \nFragoso MCBV\n\n. An overview of the heterogeneous causes of cushing syndrome resulting from primary macronodular adrenal hyperplasia (PMAH). J Endocr Soc 2022 6 bvac041. (https:\/\/doi.org\/10.1210\/jendso\/bvac041)"},{"key":"bib4","series-title":"Best Pract Res Clin Endocrinol Metabol","first-page":"165","article-title":"Aberrant G-protein coupled hormone receptor in adrenal diseases","volume":"32","author":"St-Jean M","year":"2018","unstructured":"St-Jean M\n, \nGhorayeb NE\n, \nBourdeau I\n, et al.\n Aberrant G-protein coupled hormone receptor in adrenal diseases. Best Pract Res Clin Endocrinol Metabol 2018 32 165\u2013187. (https:\/\/doi.org\/10.1016\/j.beem.2018.01.003)"},{"key":"bib5","series-title":"N Engl J Med","first-page":"1577","article-title":"Leuprolide acetate therapy in luteinizing hormone-dependent Cushing\u2019s syndrome","volume":"341","author":"Lacroix A","year":"1999","unstructured":"Lacroix A\n, \nHamet P\n & \nBoutin JM\n\n. Leuprolide acetate therapy in luteinizing hormone-dependent Cushing\u2019s syndrome. N Engl J Med 1999 341 1577\u20131581. (https:\/\/doi.org\/10.1056\/nejm199911183412104)"},{"key":"bib6","series-title":"J Clin Endocrinol Metab","first-page":"5534","article-title":"Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing\u2019s syndrome","volume":"86","author":"Bourdeau I","year":"2001","unstructured":"Bourdeau I\n, \nD\u2019Amour P\n, \nHamet P\n, et al.\n Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing\u2019s syndrome. J Clin Endocrinol Metab 2001 86 5534\u20135540. (https:\/\/doi.org\/10.1210\/jcem.86.11.8062)"},{"key":"bib7","series-title":"Endocr Pract","first-page":"e77","article-title":"Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: is medical treatment always an option?","volume":"19","author":"Karapanou O","year":"2013","unstructured":"Karapanou O\n, \nVlassopoulou B\n, \nTzanela M\n, et al.\n Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: is medical treatment always an option? Endocr Pract 2013 19 e77\u2013e82. 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An overview of the heterogeneous causes of cushing syndrome resulting from primary macronodular adrenal hyperplasia (PMAH). J Endocr Soc 2022 6 bvac041. (https:\/\/doi.org\/10.1210\/jendso\/bvac041)"},{"key":"bib4","series-title":"Best Pract Res Clin Endocrinol Metabol","first-page":"165","article-title":"Aberrant G-protein coupled hormone receptor in adrenal diseases","volume":"32","author":"St-Jean M","year":"2018","unstructured":"St-Jean M\n, \nGhorayeb NE\n, \nBourdeau I\n, et al.\n Aberrant G-protein coupled hormone receptor in adrenal diseases. Best Pract Res Clin Endocrinol Metabol 2018 32 165\u2013187. (https:\/\/doi.org\/10.1016\/j.beem.2018.01.003)"},{"key":"bib5","series-title":"N Engl J Med","first-page":"1577","article-title":"Leuprolide acetate therapy in luteinizing hormone-dependent Cushing\u2019s syndrome","volume":"341","author":"Lacroix A","year":"1999","unstructured":"Lacroix A\n, \nHamet P\n & \nBoutin JM\n\n. Leuprolide acetate therapy in luteinizing hormone-dependent Cushing\u2019s syndrome. N Engl J Med 1999 341 1577\u20131581. (https:\/\/doi.org\/10.1056\/nejm199911183412104)"},{"key":"bib6","series-title":"J Clin Endocrinol Metab","first-page":"5534","article-title":"Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing\u2019s syndrome","volume":"86","author":"Bourdeau I","year":"2001","unstructured":"Bourdeau I\n, \nD\u2019Amour P\n, \nHamet P\n, et al.\n Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing\u2019s syndrome. J Clin Endocrinol Metab 2001 86 5534\u20135540. (https:\/\/doi.org\/10.1210\/jcem.86.11.8062)"},{"key":"bib7","series-title":"Endocr Pract","first-page":"e77","article-title":"Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: is medical treatment always an option?","volume":"19","author":"Karapanou O","year":"2013","unstructured":"Karapanou O\n, \nVlassopoulou B\n, \nTzanela M\n, et al.\n Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: is medical treatment always an option? Endocr Pract 2013 19 e77\u2013e82. (https:\/\/doi.org\/10.4158\/ep12346.cr)"},{"key":"bib8","series-title":"Neth J Med","first-page":"456","article-title":"Leuprolide acetate therapy in LH-dependent Cushing\u2019s syndrome: in vivo and in vitro observations","volume":"62","author":"Bovenberg SA","year":"2004","unstructured":"Bovenberg SA\n, \nPieters GFFM\n, \nHofland LJ\n, et al.\n Leuprolide acetate therapy in LH-dependent Cushing\u2019s syndrome: in vivo and in vitro observations. Neth J Med 2004 62 456\u2013458."},{"key":"bib9","series-title":"Ann Intern Med","first-page":"1041","article-title":"Association between mortality and levels of autonomous cortisol secretion by adrenal incidentalomas","volume":"174","author":"Kjellbom A","year":"2021","unstructured":"Kjellbom A\n, \nLindgren O\n, \nPuvaneswaralingam S\n, et al.\n Association between mortality and levels of autonomous cortisol secretion by adrenal incidentalomas. Ann Intern Med 2021 174 1041\u20131049. (https:\/\/doi.org\/10.7326\/m20-7946)"},{"key":"bib10","series-title":"Hormones","first-page":"235","article-title":"The effect of unilateral adrenalectomy on patients with primary bilateral macronodular adrenal hyperplasia","volume":"22","author":"Yu Z","year":"2023","unstructured":"Yu Z\n, \nGao J\n & \nSun F\n\n. The effect of unilateral adrenalectomy on patients with primary bilateral macronodular adrenal hyperplasia. Hormones 2023 22 235\u2013242. 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