Cushing's Syndrome in the Elderly

Aleksandra Zdrojowy-Wełna; Elena Valassi

doi:10.1055/a-2317-8821

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2024; 132(12): 705-711
DOI: 10.1055/a-2317-8821

Review

Cushing's Syndrome in the Elderly

Aleksandra Zdrojowy-Wełna

¹Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland

²Endocrinology Department, Wroclaw University Hospital, Wroclaw, Poland

,

Elena Valassi

³Endocrinology and Nutrition Department, Germans Trias i Pujol Hospital and Research Institute, Badalona, Spain

⁴School of Medicine, Universitat Internacional de Catalunya (UIC), Barcelona, Spain.

› Author Affiliations

Abstract

Management of Cushing’s syndrome (CS) can be particularly challenging in older patients, compared with younger individuals, due to the lack of several clinical features associated with cortisol excess along with a greater burden of associated comorbidities. Moreover, the interpretation of diagnostic tests could be influenced by age-related physiological changes in cortisol secretion. While mortality is higher and quality of life is more impaired in the elderly with CS as compared with the younger, there is currently no agreement on the most effective therapeutic options in aged individuals, and safety data concerning medical treatment are scanty. In this review, we summarize the current knowledge about age-related differences in CS etiology, clinical presentation, treatment, and outcomes and describe the potential underlying mechanisms.

Keywords

Cushing’s syndrome - older patients - aging - hypercortisolism

Full Text

References

References
1 Valassi E. Clinical presentation and etiology of Cushing’s syndrome: Data from ERCUSYN. J Neuroendocrinol 2022; 34: e13114
2 Wengander S, Trimpou P, Papakokkinou E. et al. The incidence of endogenous Cushing’s syndrome in the modern era. Clin Endocrinol (Oxf) 2019; 91: 263-270
3 Rubinstein G, Osswald A, Hoster E. et al. Time to diagnosis in Cushing’s syndrome: A meta-analysis based on 5367 patients. J Clin Endocrinol Metab 2020; 105 dgz136
4 Braun LT, Riester A, Oßwald-Kopp A. et al. Toward a diagnostic score in Cushing’s syndrome. Front Endocrinol 2019; 10: 766
5 Kowal P, Dowd J. Definition of an older person. Proposed working definition of an older person in Africa for the MDS Project. Geneva: World Health Organization; 2001
6 Akirov A, Dery L, Fleseriu M. et al. Cushing’s syndrome in women: Age-related differences in etiology and clinical picture. Pituitary 2023; 26: 144-151
7 Ebbehoj A, Li D, Kaur RJ. et al. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: A population-based cohort study. Lancet Diabetes Endocrinol. 2020. 8. 894-902
8 Zavatta G, Vicennati V, Altieri P. et al. Mild autonomous cortisol secretion in adrenal incidentalomas and risk of fragility fractures: A large cross-sectional study. Eur J Endocrinol 2023; 188: 343-352
9 Amodru V, Ferriere A, Tabarin A. et al. Cushing’s syndrome in the elderly: Data from the European Registry on Cushing’s syndrome. Eur J Endocrinol 2023; 188: 395-406
10 Qiao N, Swearingen B, Tritos NA. Cushing’s disease in older patients: Presentation and outcome. Clin Endocrinol (Oxf) 2018; 89: 444-453
11 Storr HL, Isidori AM, Monson JP. et al. Prepubertal Cushing’s disease is more common in males, but there is no increase in severity at diagnosis. J Clin Endocrinol Metab 2004; 89: 3818-3820
12 Pecori Giraldi F, Cassarino MF, Sesta A. et al. Sexual dimorphism in cellular and molecular features in human ACTH-secreting pituitary adenomas. Cancers 2020; 12: 669
13 Young J, Haissaguerre M, Viera-Pinto O. et al. Management of endocrine disease: Cushing’s syndrome due to ectopic ACTH secretion: An expert operational opinion. Eur J Endocrinol 2020; 182: R29-R58
14 Kamp K, Alwani RA, Korpershoek E. et al. Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors. Eur J Endocrinol 2016; 174: 271-280
15 Beuschlein F, Hammer GD. Ectopic pro-opiomelanocortin syndrome. Endocrinol Metab Clin North Am 2002; 31: 191-234
16 Hayes AR, Grossman AB. The ectopic adrenocorticotropic hormone syndrome. Endocrinol Metab Clin North Am 2018; 47: 409-425
17 Ilias I, Torpy DJ, Pacak K. et al. Cushing’s syndrome due to ectopic corticotropin secretion: Twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab 2005; 90: 4955-4962
18 Rockall AG, Sohaib SA, Evans D. et al. Computed tomography assessment of fat distribution in male and female patients with Cushing’s syndrome. Eur J Endocrinol 2003; 149: 561-567
19 Ferraù F, Korbonits M. Metabolic comorbidities in Cushing’s syndrome. Eur J Endocrinol 2015; 173: M133-M157
20 Nowotny HF, Braun L, Vogel F. et al. 11-Oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing’s disease. Eur J Endocrinol 2022; 187: 663-673
21 Nanba AT, Rege J, Ren J. et al. 11-Oxygenated C19 steroids do not decline with age in women. J Clin Endocrinol Metab 2019; 104: 2615-2622
22 Liao YH, Chen SY, Chou SY. et al. Determination of chronological aging parameters in epidermal keratinocytes by in vivo harmonic generation microscopy. Biomed Opt Express 2013; 4: 77-88
23 Cruz-Jentoft AJ, Bahat G, Bauer J. et al. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 2019; 48: 16-31
24 Dardevet D, Sornet C, Taillandier D. et al. Sensitivity and protein turnover response to glucocorticoids are different in skeletal muscle from adult and old rats. Lack of regulation of the ubiquitin-proteasome proteolytic pathway in aging. J Clin Invest 1995; 96: 2113-2119
25 Rieu I, Sornet C, Grizard J. et al. Glucocorticoid excess induces a prolonged leucine resistance on muscle protein synthesis in old rats. Exp Gerontol 2004; 39: 1315-1321
26 Vogel F, Braun LT, Rubinstein G. et al. Persisting muscle dysfunction in Cushing’s syndrome despite biochemical remission. J Clin Endocrinol Metab 2020; 105: e4490-e4498
27 Cuthbertson DJ, Bell JA, Ng SY. et al. Dynapenic obesity and the risk of incident type 2 diabetes: The English Longitudinal Study of Ageing. Diabet Med J Br Diabet Assoc 2016; 33: 1052-1059
28 Vogel F, Braun L, Rubinstein G. et al. Patients with low IGF-I after curative surgery for Cushing’s syndrome have an adverse long-term outcome of hypercortisolism-induced myopathy. Eur J Endocrinol 2021; 184: 813-821
29 Zheng H, Wang Q, Cui Q. et al. The hypothalamic-pituitary-gonad axis in male Cushing’s disease before and after curative surgery. Endocrine 2022; 77: 357-362
30 Hassan-Smith ZK, Morgan SA, Sherlock M. et al. Gender-specific differences in skeletal muscle 11β-HSD1 expression across healthy aging. J Clin Endocrinol Metab 2015; 100: 2673-2681
31 Giuliodori A, Soudah E, Malouf J. et al. Evaluation of bone-related mechanical properties in female patients with long-term remission of Cushing’s syndrome using quantitative computed tomography–based finite element analysis. Eur J Endocrinol 2024; 190: 86-95
32 Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002; 23: 279-302
33 Chin KY, Ima-Nirwana S, Mohamed IN. et al. Insulin-like growth factor-1 is a mediator of age-related decline of bone health status in men. Aging Male Off J Int Soc Study Aging Male 2014; 17: 102-106
34 Zhou H, Cooper MS, Seibel MJ. Endogenous glucocorticoids and bone. Bone Res 2013; 1: 107-119
35 Zilio M, Mazzai L, Sartori MT. et al. A venous thromboembolism risk assessment model for patients with Cushing’s syndrome. Endocrine 2016; 52: 322-332
36 Isand K, Feelders R, Brue T. et al. High prevalence of venous thrombotic events in Cushing’s syndrome: Data from ERCUSYN and details in relation to surgery. Eur J Endocrinol 2024; 190: 75-85
37 Piasecka M, Papakokkinou E, Valassi E. et al. Psychiatric and neurocognitive consequences of endogenous hypercortisolism. J Intern Med 2020; 288: 168-182
38 Anderson RM, Birnie AK, Koblesky NK. et al. Adrenocortical status predicts the degree of age-related deficits in prefrontal structural plasticity and working memory. J Neurosci 2014; 34: 8387-8397
39 Resmini E, Santos A, Gómez-Anson B. et al. Verbal and visual memory performance and hippocampal volumes, measured by 3-Tesla magnetic resonance imaging, in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2012; 97: 663-671
40 Papakokkinou E, Ragnarsson O. Functional brain alterations in Cushing’s syndrome. Front Endocrinol 2023; 14: 1163482
41 Hegeman JM, de Waal MWM, Comijs HC. et al. Depression in later life: A more somatic presentation?. J Affect Disord 2015; 170: 196-202
42 Lyu X, Zhang D, Pan H. et al. Machine learning models for differential diagnosis of Cushing’s disease and ectopic ACTH secretion syndrome. Endocrine 2023; 80: 639-646
43 Wudy SA, Hartmann MF, Remer T. Sexual dimorphism in cortisol secretion starts after age 10 in healthy children: Urinary cortisol metabolite excretion rates during growth. Am J Physiol Endocrinol Metab 2007; 293: E970-E976
44 Moffat SD, An Y, Resnick SM. et al Longitudinal change in cortisol levels across the adult life span. J Gerontol A Biol Sci Med Sci 20 2020; 75: 394-400
45 Purnell JQ, Brandon DD, Isabelle LM. et al. Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women. J Clin Endocrinol Metab 2004; 89: 281-287
46 Otte C, Hart S, Neylan TC. et al. A meta-analysis of cortisol response to challenge in human aging: Importance of gender. Psychoneuroendocrinology 2005; 30: 80-91
47 Mikneviciute G, Pulopulos MM, Allaert J. et al. Adult age differences in the psychophysiological response to acute stress. Psychoneuroendocrinology 2023; 153: 106111
48 Newell-Price J, Pivonello R, Tabarin A. et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease. Eur J Endocrinol 2020; 182: 207-217
49 Coelli S, Farias CB, Soares AA. et al Influence of age, gender and body mass index on late-night salivary cortisol in healthy adults. Clin Chem Lab Med CCLM 2017; 55 Available from: https://www.degruyter.com/document/
50 Thakur JD, Corlin A, Mallari RJ. et al. Complication avoidance protocols in endoscopic pituitary adenoma surgery: A retrospective cohort study in 514 patients. Pituitary 2021; 24: 930-942
51 Ünal M, Selek A, Sözen M. et al. Recurrent Cushing’s disease in adults: Predictors and long-term follow-up. Horm Metab Res Horm Stoffwechselforschung Horm Metab 2023; 55: 520-527
52 Liu Y, Liu X, Hong X. et al. Prediction of recurrence after transsphenoidal surgery for Cushing’s disease: The use of machine learning algorithms. Neuroendocrinology 2019; 108: 201-210
53 Pivonello R, Fleseriu M, Newell-Price J. et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): A multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 2020; 8: 748-761
54 Gadelha M, Bex M, Feelders RA. et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab 2022; 107: e2882-e2895
55 Berwaerts JJ, Verhelst JA, Verhaert GC. et al. Corticotropin-dependent Cushing’s syndrome in older people: Presentation of five cases and therapeutical use of ketoconazole. J Am Geriatr Soc 1998; 46: 880-884
56 Castinetti F, Guignat L, Giraud P. et al. Ketoconazole in Cushing’s disease: Is it worth a try?. J Clin Endocrinol Metab 2014; 99: 1623-1630
57 Daniel E, Aylwin S, Mustafa O. et al. Effectiveness of metyrapone in treating Cushing’s syndrome: A retrospective multicenter study in 195 patients. J Clin Endocrinol Metab 2015; 100: 4146-4154
58 Carroll TB, Peppard WJ, Herrmann DJ. et al. Continuous etomidate infusion for the management of severe Cushing syndrome: Validation of a standard protocol. J Endocr Soc 2019; 3: 1-12
59 Baudry C, Coste J, Bou Khalil R. et al. Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol 2012; 167: 473-481
60 Petersenn S, Salgado LR, Schopohl J. et al. Long-term treatment of Cushing’s disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial. Endocrine 2017; 57: 156-165
61 Castinetti F, Brue T, Ragnarsson O. Radiotherapy as a tool for the treatment of Cushing’s disease. Eur J Endocrinol 2019; 180: D9-D18
62 Mehta GU, Ding D, Patibandla MR. et al. Stereotactic radiosurgery for Cushing disease: Results of an international, multicenter study. J Clin Endocrinol Metab 2017; 102: 4284-4291
63 Ntali G, Asimakopoulou A, Siamatras T. et al. Mortality in Cushing’s syndrome: Systematic analysis of a large series with prolonged follow-up. Eur J Endocrinol 2013; 169: 715-723
64 Yaneva M, Kalinov K, Zacharieva S. Mortality in Cushing’s syndrome: Data from 386 patients from a single tertiary referral center. Eur J Endocrinol 2013; 169: 621-627
65 Lambert JK, Goldberg L, Fayngold S. et al. Predictors of mortality and long-term outcomes in treated Cushing’s disease: A study of 346 patients. J Clin Endocrinol Metab 2013; 98: 1022-1030
66 Valassi E, Tabarin A, Brue T. et al. High mortality within 90 days of diagnosis in patients with Cushing’s syndrome: Results from the ERCUSYN registry. Eur J Endocrinol 2019; 181: 461-472
67 Isidori AM, Kaltsas GA, Pozza C. et al. The ectopic adrenocorticotropin syndrome: Clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab 2006; 91: 371-377
68 Santos A, Resmini E, Martínez Momblán MA. et al Quality of life in patients with Cushing’s disease. Front Endocrinol 2019; 10: 862 Available from: https://www.frontiersin.org/article/10.3389/fendo.2019.00862/full
69 Milian M, Honegger J, Teufel P. et al. Tuebingen CD-25 is a sensitive tool to investigate health-related quality of life in Cushing’s disease patients in the course of the disease. Neuroendocrinology 2013; 98: 188-199
70 Rakovec M, Zhu W, Khalafallah AM. et al. Patient reported outcomes and treatment satisfaction in patients with Cushing syndrome. Endocrine 2023; 79: 161-170
71 Gruber HJ, Semeraro MD, Renner W. et al. Telomeres and age-related diseases. Biomedicines 2021; 9: 1335
72 Calado RT, Young NS. Telomere diseases. N Engl J Med 2009; 361: 2353-2365
73 Simon NM, Smoller JW, McNamara KL. et al. Telomere shortening and mood disorders: Preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry 2006; 60: 432-435
74 Daubenmier J, Lin J, Blackburn E. et al. Changes in stress, eating, and metabolic factors are related to changes in telomerase activity in a randomized mindfulness intervention pilot study. Psychoneuroendocrinology 2012; 37: 917-928
75 Choi J, Fauce SR, Effros RB. Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun 2008; 22: 600-605
76 Aulinas A, Ramírez MJ, Barahona MJ. et al. Telomere length analysis in Cushing’s syndrome. Eur J Endocrinol 2014; 171: 21-29