Download PDF
Exp Clin Endocrinol Diabetes 2025; 133(05): 235-245
DOI: 10.1055/a-2559-9643
Article

Efficacy of Propranolol Combined with Different Modalities of Unilateral Adrenalectomy in a Case Series of 4 ARMC5-mutated Patients

Fan Yu
1   Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China (Ringgold ID: RIN74734)
2   Department of Endocrinology, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, China
,
Baowen Yu
3   Nanjing First Hospital, Nanjing, China (Ringgold ID: RIN74734)
,
Hongwen Zhou
1   Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China (Ringgold ID: RIN74734)
,
He Wei
1   Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China (Ringgold ID: RIN74734)
,
Hong-Qi Fan
1   Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China (Ringgold ID: RIN74734)
› Author AffiliationsSupported by: National Natural Science Foundation of China 81100578
Supported by: Specialized Research Fund for the Doctoral Program of Higher Education of China 20113234120011
› Further Information
Also available at
    Permissions and Reprints

Abstract

Context

Limited research has explored the efficacy of β-blockers in combination with unilateral total, subtotal, or partial adrenalectomy in ARMC5-mutated patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH). Additionally, there is no consensus on determining the optimal side for adrenal gland resection.

Objective

To assess the clinical utility of three unilateral adrenalectomy (ULA) modalities—total, subtotal, and partial—combined with β-blocker treatment in patients with PBMAH and Cushing’s syndrome (CS).

Patients and Methods

This study was conducted at a single tertiary referral center involving a series of four patients with suspected CS. Diagnosis of PBMAH was confirmed through dexamethasone suppression testing, evaluation of ectopic receptor expression, and whole-exome sequencing. Three patients underwent unilateral total, subtotal, or partial adrenalectomy, respectively, while one patient declined surgery. All patients received β-blocker treatment.

Results

The median treatment duration among the four ARMC5-mutuated PBMAH patients was 30.5 months (range: 6–45 months). Two patients who underwent total or subtotal adrenalectomy on the side with more pronounced nodularity showed postoperative improvement in clinical CS signs, glycemic control, and hypertension. These two patients, along with another patient with bilateral diffuse (non-nodular) adrenal hyperplasia who declined surgery, showed further improvement in hypercortisolism and cortisol/adrenocorticotropic hormone (ACTH) ratio (CAR: plasma cortisol (nmol/L)/plasma ACTH (pg/ml), newly reported as a reliable parameter of cortisol secretory capacity in patients with adrenal CS) after propranolol treatment. The patient who underwent partial adrenalectomy on the side with less pronounced nodularity showed no significant improvement in hypercortisolism or CAR, and the response to propranolol was also unsatisfactory. All four cases harbored pathogenic variants in the ARMC gene, including two novel germline mutations.

Conclusion

In ARMC5-mutuated patients with PBMAH, unilateral total adrenalectomy on the side with more pronounced nodularity appears to be an effective treatment option. Propranolol may be considered as an alternative or adjunctive therapy to ULA for managing hypercortisolism in those with ARMC5 mutations.

Keywords

β-blocker - Cushing’s syndrome - PBMAH - Unilateral adrenalectomy - ARMC5


Publication History

Received: 25 November 2024

Accepted after revision: 07 March 2025

Article published online:
12 May 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Kirschner MA, Powell RD, Lipsett MB. Cushing’s syndrome: Nodular cortical hyperplasia of adrenal glands with clinical and pathological features suggesting adrenocortical tumor. J Clin Endocrinol Metab 1964; 24: 947-955
    CrossrefPubMedSearch in Google Scholar
  • 2 Araujo-Castro M, Marazuela M. Cushing’s syndrome due to bilateral adrenal cortical disease: Bilateral macronodular adrenal cortical disease and bilateral micronodular adrenal cortical disease. Endocr Pathol 2022; 33: 155-196
    CrossrefPubMedSearch in Google Scholar
  • 3 Debillon E, Velayoudom-Cephise FL, Salenave S. et al. Unilateral adrenalectomy as a first-line treatment of Cushing’s syndrome in patients with primary bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2015; 100: 4417-4424
    CrossrefPubMedSearch in Google Scholar
  • 4 Nieman LK, Biller BM, Findling JW. et al. Treatment of Cushing’s syndrome: An Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab 2015; 100: 2807-2831
    CrossrefPubMedSearch in Google Scholar
  • 5 Gagliardi L, Schreiber AW, Hahn CN. et al. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2014; 99: E1784-E1792
    CrossrefPubMedSearch in Google Scholar
  • 6 Fassnacht M, Tsagarakis S, Terzolo M. et al. 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-G42
    CrossrefPubMedSearch in Google Scholar
  • 7 De Venanzi A, Alencar GA, Bourdeau I. et al. Primary bilateral macronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2014; 21: 177-184
    CrossrefPubMedSearch in Google Scholar
  • 8 Bertherat J, Bourdeau I, Bouys L. et al. Clinical, pathophysiologic, genetic, and therapeutic progress in primary bilateral macronodular adrenal hyperplasia. Endocr Rev 2023; 44: 567-628
    CrossrefPubMedSearch in Google Scholar
  • 9 Fragoso MC, Domenice S, Latronico AC. et al. Cushing’s syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J Clin Endocrinol Metab 2003; 88: 2147-2151
    CrossrefPubMedSearch in Google Scholar
  • 10 Hsiao HP, Kirschner LS, Bourdeau I. et al. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab 2009; 94: 2930-2937
    CrossrefPubMedSearch in Google Scholar
  • 11 Bouys L, Vaczlavik A, Jouinot A. et al. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients. Eur J Endocrinol 2022; 187: 123-134
    CrossrefPubMedSearch in Google Scholar
  • 12 Emms H, Tsirou I, Cranston T. et al. Do patients with incidentally discovered bilateral adrenal nodules represent an early form of ARMC5-mediated bilateral macronodular hyperplasia?. Endocrine 2016; 53: 801-808
    CrossrefPubMedSearch in Google Scholar
  • 13 Ritzel K, Beuschlein F, Mickisch A. et al. Clinical review: Outcome of bilateral adrenalectomy in Cushing’s syndrome: A systematic review. J Clin Endocrinol Metab 2013; 98: 3939-3948
    CrossrefPubMedSearch in Google Scholar
  • 14 Lamas C, Alfaro JJ, Lucas T. et al. Is unilateral adrenalectomy an alternative treatment for ACTH-independent macronodular adrenal hyperplasia? Long-term follow-up of four cases. Eur J Endocrinol 2002; 146: 237-240
    CrossrefPubMedSearch in Google Scholar
  • 15 Ito T, Kurita Y, Shinbo H. et al. Successful treatment for adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with laparoscopic adrenalectomy: A case series. J Med Case Rep 2012; 6: 312
    CrossrefPubMedSearch in Google Scholar
  • 16 Albiger NM, Ceccato F, Zilio M. et al. An analysis of different therapeutic options in patients with Cushing’s syndrome due to bilateral macronodular adrenal hyperplasia: A single-centre experience. Clin Endocrinol (Oxf) 2015; 82: 808-815
    CrossrefPubMedSearch in Google Scholar
  • 17 Di Dalmazi G, Reincke M. Adrenal surgery for Cushing’s syndrome: An update. Endocrinol Metab Clin North Am 2018; 47: 385-394
    CrossrefPubMedSearch in Google Scholar
  • 18 Sheikh-Ahmad M, Dickstein G, Matter I. et al. Unilateral adrenalectomy for primary bilateral macronodular adrenal hyperplasia: Analysis of 71 cases. Exp Clin Endocrinol Diabetes 2020; 128: 827-834
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Iwamoto Y, Tatsumi F, Itoh T. et al. Usefulness of cortisol/ACTH ratio (CAR) for diagnosis of Cushing’s syndrome: Comparison of CAR with findings in dexamethasone suppression test. Sci Rep 2022; 12: 17680
    CrossrefPubMedSearch in Google Scholar
  • 20 Lacroix A, Tremblay J, Rousseau G. et al. Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med 1997; 337: 1429-1434
    CrossrefPubMedSearch in Google Scholar
  • 21 Cohan P, East HE, Galati SJ. et al. Mifepristone treatment in four cases of primary bilateral macronodular adrenal hyperplasia (BMAH). J Clin Endocrinol Metab 2019; 104: 6279-6290
    CrossrefPubMedSearch in Google Scholar
  • 22 Karapanou O, Vlassopoulou B, Tzanela M. et al. Adrenocorticotropic hormone independent macronodular adrenal hyperplasia due to aberrant receptor expression: Is medical treatment always an option?. Endocr Pract 2013; 19: e77-e82
    CrossrefPubMedSearch in Google Scholar
  • 23 Preumont V, Mermejo LM, Damoiseaux P. et al. Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing’s syndrome. Horm Metab Res 2011; 43: 287-291
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Libé R, Coste J, Guignat L. et al. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: A frequent finding in a prospective study of 32 patients with overt or subclinical Cushing’s syndrome. Eur J Endocrinol 2010; 163: 129-138
    CrossrefPubMedSearch in Google Scholar
  • 25 Corcuff JB, Young J, Masquefa-Giraud P. et al. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. Eur J Endocrinol 2015; 172: 473-481
    CrossrefPubMedSearch in Google Scholar
  • 26 Bourdeau I, Oble S, Magne F. et al. ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia. Eur J Endocrinol 2016; 174: 85-96
    CrossrefPubMedSearch in Google Scholar
  • 27 Nawaz MO, Henze DK. Premature deaths in Brazil associated with long-term exposure to PM2.5 from Amazon fires between 2016 and 2019. Geohealth 2020; 4: e2020GH000268
    CrossrefPubMedSearch in Google Scholar
  • 28 Mircescu H, Jilwan J, N’Diaye N. et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome?. J Clin Endocrinol Metab 2000; 85: 3531-3536
    CrossrefPubMedSearch in Google Scholar
  • 29 Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone--dependent Cushing’s syndrome. N Engl J Med 1999; 341: 1577-1581
    CrossrefPubMedSearch in Google Scholar
  • 30 Cavalcante IP, Berthon A, Fragoso MC. et al. Primary bilateral macronodular adrenal hyperplasia: Definitely a genetic disease. Nat Rev Endocrinol 2022; 18: 699-711
    CrossrefPubMedSearch in Google Scholar
  • 31 Chasseloup F, Bourdeau I, Tabarin A. et al. Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: A multicentre, retrospective, cohort study. Lancet Diabetes Endocrinol 2021; 9: 813-824
    CrossrefPubMedSearch in Google Scholar
  • 32 Vaczlavik A, Bouys L, Violon F. et al. KDM1A inactivation causes hereditary food-dependent Cushing syndrome. Genet Med 2022; 24: 374-383
    CrossrefPubMedSearch in Google Scholar