Ivana Kraljevic1,2*- 1School of Medicine, University of Zagreb, Zagreb, Croatia
- 2Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia
Editorial on the Research Topic
A year in review: discussions in adrenal endocrinology
Introduction
The field of Adrenal Endocrinology has experienced remarkable growth over the last few years. As research and clinical practice in this domain continues to evolve, it becomes imperative to emphasize the critical role of informed discussions among researchers, clinicians, and stakeholders. In this editorial, we shed light on the significance of discussions in Adrenal Endocrinology. We present different topics and discuss various areas of Adrenal Endocrinology.
The article” Predicting morphological and functional variations of benign adrenal incidentalomas in relation to initial characteristics” discusses current issues for the follow-up of adrenal incidentalomas (Parazzoli et al.). According to the current guidelines of the European Society of Endocrinology (1), patients diagnosed with adrenal incidentalomas (AI) should undergo a comprehensive evaluation at the time of diagnosis to assess the potential malignancy of the tumor and the presence of excess adrenal hormones. If the adrenal mass is less than 4 cm and shows benign characteristics with normal hormone activity during the initial assessment, no further investigations are necessary due to the low risk of malignancy or functional changes (1).
However, some other guidelines (2) and consensus positions (3–5) recommend regular radiological and biochemical follow-up for all adrenal masses, regardless of their characteristics. The following is based on the possibility of changes in their nature over time, even if they appear benign initially.
Few studies have addressed the long-term follow-up of unresected AI, making the usefulness and timing of reassessment unclear. A recent study by Ceccato et al. (6) focused on radiological modifications (diameter and lipid content) in a large cohort of AI patients, according to their cortisol secretion, after a long-term follow-up. The authors suggest that follow-up imaging should be performed around 5 years after diagnosis, especially in patients with autonomous cortisol secretion (ACS), lipid-poor adenomas, and a large diameter at baseline.
Although there is no clear consensus on predictive criteria, adrenal adenomas larger than 2.4 cm may deserve more attention, as they pose a risk of functional progression. ACS may occur in a significant number of patients, especially when there is a larger initial adenoma diameter, higher cortisol levels, and cardiovascular risk factors. The occurrence of cortisol hypersecretion may exacerbate cardiovascular and metabolic comorbidities.
The risk of morphological and functional changes in AI increases over time, particularly after 5-10 years of follow-up, but it is currently difficult to predict. Therefore, discontinuing the follow-up in patients with NFAT may carry risks, and all these factors should be considered to determine the best management approach for these patients.
The article “A Spatiotemporal Steroidogenic Regulatory Network in Human Fetal Adrenal Glands and Gonads” presents an intriguing study with significant potential for advancing our understanding of steroid hormone regulation during human development (Wang et al.). In this research, the authors meticulously mapped the adrenal glands and gonads of fetuses aged 7-14 weeks. It sheds light on the role of fetal adrenal glands and gonads in influencing the process of sexual differentiation. The study’s results can be outlined as follows: The adrenal glands start expressing steroidogenic enzyme genes around seven weeks, producing steroid hormones much earlier than the testis. The expression patterns of steroidogenic enzyme genes in the testis suggest that it can synthesize testosterone de novo or utilize DHEA from the adrenal gland. Females exhibit an HSD3B2 expression peak at ten weeks. While the adrenal glands might synthesize small amounts of DHT, steroidogenic enzyme expression in ovaries remains limited until 14 weeks.
In the article “Adrenal crisis in infants and young children with adrenal insufficiency: Management and prevention” there are summarized current clinical practice standards for adrenal crisis and different treatment modalities in a group of children with adrenal insufficiency (Bizzari et al.).
Fifty-one children were investigated using various adrenal medications. The overall number of adrenal crisis episodes was 7.3/patient/yr in children <4 yrs and 4.9/patient/yr in children >4 yrs. Hospital admissions averaged 0.5/patient/yr in children <4 yrs and 0.53/patient/yr in children >4 yrs. The micronized weighted formulation showed promising results, with no suspected adrenal crises reported during the 6-month observation period.
Key measures to prevent adrenal crises include parental education on stress dosing (7), using parenteral hydrocortisone when needed, and communication devices to alert healthcare workers (8). Awareness of potential causes and promptly diagnosing AI in children with relevant symptoms are vital in managing adrenal crises.
The article “The promising role of risk scoring system for Cushing syndrome: Time to reconsider current screening recommendations” suggests that risk-scoring systems may offer significant potential (Lam-Chung and Cuevas-Ramos).
The authors review the latest progress in Cushing syndrome’s clinical risk scoring system. The prevalence of endogenous hypercortisolism is rising due to conditions like T2D, obesity, metabolic syndrome, and depression (9, 10). To address this, diagnostic scores based solely on clinical signs (11, 12) could be valuable for guiding physicians in conducting initial screening tests. A standardized approach using a clinical score system based on evidence can expedite the diagnosis of CS, leading to timely identification and reduced morbidity with fewer long-term consequences (13–15).
The article “Total versus partial adrenalectomy in bilateral pheochromocytoma – a systematic review and meta-analysis” addresses a significant and clinically relevant topic in managing bilateral pheochromocytoma (Zawadzka et al.).
The analysis comprised 25 studies involving 1444 patients. Patients who underwent partial adrenalectomy had a lower risk of losing adrenal hormone function during follow-up and needing steroid therapy (RR: 0.32, 95% CI: 0.26-0.38, P < 0.00001). They also had a lower odds ratio for developing acute adrenal crisis (OR: 0.3, 95% CI: 0.1-0.91, P=0.03). However, partial adrenalectomy was associated with a higher risk of local tumor recurrence than total adrenalectomy (OR: 3.72, 95% CI: 1.54-8.96, P=0.003) (16–26).
In five studies comparing TA and PA for pheochromocytoma (16, 17, 20–22), no significant difference in the development of metastases was found (OR 1.47, 95% CI: 0.48-4.44, P=0.5, I2 = 0%). The follow-up durations ranged from 4.9 to 12.2 years, with no metastases reported in either group during follow-up periods of 6 to 16.7 years.
In conclusion, partial adrenalectomy for bilateral pheochromocytoma offers a chance of preserving adrenal hormonal function but comes with an increased risk of local tumor recurrence. However, there was no significant difference in the risk of metastasis and overall mortality between the groups undergoing total or partial adrenalectomy.
The article “Tumour microenvironment in pheochromocytoma and paraganglioma” reviews these tumors’ microenvironment (TME) characteristics and provides valuable insights into their biology, behavior, and potential therapeutic targets (Martinelli et al.).
Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumors with around 10-15% developing metastatic forms and a poor 37% mortality rate at five years (27, 28). SDHB mutations are associated with metastatic conditions (29). This review explores the roles of TME cells like cancer-associated fibroblasts and tumor-associated macrophages and non-cellular components like growth factors, extracellular vesicles, and extracellular matrix in Pheo/PGL growth and progression (30, 31). TME cells produce numerous growth factors and cytokines, facilitating close crosstalk with tumor cells. This interaction supports cancer cell survival, promotes angiogenesis, and fosters resistance to therapies (32, 33). Moreover, immune cells within the tumor release immunosuppressive mediators that dampen host-mediated antitumor responses, further aiding tumor progression (34). The significance of succinate as an oncometabolite and its receptor SUCNR1 in carcinogenesis is also analyzed (35, 36). Therefore, exploring novel molecular targets, including the TME, is crucial to enhance and diversify existing therapies for improved treatment outcomes.
Conclusion
The significance of discussions in Adrenal Endocrinology cannot be overstated. By embracing open and informed dialogues, we can accelerate advancements in research, improve patient care, and address the challenges posed by adrenal gland disorders. Engaging in these discussions allows us to unlock the full potential of knowledge and collaboration in this field.
Author contributions
IK: Writing – original draft.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol (2016) 175(2):G1–G34. doi: 10.1530/EJE-16-0467
2. Zeiger MA, Thompson GB, Duh Q-Y, Hamrahian AH, Angelos P, Elaraj D, et al. American Association of clinical endocrinologists and American association of endocrine surgeons medical guidelines for the management of adrenal incidentalomas: executive summary of recommendations. Endocr Pract (2009) 5:450–3. doi: 10.4158/EP.15.5.450
3. Grumbach MM, Biller BMK, Braunstein GD, Campbell KK, Aidan Carney J, Godley PA, et al. Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med (2003) 138:424–9. doi: 10.7326/0003-4819-138-5-200303040-00013
4. Tabarin A, Bardet S, Bertherat J, Dupas B, Chabre O, Hamoir E, et al. Exploration and management of adrenal incidentalomas.: French society of endocrinology consensus. Ann Endocrinol (Paris) (2008) 69:487–500. doi: 10.1016/J.ANDO.2008.09.003
5. Bednarczuk T, Bolanowski M, Sworczak K, Górnicka B, Cieszanowski A, Otto M, et al. Adrenal incidentaloma in adults - management recommendations by the polish society of endocrinology. Endokrynol Pol (2016) 67:234–58. doi: 10.5603/EP.A2016.0039
6. Ceccato F, Tizianel I, Voltan G, Maggetto G, Merante Boschin I, Quaia E, et al. Attenuation value in adrenal incidentalomas: a longitudinal study. Front Endocrinol (Lausanne) (2021) 12:794197. doi: 10.3389/fendo.2021.794197
7. Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and treatment of primary adrenal insufficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab (2016) 101(2):364–89. doi: 10.1210/jc.2015-1710
8. Ceccato F, Voltan G, Sabbadin C, Camozzi V, Merante Boschin I, Mian C, et al. Tele-medicine versus face-to-face consultation in endocrine outpatients clinic during COVID-19 outbreak: A single-center experience during the lockdown period. J Endocrinol Invest (2021) 44(8):1689–98. doi: 10.1007/s40618-020-01476-2
9. Cooper AJ, Gupta SR, Moustafa AF, Chao AM. Sex/Gender differences in obesity prevalence, comorbidities, and treatment. Curr Obes Rep (2021) 10(4):458–66. doi: 10.1007/s13679-021-00453-x
10. Ferrari AJ, Santomauro DF, Herrera AMM, Shadid J, Ashbaugh C, Erskine HE, et al. Global, regional, and national burden of 12mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the global burden of disease study 2019. Lancet Psychiatry (2022) 9(2):137–50. doi: 10.1016/S2215-0366(21)00395-3
11. Sharma ST, Nieman LK, Feelders RA. Comorbidities in Cushing's disease. Pituitary (2015) 18(2):188–94. doi: 10.1007/s11102-015-0645-6
12. Nieman LK. Cushing's syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol (2015) 173(4):M33–8. doi: 10.1530/EJE-15-0464
13. Braun LT, Riester A, Oßwald-Kopp A, Fazel J, Rubinstein G, Bidlingmaier M, et al. Toward a diagnostic score in Cushing's syndrome. Front Endocrinol (2019) 10:766. doi: 10.3389/fendo.2019.00766
14. León-Justel A, Madrazo-Atutxa A, Alvarez-Rios AI, Infantes-Fontán R, Garcia-Arnés JA, Lillo-Muñoz JA, et al. A probabilistic model for Cushing's syndrome screening in At-risk populations: A prospective multicenter study. J Clin Endocrinol Metab (2016) 101(10):3747–54. doi: 10.1210/jc.2016-1673
15. Parasiliti-Caprino M, Bioletto F, Frigerio T, D'Angelo V, Ceccato F, Ferraù F, et al. A new clinical model to estimate the pre-test probability of Cushing's syndrome: The Cushing score. Front Endocrinol (Lausanne) (2021) 12:747549. doi: 10.3389/fendo.2021.747549
16. Asari R, Scheuba C, Kaczirek K, Niederle B. Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A. Arch Surg (2006) 141(12):1199–205. doi: 10.1001/ARCHSURG.141.12.1199
17. Goretzki PE, Simon D, Dotzenrath C, Röher HD. Surgery for pheochromocytoma in MEN II patients - a radical versus a limited approach. Acta Chir Austriaca (1996) 28:296–9. doi: 10.1007/BF02629281
18. Walz MK, Alesina PF, Wenger FA, Koch JA, Neumann HPH, Petersenn S, et al. Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: Results of 161 tumors in 126 patients. World J Surg (2006) 30(5):899–908. doi: 10.1007/S00268-005-0373-6
19. Grubbs EG, Rich TA, Ng C, Bhosale PR, Jimenez C, Evans DB, et al. Long-term outcomes of surgical treatment for hereditary pheochromocytoma. J Am Coll Surg (2013) 216(2):280–9. doi: 10.1016/J.JAMCOLLSURG.2012.10.012
20. Inabnet WB, Caragliano P, Pertsemlidis D. Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery (2000) 128(6):1007–12. doi: 10.1067/MSY.2000.110846
21. Kittah NE, Gruber LM, Bancos I, Hamidi O, Tamhane S, Iñiguez-Ariza N, et al. Bilateral pheochromocytoma: Clinical characteristics, treatment and longitudinal follow-up. Clin Endocrinol (2020) 93(3):288–95. doi: 10.1111/CEN.14222
22. Neumann HPH, Tsoy U, Bancos I, Amodru V, Walz MK, Tirosh A, et al. Comparison of pheochromocytoma-specific morbidity and mortality among adults with bilateral pheochromocytomas undergoing total adrenalectomy vs cortical-sparing adrenalectomy. JAMA Netw Open (2019) 2(8):e198898. doi: 10.1001/JAMANETWORKOPEN.2019.8898
23. Rajan S, Zaidi G, Agarwal G, Mishra A, Agarwal A, Mishra SK, et al. Genotypephenotype correlation in Indian patients with MEN2-associated pheochromocytoma and comparison of clinico-pathological attributes with apparently sporadic adrenal pheochromocytoma. World J Surg (2016) 40(3):690–6. doi: 10.1007/S00268-015-3255-6
24. Sanford T, Gomella PT, Siddiqui R, Su D, An JY, Bratslavsky G, et al. Long term outcomes for patients with von hippel-lindau and pheochromocytoma: Defining the role of active surveillance. Urol Oncol (2021) 39(2):134.e1–8. doi: 10.1016/J.UROLONC.2020.11.019
25. Scholten A, Valk GD, Ulfman D, Borel RIHM, Vriens MR. Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Ann Surg (2011) 254(6):1022–7. doi: 10.1097/SLA.0B013E318237480C
26. Yip L, Lee JE, Shapiro SE, Waguespack SG, Sherman SI, Hoff AO, et al. Surgical management of hereditary pheochromocytoma. J Am Coll Surg (2004) 198(4):525–34. doi: 10.1016/J.JAMCOLLSURG.2003.12.001
27. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab (2014) 99:1915–42. doi: 10.1210/jc.2014-1498
28. Raleigh DR, Solomon DA, Lloyd SA, Lazar A, Garcia MA, Sneed PK, et al. Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome. Neuro Oncol (2017) 19:78–88. doi: 10.1093/neuonc/now105
29. Andrews KA, Ascher DB, Pires DEV, Barnes DR, Vialard L, Casey RT, et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes. J Med Genet (2018) 55:384–94. doi: 10.1136/jmedgenet-2017-105127
30. Shoucair I, Weber Mello F, Jabalee J, Maleki S, Garnis C. The role of cancerassociated fibroblasts and extracellular vesicles in tumorigenesis. Int J Mol Sci (2020) 21(18):6837. doi: 10.3390/ijms21186837
31. Ribeiro Franco PI, Rodrigues AP, de Menezes LB, Pacheco Miguel M. Tumor microenvironment components: Allies of cancer progression. Pathol Res Pract (2020) 216:152729. doi: 10.1016/j.prp.2019.152729
32. Gao X, Yamazaki Y, Pecori A, Tezuka Y, Ono Y, Omata K, et al. Histopathological analysis of tumor microenvironment and angiogenesis in pheochromocytoma. Front Endocrinol (Lausanne) (2020) 11:587779. doi: 10.3389/fendo.2020.587779
33. Gupta S, Roy A, Dwarakanath BS. Metabolic cooperation and competition in the tumor microenvironment: Implications for therapy. Front Oncol (2017) 7:68. doi: 10.3389/fonc.2017.00068
34. Tufton N, Hearnden RJ, Berney DM, Drake WM, Parvanta L, Chapple JP, et al. The immune cell infiltrate in the tumour microenvironment of phaeochromocytomas and paragangliomas. Endocr Relat Cancer (2022) 29:589–98. doi: 10.1530/ERC-22-0020
35. Richter S, Peitzsch M, Rapizzi E, Lenders JW, Qin N, de Cubas AA, et al. Krebs Cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. J Clin Endocrinol Metab (2014) 99:3903–11. doi: 10.1210/jc.2014-2151
Keywords: adrenal gland, discussion, endocrinology, incidentaloma, pheochromocytoma, adrenal insufficiency, tumour microenvironment, partial adrenalectomy
Citation: Kraljevic I (2023) Editorial: A year in review: discussions in adrenal endocrinology. Front. Endocrinol. 14:1291582. doi: 10.3389/fendo.2023.1291582
Received: 09 September 2023; Accepted: 13 September 2023;
Published: 22 September 2023.
Edited and Reviewed by:
Henrik Falhammar, Karolinska Institutet (KI), SwedenCopyright © 2023 Kraljevic. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ivana Kraljevic, ivana.kraljevic@gmail.com