Endocrinology

About the research

Pituitary research focuses on hypothalamo-pituitary disease including pituitary and other sellar/parasellar tumours, hypothalamic and pituitary dysfunction and the consequences of pituitary tumours and their treatment, employing clinical and translational approaches (Karavitaki). We are particularly interested in the identification of markers of diagnostic, prognostic and therapeutic significance; systemic biobanking of patients and detailed phenotyping facilitate these aims (Birmingham Pituitary Biobank). In collaborative studies, we look at the pathogenesis of pituitary tumours, long-term outcomes of various management approaches and prognostic parameters. Novel treatments for pituitary tumours and relevant clinical trials are further areas of our work.

Publications

Karavitaki N, Bettinger JJ, Biermasz N, Christ-Crain M, Gadelha MR, Inder WJ, Tsourdi E, Wakeman SE, Zatelli M. Exogenous Opioids and the Human Endocrine System: An Endocrine Society Scientific Statement. Endocr Rev. 2024 Nov 22;45(6):773-794. doi: 10.1210/endrev/bnae023. PMID: 39441725.

Fountas A, Coulden A, Fernández-García S, Tsermoulas G, Allotey J, Karavitaki N. Central diabetes insipidus (vasopressin deficiency) after surgery for pituitary tumours: a systematic review and meta-analysis. Eur J Endocrinol. 2024 Jul 2;191(1):S1-S13. doi: 10.1093/ejendo/lvae084. PMID: 38996052.

Urwyler SA, Samperi I, Lithgow K, Mavilakandy A, Matheou M, Bradley K, Pal A, Reddy NL, Ay J, Karavitaki N. Efficacy of cabergoline in non-irradiated patients with acromegaly: a multi-centre cohort study. Eur J Endocrinol. 2024 Jan 17:lvae003. doi: 10.1093/ejendo/lvae003. Epub ahead of print. PMID: 38231133.

Hamblin R, Fountas A, Lithgow K, Loughrey PB, Bonanos E, Shinwari SK, Mitchell K, Shah S, Grixti L, Matheou M, Isand K, McLaren DS, Surya A, Ullah HZ, Klaucane K, Jayasuriya A, Bhatti S, Mavilakandy A, Ahsan M, Mathew S, Hussein Z, Jansz T, Wunna W, MacFarlane J, Ayuk J, Abraham P, Drake WM, Gurnell M, Brooke A, Baldeweg SE, Sam AH, Martin N, Higham C, Reddy N, Levy MJ, Ahluwalia R, Newell-Price J, Vamvakopoulos J, Krishnan A, Lansdown A, Murray RD, Pal A, Bradley K, Mamoojee Y, Purewal T, Panicker J, Freel EM, Hasan F, Kumar M, Jose B, Hunter SJ, Karavitaki N. Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium. Eur J Endocrinol. 2023 Jul 20;189(1):87-95. doi: 10.1093/ejendo/lvad070. PMID: 37345849.

Atila C, Loughrey PB, Garrahy A, Winzeler B, Refardt J, Gildroy P, Hamza M, Pal A, Verbalis JG, Thompson CJ, Hemkens LG, Hunter SJ, Sherlock M, Levy MJ, Karavitaki N, Newell-Price J, Wass JAH, Christ-Crain M. Central diabetes insipidus from a patient's perspective: management, psychological co- morbidities, and renaming of the condition: results from an international web- based survey. Lancet Diabetes Endocrinol. 2022 Oct;10(10):700-709. doi: 10.1016/S2213-8587(22)00219-4. Epub 2022 Aug 22. PMID: 36007536.

Hamblin R, Vardon A, Akpalu J, Tampourlou M, Spiliotis I, Sbardella E, Lynch J, Shankaran V, Mavilakandy A, Gagliardi I, Meade S, Hobbs C, Cameron A, Levy MJ, Ayuk J, Grossman A, Ambrosio MR, Zatelli MC, Reddy N, Bradley K, Murray RD, Pal A, Karavitaki N. Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance. Lancet Diabetes Endocrinol. 2022 Aug;10(8):581-588. doi: 10.1016/S2213-8587(22)00160-7. Epub 2022 Jul 1. PMID: 35780804

 

About the research

Thyroid tumour research comprises a large programme (McCabe) aimed at improving radioiodine treatment of aggressive thyroid cancers via new understanding of sodium iodide symporter (NIS) trafficking. Via novel high-throughput drug screening, several drugs have been identified that increase NIS function at the plasma membrane, now systematically appraised in thyroid and breast cancer models. Tumour recurrence and prognosis is being evaluated via novel sequencing technologies (Nieto). Vicki Smith investigates the roles of the understudied proto-oncogenes PBF and PTTG in thyroid cancer, focussing on cellular signalling pathways and the interplay between signal transduction and actin dynamics that drives tumour cell motility and invasion. Nadia Schoenmakers has a particular interest in congenital thyroid disorders. She explores the basis for congenital hypothyroidism (CH) and its associated phenotypes, though a programme of basic and clinical research including the consequences of de novo mutations and the role of micronutrient status and environmental contributors to CH.

Publications

Combined Vorinostat and Chloroquine Inhibit Sodium-Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo. Read ML, Brookes K, Zha L, Manivannan S, Kim J, Kocbiyik M, Fletcher A, Gorvin CM, Firth G, Fruhwirth GO, Nicola JP, Jhiang S, Ringel MD, Campbell MJ, Sunassee K, Blower PJ, Boelaert K, Nieto HR, Smith VE, McCabe CJ.Clin Cancer Res. 2024 Apr 1;30(7):1352-1366. doi: 10.1158/1078-0432.CCR-23-2043.

A developmental cell atlas of the human thyroid gland. Massalha H, Trinh MK, Armingol E, Tuck L, Predeus A, Mazin P, Sancho-Serra C, Oszlanczi A, Wood Y, Parks C, Ogbonnah T, Whitfield HJ, Kelava I, Behjati S, Vento-Tormo R, Schoenmakers N bioRxiv 2024.08.22.609152; doi: https://doi.org/10.1101/2024.08.22.609152 

Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter. Read ML, Brookes K, Thornton CEM, Fletcher A, Nieto HR, Alshahrani M, Khan R, Borges de Souza P, Zha L, Webster JRM, Alderwick LJ, Campbell MJ, Boelaert K, Smith VE, McCabe CJ.Cell Chem Biol. 2022 Mar 17;29(3):502-516.e7. doi: 10.1016/j.chembiol.2021.07.016. Epub 2021 Sep 13.

Nieto HR, Thornton CEM, Brookes K, de Menezes AN, Fletcher A, Alshahrani M, Kocbiyik M, Sharma N, Boelaert K, Cazier JB, Mehanna H, Smith VE, Read ML, McCabe CJ. 2021. Recurrence of Papillary Thyroid Cancer: A Systematic Appraisal of Risk Factors. J Clin Endocrinol Metab. 107(5):1392-1406

Targeting novel sodium iodide symporter interactors ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP) enhances radioiodine uptake. Fletcher A, Read ML, Thornton CEM, Larner DP, Poole VL, Brookes K, Nieto HR, Alshahrani M, Thompson RJ, Lavery GG, Landa I, Fagin JA, Campbell MJ, Boelaert K, Turnell AS, Smith VE, McCabe CJ. Cancer Research 2020 80(1):102-115

Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism. Cangul H, Liao XH, Schoenmakers E, Kero J, Barone S, Srichomkwun P, Iwayama H, Serra EG, Saglam H, Eren E, Tarim O, Nicholas AK, Zvetkova I, Anderson CA, Frankl FEK, Boelaert K, Ojaniemi M, Jääskeläinen J, Patyra K, Löf C, Williams ED; UK10K Consortium; Soleimani M, Barrett T, Maher ER, Chatterjee VK, Refetoff S, Schoenmakers N. JCI Insight. 2018 Oct 18;3(20):e99631

About the research

Adrenal tumour research focusses on both common conditions (adrenal incidentaloma – 5% of the population with metabolic disease burden, Conn’s syndrome affecting 10% of hypertensives) and rare but devastating adrenocortical carcinoma (ACC; 5-year survival rate 30-40%). Through the European Network for the Study of Adrenal Tumours (ENSAT) we have access to a global network of other internationally leading teams (www.ensat.org). Our Adrenal team at MSS together with the Adrenal Tumour Service at the Endocrine Department of Queen Elizabeth Hospital Birmingham has received accreditation as European Centre of Excellence for Adrenal Tumours in 2022.

Ronchi has developed novel applications of targeted molecular analyses including an easy-applicable targeted sequencing approach for risk stratification of ACC and a liquid biopsy approach for rapid detection of ACC recurrence. In collaboration with Chortis and Tourigny, she also uses novel cell and tissue-based models for the identification of novel therapeutic targets for ACC treatment.

Combining mass spectrometry-based urine multi-steroid profiling and machine learning methods for data analysis, we have used a urine steroid metabolomics approach to uncover prevalent cortisol excess in mineralocorticoid hypertension and to develop a biomarker tool for the non-invasive diagnosis of ACC, then validated in an ENSAT multi-centre trial (EURINE-ACT)(Taylor, Prete), now in the process of roll-out to clinical practice. In addition, Prete’s work targets the metabolic impact of mild autonomous cortisol excess (MACE) in adrenal incidentalomas and the significance of mineralocorticoid excess in hypertension.

Publications

Cellular landscape of adrenocortical carcinoma at single-nuclei resolution. Tourigny DS, Altieri B, Secener KA, Sbiera S, Schauer MP, Arampatzi P, Herterich S, Sauer S, Fassnacht M, Ronchi CL. Mol Cell Endocrinol. 2024 Sep 1;590:112272. doi: 10.1016/j.mce.2024.112272.

Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma. Lippert J, Smith G, Appenzeller S, Landwehr LS, Prete A, Steinhauer S, Asia M, Urlaub H, Elhassan YS, Kircher S, Arlt W, Fassnacht M, Altieri B, Ronchi CL. Eur J Endocrinol. 2024 Mar 2;190(3):234-247. doi: 10.1093/ejendo/lvae022.

Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation. Elhassan YS, Appenzeller S, Landwehr LS, Lippert J, Popat D, Gilligan LC, Abdi L, Goh E, Diaz-Cano S, Kircher S, Gramlich S, Sutcliffe RP, Thangaratinam S, Chan LF, Fassnacht M, Arlt W, Ronchi CL. Eur J Endocrinol. 2024 Aug 30;191(3):334-344. doi: 10.1093/ejendo/lvae106.

Inflammation-based scores in benign adrenocortical tumours are linked to the degree of cortisol excess: a retrospective single-centre study. Favero V, Prete A, Mangone A, Elhassan YS, Pucino V, Asia M, Hardy R, Chiodini I, Ronchi CL. Eur J Endocrinol. 2023 Nov 8;189(5):517-526. doi: 10.1093/ejendo/lvad151.

Pheochromocytomas Most Commonly Present As Adrenal Incidentalomas: A Large Tertiary Center Experience. Aggarwal S, Prete A, Chortis V, Asia M, Sutcliffe RP, Arlt W, Ronchi CL, Karavitaki N, Ayuk J, Elhassan YS. J Clin Endocrinol Metab. 2023 Dec 21;109(1):e389-e396. doi: 10.1210/clinem/dgad401

About the research

The steroid endocrinology team (Baranowski, Chortis, Foster, Idkowiak, Muller, Prete, Ronchi, and Taylor) research disorders related to steroidogenesis in children and adults. They utilise laboratory based assays and the state-of-the-art Steroid Metabolome Analysis Core (SMAC, Taylor) as well as advanced mathematical modelling (Zavala) to focus on steroid metabolism, biochemistry and pathophysiology. Their research encompasses clinical, translational and laboratory based studies which aim to advance diagnostics, prognostics and treatments of conditions related to steroid metabolism such as adrenal cancer, steroid excess, adrenal insufficiency, congenital adrenal hyperplasia, trauma and inborn disorders of steroidogenesis.

Publications

Klaas, S, Upton, T, Zavala, E, Lawton, MA, Bensing, S, Berinder, K, Botusan, I, Grytaas, M, Methlie, P, Øksnes, M, Russell, G, Vassiliadi, DA & Lightman, SL 2024, 'Awakening not associated with an increased rate of cortisol secretion', Proceedings of the Royal Society B: Biological Sciences. https://research.birmingham.ac.uk/en/publications/awakening-not-associated-with-an-increased-rate-of-cortisol-secre

Upton TJ, Zavala E, Methlie P, Kämpe O, Tsagarakis S, Øksnes M, Bensing S, Vassiliadi DA, Grytaas MA, Botusan IR, Ueland G, Berinder K, Simunkova K, Balomenaki M, Margaritopoulos D, Henne N, Crossley R, Russell G, Husebye ES, Lightman SL. High-resolution daily profiles of tissue adrenal steroids by portable automated collection. 2023. Science Translational Medicine. https://www.science.org/doi/full/10.1126/scitranslmed.adg8464

The ultra-acute steroid response to traumatic injury: a cohort study. Bentley C, Hazeldine J, Bravo L, Taylor AE, Gilligan LC, Shaheen F, Acharjee A, Gkoutos G, Foster MA, Arlt W, Lord JM. Eur J Endocrinol. 2023 Mar 2;188(3):lvad024. doi: 10.1093/ejendo/lvad024.PMID: 36809311

New structural insights provide a different angle on steroid sulfatase action. Foster PA, Mueller JW. J Steroid Biochem Mol Biol. 2023 Sep;232:106353. doi: 10.1016/j.jsbmb.2023.106353. Epub 2023 Jun 17. PMID: 37331434

Circulating Conjugated and Unconjugated Vitamin D Metabolite Measurements by Liquid Chromatography Mass Spectrometry. Jenkinson C, Desai R, McLeod MD, Wolf Mueller J, Hewison M, Handelsman DJ. J Clin Endocrinol Metab. 2022 Jan 18;107(2):435-449. doi: 10.1210/clinem/dgab708. PMID: 34570174

About the research

Our research into endocrine-related cancers spans the understanding of basic steroidal metabolism to drug discovery and translational clinical medicine. By using our Steroid Metabolome Analysis Core, we are investigating how mapping steroid output from endocrine-related cancers can inform new diagnostic tests and drug discovery opportunities. In particular, we have an interest in identifying new drugs effective against many malignancies, such as breast cancer (Foster) and adrenocortical carcinoma (Ronchi, Foster). Indeed, our recent studies have shown how measuring steroid output in ovarian cancer patients may be a novel diagnostic tool for identifying tumour subtypes (Foster). 

Publications

PLK1 inhibitors as a new targeted treatment for adrenocortical carcinoma. Warmington E, Smith G, Chortis V, Liang R, Lippert J, Steinhauer S, Landwehr LS, Hantel C, Kiseljak-Vassiliades K, Wierman ME, Altieri B, Foster PA, Ronchi CL. Endocr Connect. 2023 Dec 14;13(1):e230403.

Pyridine based dual binding site aromatase (CYP19A1) inhibitors. Eissa AG, Powell LE, Gee J, Foster PA, Simons C. RSC Med Chem. 2023 Jan 3;14(2):356-366.

4th generation nonsteroidal aromatase inhibitors: An iterative SAR-guided design, synthesis, and biological evaluation towards picomolar dual binding inhibitors. Eissa AG, Barrow D, Gee J, Powell LE, Foster PA, Simons C. Eur J Med Chem. 2022 Oct 5;240:114569.

About the research

One particular strength is our ability to develop innovative microscopy methodologies (Calebiro), in combination with new biosensors, to monitor receptor signalling directly in living cells and tissues with unprecedented spatiotemporal resolution. This is combined with novel mathematical and computational approaches to extract quantitative information from complex imaging data and model receptor signalling at both molecular and cellular level.

Publications

Plasma membrane preassociation drives β-arrestin coupling to receptors and activation. Grimes J, Koszegi Z, Lanoiselée Y, Miljus T, O'Brien SL, Stepniewski TM, Medel-Lacruz B, Baidya M, Makarova M, Mistry R, Goulding J, Drube J, Hoffmann C, Owen DM, Shukla AK, Selent J, Hill SJ, Calebiro D. Cell. 2023 May 11;186(10):2238-2255.e20. doi: 10.1016/j.cell.2023.04.018. Epub 2023 May 4.

Filamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane. Jobin ML, Siddig S, Koszegi Z, Lanoiselée Y, Khayenko V, Sungkaworn T, Werner C, Seier K, Misigaiski C, Mantovani G, Sauer M, Maric HM, Calebiro D. Nat Commun. 2023 Jan 3;14(1):34. doi: 10.1038/s41467-022-35708-1.PMID: 36596803 

ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP. Rahbani JF, Scholtes C, Lagarde DM, Hussain MF, Roesler A, Dykstra CB, Bunk J, Samborska B, O'Brien SL, Tripp E, Pacis A, Angueira AR, Johansen OS, Cinkornpumin J, Hossain I, Lynes MD, Zhang Y, White AP, Pastor WA, Chondronikola M, Sidossis L, Klein S, Kralli A, Cypess AM, Pedersen SB, Jessen N, Tseng YH, Gerhart-Hines Z, Seale P, Calebiro D, Giguère V, Kazak L. Nat Metab. 2022 Nov;4(11):1459-1473. doi: 10.1038/s42255-022-00667-w. Epub 2022 Nov 7.PMID: 36344764 

PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser¹¹⁴ phosphorylation. Weigand I, Ronchi CL, Vanselow JT, Bathon K, Lenz K, Herterich S, Schlosser A, Kroiss M, Fassnacht M, Calebiro D, Sbiera S. Sci Adv. 2021 Feb 19;7(8):eabd4176. doi: 10.1126/sciadv.abd4176. Print 2021 Feb.PMID: 33608270