Leah Theresa Braun

Ludwig-Maximilians-Universität München; Medizinische Klinik und Poliklinik IV

Research theme: 

Improving diagnostics in Cushing’s syndrome

Abstract: 

Diagnosing endogenous Cushing’s syndrome (CS) is one of the most challenging fields in internal medicine, especially in early stages of cortisol excess. Assessing and subtyping the urinary steroid metabolome using gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not been exploited so far. In this explorative study, we analyzed urinary steroid metabolome in patients with Cushing’s disease, with different forms of adrenal CS (unilateral and bilateral) and a group of patients in whom Cushing’s syndrome was clinically suspected but finally excluded. Main aim of the study is to distinguish patients with and without CS by their specific metabotype. We used targeted steroid analysis by GC-MS to quantify excretion rates of 36 hormone metabolites in 24-hr urinary specimens. Precursor/product ratios were used to characterize enzyme activities. We investigated 44 patients with Cushing’s disease (CD), 35 with unilateral cortisol-producing adenoma, 54 with primary bilateral macronodular adrenal hyperplasia (PBMAH), and 93 ruled-out CS. Forty healthy volunteers served as controls. Cluster-Analysis revealed five urinary steroid metabotypes. Patients with Cushing’s disease and with ACTH-independent CS can be clearly differentiated from healthy controls and patients with exclusion of CS. Regarding overall differentiation of CS patients from controls, the biomarkers THS, THF/THE and (An + Et)/(11β-OH-An + 11β-OH-Et) allowed excellent discrimination (AUC = 0.96). 92% of patients were correctly classified using these three parameters. To conclude, GC-MS based urinary steroid metabotyping allows a very good identification of patients with endogenous CS and differentiation of its subtypes.

Publications 2020-2022:

2022

Nowotny HF, Vogel F, Bidlingmaier M, Braun L, Reincke M, Tschaidse L, Auer M, Lottspeich C, Hawley J, Adaway J, Keevil B, Schilbach K, Reisch N. 11-oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing’s disease. Eur J Endocrinol. (under revision).

Tausendfreund O*, Braun LT*, Schmidmaier R. Types of therapeutic errors in the management of osteoporosis made by physicians and medical students. BMC Med Educ. 2022 (accepted).

Kunzelmann AK, Binder K, Fischer MR, Reincke M, Braun LT, Schmidmaier R. Improving Diagnostic Efficiency with Frequency Double-Trees and Frequency Nets in Bayesian Reasoning. MDM Policy Pract. 2022 Mar 16;7(1):23814683221086623. doi: 10.1177/23814683221086623. PMID: 35321028; PMCID: PMC8935422.

Braun LT, Vogel F, Reincke M. Long-term morbidity and mortality in patients with Cushing’s syndrome. J Neuroendocrinol. 2022 Mar 4:e13113. doi: 10.1111/jne.13113. Epub ahead of print. PMID: 35312199.

Rubinstein G, Osswald A, Braun LT, Vogel F, Kroiss M, Pilz S, Deniz S, Aigner L, Knösel T, Bertherat J, Bouys L, Ladurner R, Riester A, Bidlingmaier M, Beuschlein F, Reincke M. The role of adrenal venous sampling (AVS) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH): a study of 16 patients. Endocrine. 2022 Mar 10. doi: 10.1007/s12020-022-03020-z. Epub ahead of print. PMID: 35274284.

Braun LT, Vogel F, Zopp S, Rubinstein G, Schilbach K, Künzel H, Beuschlein F, Reincke M. Diurnal Salivary Cortisol Profiles in Patients with Cushing’s Syndrome. Exp Clin Endocrinol Diabetes. 2022 Jan 17. doi: 10.1055/a-1719-5381. Epub ahead of print. PMID: 35038761.

Vogel F, Braun L, Reincke M. Morbidität und Mortalität beim Cushing-Syndrom [Morbidity and mortality in Cushing’s syndrome]. Internist (Berl). 2022 Jan;63(1):34-42. German. doi: 10.1007/s00108-021-01222-7. Epub 2021 Dec 20. PMID: 34928397.

Armignacco R, Jouinot A, Bouys L, Septier A, Lartigue T, Neou M, Gaspar C, Perlemoine K, Braun L, Riester A, Bonnet-Serrano F, Blanchard A, Amar L, Scaroni C, Ceccato F, Rossi GP, Williams TA, Larsen CK, Allassonnière S, Zennaro MC, Beuschlein F, Reincke M, Bertherat J, Assié G. Identification of glucocorticoid-related molecular signature by whole blood methylome analysis. Eur J Endocrinol. 2022 Jan 13;186(2):297-308. doi: 10.1530/EJE-21-0907. PMID: 34914631; PMCID: PMC8789024.

2021

Vogel F, Braun L, Rubinstein G, Zopp S, Oßwald A, Schilbach K, Schmidmaier R, Bidlingmaier M, Reincke M. Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study. Front Endocrinol (Lausanne). 2021 Oct 27;12:765067. doi: 10.3389/fendo.2021.765067. PMID: 34777259; PMCID: PMC8578886.

Lottspeich C, Braun LT, Fischer MR, Schmidmaier R. Simulated ward round training in the medical curriculum Munich. GMS J Med Educ. 2021 Apr 15;38(4):Doc75. doi: 10.3205/zma001471. PMID: 34056064; PMCID: PMC8136345.

Braun LT, Reincke M. The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2-Year Follow-Up Study. J Bone Miner Res. 2021 Nov;36(11):2281-2282. doi: 10.1002/jbmr.4309. Epub 2021 Apr 26. PMID: 33900642.

Braun LT, Zopp S, Vogel F, Honegger J, Rubinstein G, Schilbach K, Künzel H, Beuschlein F, Reincke M. Signs, symptoms and biochemistry in recurrent Cushing disease: a prospective pilot study. Endocrine. 2021 Sep;73(3):762-766. doi: 10.1007/s12020-021-02719-9. Epub 2021 Apr 19. PMID: 33871792; PMCID: PMC8325659.

Vogel F, Braun L, Rubinstein G, Zopp S, Benedix S, Schneider H, Ritzel K, Schilbach K, Schmidmaier R, Beuschlein F, Bidlingmaier M, Reincke M. 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 May 4;184(6):813-821. doi: 10.1530/EJE-20-1285. PMID: 33830940.

Heger E, Rubinstein G, Braun LT, Zopp S, Honegger J, Seidensticker M, Reincke M, Oßwald A. Chemosensory dysfunction in Cushing’s syndrome. Endocrine. 2021 Sep;73(3):674-681. doi: 10.1007/s12020-021-02707-z. Epub 2021 Apr 5. PMID: 33821391; PMCID: PMC8325648.

Röcker N, Lottspeich C, Braun LT, Lenzer B, Frey J, Fischer MR, Schmidmaier R. Implementation of self-directed learning within clinical clerkships. GMS J Med Educ. 2021 Feb 15;38(2):Doc43. doi: 10.3205/zma001439. PMID: 33763528; PMCID: PMC7958912.

Vetrivel S, Zhang R, Engel M, Altieri B, Braun L, Osswald A, Bidlingmaier M, Fassnacht M, Beuschlein F, Reincke M, Chen A, Sbiera S, Riester A. Circulating microRNA Expression in Cushing’s Syndrome. Front Endocrinol (Lausanne). 2021 Feb 22;12:620012. doi: 10.3389/fendo.2021.620012. PMID: 33692756; PMCID: PMC7937959.

Binder K, Krauss S, Schmidmaier R, Braun LT. Natural frequency trees improve diagnostic efficiency in Bayesian reasoning. Adv Health Sci Educ Theory Pract. 2021 Aug;26(3):847-863. doi: 10.1007/s10459-020-10025-8. Epub 2021 Feb 12. PMID: 33599875; PMCID: PMC8338842.

2020

Wurth R, Tirosh A, Kamilaris CDC, Camacho J, Faucz FR, Maria AG, Berthon A, Papadakis GZ, Nilubol N, Hamimi A, Gharib AM, Demidowich A, Zilbermint M, Eisenhofer G, Braun L, Reincke M, Stratakis CA, Hannah-Shmouni F. Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia. J Endocr Soc. 2020 Oct 29;5(1):bvaa162. doi: 10.1210/jendso/bvaa162. PMID: 33305158; PMCID: PMC7716656.

Vogel F, Braun LT, Rubinstein G, Zopp S, Künzel H, Strasding F, Albani A, Riester A, Schmidmaier R, Bidlingmaier M, Quinkler M, Deutschbein T, Beuschlein F, Reincke M. Persisting Muscle Dysfunction in Cushing’s Syndrome Despite Biochemical Remission. J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4490–8. doi: 10.1210/clinem/dgaa625. PMID: 32882010; PMCID: PMC7538105.

Braun LT, Rubinstein G, Zopp S, Vogel F, Schmid-Tannwald C, Escudero MP, Honegger J, Ladurner R, Reincke M. Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment. Endocrine. 2020 Nov;70(2):218-231. doi: 10.1007/s12020-020-02432-z. Epub 2020 Aug 2. PMID: 32743767; PMCID: PMC7396205.

Adolf C, Braun LT, Fuss CT, Hahner S, Künzel H, Handgriff L, Sturm L, Heinrich DA, Schneider H, Bidlingmaier M, Reincke M. Spironolactone reduces biochemical markers of bone turnover in postmenopausal women with primary aldosteronism. Endocrine. 2020 Sep;69(3):625-633. doi: 10.1007/s12020-020-02348-8. Epub 2020 Jun 27. Erratum in: Endocrine. 2022 Jan;75(1):312. PMID: 32594379; PMCID: PMC8514385.

Handgriff L, Adolf C, Heinrich DA, Braun L, Nirschl N, Sturm L, Ladurner R, Ricke J, Seidensticker M, Bidlingmaier M, Reincke M. The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease. Horm Metab Res. 2020 Jun;52(6):404-411. doi: 10.1055/a-1164-1944. Epub 2020 May 13. PMID: 32403151; PMCID: PMC7746512.

Braun LT, Fazel J, Zopp S, Benedix S, Osswald-Kopp A, Riester A, Rubinstein G, Seidensticker M, Beuschlein F, Drey M, Bidlingmaier M, Schmidmaier R, Reincke M. The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2-Year Follow-Up Study. J Bone Miner Res. 2020 Sep;35(9):1711-1717. doi: 10.1002/jbmr.4033. Epub 2020 May 8. PMID: 32315096.

Braun LT, Reincke M. What is the role of medical therapy in adrenal-dependent Cushing’s syndrome? Best Pract Res Clin Endocrinol Metab. 2020 May;34(3):101376. doi: 10.1016/j.beem.2020.101376. Epub 2020 Jan 31. PMID: 32063487.

Rubinstein G, Osswald A, Hoster E, Losa M, Elenkova A, Zacharieva S, Machado MC, Hanzu FA, Zopp S, Ritzel K, Riester A, Braun LT, Kreitschmann-Andermahr I, Storr HL, Bansal P, Barahona MJ, Cosaro E, Dogansen SC, Johnston PC, Santos de Oliveira R, Raftopoulos C, Scaroni C, Valassi E, van der Werff SJA, Schopohl J, Beuschlein F, Reincke M. Time to Diagnosis in Cushing’s Syndrome: A Meta-Analysis Based on 5367 Patients. J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgz136. doi: 10.1210/clinem/dgz136. PMID: 31665382.

Müller LM, Kienitz T, Deutschbein T, Riester A, Hahner S, Burger-Stritt S, Berr CM, Oßwald A, Braun L, Rubinstein G, Reincke M, Quinkler M. Glucocorticoid Receptor Polymorphisms Influence Muscle Strength in Cushing’s Syndrome. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz052. doi: 10.1210/clinem/dgz052. PMID: 31613324.

Beckers MA, Braun LT, Epstein N, Fischer MR, Schmidmaier R. Die Facharztprüfung Innere Medizin: Eine qualitative und quantitative Analyse von Gedächtnisprotokollen [The specialist examination in internal medicine: a qualitative and quantitative analysis of minutes from memory]. Dtsch Med Wochenschr. 2020 Jan;145(2):e10-e17. German. doi: 10.1055/a-0970-6348. Epub 2019 Sep 23. PMID: 31546268.

Conference contributions 2020-2022:

Kongress der Deutschen Gesellschaft für Endokrinologie, Gießen, 2020

• Talk: The effects of biochemical remission on bone metabolism in Cushing‘s syndrome: a two-years follow-up study
• Poster: Urinary Steroid Metabolome Analysis by GC-MS reveals Plurihormonal Steroid Secretion in Cushing’s Disease

22nd Annual Meeting Young Active Research in Endocrinology January 29th, 2021

• Talk: Bone health in Cushing’s Syndrome

Kongress der Deutschen Gesellschaft für Endokrinologie, online, 2022

• Talk: GC-MS urinary steroid metabotyping of patients with endogenous Cushing‘s syndrome
• Satelliten-Symposium: Isturisa® in der Therapie des endogenen Cushing-Syndroms:

Die Therapie mit Osilodrostat – ein Einblick in die Praxis

• Poster: The Endocrine Society Practice Guideline revisited: Why do nowadays patients undergo screening for Cushing’ syndrome, and with which Outcome?

ECE 2022, Milan

• Poster: The Endocrine Society Practice Guideline revisited: Why do nowadays patients undergo screening for Cushing’ syndrome, and with which Outcome?

Awards 2020-2022:

Von Recklinghausen-Preis der Deutschen Gesellschaft für Endokrinologie (September 2020), Preisgeld: 2.500 Euro

Early-career travel grant for the “Steroids, Mass Spectrometry and Endocrinology – Past, Present and Future” Symposium in Birmingham on 22-23 April 2022