The Landscape of Androgens in Cushing’s Syndrome

Hanna F. Nowotny; Leah Braun; Nicole Reisch

doi:10.1055/a-2333-1907

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

Exp Clin Endocrinol Diabetes 2024; 132(12): 670-677
DOI: 10.1055/a-2333-1907

Review

The Landscape of Androgens in Cushing’s Syndrome

Hanna F. Nowotny

¹Department of Medicine IV, LMU University Hospital, LMU Munich

,

Leah Braun

¹Department of Medicine IV, LMU University Hospital, LMU Munich

,

Nicole Reisch

¹Department of Medicine IV, LMU University Hospital, LMU Munich

› Institutsangaben

Abstract

Hyperandrogenemia in patients with Cushing’s syndrome (CS) presents a diagnostic pitfall due to its rare occurrence and overlapping symptoms with more common conditions like polycystic ovary syndrome (PCOS). This review explores the significance of androgen dysregulation in CS, focusing on both classical and 11-oxygenated androgens. While classical androgens contribute to hyperandrogenism in CS, their levels alone do not fully account for clinical symptoms. Recent research highlights the overlooked role of 11oxC19 androgens, particularly 11OHA4 and 11KT, in driving hyperandrogenic manifestations across all CS subtypes. These adrenal-specific and highly potent androgens offer stable expression throughout the lifespan of a woman, serving as valuable diagnostic biomarkers. Understanding their prominence not only aids in subtype differentiation but also provides insights into the complex nature of androgen dysregulation in CS. Recognizing the diagnostic potential of 11oxC19 androgens promises to refine diagnostic approaches and improve clinical management strategies for patients with CS.

Keywords

Cushing’s syndrome - androgens - 11-oxygenated androgens - hyperandrogenemia

Volltext

Referenzen

References
1 Giuffrida G, Crisafulli S, Ferrau F. et al. Global Cushing's disease epidemiology: A systematic review and meta-analysis of observational studies. J Endocrinol Invest 2022; 45: 1235-1246
2 Newell-Price J, Bertagna X, Grossman AB. et al. Cushing's syndrome. Lancet 2006; 367: 1605-1617
3 Pivonello R, De Martino MC, De Leo M. et al Cushing's Syndrome. Endocrinol Metab Clin North Am 2008; 37: 135-149 ix
4 Lacroix A, Feelders RA, Stratakis CA. et al. Cushing's syndrome. Lancet 2015; 386: 913-927
5 Braun LT, Riester A, Osswald-Kopp A. et al. Toward a diagnostic score in Cushing's syndrome. Front Endocrinol (Lausanne) 2019; 10: 766
6 Feelders RA, Pulgar SJ, Kempel A. et al. The burden of Cushing's disease: Clinical and health-related quality of life aspects. Eur J Endocrinol 2012; 167: 311-326
7 Valassi E, Santos A, Yaneva M. et al. The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol 2011; 165: 383-392
8 Sharma ST, Nieman LK, Feelders RA. Cushing's syndrome: Epidemiology and developments in disease management. Clin Epidemiol 2015; 7: 281-293
9 The Lancet Regional H-E. Polycystic ovary syndrome: What more can be done for patients?. Lancet Reg Health Eur 2022; 21: 100524
10 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
11 Arnaldi G, Martino M. Androgens in Cushing's Syndrome. Front Horm Res 2019; 53: 77-91
12 Barbetta L, Dall'Asta C, Re T. et al. Androgen secretion in ectopic ACTH syndrome and in Cushing's disease: Modifications before and after surgery. Horm Metab Res 2001; 33: 596-601
13 Cunningham SK, McKenna TJ. Dissociation of adrenal androgen and cortisol secretion in Cushing's syndrome. Clin Endocrinol (Oxf) 1994; 41: 795-800
14 Eisenhofer G, Masjkur J, Peitzsch M. et al. Plasma steroid metabolome profiling for diagnosis and subtyping patients with Cushing syndrome. Clin Chem 2018; 64: 586-596
15 Hana V, Jezkova J, Kosak M. et al. Serum steroid profiling in Cushing's syndrome patients. J Steroid Biochem Mol Biol 2019; 192: 105410
16 Schiffer L, Adaway JE, Arlt W. et al. A liquid chromatography-tandem mass spectrometry assay for the profiling of classical and 11-oxygenated androgens in saliva. Ann Clin Biochem 2019; 56: 564-573
17 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
18 Burger HG. Androgen production in women. Fertil Steril 2002; 77: S3-S5
19 Naamneh Elzenaty R, du Toit T, Fluck CE. Basics of androgen synthesis and action. Best Pract Res Clin Endocrinol Metab 2022; 36: 101665
20 Sharma A, Welt CK. Practical approach to hyperandrogenism in women. Med Clin North Am 2021; 105: 1099-1116
21 Turcu A, Smith JM, Auchus R. et al. Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions. Compr Physiol 2014; 4: 1369-1381
22 Turcu AF, Rege J, Auchus RJ. et al. 11-Oxygenated androgens in health and disease. Nat Rev Endocrinol 2020; 16: 284-296
23 Puurunen J, Piltonen T, Jaakkola P. et al. Adrenal androgen production capacity remains high up to menopause in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2009; 94: 1973-1978
24 Schiffer L, Barnard L, Baranowski ES. et al. Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review. J Steroid Biochem Mol Biol 2019; 194: 105439
25 Schiffer L, Arlt W, O'Reilly MW. Understanding the role of androgen action in female adipose tissue. Front Horm Res 2019; 53: 33-49
26 O'Reilly MW, Kempegowda P, Walsh M. et al. AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2017; 102: 3327-3339
27 Cussen L, McDonnell T, Bennett G. et al. Approach to androgen excess in women: Clinical and biochemical insights. Clin Endocrinol (Oxf) 2022; 97: 174-186
28 Konings G, Brentjens L, Delvoux B. et al. Intracrine regulation of estrogen and other sex steroid levels in endometrium and non-gynecological tissues; pathology, physiology, and drug discovery. Front Pharmacol 2018; 9: 940
29 Purushottamachar P, Njar VC. A new simple and high-yield synthesis of 5alpha-dihydrotestosterone (DHT), a potent androgen receptor agonist. Steroids 2012; 77: 1530-1534
30 Storbeck KH, O'Reilly MW. The clinical and biochemical significance of 11-oxygenated androgens in human health and disease. Eur J Endocrinol 2023; 188: R98-R109
31 Swart AC, Schloms L, Storbeck KH. et al. 11beta-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5alpha-reductase yielding 11beta-hydroxy-5alpha-androstanedione. J Steroid Biochem Mol Biol 2013; 138: 132-142
32 Rege J, Nakamura Y, Satoh F. et al. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab 2013; 98: 1182-1188
33 Turcu AF, Nanba AT, Chomic R. et al. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol 2016; 174: 601-609
34 Barnard L, Schiffer L, Louw du-Toit R. et al. 11-Oxygenated estrogens are a novel class of human estrogens but do not contribute to the circulating estrogen pool. Endocrinology 2021; 162: bqaa231
35 Oestlund I, Snoep J, Schiffer L. et al. The glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 catalyzes the activation of testosterone. J Steroid Biochem Mol Biol 2024; 236: 106436
36 Gent R, du Toit T, Bloem LM. et al. The 11beta-hydroxysteroid dehydrogenase isoforms: Pivotal catalytic activities yield potent C11-oxy C(19) steroids with 11betaHSD2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis. J Steroid Biochem Mol Biol 2019; 189: 116-126
37 Storbeck KH, Bloem LM, Africander D. et al. 11beta-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: A putative role in castration resistant prostate cancer?. Mol Cell Endocrinol 2013; 377: 135-146
38 Rege J, Turcu AF, Kasa-Vubu JZ. et al. 11-Ketotestosterone is the dominant circulating bioactive androgen during normal and premature adrenarche. J Clin Endocrinol Metab 2018; 103: 4589-4598
39 Pretorius E, Africander DJ, Vlok M. et al. 11-Ketotestosterone and 11-ketodihydrotestosterone in castration resistant prostate cancer: Potent androgens which can no longer be ignored. PLoS One 2016; 11: e0159867
40 Turcu AF, Zhao L, Chen X. et al. Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men. Eur J Endocrinol 2021; 185: K1-K6
41 Nowotny HF, Auer MK, Lottspeich C. et al. Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2021; 106: e4509-e4519
42 Burger HG, Dudley EC, Cui J. et al. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000; 85: 2832-2838
43 Eisenhofer G, Peitzsch M, Kaden D. et al. Reference intervals for plasma concentrations of adrenal steroids measured by LC-MS/MS: Impact of gender, age, oral contraceptives, body mass index and blood pressure status. Clin Chim Acta 2017; 470: 115-124
44 Elmlinger MW, Kuhnel W, Wormstall H. et al. Reference intervals for testosterone, androstenedione and SHBG levels in healthy females and males from birth until old age. Clin Lab 2005; 51: 625-632
45 Haring R, Hannemann A, John U. et al. Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2012; 97: 408-415
46 Rothman MS, Carlson NE, Xu M. et al. Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry. Steroids 2011; 76: 177-182
47 Davison SL, Bell R, Donath S. et al. Androgen levels in adult females: Changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005; 90: 3847-3853
48 Parker CR, Slayden SM, Azziz R. et al. Effects of aging on adrenal function in the human: Responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women. J Clin Endocrinol Metab 2000; 85: 48-54
49 Parker CR. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids 1999; 64: 640-647
50 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
51 Rainey WE, Carr BR, Sasano H. et al. Dissecting human adrenal androgen production. Trends Endocrinol Metab 2002; 13: 234-239
52 Miller WL. Androgen synthesis in adrenarche. Rev Endocr Metab Disord 2009; 10: 3-17
53 Havelock JC, Auchus RJ, Rainey WE. The rise in adrenal androgen biosynthesis: Adrenarche. Semin Reprod Med 2004; 22: 337-347
54 Turcu AF, Mallappa A, Elman MS. et al. 11-Oxygenated androgens are biomarkers of adrenal volume and testicular adrenal rest tumors in 21-hydroxylase deficiency. J Clin Endocrinol Metab 2017; 102: 2701-2710
55 Stahl NL, Teeslink CR, Beauchamps G. et al. Serum testosterone levels in hirsute women: A comparison of adrenal, ovarian and peripheral vein values. Obstet Gynecol 1973; 41: 650-654
56 Stahl NL, Teeslink CR, Greenblatt RB. Ovarian, adrenal, and peripheral testosterone levels in the polycystic ovary syndrome. Am J Obstet Gynecol 1973; 117: 194-200
57 Barnes RB, Rosenfield RL, Burstein S. et al. Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med 1989; 320: 559-565
58 Ehrmann DA, Rosenfield RL, Barnes RB. et al. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 1992; 327: 157-162
59 Lachelin GC, Judd HL, Swanson SC. et al. Long term effects of nightly dexamethasone administration in patients with polycystic ovarian disease. J Clin Endocrinol Metab 1982; 55: 768-773
60 Azziz R, Black V, Hines GA. et al. Adrenal androgen excess in the polycystic ovary syndrome: Sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1998; 83: 2317-2323
61 Hoffman DI, Klove K, Lobo RA. The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril 1984; 42: 76-81
62 Lucky AW, Rosenfield RL, McGuire J. et al. Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: Adrenal enzyme defects and exaggerated adrenarche. J Clin Endocrinol Metab 1986; 62: 840-848
63 Carmina E, Stanczyk FZ, Chang L. et al. The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women. Fertil Steril 1992; 58: 148-152
64 Stanczyk FZ, Chang L, Carmina E. et al. Is 11 beta-hydroxyandrostenedione a better marker of adrenal androgen excess than dehydroepiandrosterone sulfate?. Am J Obstet Gynecol 1991; 165: 1837-1842
65 Azziz R, Boots LR, Parker CR. et al. 11 beta-hydroxylase deficiency in hyperandrogenism. Fertil Steril 1991; 55: 733-741
66 Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD. et al. Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab 1998; 83: 3083-3088
67 Kaltsas GA, Korbonits M, Isidori AM. et al. How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing's syndrome?. Clin Endocrinol (Oxf) 2000; 53: 493-500
68 Yamaji T, Ishibashi M, Sekihara H. et al. Serum dehydroepiandrosterone sulfate in Cushing's syndrome. J Clin Endocrinol Metab 1984; 59: 1164-1168
69 Dupuis CC, Storr HL, Perry LA. et al. Abnormal puberty in paediatric Cushing's disease: Relationship with adrenal androgen, sex hormone binding globulin and gonadotrophin concentrations. Clin Endocrinol (Oxf) 2007; 66: 838-843
70 White MC, Sanderson J, Mashiter K. et al. Gonadotrophin levels in women with Cushing's syndrome before and after treatment. Clin Endocrinol (Oxf) 1981; 14: 23-29
71 Stachowska B, Kuliczkowska-Plaksej J, Kaluzny M. et al. Etiology, baseline clinical profile and comorbidities of patients with Cushing's syndrome at a single endocrinological center. Endocrine 2020; 70: 616-628
72 Hannah-Shmouni F, Berthon A, Faucz FR. et al. Mass spectrometry-based steroid profiling in primary bilateral macronodular adrenocortical hyperplasia. Endocr Relat Cancer 2020; 27: 403-413
73 Braun LT, Osswald A, Zopp S. et al. Delineating endogenous Cushing's syndrome by GC-MS urinary steroid metabotyping. EBioMedicine 2024; 99: 104907
74 Kubota-Nakayama F, Nakamura Y, Konosu-Fukaya S. et al. Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: Immunohistochemical analysis and quantitative real-time polymerase chain reaction studies. Hum Pathol 2016; 54: 165-173
75 Dorfman RI. In vivo metabolism of neutral steroid hormones. J Clin Endocrinol Metab 1954; 14: 318-325