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Endogenous Cushing’s syndrome during pregnancy

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Abstract

Endogenous Cushing’s syndrome (CS) is rare during pregnancy, probably because hypercortisolism induces anovulation and infertility. To date, slightly above 200 cases have been reported in the literature. The most frequent etiology of CS diagnosed during gestation is from primary adrenal causes, namely adrenal adenomas and an entity called pregnancy-induced CS. The latter can be secondary to the aberrant adrenal expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) in the adrenal lesions. Diagnosis of CS during pregnancy is extremely challenging, as a consequence of the physiologic hypercortisolism normally present during pregnancy. Assessment of excess cortisol production tests should be interpreted cautiously using adapted upper limits of normal criteria for pregnant patients and a high index of suspicion is required for diagnosis. Imaging is also limited due to high risk of radiation exposure with computed tomography and teratogenicity with contrast agents. The optimal treatment strategy is surgical resection of adrenal adenoma or pituitary adenoma, ideally before 24 weeks of gestation to reduce the risk of maternal and fetal complications. In mild cases, surgery can be postponed until after delivery and treatment should focus on controlling metabolic complications of hypercortisolism, such as hypertension and dysglycemia. Maternal and fetal outcomes of excess cortisol exposure, except fetal loss, are not readily improved by successful treatment of hypercortisolism.

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Abbreviations

ACC :

Adrenocortical carcinoma.

ACTH :

Adrenocorticotropic hormone.

cAMP :

Cyclic adenosine monophosphate.

BIPSS :

Bilateral inferior petrosal sinus sampling.

11-ßHSD2 :

11beta-hydroxysteroid dehydrogenase type 2.

CBG :

Cortisol-binding globulin.

CD :

Cushing’s disease.

CS :

Cushing’s syndrome.

CRH :

Corticotropin-releasing hormone.

CRH-bp :

CRH- binding protein.

CT :

Computed tomography.

DHEA :

Dehydroepiandrosterone.

DHEAS :

Dehydroepiandrosterone sulfate.

DST :

Dexamethasone suppression test.

ER :

Estrogen receptors.

FDA :

Food and Drug Administration.

GC :

Glucocorticoids.

GIP :

Glucose-dependent insulinotropic polypeptide.

GIPR :

GIP receptor.

GnRH :

Gonadotrophin-releasing hormone.

GPCR :

G-protein-coupled receptors.

hCG :

Human chorionic gonadotropin.

HPA :

Hypothalamic-pituitary-adrenal.

IGF1 :

Insulin-like growth factor 1.

IGF2 :

Insulin-like growth factor 2.

IUGR :

Intra-uterine growth retardation.

LC-MS/MS :

Liquid chromatography-tandem mass spectrometry.

LH :

Luteinizing hormone.

LHCGR :

Luteinizing hormone/ human chorionic gonadotropin receptor.

LNSC :

Late-night salivary cortisol.

MC2R :

Melanocortin 2 receptor.

MRI :

Magnetic resonance imaging.

PBMAH :

Primary bilateral macronodular adrenal hyperplasia.

PKA :

Protein kinase A.

POMC :

Proopiomelanocortin.

PPNAD :

Primary pigmented nodular adrenocortical disease.

RT-PCR :

Reverse transcription-polymerase chain reaction.

UCNs :

Urocortins.

UFC :

Urinary free cortisol.

ULN :

Upper limit of normal.

References

  1. Barbot M, Zilio M, Scaroni C. Cushing’s syndrome: Overview of clinical presentation, diagnostic tools and complications. Best Practice & Research Clinical Endocrinology & Metabolism. 2020;34(2):101380. https://doi.org/10.1016/j.beem.2020.101380.

    Article  CAS  Google Scholar 

  2. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet (London England). 2015;386(9996):913–27. https://doi.org/10.1016/S0140-6736(14)61375-1.

    Article  CAS  Google Scholar 

  3. Hakami OA, Ahmed S, Karavitaki N. Epidemiology and mortality of Cushing’s syndrome. Best Practice & Research Clinical Endocrinology & Metabolism. 2021;35(1):101521. https://doi.org/10.1016/j.beem.2021.101521.

    Article  CAS  Google Scholar 

  4. Wengander S, Trimpou P, Papakokkinou E, Ragnarsson O. The incidence of endogenous Cushing’s syndrome in the modern era. Clin Endocrinol. 2019;91(2):263–70. https://doi.org/10.1111/cen.14014.

    Article  CAS  Google Scholar 

  5. Ahn CH, Kim JH, Park MY, Kim SW. Epidemiology and Comorbidity of Adrenal Cushing Syndrome: A Nationwide Cohort Study. J Clin Endocrinol Metab. 2021;106(3):e1362–72. https://doi.org/10.1210/clinem/dgaa752.

    Article  Google Scholar 

  6. Steffensen C, Bak AM, Rubeck KZ, Jørgensen JOL. Epidemiology of Cushing’s Syndrome. Neuroendocrinology. 2010;92(Suppl):1), 1–5. https://doi.org/10.1159/000314297.

    Article  CAS  Google Scholar 

  7. Kyriakos G, Farmaki P, Voutyritsa E, Patsouras A, Quiles-Sánchez LV, Damaskos C, Stelianidi A, Pastor-Alcaraz A, Palomero-Entrenas P, Diamantis E. Cushing’s syndrome in pregnancy: A review of reported cases. Endokrynologia Polska. 2021;72(1):64–72. https://doi.org/10.5603/EP.a2020.0089.

    Article  CAS  Google Scholar 

  8. Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy R, Webb SM. Cushing’s syndrome and pregnancy outcomes: A systematic review of published cases. Endocrine. 2017;55(2):555–63. https://doi.org/10.1007/s12020-016-1117-0.

    Article  CAS  Google Scholar 

  9. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: Challenges in disease detection and treatment. Endocr Rev. 2005;26(6):775–99. https://doi.org/10.1210/er.2004-0025.

    Article  CAS  Google Scholar 

  10. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s Syndrome during Pregnancy: Personal Experience and Review of the Literature. The J Clin Endocrinology Metabolism. 2005;90(5):3077–83. https://doi.org/10.1210/jc.2004-2361.

    Article  CAS  Google Scholar 

  11. Brue T, Amodru V, Castinetti F. MANAGEMENT OF ENDOCRINE DISEASE: Management of Cushing’s syndrome during pregnancy: solved and unsolved questions. Eur J Endocrinol. 2018;178(6):R259–66. https://doi.org/10.1530/EJE-17-1058.

    Article  CAS  Google Scholar 

  12. Manoharan M, Sinha P, Sibtain S. Adrenal disorders in pregnancy, labour and postpartum—An overview. J Obstet Gynaecology: J Inst Obstet Gynecol. 2020;40(6):749–58. https://doi.org/10.1080/01443615.2019.1648395.

    Article  CAS  Google Scholar 

  13. St-Jean M, Bourdeau I, Lacroix A. (2020). Chapter 25—Adrenal Pathologies During Pregnancy and Postpartum. In C. S. Kovacs & C. L. Deal, editors, Maternal-Fetal and Neonatal Endocrinology (pp. 417–454). Academic Press. https://doi.org/10.1016/B978-0-12-814823-5.00025-8.

  14. Wallace C, Toth EL, Lewanczuk RZ, Siminoski K. Pregnancy-induced Cushing’s syndrome in multiple pregnancies. J Clin Endocrinol Metab. 1996;81(1):15–21. https://doi.org/10.1210/jcem.81.1.8550743.

    Article  CAS  Google Scholar 

  15. Hána V, Dokoupilová M, Marek J, Plavka R. Recurrent ACTH-independent Cushing’s syndrome in multiple pregnancies and its treatment with metyrapone. Clin Endocrinol. 2001;54(2):277–81. https://doi.org/10.1046/j.1365-2265.2001.01055.x.

    Article  Google Scholar 

  16. Machado MC, Fragoso MCBV, Bronstein MD. Pregnancy in Patients with Cushing’s Syndrome. Endocrinol Metab Clin North Am. 2018;47(2):441–9. https://doi.org/10.1016/j.ecl.2018.02.004.

    Article  Google Scholar 

  17. ATSUSHI S, MARJORIE ANTHONY,SL, ANDREW ML, N. M., TOSHIHIRO, S., & DOROTHY TK. (1984). IMMUNOREACTIVE CORTICOTROPIN-RELEASING FACTOR IS PRESENT IN HUMAN MATERNAL PLASMA DURING THE THIRD TRIMESTER OF PREGNANCY. The J Clin Endocrinology Metabolism, 59(4), 812–4. https://doi.org/10.1210/jcem-59-4-812.

  18. Pofi R, Tomlinson JW. Glucocorticoids in pregnancy. Obstetric Med. 2020;13(2):62–9. https://doi.org/10.1177/1753495X19847832.

  19. Petraglia F, Sawchenko PE, Rivier J, Vale W. Evidence for local stimulation of ACTH secretion by corticotropin-releasing factor in human placenta. Nature. 1987;328(6132):717–9. https://doi.org/10.1038/328717a0.

  20. St-Jean M, Bourdeau I, Lacroix A. (2020). Adrenal Cortex and Medulla Physiology During Pregnancy, Labor, and Puerperium. https://doi.org/10.1016/b978-0-12-814823-5.00008-8.

  21. Robinson BG, Emanuel RL, Frim DM, Majzoub JA. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci USA. 1988;85(14):5244–8. https://doi.org/10.1073/pnas.85.14.5244.

    Article  CAS  Google Scholar 

  22. Demey-Ponsart E, Foidart JM, Sulon J, Sodoyez JC. Serum CBG, free and total cortisol and circadian patterns of adrenal function in normal pregnancy. J Steroid Biochem. 1982;16(2):165–9. https://doi.org/10.1016/0022-4731(82)90163-7.

    Article  CAS  Google Scholar 

  23. Carr BR, Parker CR, Madden JD, MacDonald PC, Porter JC. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol. 1981;139(4):416–22. https://doi.org/10.1016/0002-9378(81)90318-5.

    Article  CAS  Google Scholar 

  24. Jung C, Ho JT, Torpy DJ, Rogers A, Doogue M, Lewis JG, Czajko RJ, Inder WJ. A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum. J Clin Endocrinol Metab. 2011;96(5):1533–40. https://doi.org/10.1210/jc.2010-2395.

    Article  CAS  Google Scholar 

  25. Nolten WE, Lindheimer MD, Rueckert PA, Oparil S, Ehrlich EN. Diurnal patterns and regulation of cortisol secretion in pregnancy. J Clin Endocrinol Metab. 1980;51(3):466–72. https://doi.org/10.1210/jcem-51-3-466.

    Article  CAS  Google Scholar 

  26. Bronstein MD, Machado MC, Fragoso MCBV. MANAGEMENT OF ENDOCRINE DISEASE: Management of pregnant patients with Cushing’s syndrome. Eur J Endocrinol. 2015;173(2):R85–91. https://doi.org/10.1530/EJE-14-1130.

    Article  CAS  Google Scholar 

  27. Duthie L, Reynolds RM. Changes in the Maternal Hypothalamic-Pituitary-Adrenal Axis in Pregnancy and Postpartum: Influences on Maternal and Fetal Outcomes. Neuroendocrinology. 2013;98(2):106–15. https://doi.org/10.1159/000354702.

    Article  CAS  Google Scholar 

  28. Wilson M, Morganti AA, Zervoudakis I, Letcher RL, Romney BM, Von Oeyon P, Papera S, Sealey JE, Laragh JH. Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med. 1980;68(1):97–104. https://doi.org/10.1016/0002-9343(80)90178-3.

    Article  CAS  Google Scholar 

  29. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, Boguszewski CL, Bronstein MD, Buchfelder M, Carmichael JD, Casanueva FF, Castinetti F, Chanson P, Findling J, Gadelha M, Geer EB, Giustina A, Grossman A, Gurnell M, … Biller BMK. Consensus on diagnosis and management of Cushing’s disease: A guideline update. The Lancet Diabetes & Endocrinology. 2021;9(12):847–75. https://doi.org/10.1016/S2213-8587(21)00235-7.

    Article  Google Scholar 

  30. Juszczak A, Morris D, Grossman A. Cushing’s Syndrome. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, … Wilson DP, editors. Endotext. MDText.com, Inc; 2000. http://www.ncbi.nlm.nih.gov/books/NBK279088/.

  31. Polat Korkmaz O, Karayel B, Korkmaz M, Haliloglu O, Sahin S, Durcan E, Oren MM, Kadioglu P. (2019). RELIABILITY OF THE CORTICOTROPIN RELEASING HORMONE STIMULATION TEST FOR DIFFERENTIATING BETWEEN ACTH DEPENDENT AND INDEPENDENT CUSHING SYNDROME. Acta Endocrinologica (Bucharest, Romania: 2005), 15(2), 195–202. https://doi.org/10.4183/aeb.2019.195.

  32. Tang K, Lu L, Feng M, Zhang H, Chen K, Sun X, Zhu H, Wang R, Lu Z. The Incidence of Pregnancy-Associated Cushing’s Disease and Its Relation to Pregnancy: A Retrospective Study. Front Endocrinol. 2020;11:305. https://doi.org/10.3389/fendo.2020.00305.

    Article  Google Scholar 

  33. Cremoux P de, Rosenberg D, Goussard J, Brémont-Weil C, Tissier F, Tran-Perennou C, Groussin L, Bertagna X, Bertherat J, Raffin-Sanson M-L. Expression of progesterone and estradiol receptors in normal adrenal cortex, adrenocortical tumors, and primary pigmented nodular adrenocortical disease. Endocrine-related Cancer. 2008;15(2):465–74. https://doi.org/10.1677/ERC-07-0081.

    Article  CAS  Google Scholar 

  34. Spaniol A, Mulla BM, Daily JG, Ennen CS. Carney complex: A rare cause of Cushing syndrome in pregnancy. Obstet Gynecol. 2014;124(2 Pt 2 Suppl 1):426–8. https://doi.org/10.1097/AOG.0000000000000340.

    Article  Google Scholar 

  35. Ralser DJ, Strizek B, Kupczyk P, Stoffel-Wagner B, Altengarten J, Müller A, Woelfle J, Gembruch U, Klingmueller D, Merz WM, Paschkowiak-Christes A. Obstetric and Neonatal Outcome of Pregnancy in Carney Complex: A Case Report. Front Endocrinol. 2020;11:296. https://doi.org/10.3389/fendo.2020.00296.

    Article  Google Scholar 

  36. Reschke K, Klose S, Mohnike K, Buhtz P, Roessner A, Lehnert H. (2002). [Manifestation of Cushing syndrome and osteoporotic fractures in pregnancy in a patient with Carney complex]. Medizinische Klinik (Munich, Germany: 1983), 97(2), 91–95. https://doi.org/10.1007/s00063-002-1131-2.

  37. Schulz S, Redlich A, Köppe I, Reschke K, Weise W. Carney complex—An unexpected finding during puerperium. Gynecol Obstet Invest. 2001;51(3):211–3. https://doi.org/10.1159/000052927.

    Article  CAS  Google Scholar 

  38. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, Perry LA, Grossman AB, Besser GM, Trainer PJ. Menstrual abnormalities in women with Cushing’s disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab. 1998;83(9):3083–8. https://doi.org/10.1210/jcem.83.9.5084.

    Article  CAS  Google Scholar 

  39. Kaltsas GA, Korbonits M, Isidori AM, Webb JA, Trainer PJ, Monson JP, Besser GM, Grossman AB. How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing’s syndrome? Clin Endocrinol. 2000;53(4):493–500. https://doi.org/10.1046/j.1365-2265.2000.01117.x.

    Article  CAS  Google Scholar 

  40. Raffin-Sanson M-L, Abiven G, Ritzel K, de Corbière P, Cazabat L, Zaharia R, Groussin L, Libe R, Bertherat J, Fassnacht M, Bertagna X. [Adrenocortical carcinoma and pregnancy]. Ann D’endocrinologie. 2016;77(2):139–47. https://doi.org/10.1016/j.ando.2016.04.024.

    Article  Google Scholar 

  41. Andreescu CE, Alwani RA, Hofland J, Looijenga LHJ, de Herder WW, Hofland LJ, Feelders RA. Adrenal Cushing’s syndrome during pregnancy. Eur J Endocrinol. 2017;177(5):K13–20. https://doi.org/10.1530/EJE-17-0263.

    Article  CAS  Google Scholar 

  42. Luger A, Broersen LHA, Biermasz NR, Biller BMK, Buchfelder M, Chanson P, Jorgensen JOL, Kelestimur F, Llahana S, Maiter D, Mintziori G, Petraglia F, Verkauskiene R, Webb SM, Dekkers OM. ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021;185(3):G1–33. https://doi.org/10.1530/EJE-21-0462.

    Article  CAS  Google Scholar 

  43. Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. The J Clin Endocrinology Metabolism. 2008;93(5):1526–40. https://doi.org/10.1210/jc.2008-0125.

    Article  CAS  Google Scholar 

  44. Affinati AH, Auchus RJ. Endocrine causes of hypertension in pregnancy. Gland Surg. 2020;9(1):69–79. https://doi.org/10.21037/gs.2019.12.04.

    Article  Google Scholar 

  45. Prebtani AP, Donat D, Ezzat S. Worrisome striae in pregnancy. Lancet (London England). 2000;355(9216):1692. https://doi.org/10.1016/s0140-6736(00)02242-x.

    Article  CAS  Google Scholar 

  46. Dong D, Li H, Xiao H. The diagnosis and management of Cushing syndrome during pregnancy. J Obstet Gynaecol. 2015;35(1):94–6. https://doi.org/10.3109/01443615.2014.937331.

    Article  CAS  Google Scholar 

  47. Abiven-Lepage G, Coste J, Tissier F, Groussin L, Billaud L, Dousset B, Goffinet F, Bertagna X, Bertherat J, Raffin-Sanson M-L. Adrenocortical carcinoma and pregnancy: Clinical and biological features and prognosis. Eur J Endocrinol. 2010;163(5):793–800. https://doi.org/10.1530/EJE-10-0412.

    Article  CAS  Google Scholar 

  48. Manetti L, Rossi G, Grasso L, Raffaelli V, Scattina I, Sarto SD, Cosottini M, Iannelli A, Gasperi M, Bogazzi F, Martino E. Usefulness of salivary cortisol in the diagnosis of hypercortisolism: Comparison with serum and urinary cortisol. Eur J Endocrinol. 2013;168(3):315–21. https://doi.org/10.1530/EJE-12-0685.

    Article  CAS  Google Scholar 

  49. Ambroziak U, Kondracka A, Bartoszewicz Z, Krasnodębska-Kiljańska M, Bednarczuk T. The morning and late-night salivary cortisol ranges for healthy women may be used in pregnancy. Clin Endocrinol. 2015;83(6):774–8. https://doi.org/10.1111/cen.12853.

    Article  CAS  Google Scholar 

  50. Lopes LML, Francisco RPV, Galletta MAK, Bronstein MD. Determination of nighttime salivary cortisol during pregnancy: Comparison with values in non-pregnancy and Cushing’s disease. Pituitary. 2016;19(1):30–8. https://doi.org/10.1007/s11102-015-0680-3.

    Article  CAS  Google Scholar 

  51. Odagiri E, Ishiwatari N, Abe Y, Jibiki K, Adachi T, Demura R, Demura H, Shizume K. Hypercortisolism and the resistance to dexamethasone suppression during gestation. Endocrinologia Japonica. 1988;35(5):685–90. https://doi.org/10.1507/endocrj1954.35.685.

    Article  CAS  Google Scholar 

  52. Caimari F, Corcoy R, Webb SM. Cushing’s disease: Major difficulties in diagnosis and management during pregnancy. Minerva Endocrinol. 2018;43(4):435–45. https://doi.org/10.23736/S0391-1977.18.02803-1.

    Article  Google Scholar 

  53. Berlińska A, Świątkowska-Stodulska R, Sworczak K. Factors Affecting Dexamethasone Suppression Test Results. Experimental and Clinical Endocrinology & Diabetes: Official Journal German Society of Endocrinology [and] German Diabetes Association. 2020;128(10):667–71. https://doi.org/10.1055/a-1017-3217.

    Article  CAS  Google Scholar 

  54. Owens PC, Smith R, Brinsmead MW, Hall C, Rowley M, Hurt D, Lovelock M, Chan EC, Cubis J, Lewin T. Postnatal disappearance of the pregnancy-associated reduced sensitivity of plasma cortisol to feedback inhibition. Life Sci. 1987;41(14):1745–50. https://doi.org/10.1016/0024-3205(87)90603-5.

    Article  CAS  Google Scholar 

  55. Hodes A, Meyer J, Lodish MB, Stratakis CA, Zilbermint M. Mini-review of hair cortisol concentration for evaluation of Cushing syndrome. Expert Rev Endocrinology Metabolism. 2018;13(5):225–31. https://doi.org/10.1080/17446651.2018.1517043.

    Article  CAS  Google Scholar 

  56. Kumar A, Kanwar J, Bharti N, Agrawal V, Bhatia E, Yadav SC. Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing’s Syndrome. Endocr Practice: Official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2021;27(7):723–7. https://doi.org/10.1016/j.eprac.2020.12.011.

    Article  Google Scholar 

  57. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M. Diagnosis and complications of Cushing’s syndrome: A consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593–602. https://doi.org/10.1210/jc.2003-030871.

    Article  CAS  Google Scholar 

  58. Aron DC, Raff H, Findling JW. Effectiveness versus efficacy: The limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 1997;82(6):1780–5. https://doi.org/10.1210/jcem.82.6.3991.

    Article  CAS  Google Scholar 

  59. Reimondo G, Paccotti P, Minetto M, Termine A, Stura G, Bergui M, Angeli A, Terzolo M. The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing’s syndrome. Clin Endocrinol. 2003;58(6):718–24. https://doi.org/10.1046/j.1365-2265.2003.01776.x.

    Article  CAS  Google Scholar 

  60. Schulte HM, Weisner D, Allolio B. The corticotrophin releasing hormone test in late pregnancy: Lack of adrenocorticotrophin and cortisol response. Clin Endocrinol. 1990;33(1):99–106. https://doi.org/10.1111/j.1365-2265.1990.tb00470.x.

    Article  CAS  Google Scholar 

  61. SUDA T, USHIYAMA IWASHITA,M, TOZAWA T, SUMITOMO F, NAKAGAMI T, Y., DEMURA, H., & SHIZUME K. Responses to Corticotropin-Releasing Hormone and Its Bound and Free Forms in Pregnant and Nonpregnant Women*. The J Clin Endocrinology Metabolism. 1989;69(1):38–42. https://doi.org/10.1210/jcem-69-1-38.

    Article  CAS  Google Scholar 

  62. Vilar L, Freitas MdaC, Lima LHC, Lyra R, Kater CE. Cushing’s syndrome in pregnancy: An overview. Arquivos Brasileiros de Endocrinologia & Metabologia. 2007;51:1293–302. https://doi.org/10.1590/S0004-27302007000800015.

    Article  Google Scholar 

  63. Calina D, Docea AO, Golokhvast KS, Sifakis S, Tsatsakis A, Makrigiannakis A. Management of Endocrinopathies in Pregnancy: A Review of Current Evidence. Int J Environ Res Public Health. 2019;16(5):E781. https://doi.org/10.3390/ijerph16050781.

    Article  CAS  Google Scholar 

  64. Fassnacht M, Dekkers O, Else T, Baudin E, Berruti A, de Krijger R, Haak H, Mihai R, Assie G, Terzolo M. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1–46. https://doi.org/10.1530/EJE-18-0608.

    Article  CAS  Google Scholar 

  65. Makieva S, Saunders PTK, Norman JE. Androgens in pregnancy: Roles in parturition. Hum Reprod Update. 2014;20(4):542–59. https://doi.org/10.1093/humupd/dmu008.

    Article  CAS  Google Scholar 

  66. Committee Opinion No. 723: Guidelines for Diagnostic Imaging During Pregnancy and Lactation. (2017). Obstetrics and Gynecology, 130(4), e210–e216. https://doi.org/10.1097/AOG.0000000000002355.

  67. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. 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):G1–34. https://doi.org/10.1530/EJE-16-0467.

    Article  CAS  Google Scholar 

  68. Expert Panel on MR, Safety, Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG, Froelich JW, Gimbel JR, Gosbee JW, Kuhni-Kaminski E, Larson PA, Lester JW, Nyenhuis J, Schaefer DJ, Sebek EA, Weinreb J, Wilkoff BL, Woods TO, Lucey L, Hernandez D. (2013). ACR guidance document on MR safe practices: 2013. Journal of Magnetic Resonance Imaging: JMRI, 37(3), 501–530. https://doi.org/10.1002/jmri.24011.

  69. Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes. JAMA. 2016;316(9):952–61. https://doi.org/10.1001/jama.2016.12126.

    Article  Google Scholar 

  70. Tabarin A, Laurent F, Catargi B, Olivier-Puel F, Lescene R, Berge J, Galli FS, Drouillard J, Roger P, Guerin J. Comparative evaluation of conventional and dynamic magnetic resonance imaging of the pituitary gland for the diagnosis of Cushing’s disease. Clin Endocrinol. 1998;49(3):293–300. https://doi.org/10.1046/j.1365-2265.1998.00541.x.

    Article  CAS  Google Scholar 

  71. Yawar A, Zuberi LM, Haque N. Cushing’s disease and pregnancy: Case report and literature review. Endocr Practice: Official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2007;13(3):296–9. https://doi.org/10.4158/EP.13.3.296.

    Article  Google Scholar 

  72. Pinette MG, Pan YQ, Oppenheim D, Pinette SG, Blackstone J. Bilateral inferior petrosal sinus corticotropin sampling with corticotropin-releasing hormone stimulation in a pregnant patient with Cushing’s syndrome. Am J Obstet Gynecol. 1994;171(2):563–4. https://doi.org/10.1016/0002-9378(94)90303-4.

    Article  CAS  Google Scholar 

  73. St-Jean M, MacKenzie-Feder J, Bourdeau I, Lacroix A. (2019). Exacerbation of Cushing’s syndrome during pregnancy: Stimulation of a cortisol-secreting adrenocortical adenoma by ACTH originating from the foeto-placental unit. Endocrinology, Diabetes & Metabolism Case Reports, 2019, EDM180115. https://doi.org/10.1530/EDM-18-0115.

  74. Li S, Yang C, Fan J, Yao Y, Lv X, Guo Y, Zhang S. Pregnancy-induced Cushing’s syndrome with an adrenocortical adenoma overexpressing LH/hCG receptors: A case report. BMC Endocr Disorders. 2020;20(1):62. https://doi.org/10.1186/s12902-020-0539-0.

    Article  CAS  Google Scholar 

  75. Kasperlik-Zaluska AA, Szczupacka I, Leszczynska-Bystrzanowska J, Drus-Przybyszewska G. Pregnancy-dependent Cushing’s syndrome in three pregnancies. BJOG: An International Journal of Obstetrics and Gynaecology. 2000;107(6):810–2. https://doi.org/10.1111/j.1471-0528.2000.tb13348.x.

    Article  CAS  Google Scholar 

  76. Close CF, Mann MC, Watts JF, Taylor KG. ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: Control of the hypercortisolism with metyrapone. Clin Endocrinol. 1993;39(3):375–9. https://doi.org/10.1111/j.1365-2265.1993.tb02380.x.

    Article  CAS  Google Scholar 

  77. Lacroix A, Hamet P, Boutin J-M. Leuprolide Acetate Therapy in Luteinizing Hormone–Dependent Cushing’s Syndrome. N Engl J Med. 1999;341(21):1577–81. https://doi.org/10.1056/NEJM199911183412104.

    Article  CAS  Google Scholar 

  78. Kim HB, Kim MK, Kim E, Ahn KS, Kim HS, Kim NK. Cushing syndrome in pregnancy, diagnosed after delivery. Yeungnam Univ J Med. 2021;38(1):60–4. https://doi.org/10.12701/yujm.2020.00290.

    Article  Google Scholar 

  79. St-Jean M, Ghorayeb NE, Bourdeau I, Lacroix A. Aberrant G-protein coupled hormone receptor in adrenal diseases. Best Practice & Research Clinical Endocrinology & Metabolism. 2018;32(2):165–87. https://doi.org/10.1016/j.beem.2018.01.003.

    Article  CAS  Google Scholar 

  80. Plöckinger U, Chrusciel M, Doroszko M, Saeger W, Blankenstein O, Weizsäcker K, Kroiss M, Hauptmann K, Radke C, Pöllinger A, Tiling N, Steinmüller T, Huhtaniemi I, Quinkler M, Bertherat J, Lacroix A, Rahman N. Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome. J Endocr Soc. 2017;1(1):57–71. https://doi.org/10.1210/js.2016-1021.

    Article  CAS  Google Scholar 

  81. Christopoulos S, Bourdeau I, Lacroix A. Aberrant expression of hormone receptors in adrenal Cushing’s syndrome. Pituitary. 2004;7(4):225–35. https://doi.org/10.1007/s11102-005-1083-7.

    Article  CAS  Google Scholar 

  82. Yin X, Liu J. Estrogen receptor α plays an important role in Cushing’s syndrome during pregnancy. Med Hypotheses. 2020;143:109817. https://doi.org/10.1016/j.mehy.2020.109817.

    Article  CAS  Google Scholar 

  83. Aron DC, Schnall AM, Sheeler LR. Spontaneous resolution of Cushing’s syndrome after pregnancy. American J Obstetrics Gynecology. 1990;162(2):472–4. https://doi.org/10.1016/0002-9378(90)90413-2.

    Article  CAS  Google Scholar 

  84. Mazzuco TL, Chabre O, Feige J-J, Thomas M. Aberrant expression of human luteinizing hormone receptor by adrenocortical cells is sufficient to provoke both hyperplasia and Cushing’s syndrome features. J Clin Endocrinol Metab. 2006;91(1):196–203. https://doi.org/10.1210/jc.2005-1975.

    Article  CAS  Google Scholar 

  85. The Lancet Diabetes & Endocrinology, 9(12), 813–824. https://doi.org/10.1016/S2213-8587(21)00236-9.

  86. Willenberg HS, Haase M, Papewalis C, Schott M, Scherbaum WA, Bornstein SR. Corticotropin-releasing hormone receptor expression on normal and tumorous human adrenocortical cells. Neuroendocrinology. 2005;82(5–6):274–81. https://doi.org/10.1159/000093126.

    Article  CAS  Google Scholar 

  87. Altieri B, Tirabassi G, Casa SD, Ronchi CL, Balercia G, Orio F, Pontecorvi A, Colao A, Muscogiuri G. Adrenocortical tumors and insulin resistance: What is the first step? Int J Cancer. 2016;138(12):2785–94. https://doi.org/10.1002/ijc.29950.

    Article  CAS  Google Scholar 

  88. Nadella KS, Berthon A, Almeida MQ, Levy I, Faucz FR, Stratakis CA. Insulin-like growth factor 2 (IGF2) expression in adrenocortical disease due to PRKAR1A mutations compared to other benign adrenal tumors. Endocrine. 2021. https://doi.org/10.1007/s12020-020-02583-z.

    Article  Google Scholar 

  89. Ilvesmäki V, Kahri AI, Miettinen PJ, Voutilainen R. Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: High IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab. 1993;77(3):852–8. https://doi.org/10.1210/jcem.77.3.8370710.

    Article  Google Scholar 

  90. Montanaro D, Maggiolini M, Recchia AG, Sirianni R, Aquila S, Barzon L, Fallo F, Andò S, Pezzi V. Antiestrogens upregulate estrogen receptor beta expression and inhibit adrenocortical H295R cell proliferation. J Mol Endocrinol. 2005;35(2):245–56. https://doi.org/10.1677/jme.1.01806.

    Article  CAS  Google Scholar 

  91. Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe JJ, Barrow R. Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. The J Clin Endocrinology Metabolism. 1993;77(2):494–7. https://doi.org/10.1210/jcem.77.2.8345057.

    Article  CAS  Google Scholar 

  92. Kurtoğlu S, Sarıcı D, Akın MA, Daar G, Korkmaz L, Memur Ş. Fetal adrenal suppression due to maternal corticosteroid use: Case report. J Clin Res Pediatr Endocrinol. 2011;3(3):160–2. https://doi.org/10.4274/jcrpe.v3i3.31.

    Article  Google Scholar 

  93. de Vetten L, van Stuijvenberg M, Kema IP, Bocca G. Maternal use of prednisolone is unlikely to be associated with neonatal adrenal suppression—A single-center study of 16 cases. Eur J Pediatrics. 2017;176(8):1131–6. https://doi.org/10.1007/s00431-017-2949-1.

    Article  CAS  Google Scholar 

  94. Sridharan K, Sahoo J, Palui R, Patil M, Kamalanathan S, Ramesh AS, Kubera NS. Diagnosis and treatment outcomes of Cushing’s disease during pregnancy. Pituitary. 2021. https://doi.org/10.1007/s11102-021-01142-7.

    Article  Google Scholar 

  95. Jolly K, Darr A, Arlt W, Ahmed S, Karavitaki N. Surgery for Cushing’s disease in pregnancy: Our experience and a literature review. Ann R Coll Surg Engl. 2019;101(1):e26–31. https://doi.org/10.1308/rcsann.2018.0175.

    Article  CAS  Google Scholar 

  96. Wang W, Yuan F, Xu D. Cushing’s syndrome during pregnancy caused by adrenal cortical adenoma: A case report and literature review. Front Med. 2015;9(3):380–3. https://doi.org/10.1007/s11684-015-0407-x.

    Article  Google Scholar 

  97. Libé R. Adrenocortical carcinoma (ACC): Diagnosis, prognosis, and treatment. Front Cell Dev Biology. 2015;3:45. https://doi.org/10.3389/fcell.2015.00045.

    Article  Google Scholar 

  98. Castinetti F, Nieman LK, Reincke M, Newell-Price J. Approach to the Patient Treated with Steroidogenesis Inhibitors. J Clin Endocrinol Metab. 2021;106(7):2114–23. https://doi.org/10.1210/clinem/dgab122.

    Article  Google Scholar 

  99. Sek KS-Y, Deepak DS, Lee KO. (2017). Use of cabergoline for the management of persistent Cushing’s disease in pregnancy. BMJ Case Reports, 2017, bcr-2016-217855. https://doi.org/10.1136/bcr-2016-217855.

  100. Woo I, Ehsanipoor RM. Cabergoline therapy for Cushing disease throughout pregnancy. Obstet Gynecol. 2013;122(2 Pt 2):485–7. https://doi.org/10.1097/AOG.0b013e31829e398a.

    Article  Google Scholar 

  101. Nakhleh A, Saiegh L, Reut M, Ahmad MS, Pearl IW, Shechner C. Cabergoline treatment for recurrent Cushing’s disease during pregnancy. Hormones (Athens Greece). 2016;15(3):453–8. https://doi.org/10.14310/horm.2002.1685.

    Article  Google Scholar 

  102. Berwaerts J, Verhelst J, Mahler C, Abs R. Cushing’s syndrome in pregnancy treated by ketoconazole: Case report and review of the literature. Gynecol Endocrinology: Official J Int Soc Gynecol Endocrinol. 1999;13(3):175–82. https://doi.org/10.3109/09513599909167552.

    Article  CAS  Google Scholar 

  103. Hochman C, Cristante J, Geslot A, Salenave S, Sonnet E, Briet C, Bachelot A, Chevalier N, Gilly O, Brue T, Hadjadj S, Kerlan V, Chanson P, Vezzosi D, Chabre O, Drui D, Castinetti F. Pre-term birth in women exposed to Cushing’s disease: The baby-cush study. Eur J Endocrinol. 2021;184(3):469–76. https://doi.org/10.1530/EJE-20-1224.

    Article  Google Scholar 

  104. Morris LF, Park S, Daskivich T, Churchill BM, Rao CV, Lei Z, Martinez DS, Yeh MW. Virilization of a female infant by a maternal adrenocortical carcinoma. Endocr Practice: Official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2011;17(2):e26–31. https://doi.org/10.4158/EP10209.CR.

    Article  Google Scholar 

  105. Mürset G, Zachmann M, Prader A, Fischer J, Labhart A. Male external genitalia of a girl caused by a virilizing adrenal tumour in the mother. Case report and steroid studies. Acta Endocrinol. 1970;65(4):627–38. https://doi.org/10.1530/acta.0.0650627.

    Article  Google Scholar 

  106. Miyata M, Nishihara M, Tokunaka S, Yachiku S. A maternal functioning adrenocortical adenoma causing fetal female pseudohermaphroditism. J Urol. 1989;142(3):806–8. https://doi.org/10.1016/s0022-5347(17)38897-3.

    Article  CAS  Google Scholar 

  107. van der Pas R, Leebeek FWG, Hofland LJ, de Herder WW, Feelders RA. Hypercoagulability in Cushing’s syndrome: Prevalence, pathogenesis and treatment. Clin Endocrinol. 2013;78(4):481–8. https://doi.org/10.1111/cen.12094.

    Article  CAS  Google Scholar 

  108. Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M. Oral Contraceptives and HRT Risk of Thrombosis. Clin Appl Thrombosis/Hemostasis: Official J Int Acad Clin Appl Thrombosis/Hemostasis. 2018;24(2):217–25. https://doi.org/10.1177/1076029616683802.

    Article  CAS  Google Scholar 

  109. Chabre O. (2014). [Cushing syndrome: Physiopathology, etiology and principles of therapy]. Presse Medicale (Paris, France: 1983), 43(4 Pt 1), 376–392. https://doi.org/10.1016/j.lpm.2014.02.001.

  110. Hotham NJ, Ilett KF, Hackett LP, Morton MR, Muller P, Hague WM. Transfer of Metyrapone and Its Metabolite, rac-Metyrapol, Into Breast Milk. J Hum Lactation. 2009;25(4):451–4. https://doi.org/10.1177/0890334409345496.

    Article  Google Scholar 

  111. Boronat M, Marrero D, López-Plasencia Y, Barber M, Schamann Y, Nóvoa FJ. Successful outcome of pregnancy in a patient with Cushing’s disease under treatment with ketoconazole during the first trimester of gestation. Gynecol Endocrinology: Official J Int Soc Gynecol Endocrinol. 2011;27(9):675–7. https://doi.org/10.3109/09513590.2010.521268.

    Article  Google Scholar 

  112. Moretti ME, Ito S, Koren G. Disposition of maternal ketoconazole in breast milk. Am J Obstet Gynecol. 1995;173(5):1625–6. https://doi.org/10.1016/0002-9378(95)90662-2.

    Article  CAS  Google Scholar 

  113. Cyproheptadine. (2006). In Drugs and Lactation Database (LactMed). National Library of Medicine (US). http://www.ncbi.nlm.nih.gov/books/NBK501693/.

  114. Kojori F, Cronin CMG, Salamon E, Burym C, Sellers EAC. Normal adrenal function in an infant following a pregnancy complicated by maternal adrenal cortical carcinoma and mitotane exposure. Journal of Pediatric Endocrinology & Metabolism: JPEM. 2011;24(3–4):203–4. https://doi.org/10.1515/jpem.2011.123.

    Article  Google Scholar 

  115. Tripto-Shkolnik L, Blumenfeld Z, Bronshtein M, Salmon A, Jaffe A. Pregnancy in a Patient With Adrenal Carcinoma Treated With Mitotane: A Case Report and Review of Literature. The J Clin Endocrinology Metabolism. 2013;98(2):443–7. https://doi.org/10.1210/jc.2012-2839.

    Article  CAS  Google Scholar 

  116. Abucham J, Bronstein MD, Dias ML. MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and pregnancy: a contemporary review. Eur J Endocrinol. 2017;177(1):R1–12. https://doi.org/10.1530/EJE-16-1059.

    Article  CAS  Google Scholar 

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  1. Division of Endocrinology, Department of Medicine Research Center, Centre hospitalier de l’Université de Montréal (CHUM), CHUM 900 Saint-Denis Street, H2X 0A9, Montréal, Québec, Canada

    Nada Younes, Isabelle Bourdeau & André Lacroix

  2. Division of Endocrinology, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Québec, Canada

    Matthieu St-Jean

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  1. Nada Younes
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A.L. conceived the objectives and plan of this review, N.Y. performed the literature search with MSJ and wrote the first draft. M.SJ, I.B., and A.L, critically revised the article. All authors approved the final manuscript.

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Correspondence to André Lacroix.

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Younes, N., St-Jean, M., Bourdeau, I. et al. Endogenous Cushing’s syndrome during pregnancy. Rev Endocr Metab Disord 24, 23–38 (2023). https://doi.org/10.1007/s11154-022-09731-y

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