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Horm Metab Res 2016; 48(10): 677-681
DOI: 10.1055/s-0042-115644
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Diurnal Plasma Cortisol Measurements Utility in Differentiating Various Etiologies of Endogenous Cushing Syndrome

A. Tirosh
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
M. B. Lodish
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
,
G. Z. Papadakis
2   Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA
,
C. Lyssikatos
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
,
E. Belyavskaya
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
,
C. A. Stratakis
1   Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
› Author Affiliations
Further Information

Publication History

received 08 June 2016

accepted 11 August 2016

Publication Date:
19 September 2016 (online)

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Abstract

Cortisol diurnal variation may be abnormal among patients with endogenous Cushing syndrome (CS). The study objective was to compare the plasma cortisol AM/PM ratios between different etiologies of CS. This is a retrospective cohort study, conducted at a clinical research center. Adult patients with CS that underwent adrenalectomy or trans-sphenoidal surgery (n=105) were divided to those with a pathologically confirmed diagnosis of Cushing disease (n=21) and those with primary adrenal CS, including unilateral adrenal adenoma (n=28), adrenocortical hyperplasia (n=45), and primary pigmented nodular adrenocortical disease (PPNAD, n=11). Diurnal plasma cortisol measurements were obtained at 11:30 PM and midnight and at 7:30 and 8:00 AM. The ratios between the mean morning levels and mean late-night levels were calculated. Mean plasma cortisol AM/PM ratio was lower among CD patients compared to those with primary adrenal CS (1.4±0.6 vs. 2.3±1.5, p<0.001, respectively). An AM/PM cortisol ratio≥2.0 among patients with unsuppressed ACTH (>15 pg/ml) excludes CD with a 85.0% specificity and a negative predictive value (NPV) of 90.9%. Among patients with primary adrenal CS, an AM/PM cortisol≥1.2 had specificity and NPV of 100% for ruling out a diagnosis of PPNAD. Plasma cortisol AM/PM ratios are lower among patients with CD compared with primary adrenal CS, and may aid in the differential diagnosis of endogenous hypercortisolemia.

Key words

cortisol - cushing syndrome - diurnal
 

  • References

  • 1 Nieman L, Biller B, Findling J, Newell-Price J, Savage M, Stewart P, Montori VM. The diagnosis of Cushing’s syndrome: An Endocrine Society Clinical Practice Guideline. Clin Endocrinol Metab 2008; 95: 1526-1540
    PubMedGoogle Scholar
  • 2 Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet (London, England) 2015; 386: 913-927
    CrossrefPubMedGoogle Scholar
  • 3 Lindholm J, Juul S, Jørgensen JOL, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jørgensen J, Kosteljanetz M, Kristensen LØ, Laurberg P, Schmidt K, Weeke J. Incidence and Late Prognosis of Cushing’s Syndrome: A Population-Based Study 1. J Clin Endocrinol Metab 2001; 86: 117-123
    CrossrefPubMedGoogle Scholar
  • 4 Boscaro M, Arnaldi G. Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab 2009; 94: 3121-3131
    CrossrefPubMedGoogle Scholar
  • 5 Glass AR, Zavadil AP, Halberg F, Cornelissen G, Schaaf M. Circadian rhythm of serum cortisol in Cushing’s disease. J Clin Endocrinol Metab 1984; 59: 161-165
    CrossrefPubMedGoogle Scholar
  • 6 Refetoff S, Van Cauter E, Fang VS, Laderman C, Graybeal ML, Landau RL. The effect of dexamethasone on the 24-hour profiles of adrenocorticotropin and cortisol in Cushing’s syndrome. J Clin Endocrinol Metab 1985; 60: 527-535
    CrossrefPubMedGoogle Scholar
  • 7 Veldhuis JD, Iranmanesh A, Johnson ML, Lizarralde G. Amplitude, but not frequency, modulation of adrenocorticotropin secretory bursts gives rise to the nyctohemeral rhythm of the corticotropic axis in man. J Clin Endocrinol Metab 1990; 71: 452-463
    CrossrefPubMedGoogle Scholar
  • 8 Ronaldson A, Kidd T, Poole L, Leigh E, Jahangiri M, Steptoe A. Diurnal Cortisol Rhythm Is Associated With Adverse Cardiac Events and Mortality in Coronary Artery Bypass Patients. J Clin Endocrinol Metab 2015; 100: 3676-3682
    CrossrefPubMedGoogle Scholar
  • 9 Kumari M, Shipley M, Stafford M, Kivimaki M. Association of diurnal patterns in salivary cortisol with all-cause and cardiovascular mortality: findings from the Whitehall II study. J Clin Endocrinol Metab 2011; 96: 1478-1485
    CrossrefPubMedGoogle Scholar
  • 10 Raff H. Utility of salivary cortisol measurements in Cushing’s syndrome and adrenal insufficiency. J Clin Endocrinol Metab 2009; 94: 3647-3655
    CrossrefPubMedGoogle Scholar
  • 11 Papanicolaou DA, Yanovski JA, Cutler GB, Chrousos GP, Nieman LK. A Single Midnight Serum Cortisol Distinguishes Cushing’ s Syndrome from Pseudo-Cushing States. J Clin Endocrinol Metab 1998; 83: 1163-1167
    CrossrefPubMedGoogle Scholar
  • 12 Newell-Price J, Trainer P, Perry L, Wass J, Grossman A, Besser M. A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 1995; 43: 545-550
    CrossrefPubMedGoogle Scholar
  • 13 Görges R, Knappe G, Gerl H, Ventz M, Stahl F. Diagnosis of Cushing’s syndrome: re-evaluation of midnight plasma cortisol vs urinary free cortisol and low-dose dexamethasone suppression test in a large patient group. J Endocrinol Invest 1999; 22: 241-249
    CrossrefPubMedGoogle Scholar
  • 14 Pecori Giraldi F, Ambrogio AG, De Martin M, Fatti LM, Scacchi M, Cavagnini F. Specificity of first-line tests for the diagnosis of Cushing’s syndrome: assessment in a large series. J Clin Endocrinol Metab 2007; 92: 4123-4129
    CrossrefPubMedGoogle Scholar
  • 15 Stratakis CA. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin- independent Cushing syndrome). Endocr Dev 2008; 13: 117-132
    PubMedGoogle Scholar
  • 16 Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol 2015; 173: M85-M97
    CrossrefPubMedGoogle Scholar
  • 17 Rothenbuhler A, Horvath A, Libé R, Faucz FR, Fratticci A, Raffin Sanson ML, Vezzosi D, Azevedo M, Levy I, Almeida MQ, Lodish M, Nesterova M, Bertherat J, Stratakis CA. Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours. Clin Endocrinol (Oxf) 2012; 77: 195-199
    CrossrefPubMedGoogle Scholar
  • 18 Carney JA, Gaillard RC, Bertherat J, Stratakis CA. Familial micronodular adrenocortical disease, Cushing syndrome, and mutations of the gene encoding phosphodiesterase 11A4 (PDE11A). Am J Surg Pathol 2010; 34: 547-555
    CrossrefPubMedGoogle Scholar
  • 19 Assie G, Libe R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O, Lefevre L, Sibony M, Guignat L, Rodriguez S, Perlemoine K, Rene-Corail F, Letourneur F, Trabulsi B, Poussier A, Chabbert-Buffet N, Borson-Chazot F, Groussin L, Bertagna X, Stratakis CA, Ragazzon B, Bertherat J. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med 2013; 369: 2105-2114
    Google Scholar
  • 20 Oster H, Damerow S, Kiessling S, Jakubcakova V, Abraham D, Tian J, Hoffmann MW, Eichele G. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab 2006; 4: 163-173
    CrossrefPubMedGoogle Scholar
  • 21 Sederberg-Olsen P, Binder C, Kehlet H, Neville AM, Nielsen LM. Episodic variation in plasma corticosteroids in subjects with Cushing’s syndrome of differing etiology. J Clin Endocrinol Metab 1973; 36: 906-910
    CrossrefPubMedGoogle Scholar