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Cited by 336Pituitary Gland Disorders and TreatmentsAdrenal and Paraganglionic TumorsAdrenal Hormones and Disorders

Diagnosis and Management of Cushing’s Syndrome: Results of an Italian Multicentre Study 1

Invitti, Cecilia, Giraldi, Francesca Pecori, De Martin, Martina, Cavagnini, Francesco·1999·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jcem.84.2.5465
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Abstract

The past 45 yr' experience with Cushing's syndrome (CS) has led to the awareness of its complex nature and, by the same token, brought about an increase in the diagnostic and therapeutic dilemmas. We carried out a retrospective multicentre study on the diagnostic work-up and treatment in 426 patients with CS, subdivided as follows: 288 with Cushing's disease (CD), 80 with an adrenal adenoma, 24 with an adrenal carcinoma, 25 with ectopic ACTH and/or CRH secretion, and 9 with ACTH-independent nodular adrenal hyperplasia. Normal urinary free cortisol (UFC) values among multiple collections were recorded in about 10% of patients with CS. In 28% of patients with ACTH-independent CS, basal ACTH concentrations were within the normal range but did not respond to CRH stimulation. Measurement of ACTH levels by immunoradiometric assay, rather than by RIA, offered a greater chance of recognizing patients with ACTH-independent CS or ectopic secretion. A 50% increase in ACTH or cortisol levels after CRH yielded a diagnostic accuracy of 86% and 61%, respectively, in the differential diagnosis of ACTH-dependent CS. An 80% decrease in cortisol levels after 8 mg dexamethasone overnight, or in UFC values after the classical 2-day administration, excluded an ectopic secretion but carried a low negative predictive value given the high number of nonsuppressors among patients with CD. Pituitary imaging identified an adenoma in 61% of patients with CD. At inferior petrosal sinus sampling, an ACTH centre: periphery gradient after CRH less than 3, correctly classified all patients with ectopic secretion but misdiagnosed 15% of 76 patients with CD. Transsphenoidal pituitary surgery, the standard therapy for CD, resulted in complete remission (appearance of clinical signs of adrenal insufficiency associated with low/normal UFC excretion and, when available, low/normal morning plasma ACTH and cortisol levels) in 69% of patients. The overall relapse rate after pituitary surgery was 17%. The probability of relapse-free survival, as assessed by Kaplan-Meier analysis, was 95% at 12 months, 84% at 2 yr, and 80% at 3 yr. Risk of relapse was significantly correlated with postoperative baseline plasma ACTH and cortisol peak after CRH. No relapses were observed among patients who did not respond to CRH. Other therapeutic approaches for CD, such as pituitary irradiation and medical therapy, resulted in normalization of cortisol secretion in about half of treated cases. In summary, an accurate selection of the available diagnostic tools leads to the correct diagnosis in the majority of patients with CS. The therapeutic options for CD, adrenal carcinoma, and ectopic secretion are, as yet, not fully satisfactory. The high incidence of relapse after pituitary surgery calls for a prolonged follow-up.

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  • Corticotroph tumors are sensitive to CRH stimulation, and a substantial ACTH and cortisol increase (>50% of baseline) is compatible with a pituitary cause.

    “Corticotroph tumors are sensitive to CRH stimulation and a substantial ACTH and cortisol increase (> 50% of baseline) are compatible with a pituitary cause (83, 84).”

    From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [84]

  • Measurement of DHEAS concentrations and a CRH test can be helpful to differentiate an adrenal from a pituitary cause of CS.

    “Measurement of DHEAS concentrations and a CRH test can be helpful to differentiate an adrenal from a pituitary cause.”

    From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [84]

  • DHEAS secretion is partly ACTH driven, and low-normal or suppressed DHEAS levels point to an adrenal cause.

    “DHEAS secretion is partly ACTH driven and low-normal or suppressed DHEAS levels point to an adrenal cause.”

    From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [84]

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Authors
Invitti, C., Giraldi, F. P., De Martin, M., & Cavagnini, F.
Affiliations
University of Milan (IT)
Corresponding author
Cavagnini, Francesco
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
1999-02
Volume
84
Issue
2
Pages
440-448
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jcem.84.2.5465
OpenAlex
W2795482603
Cited by
336
References
35
Citations by year
2026: 2 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 15 · 2021: 12 · 2020: 17 · 2019: 20 · 2018: 14 · 2017: 10 · 2016: 13 · 2015: 19 · 2014: 13 · 2013: 15 · 2012: 11
FWCI
3.18
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
Cushing's syndrome, Cushing's disease, ectopic ACTH secretion, ACTH-independent Cushing's syndrome, adrenal adenoma, adrenocortical carcinoma, CRH stimulation test, ACTH measurement, dexamethasone suppression test, urinary free cortisol, inferior petrosal sinus sampling, transsphenoidal microsurgery, relapse, pituitary imaging, differential diagnosis
MeSH terms
Adenoma, Adolescent, Adrenal Gland Neoplasms, Adrenocorticotropic Hormone, Adult, Aged, Child, Child, Preschool, Corticotropin-Releasing Hormone, Cushing Syndrome, Diagnosis, Differential, Female, Humans, Hydrocortisone, Infant, Italy, Male, Middle Aged, Pituitary Neoplasms

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