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01-02-2025 | Cushing's Syndrome

The diagnostic value of prolactin adjustment in bilateral inferior petrosal sinus sampling for differentiating Cushing’s disease from the ectopic ACTH syndrome: a systematic review and meta-analysis

Authors: Majid Valizadeh, Amirhossein Ramezani Ahmadi, Dana Ramadhan Hussein, Farnaz Emdadi, Farhad Hosseinpanah, Ashley Grossman, Behnaz Abiri

Published in: Pituitary | Issue 1/2025

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Abstract

Background

Adrenocorticotropin (ACTH)-dependent Cushing’s syndrome can arise from a pituitary tumour (Cushing’s disease) or an ectopic ACTH-secreting tumour, making precise differentiation essential for effective treatment. Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard for this differentiation, but false-negative results can limit its accuracy. Adding prolactin (PRL) measurement to BIPSS has been proposed to improve diagnostic precision. This meta-analysis evaluates how correction for prolactin levels (‘prolactin adjustment’) affects the diagnostic value of BIPSS in distinguishing Cushing’s disease from ectopic ACTH syndrome.

Methods

A systematic literature search was conducted in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar up to July 2024. Studies were included if they provided data on BIPSS with and without PRL adjustment for ACTH-dependent Cushing’s syndrome. Data extraction and quality assessment were performed, and diagnostic accuracy metrics were analysed using bivariate generalised linear mixed modelling.

Results

A total of 10 studies with 310 participants were included. The pooled sensitivity and specificity of BIPSS with PRL adjustment were 0.96 (95% CI: 0.93–0.98) and 0.68 (95% CI: 0.52–0.81), respectively. The diagnostic odds ratio (DOR) was 48.0 (95% CI: 19.0–123.0), with a positive likelihood ratio (LR) of 3.00 (95% CI: 1.9–4.7) and a negative LR of 0.06 (95% CI: 0.03–0.12). The area under the summary receiver operating characteristic (SROC) curve was 0.95 (95% CI: 0.93–0.97). For BIPSS without PRL adjustment, the pooled sensitivity was 0.90 (95% CI: 0.86–0.93) and specificity was 0.74 (95% CI: 0.59–0.85), with a DOR of 27.0 (95% CI: 13.0–59.0). The SROC curve area was 0.92 (95% CI: 0.89–0.94). Prolactin adjustment improved sensitivity (P < 0.01) without a significant change in specificity (P = 0.13).

Conclusions

Prolactin adjustment in BIPSS slightly improves sensitivity for diagnosing Cushing’s disease but does not enhance specificity for ectopic ACTH syndrome. This highlights the value of PRL measurement in improving diagnostic accuracy and reducing false negatives, while BIPSS remains crucial for ruling out EAS in clinical practice.
Literature
1.
go back to reference Arnaldi G, Angeli A, Atkinson AB et al (2003) Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 88:5593–5602CrossRefPubMed Arnaldi G, Angeli A, Atkinson AB et al (2003) Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 88:5593–5602CrossRefPubMed
2.
go back to reference Fleseriu M, Auchus R, Bancos I et al (2021) Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 9(12):847e875CrossRef Fleseriu M, Auchus R, Bancos I et al (2021) Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 9(12):847e875CrossRef
3.
go back to reference Oldfield EH, Doppman JL, Nieman LK et al (1991) Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 325(13):897e905CrossRef Oldfield EH, Doppman JL, Nieman LK et al (1991) Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 325(13):897e905CrossRef
4.
go back to reference Chen K, Chen S, Lu L et al (2021) An optimized pathway for the differential diagnosis of ACTH-dependent Cushing’s syndrome based on low-dose dexamethasone suppression test. Front Endocrinol (Lausanne) 12:720823CrossRefPubMed Chen K, Chen S, Lu L et al (2021) An optimized pathway for the differential diagnosis of ACTH-dependent Cushing’s syndrome based on low-dose dexamethasone suppression test. Front Endocrinol (Lausanne) 12:720823CrossRefPubMed
5.
go back to reference Colao A, Faggiano A, Pivonello R, Pecori Giraldi F, Cavagnini F, Lombardi G, Study Group of the Italian Endocrinology Society on the Pathophsiology of the Hypothalamic-Pituitary-Adrenal A (2001) Inferior petrosal sinus sampling in the diferential diagnosis of Cushing’s syndrome: results of an Italian multicenter study. Eur J Endocrinol 144(5):499–507. https://doi.org/10.1530/eje.0.1440499CrossRefPubMed Colao A, Faggiano A, Pivonello R, Pecori Giraldi F, Cavagnini F, Lombardi G, Study Group of the Italian Endocrinology Society on the Pathophsiology of the Hypothalamic-Pituitary-Adrenal A (2001) Inferior petrosal sinus sampling in the diferential diagnosis of Cushing’s syndrome: results of an Italian multicenter study. Eur J Endocrinol 144(5):499–507. https://​doi.​org/​10.​1530/​eje.​0.​1440499CrossRefPubMed
6.
go back to reference Bonelli FS, Huston J 3rd, Carpenter PC, Erickson D, Young WF Jr, Meyer FB (2000) Adrenocorticotropic hormone-dependent Cushing’s syndrome: sensitivity and specifcity of inferior petrosal sinus sampling. AJNR Am J Neuroradiol 21(4):690–696PubMedPubMedCentral Bonelli FS, Huston J 3rd, Carpenter PC, Erickson D, Young WF Jr, Meyer FB (2000) Adrenocorticotropic hormone-dependent Cushing’s syndrome: sensitivity and specifcity of inferior petrosal sinus sampling. AJNR Am J Neuroradiol 21(4):690–696PubMedPubMedCentral
9.
go back to reference Swearingen B, Katznelson L, Miller K et al (2004) Diagnostic errors after inferior petrosal sinus sampling. J Clin Endocrinol Metab 89(8):3752e3763CrossRef Swearingen B, Katznelson L, Miller K et al (2004) Diagnostic errors after inferior petrosal sinus sampling. J Clin Endocrinol Metab 89(8):3752e3763CrossRef
10.
go back to reference Doppman JL, Chang R, Oldfield EH, Chrousos G, Stratakis CA, Nieman LK (1999) The hypoplastic inferior petrosal sinus: a potential source of false-negative results in petrosal sampling for Cushing’s disease. J Clin Endocrinol Metab 84(2):533e540 Doppman JL, Chang R, Oldfield EH, Chrousos G, Stratakis CA, Nieman LK (1999) The hypoplastic inferior petrosal sinus: a potential source of false-negative results in petrosal sampling for Cushing’s disease. J Clin Endocrinol Metab 84(2):533e540
11.
go back to reference Jarial KDS, Bhansali A, Mukherjee KK, Pal R, Gupta V, Sharma A, Vasishta RK, Sukumar SP, Sachdeva N, Walia R Prolactin-adjusted ACTH Ratio in Predicting Lateralization of ACTH Source During Simultaneous Bilateral Inferior Petrosal Sinus Sampling in Patients with Cushing’s Disease. Indian J Endocrinol Metab 2019 Jan-Feb;23(1):56–59. https://doi.org/10.4103/ijem.IJEM_486_18. PMID: 31016154; PMCID: PMC6446680. Jarial KDS, Bhansali A, Mukherjee KK, Pal R, Gupta V, Sharma A, Vasishta RK, Sukumar SP, Sachdeva N, Walia R Prolactin-adjusted ACTH Ratio in Predicting Lateralization of ACTH Source During Simultaneous Bilateral Inferior Petrosal Sinus Sampling in Patients with Cushing’s Disease. Indian J Endocrinol Metab 2019 Jan-Feb;23(1):56–59. https://​doi.​org/​10.​4103/​ijem.​IJEM_​486_​18. PMID: 31016154; PMCID: PMC6446680.
12.
go back to reference Findling JW, Kehoe ME, Raff H (2004) Identification of patients with Cushing’s disease with negative pituitary adrenocorticotropin gradients during inferior petrosal sinus sampling: prolactin as an index of pituitary venous effluent. J Clin Endocrinol Metab 89:6005–6009CrossRefPubMed Findling JW, Kehoe ME, Raff H (2004) Identification of patients with Cushing’s disease with negative pituitary adrenocorticotropin gradients during inferior petrosal sinus sampling: prolactin as an index of pituitary venous effluent. J Clin Endocrinol Metab 89:6005–6009CrossRefPubMed
13.
go back to reference Grant P, Dworakowska D, Carroll P (2012) Maximizing the accuracy of inferior petrosal sinus sampling: validation of the use of Prolactin as a marker of pituitary venous effluent in the diagnosis of Cushing’s disease. Clin Endocrinol 76:555–559CrossRef Grant P, Dworakowska D, Carroll P (2012) Maximizing the accuracy of inferior petrosal sinus sampling: validation of the use of Prolactin as a marker of pituitary venous effluent in the diagnosis of Cushing’s disease. Clin Endocrinol 76:555–559CrossRef
14.
go back to reference De Sousa SMC, McCormack AI, McGrath S, Torpy DJ (2017) Prolactin correction for adequacy of petrosal sinus cannulation may diminish diagnostic accuracy in Cushing’s disease. Clin Endocrinol 87:515–512CrossRef De Sousa SMC, McCormack AI, McGrath S, Torpy DJ (2017) Prolactin correction for adequacy of petrosal sinus cannulation may diminish diagnostic accuracy in Cushing’s disease. Clin Endocrinol 87:515–512CrossRef
15.
go back to reference Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 10(1):89CrossRefPubMedPubMedCentral Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 10(1):89CrossRefPubMedPubMedCentral
16.
go back to reference Whiting PF, Rutjes AW, Westwood ME et al (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155:529–536CrossRefPubMed Whiting PF, Rutjes AW, Westwood ME et al (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155:529–536CrossRefPubMed
18.
19.
go back to reference Akbari H, Ghorbani M, Kabootari M, Mehrjardi AZ, Mohajeri Tehrani MR, Malek M, Khamseh ME (2020) Usefulness of prolactin measurement in inferior petrosal sinus sampling with desmopressin for Cushing’s syndrome. Br J Neurosurg 34(3):253–257 Epub 2020 Apr 2. PMID: 32238018CrossRefPubMed Akbari H, Ghorbani M, Kabootari M, Mehrjardi AZ, Mohajeri Tehrani MR, Malek M, Khamseh ME (2020) Usefulness of prolactin measurement in inferior petrosal sinus sampling with desmopressin for Cushing’s syndrome. Br J Neurosurg 34(3):253–257 Epub 2020 Apr 2. PMID: 32238018CrossRefPubMed
21.
go back to reference Qiao X, Ye H, Zhang X, Zhao W, Zhang S, Lu B, Wang X, Zhang Z, Wu X, He M, Zhao X, Li S, Zhou L, Yang Y, Hu R, Li Y (2015) The value of prolactin in inferior petrosal sinus sampling with desmopressin stimulation in Cushing’s disease. Endocrine 48(2):644–652. https://doi.org/10.1007/s12020-014-0338-3Epub 2014 Jul 17. PMID: 25030549CrossRefPubMed Qiao X, Ye H, Zhang X, Zhao W, Zhang S, Lu B, Wang X, Zhang Z, Wu X, He M, Zhao X, Li S, Zhou L, Yang Y, Hu R, Li Y (2015) The value of prolactin in inferior petrosal sinus sampling with desmopressin stimulation in Cushing’s disease. Endocrine 48(2):644–652. https://​doi.​org/​10.​1007/​s12020-014-0338-3Epub 2014 Jul 17. PMID: 25030549CrossRefPubMed
23.
go back to reference Mulligan GB, Eray E, Faiman C, Gupta M, Pineyro MM, Makdissi A, Suh JH, Masaryk TJ, Prayson R, Weil RJ, Hamrahian AH Reduction of false-negative results in inferior petrosal sinus sampling with simultaneous prolactin and corticotropin measurement. Endocr Pract. 2011 Jan-Feb;17(1):33–40. https://doi.org/10.4158/EP10067.OR. PMID: 20713347 Mulligan GB, Eray E, Faiman C, Gupta M, Pineyro MM, Makdissi A, Suh JH, Masaryk TJ, Prayson R, Weil RJ, Hamrahian AH Reduction of false-negative results in inferior petrosal sinus sampling with simultaneous prolactin and corticotropin measurement. Endocr Pract. 2011 Jan-Feb;17(1):33–40. https://​doi.​org/​10.​4158/​EP10067.​OR. PMID: 20713347
25.
go back to reference McNally PG, Bolia A, Absalom SR, Falconer-Smith J, Howlett TA (1993) Preliminary observations using endocrine markers of pituitary venous dilution during bilateral simultaneous inferior petrosal sinus catheterization in Cushing’s syndrome: is combined CRF and TRH stimulation of value? Clin Endocrinol (Oxf). 39(6):681-6. https://doi.org/10.1111/j.1365-2265.1993.tb02427.x. PMID: 8287587 McNally PG, Bolia A, Absalom SR, Falconer-Smith J, Howlett TA (1993) Preliminary observations using endocrine markers of pituitary venous dilution during bilateral simultaneous inferior petrosal sinus catheterization in Cushing’s syndrome: is combined CRF and TRH stimulation of value? Clin Endocrinol (Oxf). 39(6):681-6. https://​doi.​org/​10.​1111/​j.​1365-2265.​1993.​tb02427.​x. PMID: 8287587
26.
go back to reference Javorsky BR, Findling JW (2010) Inferior petrosal sampling for the differential diagnosis of ACTH-dependent Cushing’s syndrome. In: Bronstein M (ed) Cushing’s syndrome: contemporary endocrinology. Humana, Totowa, NJ, pp 105–119CrossRef Javorsky BR, Findling JW (2010) Inferior petrosal sampling for the differential diagnosis of ACTH-dependent Cushing’s syndrome. In: Bronstein M (ed) Cushing’s syndrome: contemporary endocrinology. Humana, Totowa, NJ, pp 105–119CrossRef
27.
go back to reference McNally PG, Bolia A, Absalom SR et al (1993) Preliminary observations using endocrine markers of pituitary venous dilution during bilateral simultaneous inferior petrosal sinus catheterization in Cushing’s syndrome: is combined CRF and TRH stimulation of value? Clin Endocrinol (Oxf) 39:681–686CrossRefPubMed McNally PG, Bolia A, Absalom SR et al (1993) Preliminary observations using endocrine markers of pituitary venous dilution during bilateral simultaneous inferior petrosal sinus catheterization in Cushing’s syndrome: is combined CRF and TRH stimulation of value? Clin Endocrinol (Oxf) 39:681–686CrossRefPubMed
28.
go back to reference Grant P, Dworakowska D, Carroll P (2012) Maximizing the accuracy of Inferior petrosal sinus sampling: validation of the use of Prolactin as a marker of pituitary venous effluent in the diagnosis of Cushing’s disease. Clin Endocrinol (Oxf) 76:555–559CrossRefPubMed Grant P, Dworakowska D, Carroll P (2012) Maximizing the accuracy of Inferior petrosal sinus sampling: validation of the use of Prolactin as a marker of pituitary venous effluent in the diagnosis of Cushing’s disease. Clin Endocrinol (Oxf) 76:555–559CrossRefPubMed
29.
go back to reference Qiao X, Ye H, Zhang X et al (2015) The value of prolactin in inferior petrosal sinus sampling with desmopressin stimulation in Cushing’s disease. Endocrine 48:644–652CrossRefPubMed Qiao X, Ye H, Zhang X et al (2015) The value of prolactin in inferior petrosal sinus sampling with desmopressin stimulation in Cushing’s disease. Endocrine 48:644–652CrossRefPubMed
30.
go back to reference Sharma ST, Nieman LK (2013) Is prolactin measurement of value during inferior petrosal sinus sampling in patients with adrenocorticotropic hormone -dependent Cushing’s syndrome? J Endocrinol Invest 36:1112–1116PubMedPubMedCentral Sharma ST, Nieman LK (2013) Is prolactin measurement of value during inferior petrosal sinus sampling in patients with adrenocorticotropic hormone -dependent Cushing’s syndrome? J Endocrinol Invest 36:1112–1116PubMedPubMedCentral
31.
go back to reference Sharma ST, Raff H, Nieman LK (2011) Prolactin as a marker of successful catheterization during IPSS in patients with ACTH -dependent Cushing’s syndrome. J Clin Endocrinol Metab 96:3687–3694CrossRefPubMedPubMedCentral Sharma ST, Raff H, Nieman LK (2011) Prolactin as a marker of successful catheterization during IPSS in patients with ACTH -dependent Cushing’s syndrome. J Clin Endocrinol Metab 96:3687–3694CrossRefPubMedPubMedCentral
32.
go back to reference Sharma ST, Nieman LK (2013) Is prolactin measurement of value during inferior petrosal sinus sampling in patients with ACTHdependent Cushing’s syndrome? J Endocrinol Invest 36:1112–1116PubMedPubMedCentral Sharma ST, Nieman LK (2013) Is prolactin measurement of value during inferior petrosal sinus sampling in patients with ACTHdependent Cushing’s syndrome? J Endocrinol Invest 36:1112–1116PubMedPubMedCentral
33.
go back to reference Qiao X, Ye H, Zhang X, Zhao W, Zhang S, Lu B et al (2015) The value of prolactin in inferior petrosal sinus sampling with desmopressin stimulation in Cushing’s disease. Endocrine 48:644–652CrossRefPubMed Qiao X, Ye H, Zhang X, Zhao W, Zhang S, Lu B et al (2015) The value of prolactin in inferior petrosal sinus sampling with desmopressin stimulation in Cushing’s disease. Endocrine 48:644–652CrossRefPubMed
34.
go back to reference Detomas M, Ritzel K, Nasi-Kordhishti I, Schernthaner-Reiter MH, Losa M, Tröger V, Altieri B, Kroiss M, Kickuth R, Fassnacht M, Micko A, Honegger J, Reincke M, Deutschbein T Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing’s syndrome: results from a retrospective multicenter study. Eur J Endocrinol 2023 May 18:lvad050. https://doi.org/10.1093/ejendo/lvad050. Epub ahead of print. PMID: 37200460. Detomas M, Ritzel K, Nasi-Kordhishti I, Schernthaner-Reiter MH, Losa M, Tröger V, Altieri B, Kroiss M, Kickuth R, Fassnacht M, Micko A, Honegger J, Reincke M, Deutschbein T Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing’s syndrome: results from a retrospective multicenter study. Eur J Endocrinol 2023 May 18:lvad050. https://​doi.​org/​10.​1093/​ejendo/​lvad050. Epub ahead of print. PMID: 37200460.
Metadata
Title
The diagnostic value of prolactin adjustment in bilateral inferior petrosal sinus sampling for differentiating Cushing’s disease from the ectopic ACTH syndrome: a systematic review and meta-analysis
Authors
Majid Valizadeh
Amirhossein Ramezani Ahmadi
Dana Ramadhan Hussein
Farnaz Emdadi
Farhad Hosseinpanah
Ashley Grossman
Behnaz Abiri
Publication date
01-02-2025
Publisher
Springer US
Published in
Pituitary / Issue 1/2025
Print ISSN: 1386-341X
Electronic ISSN: 1573-7403
DOI
https://doi.org/10.1007/s11102-024-01474-0

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