The role of prolactin gradient and normalized ACTH/prolactin ratio in the improvement of sensitivity and specificity of selective blood sampling from inferior petrosal sinuses for differential diagnostics of ACTH-dependent hypercorticism

The present study included patients with confirmed diagnosis of ACTH-dependent hypercorticism admitted to the Department of Neuroendocrinology and Osteopathies, Endocrinological Research Centre, between 2008 and 2012. Selective blood sampling from the inferior petrosal sinuses was performed with the stimulation by decompressin administered intravenously at a dose of 8 mcg. The normalized ACTH/prolactin ratio was calculated by dividing the maximum ACTH gradient following decompressin stimulation by the ipsilateral prolactin gradient. The cut off values were calculated from the operating characteristic curves as follows: 1.5 for the prolactin gradient (sensitivity 92.5%, specificity 100%) and 1.18 for the normalized ACTH/prolactin ratio (sensitivity 85.9%; 95% CI 76.8-93.4, specificity 100%; 95% CI 60.9-100). In the study cohort (n=70), the normalized ACTH/prolactin ratio proved to be a more specific but less sensitive parameter than the routine analysis of the ACTH gradient (sensitivity 98.4%, specificity 83.3%). Areas under the operating characteristic curves were on the whole identical. However, comparison of the diagnostic value of selective blood sampling from the inferior petrosal sinuses in combination of the determination of the prolactin gradient and normalized ACTH/prolactin ratio with the results obtained in the patients in whom the catheter position was not controlled (n=47) revealed the advantages of the former approach in terms of both the number of unverified causes of hypercorticism (1 versus 6) and the area under the operating characteristic curves 0.964 (95% CI 0.897-1.032) among 70 patients and 0.910 (95% CI 0.821-0.998) among the first 47 patients (included in the analysis confined to the confirmed cases). It is concluded that the determination of the prolactin gradient and calculation of the normalized ACTH/prolactin ratio allow to increase the diagnostic value of selective blood sampling from the inferior petrosal sinuses under decompressin stimulation. This inference is especially true of doubtful cases.

ACTH-dependent hypercorticism, selective blood sampling from the inferior petrosal sinuses, decompressin, normalized ACTH/prolactin ratio, prolactin.

1. Дедов И.И., Белая Ж.Е., Ситкин И.И., Марова Е.И., Пржиялковская Е.Г., Ремизов О.В., Рожинская Л.Я. Значение метода селективного забора крови из нижних каменистых синусов в дифференциальной диагностике АКТГ-зависимого гиперкортицизма. Пробл эндокринол 2009; 55: 35-40.

2. Utz A., Biller B.M.K. The role of bilateral inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome. Arq Bras Endocrinol Metabol 2007; 51: 1129-1338.

3. Newell-Price J., Bertagna X., Grossman A.B., Nieman L.K. Cushing's syndrome, Lancet 2006; 367: 1605-1617.

4. Machado M.C., de Sa S.V., Domenice S., Candida M.B., Fragoso V., Puglia P.J., Pereira M.A.A. The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH-dependent Cushing's syndrome. Clin Endocrinol 2007; 66: 136-142.

5. Castinetti F., Morange I., Dufour H., Jaquet P., Conte-Devolx B., Girard N., Brue T. Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome. Eur J Endocrinol 2007; 157: 271-277.

6. Дедов И.И., Ситкин И.И., Белая Ж.Е., Марова Е.И., Пржиялковская Е.Г., Ремизов О.В., Рожинская Л.Я. Первый опыт использования селективного забора крови из нижних каменистых синусов в России (клиническое наблюдение). Пробл эндокринол 2009; 55:11-16.

7. Белая Ж.Е., Рожинская Л.Я., Ситкин И.И., Карселадзе А.И., Аблицов Ю.А., Аблицов А.Ю., Лобода Ю.В., Ремизов О.В., Алексеева Т.Р., Горбунова В.А., Волова Н.Л. Клинический случай АКТГ-эктопированного синдрома. Вестн РОНЦ им. Н.Н. Блохина РАМН 2010; 21: 4: 46-51.

8. Дзеранова Л.К., Панкратова Ю.В., Белая Ж.Е., Пигарова Е.А., Манченко О.В., Рожинская Л.Я., Григорьев А.Ю., Колесникова Г.С. Гиперкортицизм и метаболический синдром: сложности дифференциальной диагностики и лечения. Ожирение и метаболизм 2012; 31: 2: 57-61.

9. Swearingen B., Katznelson L., Miller K., Grinspoon S., Waltman A., Dorer D.J., Klibanski A., Biller B.M. Diagnostic errors after inferior petrosal sinus sampling. J Clin Endocrinol Metabol 2004; 89: 3752-3763.

10. Doppman J.L., Chang R., Oldfield E.H., Chrousos G., Stratakis C.A., Nieman L.K. The hypoplastic inferior petrosal sinus: a potential source of false-negative results in petrosal sampling for Cushing's disease. J Clin Endocrinol Metabol 1999; 84: 533-540.

11. Lopez J., Barcello B., Lucas T., Salame F., Alameda C., Boronat M., Salto L., Estrada J. Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results. Clin Endocrinol (Oxford) 1996; 45: 147-156.

12. Zovickian J., Oldfield E.H., Doppman J.L., Culter J.G.B., Loriaux D.L. Usefulness of inferior petrosal sinus venous endocrine markers in Cushing's disease. J Clin Endocrinol Metabol 1990; 71: 1195-1201.

13. Allolio B., Gunther R.W., Benker G., Reinwein D., Winkelmann W., Schulte H.M. A multihormonal response to corticotrophin-releasing hormone in inferior petrosal sinus blood of patients with Cushing's disease. J Clin Endocrinol Metabol 1990; 71: 1195-1201.

14. McNally P.G., Bolia A., Absalom S.R., Falconer-Smith J., Howlett T.A. 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 (Oxford) 1993; 39: 681-686.

15. Findling J.W., Kehoe M.E., Raff H. 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 Metabol 2004; 89: 6005-6009.

16. Mulligan G.B., Eray E., Faiman C., Gupta M., Pineyro M.M., Makdissi A., Suh J.H., Masaryk T.J., Prayson R., Weil R.J., Hamrahian A.H. Reduction of false negative results in inferior petrosal sinus sampling with simultaneous prolactin and corticotrophin measurement. Endocrinol Pract 2011; 17: 33-40.

17. Heaney A.P., Melmed S. Molecular targets in pituitary tumors. Nat Rev Cancer 2004; 4: 285-295.

18. Sharma S.T., Raff H., Nieman L.K. Prolactin as a marker of successful catheterization during IPPS in patients with ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metabol 2011; 96: 3687-3694.

19. Nieman L.K., Biller B.M.K., Finding J.W., Newell-Price J., Savage M.O., Stewart P.M., Montori V.M. The diagnosis of Cushing's syndrome: an endocrine society clinical practice guideline. J. Clin Endocrinol Metabol 2008; 93: 1526-1540.

20. Белая Ж.Е., Рожинская Л.Я., Мельниченко Г.А., Дедов И.И. Современный взгляд на скрининг и диагностику эндогенного гиперкортицизма. Пробл эндокринол 2012; 58: 35-41.

21. Марова Е.И., Арапова С.Д., Белая Ж.Е., Рожинская Л.Я., Колесникова Г.С., Воронцов А.В. Болезнь Иценко-Кушинга: клиника, диагностика, лечение. Под ред. И.И. Дедова, Г.А. Мельниченко. Практическое руководство для врачей. М 2012.

22. Белая Ж.Е., Ильин А.В., Мельниченко Г.А., Рожинская Л.Я., Драгунова Н.В., Дзеранова Л.К., Огнева Н.А., Бутрова С.А., Трошина Е.А, Колесникова Г.С., Дедов И.И. Автоматизированный электрохемилюминесцентный метод определения кортизола в слюне для диагностики эндогенного гиперкортицизма среди пациентов с ожирением. Ожирение и метаболизм 2011; 27: 2: 56-63.

23. Oldfield E.H., Doppman J.L., Nieman L.K. Petrosal sinus sampling with and without corticotrophin-releasing hormone for the differential diagnosis of Cushing's syndrome. New Engl J Med 1991; 325: 897-905.

24. Grant P., Dworakowska D., Carroll P. Maximising 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 (Oxford) 2012; 76: 555-559.