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Cent Eur Neurosurg 2003; 64(1): 6-11
DOI: 10.1055/s-2003-37145
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© Georg Thieme Verlag Stuttgart · New York

The Use of Postoperative ACTH Levels as a Marker for Successful Transsphenoidal Microsurgery in Cushing’s Disease

Postoperative ACTH-Werte als Marker der erfolgreichen transsphenoidalen Adenomektomie bei Morbus CushingJ. Flitsch1 , U. J. Knappe1 , D. K. Lüdecke1
  • 1Arbeitsbereich Hypophysenchirurgie, Klinik für Neurochirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg
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Publication History

Publication Date:
12 February 2003 (online)

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Zusammenfassung

Fragestellung: Der unmittelbar nach Tumorentfernung stattfindende Hormonabfall von ACTH oder anderer POMC-Metabolite lässt keine Aussage hinsichtlich der Radikalität der Tumorexstirpation eines ACTH-sezernierenden Hypophysenadenoms bei Morbus Cushing zu. Dennoch sollte der Hypophysenchirurg in der Lage sein, so früh wie möglich das operative Ergebnis zu beurteilen, um gegebenenfalls eine frühe Reoperation planen zu können. Zur Zeit wird der postoperative Abfall des Kortisols in den subnormalen Bereich als Kriterium für die Heilung weitgehend anerkannt. In dieser Studie untersuchten wir, ob frühe postoperative ACTH-Bestimmungen als Marker für das unmittelbare postoperative Ergebnis als auch für die Langzeitremission aussagekräftig sind.
Methode: In diesem prospektiven Studiendesign wurden 147 Patienten, die sich von 1990 bis 1996 einer primären Operation bei Morbus Cushing unterzogen, untersucht. Der frühe postoperative ACTH-Abfall wurde bestimmt und mit dem Langzeitverlauf verglichen. ACTH-Bestimmungen wurden unmittelbar nach Tumorausräumung, nach 1, 2, 4, 8 und 12 Stunden sowie am darauffolgenden Morgen durchgeführt. Weitere ACTH-Bestimmungen folgten an verschiedenen Tagen während des stationären Aufenthaltes. Glukokortikoide wurden erst bei Nachweis des Hypokortisolismus substituiert.
Ergebnisse: Bei 95 Operationen (65 %) wurden postoperativ subnormale ACTH-Werte (< 10 ng/l) während des stationären Aufenthaltes gemessen. Zwei dieser Patienten erlitten ein Rezidiv des Morbus Cushing nach 66 bzw. 100 Monaten (2 %). Von 29 Patienten, die postoperativ ACTH-Werte zwischen 10 und 20 ng/l aufwiesen (20 %), benötigte ein Patient eine weitere Behandlung für den persistierenden (3,5 %) bzw. ein Patient für den rezidivierenden Morbus Cushing (3,5 %). Zwölf Patienten (8 %) wiesen postoperativ ACTH-Werte zwischen 20 und 30 ng/l auf, davon wurde ein Patient am persistierenden (8 %) bzw. 4 Patienten am rezidivierenden Morbus Cushing behandelt (33 %). Im Falle von 11 Patienten mit ACTH-Werten über 30 ng/l (7 %) bestand bei 8 Patienten die Erkrankung weiter fort (73 %) bzw. rezidivierte bei zwei Patienten (18 %).
Schlussfolgerung: Subnormale (< 10 ng/l) bzw. niedrig normale (< 20 ng/l) postoperative ACTH-Werte innerhalb der ersten sieben postoperativen Tage können als frühe Marker sowohl für die komplette Tumorextirpation als auch für die Langzeitremission bei Morbus Cushing angesehen werden. Das Risiko einer persistierenden oder rezidivierenden Erkrankung steigt mit der Höhe der postoperativen ACTH-Werte. Bei normalen ACTH-Spiegeln sind weitere Untersuchungen der ACTH- Kortisol-Sekretion wie zum Beispiel Funktionstests indiziert.

Abstract

Objectives: The declines of ACTH and other POMC metabolites immediately after tumor extirpation do not predict the complete tumor removal of an ACTH-secreting pituitary adenoma in Cushing’s disease. However, the pituitary surgeon should be in a position to evaluate the surgical result as soon as possible for the eventual planning of early repeat surgery. So far, subnormal serum cortisol levels after surgery are widely accepted as the criterion for cure. We investigated whether the early postoperative ACTH concentration is a reliable marker for the initial surgical outcome as well as the long-term remission.
Methods: In a prospective study, 147 patients undergoing primary transsphenoidal microsurgery for Cushing’s disease between 1990 and 1996 were investigated. The early postoperative ACTH courses were reviewed and compared with the long-term outcome. ACTH measurements were performed immediately after tumor excision, 1, 2, 4, 8, and 12 hours later, and the following morning. Further ACTH levels were determined on various days of the hospital stay. Glucocorticoids were not given until hypocortisolism was proven.
Results: Ninety-five patients (65 %) presented with subnormal ACTH levels (< 10 ng/l) during their postoperative stay, of whom two patients (2 %) experienced recurrence of disease after 66 and 100 months. Of 29 procedures with early postoperative ACTH levels ranging from 10-20 ng/l (20 %), one patient received further treatment for persistent (3.5 %) and one patient for recurrent Cushing’s disease (3.5 %). Of 12 patients (8 %) with early postoperative ACTH levels in between 20 to 30 ng/l, one patient received further treatment for persistent (8 %) and four patients for recurrent disease (33 %). ACTH levels of more than 30 ng/l, found in 11 patients (7 %), were accompanied by persistent (8 patients, 73 %) or recurrent (2 patients, 18 %) Cushing’s disease.
Conclusion: Subnormal (< 10 ng/l) or low normal (< 20 ng/l) postoperative ACTH levels within the first 7 days after surgery can be regarded as early markers for complete removal of an ACTH adenoma as well as indicators for long-term outcome in Cushing’s disease. The risks of persistence or recurrence of Cushing’s disease rise with the level of early postoperative ACTH values. Normal ACTH levels should result into further evaluation of the ACTH-cortisol secretion, for example by stimulation- or suppression tests.

Schlüsselwörter

ACTH - Kortisol - Morbus Cushing - Rezidiv - Remission - Transsphenoidale Mikrochirurgie

Key words

ACTH - cortisol - cushing’s disease - recurrence - remission - transsphenoidal microsurgery

References

  • 1 Abe T, Lüdecke D K. Recent results of secondary transnasal surgery for residual or recurring acromegaly.  Neurosurgery. 1998;  42 1013-1021
    CrossrefPubMedGoogle Scholar
  • 2 Abe T, Lüdecke D K. Recent primary transnasal surgical outcomes associated with intraoperative growth hormone measurement in acromegaly.  Clin Endocrinol. 1999;  50 27-35
    CrossrefPubMedGoogle Scholar
  • 3 Bochicchio D, Losa M, Buchfelder M. and the European Cushing’s Disease Survey Study Group . Factors influencing the immediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: A retrospective study by the European Cushing’s Disease Survey Group.  J Clin Endocrinol Metab. 1995;  80 3114-3120
    CrossrefPubMedGoogle Scholar
  • 4 Buchfelder M, Fahlbusch R. Recurrences in Cushing’s disease - prediction and prevention. In: Lüdecke DK, Chrousos GP, Tolis G (eds): ACTH, Cushing’s syndrome, and other hypercortisolemic states Raven Press, New York; Progress in endocrine research and therapy, Volume 5. 1990; 281-288
    Google Scholar
  • 5 Doherty G M, Nieman L K, Cutler GB J r., Chrousos G P, Norton J A. Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing's syndrome.  Surgery. 1990;  108 1085-1090
    PubMedGoogle Scholar
  • 6 Eberwine J H, Roberts J L. Analysis of pro-opiomelanocortin gene structure and function. DNA 2. 1983; 1-8
    Google Scholar
  • 7 Fitzgerald P A, Aron C D, Findling J W, Brooks R M, Wilson C B, Tyrrell J B. Cushing’s disease; transient secondary adrenal insufficiency after selective removal of pituitary tumors. Evidence for pituitary origin.  J Clin Endocrinol Metab. 1982;  54 413-422
    PubMedGoogle Scholar
  • 8 Flitsch J, Lüdecke D K, Knappe U J, Saeger W. Correlates of long-term hypocortisolism after transsphenoidal microsurgery for Cushing’s disease.  Exp Clin Endocrinol Diabetes. 1999;  107 183-189
    PubMedGoogle Scholar
  • 9 Gomez M T, Magiakou M A, Mastorakos G, Chrousos G P. The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome.  J Clin Endocrinol Metab. 1993;  77 173-177
    CrossrefPubMedGoogle Scholar
  • 10 Graham K E, Samuels M H, Raff H, Barnwell S L, Cook D M. Intraoperative Adreno-corticotropin levels during transsphenoidal surgery for Cushing’s disease do not predict cure.  J Clin Endocrinol Metab. 1997;  82 1776-1779
    CrossrefPubMedGoogle Scholar
  • 11 Invitti C, Pecori Giraldi F, De Martin M, Cavagnini F. and the study group of the Italian Society of Endocrinology on the Pathophysiology of the hypothalamic-pituitary-adrenal axis . Diagnosis and management of Cushing’s syndrome - results of an Italian multicentre study.  J Clin Endocrinol Metab. 1999;  84 440-448
    CrossrefPubMedGoogle Scholar
  • 12 Iranmanesh A, Lizarralde G, Veldhuis J D. Coordinate activation of the corticotropic axis by insulin-induced hypoglycemia: simultaneous estimates of β-endorphin, adrenocorticotropin and cortisol secretion and disappearance in normal men.  Acta Endocrinol. 1993;  128 521-528
    PubMedGoogle Scholar
  • 13 Leinung M C, Kane L A, Scheithauer B W, Carpenter P C, Laws Jr E R, Zimmerman D. Long term follow-up of transsphenoidal surgery for the treatment of Cushing's disease in childhood.  J Clin Endocrinol Metab. 1995;  80 2475-2479
    CrossrefPubMedGoogle Scholar
  • 14 Losa M, Mortini P, Dylgjeri S, Barzaghi R, Franzin A, Mandelli C, Giovanelli M. Desmopressin stimulation test before and after pituitary surgery in patients with Cushing’s disease.  Clin Endocrinol. 2001;  55 61-68
    CrossrefPubMedGoogle Scholar
  • 15 Lüdecke D K, Müchler H C, Caselitz J, Saeger W. ACTH and cortisol patterns after selective adenomectomy in Cushing’s disease.  Acta Endocrinol Copenh. 1981;  240 61-62
    PubMedGoogle Scholar
  • 16 Lüdecke D K, Niedworok G. Results of microsurgery in Cushing’s disease and effect on hypertension.  Cardiology. 1985;  72 91-94
    PubMedGoogle Scholar
  • 17 Lüdecke D K. Intraoperative measurement of adrenocorticotropic hormone in peripituitary blood in Cushing’s disease.  Neurosurgery. 1989;  24 201-205
    PubMedGoogle Scholar
  • 18 Lüdecke D K. Recent development in the treatment of acromegaly.  Neurosurg. 1991;  Rev 8 167-173
    PubMedGoogle Scholar
  • 19 Lüdecke D K, Flitsch J, Knappe U J, Saeger W. Cushing's disease: a surgical view.  J Neuro Oncol. 2001;  54 151-166
    PubMedGoogle Scholar
  • 20 Mampalam T J, Blake Tyrrell T J, Wilson C B. Transsphenoidal microsurgery for Cushing’s disease.  Ann Intern Med. 1988;  109 487-493
    PubMedGoogle Scholar
  • 21 McCane D R, Gordon D S, Fannin T F, Hadden D R, Kennedy L, Sheridan B, Atkinson A B. Assessment of cure after transsphenoidal surgery for Cushing’s disease.  Clin Endocrinol. 1993;  38 79-86
    PubMedGoogle Scholar
  • 22 Nakane T, Kuwayama A, Watanabe M, Takahashi T, Kato T, Ichihara K, Kageyama N. Long term results of transsphenoidal adenomectomy in patients with Cushing’s disease.  Neurosurgery. 1987;  21 218-222
    PubMedGoogle Scholar
  • 23 Newell Price J DC, Norris J, Afshar F, Plowman P N, Grossman A B, Besser G M, Trainer P J. Transsphenoidal hypophysectomy in Cushing's disease - results and follow-up in 103 patients.  J Endocrinol. 1997;  152 72
    PubMedGoogle Scholar
  • 24 Newell Price J. Transsphenoidal surgery for Cushing's disease: defining cure and following outcome.  Clin Endocrinol. 2002;  56 19-21
    CrossrefPubMedGoogle Scholar
  • 25 Nishizawa S, Oki Y, Ohta S, Yokota N, Yokoyama T, Uemura K. What can predict postoperative endocrinological cure in Cushing’s disease?.  Neurosurgery. 1999;  45 239-244
    PubMedGoogle Scholar
  • 26 Pimentel-Filho F R, Cukiert A, Miyashita F, Huayllas M K, Knoepfelmacher M, Salgado L R, Liberman B. Adrenocorticotropin levels do not change during early recovery of transsphenoidal surgery for ACTH-secreting pituitary tumors.  J Endocrinol Invest. 2001;  24 83-87
    PubMedGoogle Scholar
  • 27 Raff H, Shaker J L, Nelson D K, Findling J W. Rapid measurement of corticotropin (ACTH) with a modified immunochemiluminescent assay.  Clin Chem. 1994;  40 1344
    PubMedGoogle Scholar
  • 28 Ram Z, Nieman L K, Cutler G B, Chrousos G P, Doppman J L, Oldfield E H. Early repeat surgery for persistent Cushing’s disease.  J Neurosurg. 1994;  80 37-45
    CrossrefPubMedGoogle Scholar
  • 29 Sgoutas D S, Sgoutas S A, Clark R V. Parallel assays of ß-Endorphin and ACTH in Cushing's patients undergoing petrosal sinus sampling.  Clin Biochem. 1990;  23 321-326
    PubMedGoogle Scholar
  • 30 Schrell U, Fahlbusch R, Buchfelder M, Riedl S, Stalla G K, Müller O A. Corticotropin-releasing hormone stimulation test before and after transsphenoidal selective microadenomectomy in 30 patients with Cushing’s disease.  J Clin Endocrinol Metab. 1987;  64 1150-1159
    PubMedGoogle Scholar
  • 31 Simmons N E, Alden T D, Thorner M O, Laws ER J r. Serum cortisol response to transsphenoidal surgery for Cushing’s disease.  J Neurosurg. 2001;  95 1-8
    CrossrefPubMedGoogle Scholar
  • 32 Trainer P J, Lawrie H S, Verhelst J, Howlett T A, Lowe D G, Grossman A B, Savage M O, Afshar F, Besser G M. Transsphenoidal resection in Cushing’s disease: undetectable serum cortisol as the definition of successful treatment.  Clin Endocrinol. 1993;  38 73-78
    CrossrefPubMedGoogle Scholar
  • 33 van der Berg G, van Dulken H, Frölich M, Meinders E, Roelfsema F. Can intraoperative GH measurement in acromegalic subjects predict completeness of surgery?.  Clin Endocrinol. 1998;  49 45-51
    CrossrefPubMedGoogle Scholar
  • 34 Vignati F, Berselli M E, Loli P. Early postoperative evaluation in patients with Cushing’s disease: usefulness of ovine corticotropin-releasing hormone test in the prediction of recurrence of disease.  Eur J Endocrinol. 1994;  130 235-241
    PubMedGoogle Scholar
  • 35 Yap L B, Turner H E, Adams C BT, Wass J AH. Undetectable postoperative cortisol does not always predict long-term remission in Cushing’s disease: a single center audit.  Clin Endocrinol. 2002;  56 25-31
    CrossrefPubMedGoogle Scholar

Dr. J. Flitsch

Neurochirurgische Klinik · Universitätsklinikum Hamburg-Eppendorf (UKE)

Martinistr. 52

20246 Hamburg

Phone: +49/40/4 28 03-27 65

Fax: +49/40/4 28 03-59 82

Email: flitsch@uke.uni-hamburg.de