Clinical Endocrinology (1997) 47, 199–206 Inferior petrosal sinus AVP in patients with Cushing’s syndrome Jack A. Yanovski*‡, Theodore C. Friedman‡§, Lynnette K. Nieman‡, George P. Chrousos‡, Gordon B. Cutler Jr‡, John L. Doppman² and Konstantine T. Kalogeras¶ *Office of the Director and ² Department of Diagnostic Radiology, Warren Grant Magnuson Clinical Center, ‡Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, §Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical Center Burns and Allen Research Institute, UCLA School of Medicine, Los Angeles, California and ¶The Laboratory of Clinical Neuroendocrinology, Department of Psychiatry and Human Behavior, The University of Mississippi Medical Center, School of Medicine, Jackson, Mississippi, USA (Received 16 July 1996; returned for revision 30 September 1996; finally revised 26 February 1997; accepted 19 March 1997) Summary OBJECTIVE In both normal volunteers and patients with Cushing’s disease, one dominant inferior petro- sal sinus (IPS) contains higher concentrations of AVP and ACTH than the contralateral (non-dominant) IPS, but ovine corticotrophin-releasing hormone (oCRH)- stimulated AVP in the petrosal sinuses is greater in Cushing’s disease than in normal volunteers. To dis- tinguish whether greater oCRH-releasable AVP might be specifically related to the presence of a pituitary corticotrophinoma, or be due to hypercortisolism per se, we compared IPS AVP in patients with Cushing’s disease with those of patients with other causes of Cushing’s syndrome. PATIENTS Twenty-three patients with Cushing’s disease, 16 patients with the syndrome of ectopic ACTH and seven patients with Cushing’s syndrome of adrenal origin. MEASUREMENTS AVP and ACTH, measured both before and 3, 5 and 10 minutes after oCRH in the petrosal sinuses, and in a peripheral vein. RESULTS In all three groups, AVP concentrations were lateralized such that most of the AVP was found in one, dominant IPS. oCRH significantly increased IPS ACTH only in patients with Cushing’s disease (P < 0 . 001), whereas it significantly increased dominant IPS AVP levels in all three patient groups (P < 0 . 01). However, neither dominant nor non- dominant IPS AVP (basal or oCRH-stimulated) were significantly different among patients with Cushing’s disease, ectopic ACTH or Cushing’s syndrome of adrenal origin. Basal and oCRH-stimulated IPS AVP were negatively correlated with urine free cortisol. CONCLUSIONS Inferior petrosal sinus AVP levels are similar in all forms of Cushing’s syndrome, and thus the higher inferior petrosal sinus AVP levels in patients with Cushing’s disease compared with normal volunteers are unlikely to be related specifi- cally to the presence of the pituitary cortico- trophinoma. While AVP may play a role in pituitary corticotroph tumourigenesis or may be secreted by some pituitary corticotroph tumours, the observation that CRH-stimulated inferior petrosal sinus AVP levels are higher in Cushing’s disease than in normal volunteers appears most likely to be related to the low endogenous CRH levels induced by hyper- cortisolism, rather than a consequence of Cushing’s disease itself. We hypothesize that low endogenous CRH leads to increased sensitivity of central nervous system CRH receptors to exogenous CRH, and thus to greater ovine CRH-stimulated AVP. The pathogenic mechanism underlying the formation of most pituitary corticotroph adenomas is unknown. Many hypotheses have been promulgated, including direct hyperstimulation of corticotrophs by trophic factors (Holsboer et al., 1992; Sonino et al., 1993; Friedman et al., 1996). While ACTH-secreting pituitary tumours are monoclonal in origin (Herman et al., 1990; Gicquel et al., 1992), and thus likely to result from a somatic mutation in a progenitor corticotroph cell, the possibility that tumourigenesis might be promoted by a circulating humoral factor has not been excluded (Horrocks et al., 1982; Kontula et al., 1984; Katz et al., 1986). Cortico- trophin-releasing hormone (CRH), the strongest known secre- tagogue of ACTH, has been considered unlikely to be the aetiological factor in Cushing’s disease because CRH is low in 199  1997 Blackwell Science Ltd Correspondence: J. A. Yanovski, National Institutes of Health, 10 Center Drive, MSC 1862, Building 10 Room 10N262, 9000 Rockville Pike, Bethesda, MD 20892-1862, USA. Fax: 301 402 6439. E-mail: JY15i@NIH.GOV.