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A Combined Test Using Desmopressin and Corticotropin-Releasing Hormone in the Differential Diagnosis of Cushing’s Syndrome

Departments of Endocrinology (J.N.-P., J.M., M.S., M.B., A.G.) and Chemical Endocrinology (L.P., S.M.), St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE

Address all correspondence and requests for reprints to: Dr. Ashley Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE. E-mail: a.b.grossman{at}mds.qmw.ac.uk

	Abstract

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To assess the ability of desmopressin to differentiate between pituitary and ectopic ACTH-dependent Cushing’s syndrome and to determine whether diagnostic accuracy could be improved by administering it together with human sequence CRH, we examined its effects on cortisol and ACTH secretion when given alone or in combination with CRH in patients with Cushing’s syndrome of varied etiology and compared these data to the results of a standard CRH test in the same individuals.

Each patient was studied on three occasions, in random order, separated by at least 48 h. At 0900 h, via an indwelling forearm cannula, 10 µg desmopressin, 100 µg CRH, or a combination of the two were given as an iv bolus; thereafter, blood was drawn every 15 min for 2 h. The responses to the individual agents were determined according to the timing and calculation criteria suggested by Nieman et al. (1993). A total of 25 patients with Cushing’s syndrome were studied: 17 patients with pituitary-dependent Cushing’s syndrome, Cushing’s disease (CD); 5 patients with occult ectopic ACTH secretion (EC); and 3 patients with primary adrenal (ACTH-independent) Cushing’s syndrome.

In this series, the best discrimination among ACTH-dependent patient groups was achieved using the combined test. Using the responses of plasma cortisol, all 17 patients with CD showed a rise greater than any of the 5 patients with EC, whereas 1 patient with CD showed a plasma ACTH response within the range seen in the patients with EC. Plasma cortisol responses to desmopressin alone were seen in 14 of 17 patients with CD and 1 of 5 patients with EC and, after CRH alone, in 15 of 17 patients with CD but in no patient with EC. In contrast, plasma ACTH responses after CRH alone were seen in 14 of 17 patients with CD and 2 of 5 patients with EC and, after desmopressin alone, in 12 of 17 with CD and 3 of 5 with EC, thus indicating overlapping responses between the groups and poorer discrimination. No responses were seen in the ACTH-independent group.

These data indicate that desmopressin causes the secretion of ACTH and cortisol in patients with ACTH-dependent Cushing’s syndrome, and that in combination with CRH, it may provide an improvement over the standard CRH test in the differential diagnosis of ACTH-dependent Cushing’s syndrome. Furthermore, these data suggest that there may be abnormalities in vasopressin receptor function or number in ACTH-secreting tumors.

	Introduction

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CRH IS A POTENT stimulus for the secretion of ACTH in man (1, 2) and is used in the CRH test, which has been extensively validated in the investigation and differentiation of the causes of Cushing’s syndrome (3, 4, 5). CRH causes a significant rise in plasma ACTH and cortisol in the majority of patients with pituitary-dependent Cushing’s syndrome, Cushing’s disease (CD), whereas such effects are seen only rarely in patients with the ectopic ACTH syndrome (EC) (6, 7, 8). For many years it has been known that vasopressin also stimulates ACTH release and, in particular, that it potentiates the ACTH-releasing effects of CRH (9). These actions are thought to occur via the specific corticotroph vasopressin receptor, the V₃ or V_1b receptor, which has recently been cloned (10, 11). Lysine vasopressin and arginine vasopressin have been shown to have ACTH-releasing properties similar to those of CRH when administered to patients with Cushing’s syndrome (12), although CRH appears to better discriminate between ectopic ACTH and pituitary disease (13). Furthermore, side-effects consisting of abdominal pain, nausea, and flushing have precluded the routine clinical use of vasopressin for diagnostic testing, although it has been suggested that it may be better tolerated when used as a low dose infusion in combination with CRH (14).

Desmopressin, a long acting analog of vasopressin (15), has relative specificity for the renal V₂ receptor, with little V₁-mediated pressor activity (16). Although its specific V_1b receptor activity is uncertain, it has been shown previously to have no intrinsic in vivo ACTH-releasing characteristics when given as an infusion in man (17). Desmopressin has, however, been shown to cause a significant release of cortisol and ACTH in the majority of patients with CD when given as bolus, but not in one patient with EC, and it has, therefore, been suggested that it may be used to aid the differential diagnosis of the causes of ACTH-dependent Cushing’s syndrome (18). However, previous studies have not explored whether the combination test of desmopressin and CRH would be better than either peptide alone in the differential diagnosis.

The present study, therefore, was designed to assess the effects of desmopressin on the release of ACTH and cortisol when given as an iv bolus dose, alone or in combination with CRH, to patients with Cushing’s syndrome and thus to compare the clinical utility of desmopressin and CRH as diagnostic tests. Human sequence CRH was used instead of the ovine sequence (19), as it is currently more widely available internationally.

	Subjects and Methods

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A total of 25 consecutive patients were studied on 3 occasions separated by at least 48 h: 17 patients with pituitary-dependent Cushing’s syndrome (CD; mean age, 42 yr; range, 11–73 yr), 5 patients with EC (3 women, 33, 34, and 39 yr old, with bronchial carcinoid tumors; a male, 34 yr old, with a medullary cell carcinoma of the thyroid; and a male, 62 yr old, with a disseminated carcinoid syndrome; all were occult insofar as no tumor was apparent clinically or on simple radiographic investigation), 1 female patient with a functioning adrenocortical carcinoma (65 yr old), 1 woman with a functioning adrenocortical adenoma (61 yr old), and 1 male patient (51 yr old) with ACTH-independent massive macronodular hyperplasia. The cause of Cushing’s syndrome was verified histologically after surgery in 24 of the 25 patients. In the remaining patient, all clinical features and biochemical evaluations, including the high dose dexamethasone test (8 mg/day for 48 h) and CRH-stimulated inferior-petrosal catheter studies, were completely consistent with CD, but he did not undergo transsphenoidal hypophysectomy. No patient was receiving any drug known to affect the hypothalamo-pituitary-adrenal axis. All patients gave written informed consent to the investigation, which was approved by the ethical committee of St. Bartholomew’s Hospital.

After an overnight fast, an in-dwelling forearm cannula was inserted at 0830 h; the subject remained supine for the remainder of that day’s study. At 0900 h (0 min), 10 µg desmopressin (DDAVP, Ferring, Malmo, Sweden) and saline placebo for CRH, 100 µg human sequence CRH (Ferring, Malmo, Sweden) and saline placebo for desmopressin, or a combination of these peptides were injected sequentially over periods of 15 s each. Blood was taken for estimation of plasma ACTH and cortisol at -15, 0, 15, 30, 45, 60, 90, and 120 min. Blood pressure and pulse rate were recorded by automated means (Dinamapp, Tampa, FL) at each sampling point. After testing, each subject was advised to restrict fluid intake to 2 L for the remainder of the day. The order of all investigations was randomized and run in a single blind manner.

Calculation of response criteria

Following the suggested criteria of Nieman et al. (20) using the ovine CRH test, we calculated in each patient group the percent rise in the mean circulating plasma ACTH values at 15 and 30 min and circulating plasma cortisol values at 30 and 45 min above the mean basal values at -15 and 0 min, after the administration of human CRH, desmopressin, or a combination of the two. The response criteria documented by Nieman et al. (20) that best discriminated Cushing’s disease from the ectopic ACTH syndrome were a 20% rise in circulating plasma cortisol and a 35% rise in circulating plasma ACTH; these criteria were assessed in this study.

Assays

Plasma cortisol was measured by an in-house unextracted nonchromatographic RIA; the coefficient of variation at 100 and 1000 nmol/L was 6% (21). Plasma ACTH was measured by our routine in-house Vycor (Societe-A.T.A. Geneva, Switzerland) glass-extracted RIA originally developed in 1971, which has subsequently been validated using a range of chromatographic procedures in human studies (22).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Plasma cortisol responses (Table 1 and Fig. 1)

Differential effects of CRH or desmopressin given alone. Using the response criterion of at least a 20% rise in the circulating plasma cortisol level, calculated from the ratio of the mean values at 30 and 45 min over the mean basal value (21), 15 of 17 patients with CD responded positively to CRH, but no responses were seen in the patients with EC. Using the same response criterion, 14 of 17 patients with CD responded to desmopressin, as did patient 21 with an ACTH-secreting medullary carcinoma of the thyroid. Patients 1, 2, 5, and 17 with CD showed discordant responses to CRH and desmopressin; patients 1 and 17 responded only to desmopressin, whereas patients 2 and 5 responded only to CRH (Table 1). No responses to either treatment were seen in the patients with ACTH-independent Cushing’s syndrome.

View larger version (10K): [in this window] [in a new window]   Figure 1. Percent change in plasma cortisol (mean of 30 and 45 min values vs. mean basal values at -15 and 0 min) in 17 patients with CD, 5 patients with EC, and 3 patients with an primary adrenal Cushing’s syndrome after the administration of 1) desmopressin (10 µg, iv), 2) human sequence CRH (100 µg, iv), or 3) CRH (100 µg, iv) plus desmopressin (10 µg, iv; dashed line represents 20% for the CRH alone and desmopressin alone tests and 38% for the CRH plus desmopressin test).

Plasma ACTH responses (Table 2 and Fig. 2)

Differential effects of CRH and desmopressin given alone. Using the response criterion of at least a 35% rise in plasma ACTH calculated from the ratio of the mean of the values at 15 and 30 min over the mean basal level (21), 14 of 17 patients with CD and 2 of 5 patients with EC (patients 18 and 22) responded to CRH alone. After the administration of desmopressin alone, 12 of 17 patients with CD and 3 patients with EC showed such a response (patients 19, 20, and 21). After CRH alone, 6 patients, and after desmopressin alone, 9 patients with CD responded within the range of responses seen in the patients with EC. Patients 1, 2, 5, and 17 had the same discordant responses to CRH and desmopressin using ACTH response criteria as they demonstrated using cortisol criteria (see above). Patient 4 showed a cortisol, but apparently not an ACTH, response to CRH. ACTH remained undetectable in all 3 patients with primary adrenal disease.

View larger version (9K): [in this window] [in a new window]   Figure 2. Percent change in plasma ACTH (mean of 15 and 30 min values vs. mean basal values at -15 and 0 min) in 17 patients with CD and 5 patients with EC after the administration of 1) desmopressin (10 µg, iv), 2) human sequence CRH (100 µg, iv), or 3) CRH (100 µg, iv) plus desmopressin (10 µg, iv; dashed line represents 35% for the CRH alone and desmopressin alone tests and 350% for the CRH plus desmopressin test).

Side-effects

After the administration of either peptide, adverse effects were limited to a short-lived flushing sensation (1–15 min), which was similar in nature to that after the combination treatment, but slightly longer in duration (2–20 min). After the combination treatment, three patients experienced a slight metallic taste in their throats, lasting 2–5 min. In no case was there evidence of water overload. There was no significant change in blood pressure in any patient; two patients experienced a transient (<5 min) sinus tachycardia after the combination treatment (maximum heart rates, 113 and 100 beats/min), with no symptomatic palpitations, chest pain, or fall in blood pressure.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data suggest that desmopressin causes ACTH and cortisol secretion when given on its own to patients with ACTH-dependent Cushing’s syndrome. As a test, however, when given alone it did not reliably distinguish between Cushing’s disease and the ectopic ACTH syndrome. In this and another series, CRH has a high discriminatory power when given alone, but absolute discrimination between groups is not achieved with the human sequence peptide; indeed, utilization of the ACTH responses resulted in an unacceptably low degree of specificity. When desmopressin is given in combination with CRH, we found that enhanced discrimination may be made between the ACTH-dependent groups, as a greater response is seen in patients with CD than in those with EC. After the combination treatment, a rise of over 38%, calculated from the average of the 30 and 45 min plasma cortisol samples, over the basal levels at -15 and 0 min was seen in all patients with CD, whereas in all five patients with EC it was less than this, with the highest rise in plasma cortisol being 29%. Interestingly, the plasma ACTH responses provided less discrimination, as one patient with pituitary disease demonstrated a rise within the range seen in the patients with EC. Furthermore, the test was well tolerated, with minimal symptomatic and no adverse effects, in a wide age range of patients. Asymptomatic sinus tachycardia of short duration was observed, but did not cause any cardiovascular compromise in any patient.

Vasopressin has a well documented synergistic effect with CRH for ACTH release (9, 23, 24). Desmopressin has similar ACTH-releasing effects in rats in vitro (25), and this effect is not reversed by V₂ receptor antagonists (26). Previous data in normal volunteers have not demonstrated either direct or potentiating effects of desmopressin for ACTH release when coadministered with CRH (17). Desmopressin is said to be a specific V₂ receptor agonist, and this may explain the lack of response of ACTH secretion in the normal volunteers. Desmopressin does, however, as shown in this study and previously (18), cause significant release of ACTH and cortisol in ACTH-dependent Cushing’s syndrome. Glucocorticoids have recently been shown to up-regulate the expression of the V_1b receptor in normal rat anterior pituitary glands and rescue the down-regulation seen after adrenalectomy, with similar effects reported in the vasopressin-deficient Brattleboro rat (27); thus, such up-regulation may be caused by hypercortisolemia rather than changes in vasopressin levels (27). Furthermore, the majority of human corticotroph adenomas and some ACTH-secreting bronchial carcinoids have been demonstrated to express high levels of the V_1b receptor; in contrast, the CRH receptor is expressed in corticotroph adenomas, but far less commonly in bronchial carcinoid tumors (28, 29). Taken together, these studies suggest that the effect of desmopressin in these tumors may be mediated by up-regulation of the V_1b receptor in neuroendocrine tissue, which, in turn, may reflect prevailing hypercortisolemia. It seems probable that desmopressin may show cross-affinity with the V_1b receptor when it is present in high concentrations, although it is also possible that up-regulation or aberrant expression of the V₂ receptor in ACTH-secreting cells may occur. Further, it is possible that the differentiating ability of the combined test may relate to a greater increase in the co-overexpression of the CRH and V_1b receptors in many of the corticotroph adenomas than in ectopic tumors secreting ACTH and the higher response seen in CD.

A previous report has suggested that desmopressin is a readily available and cost-effective alternative to CRH in the investigation of Cushing’s syndrome (18). Certainly, in this study it seems to have a similar, but inferior, ability to differentiate between CD and EC when analyzing either plasma ACTH or cortisol responses. Clearly, three of our five patients with EC responded to desmopressin given alone.

In conclusion, desmopressin given alone appears to cause the release of ACTH and cortisol in ACTH-dependent Cushing’s syndrome. Such effects of desmopressin suggest abnormalities in receptor number or function in these neuroendocrine ACTH-secreting tumors that merit further study. As a diagnostic test, human sequence CRH alone appears to be better than desmopressin alone in discriminating between ACTH-dependent groups, whereas the combination of the two appears to produce better results than either alone. Occult ectopic ACTH-secreting tumors can be extremely small and may offer a considerable diagnostic challenge, behaving in many ways similarly to eutopic corticotroph tumors (30). Thus, the combined test may be of considerable diagnostic utility. This is, however, a relatively small series of patients, and the percent rise criterion that distinguishes pituitary from ectopic ACTH production may need alteration with the benefit of further experience. Although we do not suggest that this combination test replace the standard CRH test, it seems probable that testing with these agents in addition to conventional testing with the high dose dexamethasone suppression test or inferior petrosal catheter studies may be of considerable clinical benefit.

	Acknowledgments

 
We are most grateful to Ferring for the supply of human sequence CRH and desmopressin, and to Debbie Grossman and Caroline Ramsey for performing the tests at our metabolic ward.

	Footnotes

 
¹ Supported by the Medical Research Council, United Kingdom.

Received October 4, 1995.

Revised June 10, 1996.

Revised August 14, 1996.

Accepted September 14, 1996.

	References

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