INTRODUCTION — Arginine-vasopressin (AVP) is the natural human nonapeptide, which (in addition to its antidiuretic, vasoconstrictive, glycogenolytic, and platelet aggregation actions) plays an important role in the regulation of the corticotropin (ACTH)-adrenal axis. AVP and some of its analogs, such as porcine 8-lysine-vasopressin (LVP) and desmopressin (1-deamino, 8-D arginine-vasopressin), have been used in a number of clinical settings. If corticotropin-releasing hormone (CRH) is available, it is the peptide of choice for the differential diagnosis of Cushing's syndrome. Desmopressin is used as an alternative when CRH is not available and is considered the vasopressin analog of choice to use for the postoperative surveillance of patients with ACTH-dependent Cushing's syndrome and for the diagnosis of pseudo-Cushing's syndrome [1].
This topic will review the various stimulation tests using the vasopressin analog desmopressin (DDAVP) in evaluating the pituitary-adrenal axis with a focus on pituitary disease. (See "Corticotropin-releasing hormone stimulation test" and "Insulin-induced hypoglycemia test" and "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test".)
Desmopressin testing for bleeding disorders is reviewed elsewhere. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP trial'.)
VASOPRESSIN PHYSIOLOGY — Arginine-vasopressin (AVP) is synthesized in the magnocellular neurons of the supraoptic and paraventricular nuclei and is stored in neurosecretory granules in the axons, which project to the posterior pituitary. In addition, AVP is co-secreted with corticotropin-releasing hormone (CRH) from smaller parvocellular neurons in a section of the paraventricular nuclei, which project their axons to the median eminence and portal system of the pituitary stalk [2]. At this site, AVP promotes the secretion of corticotropin (ACTH) via activation of arginine-vasopressin receptor 1B (AVPR1B, previously named V1B or V3 receptor) present in corticotropes [3].
Cortisol inhibits the secretion of both CRH and AVP from the paraventricular nuclei [4]. Cortisol deficiency decreases this inhibitory effect, leading to a persistent rise in vasopressin release, water retention, and hyponatremia [2,4,5]. The AVPR2 receptors on the cortical and medullary collecting kidney tubules mediate the antidiuretic response via the migration of aquaporin-2 water channels [6]. AVPR2 on vascular endothelium can modulate the release of factor VIII and von Willebrand factor [7]. Both AVPR1A and AVPR1B activate phospholipase C [3,8,9], while the AVPR2 is coupled to adenylyl cyclase [10,11].
AVP are expected to bind to all three receptors; desmopressin is a preferential AVPR2 receptor-selective agent and has only limited effects on AVPR1A and AVPR1B. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)
CLINICAL USES — Arginine-vasopressin (AVP), 8-lysine-vasopressin (LVP), and terlipressin have been used in a number of clinical settings [12]. In general, these have been abandoned (due primarily to vasopressor actions and the availability of other tests), and desmopressin is the only peptide that is currently used. Desmopressin stimulation tests have been used to:
●Distinguish between the causes of ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH syndrome)
●The desmopressin test is used most commonly in countries where corticotropin-releasing hormone (CRH) is not available, although there are some that suggest that desmopressin is equivalent or even superior.
●Stimulate ACTH secretion from corticotroph tumors during petrosal sinus sampling. Most often, desmopressin is used as a substitute for CRH, but some studies have evaluated the combination.
●Distinguish between Cushing's syndrome and pseudo-Cushing's syndrome (Dex-CRH versus desmopressin tests).
DESMOPRESSIN STIMULATION TEST PROCEDURE — The test is usually performed in the morning with the patient fasting. An intravenous (IV) line is established 30 minutes before the test is begun. Blood samples for measurement of plasma corticotropin (ACTH) and serum cortisol are obtained 15 minutes and immediately before and 15, 30, 45, 60, 90, and 120 minutes after the injection of desmopressin [13,14]. Shorter and longer versions of this test have been used [15-19]. In fact, sampling 15 minutes and immediately before, and at 15, 30, 45 and 60 minutes seems to perform as well as the 120-minute test [18].
The recommended dose of desmopressin is 10 mcg IV [13,14], although lower doses (5 to 8 mcg) have been used successfully [13,17,20].
Interpretation — It was expected that desmopressin, initially thought to be a selective AVPR2 receptor agent, would not stimulate ACTH and cortisol levels in normal individuals. However, as many as 10 percent of normal subjects do respond [13,16,17], presumably because of low-level pituitary expression of AVPR2 [21].
Side effects — Desmopressin is an AVPR2 preferential agonist and lacks the vasoconstrictive, pallor, and abdominal discomfort mediated by the AVPR1A action of the natural vasopressins. However, it shares their effect on platelets.
ACTH-DEPENDENT CUSHING'S SYNDROME — The desmopressin test is used in the evaluation of corticotropin (ACTH)-dependent Cushing's syndrome [1,22-24]. The lack of commercial availability of corticotropin-releasing hormone (CRH) in certain countries and the lower cost of desmopressin has contributed to its increased use.
Identifying the cause — Desmopressin can be used for the differential diagnosis of Cushing's syndrome. At low doses (1 ng/kg/min), desmopressin fails to potentiate the effect of CRH on ACTH release in most normal subjects [25]. At a higher dose (10 mcg intravenous [IV]), it causes an increase in plasma ACTH and serum cortisol concentrations in most patients with Cushing's disease [13,15,26-28], suggesting that the test could be used to diagnose this condition.
In patients with Cushing's disease, using criteria of a 30 or 50 percent increase in plasma ACTH in response to desmopressin, 95 and 81 percent of patients respond, respectively; using the criterion of a greater than 20 percent increase in serum cortisol, 80 to 85 percent of patients respond [13,15,27-30]. However, in some reports, 8 of 25 (32 percent) of patients with ectopic ACTH syndrome, mostly benign carcinoid tumors, also responded [13,15,17,27,28,31-34].
Desmopressin has a relatively low affinity for the AVPR1B receptor [9,35] that is found on normal pituitary corticotrophs, on most adenomatous corticotrophs, and on some ACTH-secreting bronchial carcinoid adenomas [36]. It was unclear whether this response to desmopressin was mediated by abnormal expression of the AVPR2 on the cells of the corticotroph adenomas and ectopic ACTH-producing tumors [28] or by increased expression of the AVPR1B [33]. However, a study in patients with Cushing's disease suggests that the ACTH response to desmopressin correlates better with AVPR2 expression levels than with AVPR1B [21]. A higher in vivo response to desmopressin than that observed in corticotroph adenoma cultures (compared with high in vitro CRH response) suggested that other unidentified mechanisms to stimulate ACTH release may also be implicated [37]. Responsiveness to desmopressin has been observed in a bronchial carcinoid tumor in vitro [34].
Combined with CRH — When desmopressin is given in combination with corticotropin-releasing hormone (CRH), virtually all patients with Cushing's disease have an increase in plasma ACTH concentrations, using the criterion of a 35 percent rise after CRH with desmopressin [32,38]. Some clinicians use the combined test routinely, but it is more expensive.
Some patients with ectopic ACTH secretion also respond [32,38,39]. Since obese subjects without Cushing's syndrome may have a pronounced response to the combined CRH-AVP (arginine-vasopressin) stimulation test, it is important to use the test only in the setting of confirmed Cushing's syndrome [40]. (See "Corticotropin-releasing hormone stimulation test".)
During petrosal sinus sampling — CRH is not commercially available in certain countries or is more expensive than desmopressin. Desmopressin has therefore been used in place of CRH to perform petrosal sinus sampling in small series [39,41-43]. There are differences of opinion about when to use this test clinically.
Many clinicians perform petrosal sinus sampling with CRH without first determining if the pituitary tumor responds to CRH. However, another approach is to test with desmopressin first (which is less expensive than CRH), and if the tumor is very responsive, then use desmopressin rather than CRH to stimulate ACTH during petrosal sinus sampling [44].
In a retrospective analysis of combined CRH and desmopressin testing during petrosal sinus sampling in 47 patients with proven Cushing's disease and 7 with occult ectopic ACTH-secreting tumors, a post-stimulation gradient >2 was seen in 46 of 47 and 0 of 7 patients with Cushing's disease and ectopic ACTH, respectively (diagnostic accuracy of 98.7 percent) [45]. However, desmopressin (alone or in combination with CRH) during inferior petrosal sinus sampling may, on occasion, yield a false-positive diagnosis of Cushing's disease [46]. Some studies have found that the ACTH response to desmopressin during inferior petrosal sinus sampling had a sensitivity of 95 to 99 percent for the diagnosis of Cushing's disease and was equivalent to CRH [47,48]. Similar to CRH [49], its use to accurately lateralize the corticotroph tumor is of limited value [48]. Like with CRH [50-52], the measurement of prolactin as an index of the adequacy of inferior petrosal sinus sampling venous sampling is effective with desmopressin [53].
Cushing's disease versus pseudo-Cushing's syndrome — The desmopressin test may be useful to distinguish patients with Cushing's disease from those with pseudo-Cushing's syndrome [22]. Pseudo-Cushing's syndrome is best defined as physiologic hypercortisolism and can occur in several disorders other than Cushing's syndrome [1]. Examples include pregnancy, obesity, psychological or physical stress, depression, and chronic alcoholism.
Using a criterion for response of an ACTH increase of at least 4 pmol/L [54] or 6 pmol/L [30], patients with pseudo-Cushing's syndrome are identified by a smaller increase [16,30,31,54,55]. However, the false-positive and false-negative rates are approximately 10 percent. Furthermore, 13 to 60 percent of healthy subjects respond to desmopressin (although less frequently than Cushing's disease patients). A subsequent study suggested that use of an absolute increase in ACTH of 37 pg/mL (8.1 pmol/L) has a better sensitivity (88 percent) and specificity (96 percent) [18], but this criterion has not been tested widely. Thus, caution must be used as desmopressin alone is not sufficiently specific to establish a diagnosis of Cushing's syndrome [13,14,16,26]. (See "Causes and pathophysiology of Cushing's syndrome", section on 'Pseudo-Cushing's syndrome'.)
In one head-to-head comparison, desmopressin testing had better specificity (90 percent) but less sensitivity (82 percent) [54] or perhaps better [56] than the dexamethasone suppressed-ovine CRH test (63 percent specificity; 100 percent sensitivity) for distinguishing Cushing's disease from pseudo-Cushing's syndrome. Another study suggested that the combination of dexamethasone (given in the evening) and desmopressin (8 mcg, IV), may improve performance in differentiating Cushing's disease and pseudo-Cushing's syndrome, but only nine subjects with pseudo-Cushing's syndrome were studied [20]. (See "Establishing the diagnosis of Cushing's syndrome", section on 'CRH after dexamethasone test'.)
Evaluating for remission of Cushing's disease — Postoperative desmopressin testing may be useful in individuals who had a strong response preoperatively. In a study of 14 patients in remission of their Cushing's disease by transsphenoidal microadenomectomy, none responded to CRH or desmopressin immediately after surgery, but five patients who were not cured did respond to CRH, desmopressin, or both [57]. Responsiveness to CRH returned over a period of several months as normal hypothalamic-pituitary-adrenal function was restored, but the response to desmopressin did not return. A useful approach has been suggested in which preoperative desmopressin be performed to inform the use of desmopressin to monitor patients long term for recurrence [57].
Some studies suggest that in patients who have achieved initial remission after pituitary surgery, those who have a cortisol response to follow-up desmopressin testing (>193 nmol/L [7 mcg/dL] in one report [58] or >14 percent in another [59]) are more likely to have a recurrence [58-60]. In one report, there was no concordance between the clinical response to surgery and the postoperative response to desmopressin [29]. Some studies have demonstrated that some patients who lacked a response to desmopressin after successful adenomectomy did subsequently respond, even years before frank hypercortisolism reappeared [61].
A combined dexamethasone-desmopressin test (CDDT) may also be a predictor of recurrence after pituitary surgery. Dexamethasone is added to decrease the nonspecific response of normal corticotrophs to desmopressin. In one report of 38 patients following successful pituitary surgery for Cushing's disease, 1 mg of dexamethasone was administered overnight, and 10 mcg desmopressin was injected intravenously on the following morning. An increase of serum plasma cortisol and ACTH of more than 50 percent was an early predictor of recurrence (100 percent sensitivity, 89 percent specificity) [62]. Rather than use percent changes, another study found that an increase of cortisol of 7.4 micrograms/dL (204 nmol/L) in response to desmopressin within six months of surgery was a useful cutoff to predict continued remission versus subsequent recurrence. While late-night salivary cortisol may best discriminate recurrence [63], desmopressin testing may be useful when salivary cortisol results are inconsistent or not available [64].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing's syndrome".)
SUMMARY
●Arginine-vasopressin (AVP) is synthesized in the magnocellular neurons of the supraoptic and paraventricular nuclei, which project to the neurohypophysis; it is also co-secreted with corticotropin-releasing hormone (CRH) from single parvocellular neurons in the paraventricular nuclei, which project their axons to the median eminence and portal system. AVP has three distinct receptors, which mediate a number of physiologic effects, including its antidiuretic effect and regulation of corticotropin (ACTH). (See 'Vasopressin physiology' above.)
Desmopressin stimulation tests are currently used to:
●Distinguish between the causes of ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH syndrome). (See 'Clinical uses' above and 'Identifying the cause' above.)
●The desmopressin test is used most commonly in countries where CRH is not available. (See 'Clinical uses' above.)
●Distinguish between Cushing's disease and pseudo-Cushing's syndrome. (See 'Cushing's disease versus pseudo-Cushing's syndrome' above.)
●Stimulate ACTH secretion from corticotroph tumors during petrosal sinus sampling. Most often, desmopressin is used when CRH is unavailable. Further studies may clarify whether the combined CRH and desmopressin tests are sufficiently superior to justify their increased cost. (See 'During petrosal sinus sampling' above.)
●Combined low-dose, overnight dexamethasone followed by desmopressin test on the following morning appears promising as an early predictor of recurrence of Cushing's disease following corticotroph tumor resection; long-term assessment of larger number of patients will be necessary to determine the usefulness of this test. (See 'Evaluating for remission of Cushing's disease' above.)
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
