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. Corticotropin-releasing hormone (CRH) has been widely utilized for the differential diagnosis of Cushing syndrome. However, desmopressin has been increasingly utilized in countries where CRH is not available for the differential diagnosis of ACTH-dependent hypercortisolism. It is also considered the vasopressin analog of choice to use for the postoperative surveillance of patients with ACTH-dependent Cushing syndrome and for the diagnosis of pseudo-Cushing syndrome [1-4].
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 "Insulin-induced hypoglycemia test protocol" and "Diagnosis of adrenal insufficiency in adults".)
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 [5]. 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 [6].
Cortisol inhibits the secretion of both CRH and AVP from the paraventricular nuclei [7]. Cortisol deficiency decreases this inhibitory effect, leading to a persistent rise in vasopressin release, water retention, and hyponatremia [5,7,8]. The AVPR2 receptors on the cortical and medullary collecting kidney tubules mediate the antidiuretic response via the migration of aquaporin-2 water channels [9]. AVPR2 on vascular endothelium can modulate the release of factor VIII and von Willebrand factor [10]. Both AVPR1A and AVPR1B activate phospholipase C [6,11,12], while the AVPR2 is coupled to adenylyl cyclase [13,14].
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 [15]. In general, these have been abandoned in the differential diagnosis of ACTH-dependent hypercortisolism (due primarily to vasopressor actions and the availability of other tests). Desmopressin is the only vasopressin agonist that is currently used for this purpose. Other factors contributing to the increased use of desmopressin include the lack of commercially available ovine corticotropin-releasing hormone (CRH) for injection in many countries (including the United States and Canada) and the lower cost of desmopressin. Desmopressin has also been utilized more in countries where CRH is still available, as there is growing evidence that it may be equivalent or even superior to CRH [16]. Desmopressin stimulation tests have been used to:
●Distinguish between the causes of ACTH-dependent Cushing syndrome (Cushing disease and ectopic ACTH syndrome).
●Distinguish between Cushing syndrome and pseudo-Cushing syndrome (CRH after dexamethasone test) versus desmopressin tests. (See "Establishing the diagnosis of Cushing syndrome", section on 'CRH after dexamethasone test'.)
●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 [17].
●During the follow-up of patients with Cushing disease to evaluate for possible recurrence of disease after surgical removal of their corticotrope tumor. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Recurrence'.)
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 [18,19]. Shorter and longer versions of this test have been used [3,20-24]. 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 [3,23].
The recommended dose of desmopressin is 10 mcg IV [18,19], although lower doses (5 to 8 mcg) have been used successfully [18,22,25].
Interpretation — Desmopressin, a selective AVPR2 receptor agonist, does not stimulate ACTH and cortisol levels in most healthy individuals who do not harbor ACTH-secreting corticotroph tumors. However, as many as 10 percent of healthy subjects do respond [18,21,22], presumably because of low-level pituitary expression of AVPR2 [26].
There are no accepted criteria to define a positive response to the desmopressin test [3]. Proposed criteria include the following:
●A 33 percent increase in ACTH and an 18 percent increase in cortisol [27].
●An increase in basal-to-peak cortisol greater than 20 percent or ACTH greater than 50 percent [28].
●An ACTH peak >15.8 pmol/L or an absolute increase in ACTH >8.1 pmol/L [23].
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. Symptomatic hyponatremia might occur after desmopressin injection; although uncommon patients should be advised to restrict fluid intake for 12 hours following its administration.
ACTH-DEPENDENT CUSHING SYNDROME — The desmopressin test is used in the evaluation of corticotropin (ACTH)-dependent Cushing syndrome [1,2,29,30].
Identifying the cause — Desmopressin can be used for the differential diagnosis of Cushing syndrome. At low doses (1 ng/kg/min), desmopressin fails to potentiate the effect of corticotropin-releasing hormone (CRH) on ACTH release in most normal subjects [31]. At a higher dose (10 mcg intravenous [IV]), it causes an increase in plasma ACTH and serum cortisol concentrations in most patients with Cushing disease [18,20,32-34], suggesting that the test could be used to diagnose this condition.
In patients with Cushing 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 [18,20,33-36]. However, in some reports, 8 of 25 (32 percent) of patients with ectopic ACTH syndrome, mostly benign carcinoid tumors, also responded [18,20,22,28,33,34,37-39].
Desmopressin has a relatively low affinity for the AVPR1B receptor [12,40] that is found on normal pituitary corticotrophs, on most adenomatous corticotrophs, and on some ACTH-secreting bronchial carcinoid adenomas [41]. 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 [34] or by increased expression of the AVPR1B [38]. However, a study in patients with Cushing disease suggests that the ACTH response to desmopressin correlates better with AVPR2 expression levels than with AVPR1B [26]. 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 [42]. Responsiveness to desmopressin has been observed in a bronchial carcinoid tumor in vitro [39].
Combined with CRH — When desmopressin is given in combination with corticotropin-releasing hormone (CRH), virtually all patients with Cushing disease have an increase in plasma ACTH concentrations, using the criterion of a 35 percent rise after CRH with desmopressin [37,43]. Some clinicians use the combined test routinely, but it is more expensive.
Some patients with ectopic ACTH secretion also respond [37,43,44]. Since obese subjects without Cushing 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 syndrome [45].
During petrosal sinus sampling — Desmopressin has been used in place of CRH to perform petrosal sinus sampling in small series [3,17,44,46-48]. 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 perform a desmopressin test 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 [49].
In a retrospective analysis of combined CRH and desmopressin testing during petrosal sinus sampling in 47 patients with proven Cushing 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 disease and ectopic ACTH, respectively (diagnostic accuracy of 98.7 percent) [50]. However, desmopressin (alone or in combination with CRH) during inferior petrosal sinus sampling may, on occasion, yield a false-positive diagnosis of Cushing disease [51].
Some studies and meta-analyses 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 disease and was equivalent or even superior to CRH [16,52-54]. Similar to CRH [55], its use to accurately lateralize the corticotroph tumor is of limited value [53]. Like with CRH [56-58], the measurement of prolactin as an index of the adequacy of inferior petrosal sinus sampling venous sampling is effective with desmopressin [59].
It has been suggested that desmopressin testing and the high-dose dexamethasone suppression test performed on separate occasions can reduce the need for petrosal sinus sampling [60]. A noninvasive algorithm to avoid petrosal sinus sampling has been proposed involving peripheral desmopressin and CRH testing in conjunction with pituitary and extensive whole-body imaging; this approach has the potential to avoid 47 percent of the current indications of bilateral inferior petrosal sinus sampling [27].
Cushing disease versus pseudo-Cushing syndrome — The desmopressin test may be useful to distinguish patients with Cushing disease from those with pseudo-Cushing syndrome [2]. Pseudo-Cushing syndrome is best defined as physiologic or non-neoplastic hypercortisolism and can occur in several disorders other than Cushing 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 [61] or 6 pmol/L [36], patients with pseudo-Cushing syndrome are identified by a smaller increase [21,28,36,61,62]. 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 patients with Cushing disease). 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) [23], 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 syndrome [3,18,19,21,32]. (See "Causes and pathophysiology of Cushing syndrome", section on 'Pseudo-Cushing syndrome'.)
In one head-to-head comparison, desmopressin testing had better specificity (90 percent) but less sensitivity (82 percent) [61] or perhaps better [63] than the dexamethasone suppressed-ovine CRH test (63 percent specificity; 100 percent sensitivity) for distinguishing Cushing disease from pseudo-Cushing syndrome. Another study suggested that the combination of dexamethasone (given in the evening) and desmopressin (8 mcg, IV), may improve performance in differentiating Cushing disease and pseudo-Cushing syndrome, but only nine subjects with pseudo-Cushing syndrome were studied [25]. (See "Establishing the diagnosis of Cushing syndrome", section on 'CRH after dexamethasone test'.)
Evaluating for remission of Cushing 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 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 [64]. 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 [3,64].
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 [65] or >14 percent in another [66]) are more likely to have a recurrence [65-67]. In one report, there was no concordance between the clinical response to surgery and the postoperative response to desmopressin [35]. 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 [68].
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 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) [69]. 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 [70], desmopressin testing may be useful when salivary cortisol results are inconsistent or not available [71].
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 syndrome".)
SUMMARY
●Vasopressin physiology – 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 – The desmopressin test is used most commonly in countries where CRH is not currently available or too costly; desmopressin testing is now more widely utilized and shown to be equivalent or even superior to CRH. Desmopressin stimulation tests are used for several indications:
•Cushing disease versus ectopic ACTH – Distinguish between the causes of ACTH-dependent Cushing syndrome (Cushing disease and ectopic ACTH syndrome). (See 'Clinical uses' above and 'Identifying the cause' above.)
•Cushing disease versus pseudo-Cushing – Distinguish between Cushing disease and pseudo-Cushing syndrome. (See 'Cushing disease versus pseudo-Cushing syndrome' above.)
•Combined dexamethasone-desmopressin test – Combined low-dose, overnight dexamethasone followed by desmopressin test on the following morning appears promising as an early predictor of recurrence of Cushing 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 disease' above.)
ACKNOWLEDGMENT — 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.
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