Annales d’Endocrinologie 85 (2024) 294–299

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Review article

Diabetes insipidus: Vasopressin deficiency. . .

a r t i c l e i n f o a b s t r a c t

Keywords: Diabetes insipidus is a disorder characterized by hypo-osmotic polyuria secondary to abnormal syn-
Diabetes insipidus thesis, regulation, or renal action of antidiuretic hormone. Recently, an expert group, with the support
Polyuria of patient associations, proposed that diabetes insipidus be renamed to avoid confusion with diabetes
Posterior pituitary gland
mellitus. The most common form of diabetes insipidus is secondary to a dysfunction of the neurohy-
Oxytocin
pophysis (central diabetes insipidus) and would be therefore named ‘vasopressin deficiency’. The rarer
Vasopressin deficiency
form, which is linked to renal vasopressin resistance (nephrogenic diabetes insipidus), would then be
named ‘vasopressin resistance’. The etiology of diabetes insipidus is sometimes clear, in the case of a
neurohypophyseal cause (tumoral or infiltrative damage) or a renal origin, but in some cases diabetes
insipidus can be difficult to distinguish from primary polydipsia, which is characterized by consumption
of excessive quantities of water without any abnormality in regulation or action of antidiuretic hormone.
Apart from patients’ medical history, physical examination, and imaging of the hypothalamic-pituitary
region, functional tests such as water deprivation or stimulation of copeptin by hyperosmolarity (induced
by infusion of hypertonic saline) can be proposed in order to distinguish between these different etiolo-
gies. The treatment of diabetes insipidus depends on the underlying etiology, and in the case of a central
etiology, is based on the administration of desmopressin which improves patient symptoms but does not
always result in an optimal quality of life. The cause of this altered quality of life may be oxytocin defi-
ciency, oxytocin being also secreted from the neurohypophysis, though this has not been fully established.
The possibility of a new test using stimulation of oxytocin to identify alterations in oxytocin synthesis
is of interest and would allow confirmation of a deficiency in those patients presenting with diabetes
insipidus linked to neurohypophyseal dysfunction.
© 2024 Elsevier Masson SAS. All rights reserved.

1. Introduction insipidus is a rarer form of DI, linked to resistance to the renal action
of ADH. In both cases, there is a resultant fluid imbalance due to a
Diabetes insipidus (DI) is a disorder characterized by hypo- deficiency in free water reabsorption in the renal collecting ducts
osmotic polyuria greater than 50 ml/kg bodyweight, accompanied (Fig. 1).
by compensatory polydipsia that is often greater than 3L per day. Congenital DI is rare and caused by genetic abnormalities that
DI is secondary to abnormal synthesis, regulation, or renal action affect ADH synthesis (AVP, WFS1 and PCSK1 genes). Acquired cen-
of antidiuretic hormone, ADH (or arginine vasopressin, AVP) [1,2]. tral mechanisms underlying DI are linked to the destruction of the
The most common form of DI, central diabetes insipidus, results posterior pituitary, due to tumoral, infiltrative, traumatic or vascu-
from central dysfunction of the neurohypophysis and parvocellular lar causes. Hereditary nephrogenic DI is linked to mutations in the
and magnocellular hypothalamic neurons. Nephrogenic diabetes target receptors of ADH (AVPR2 and AQP2 gene), while the acquired
forms are often iatrogenic (e.g. lithium treatment) or linked to infil-
trative diseases.
∗ Corresponding author. Service d’endocrinologie et des maladies de la reproduc-
tion, centre de référence des maladies rares de l’hypophyse, AP–HP, hôpital Bicêtre,
78, rue du Général-Leclerc, 94270 Le Kremlin Bicêtre, France. 2. Changing the nomenclature
E-mail address: [email protected] (F. Chasseloup).
1
Service d’endocrinologie, diabète et nutrition, hôpital Haut Lévêque, centre hos- An expert group has recently proposed substituting the term
pitalier universitaire de Bordeaux, avenue Magellan, 33600 Pessac, France.
2
Service d’endocrinologie et des maladies de la reproduction, centre de référence
‘diabetes insipidus’ for a term that is more representative of the
des maladies rares de l’hypophyse, AP–HP, hôpital Bicêtre, 78, rue du Général- pathophysiology of the disease, with the aim of avoiding confu-
Leclerc, 94270 Le Kremlin Bicêtre, France. sion between diabetes mellitus and diabetes insipidus [3]. The

https://doi.org/10.1016/j.ando.2023.11.006
0003-4266/© 2024 Elsevier Masson SAS. All rights reserved.
F. Chasseloup et al. Annales d’Endocrinologie 85 (2024) 294–299

Fig. 1. Diagrammatic representation of ADH (vasopressin) synthesis in the posterior pituitary and its renal action on free water reabsorption. Central diabetes insipidus, or
vasopressin deficiency, is characterized by hypo-osmotic polyuria secondary to dysfunction in synthesis or regulation of antidiuretic hormone (ADH or arginine vasopressin,
AVP). Nephrogenic diabetes insipidus is secondary to renal resistance to the ADH receptor (AVPR2). In both cases, there is a resultant fluid imbalance linked to a defect in
reabsorption of free water from renal collecting tubules. Figure created with Biorender.com.

term ‘diabetes’ means to ‘pass across’ in Greek and dates from the when hypotonic polyuria is accompanied by an obvious involve-
first description of a polyuric-polydipsic syndrome by Demetrius ment of the posterior pituitary resulting from a tumor or infiltrative
of Apamea (1st or 2nd centuries BC) [3,4]. Dr William Cullen was pathology that is visible on imaging. In the absence of a visible
then the first to make a distinction between the different forms tumor or infiltrative pathology, lack of the posterior pituitary bright
of polyuria, and Dr Johann Peter Frank, in the 18th century, added spot on T1 image sequences of the posterior pituitary can direct the
the adjective ‘insipid’ to describe the hypo-osmotic character of diagnosis towards central diabetes insipidus and make a periph-
the urine, however, the common term ‘diabetes’ was retained [4]. eral cause or primary polydipsia unlikely. However, according to
A new nomenclature has been proposed with the aim of better one study, this hyperintensity, corresponding to storage of ADH
reflecting the pathophysiology of DI, using the term ‘vasopressin in neurons of the neurohypophysis, is absent in only 70% of MRI
deficiency’ to represent central diabetes insipidus and the term imaging results of patients presenting with central DI, and is also
‘vasopressin resistance’ to represent nephrogenic DI. Apart from absent in almost 40% of patients presenting with primary polydip-
being a better reflection of the underlying pathophysiology, the sia [8]. However, it should be noted that this study did not use a
use of the new term would avoid any confusion between dia- stringent MRI procedure (in particular with saturation of fatty tis-
betes insipidus and diabetes mellitus. In fact, several dramatic cases sue to accurately distinguish between posterior pituitary and fatty
of incorrect management of patients with DI during hospitaliza- tissue of the back of the sella turcica) to optimally analyse the neu-
tion, resulting in treatment delay or errors in treatment, have been rohypophysis. In fact, few dedicated radiological studies have been
reported, with these being attributed to confusion concerning the carried out to examine the presence or absence of this hyperin-
two different diseases by medical and paramedical personnel [5]. tensity and thus these numbers could be an under-estimate [8,9].
A recent online survey of patients allowed the size of this prob- Lastly, the reduced intensity and size of the signal seen physio-
lem to be better appreciated. It showed that a quarter of patients logically in patients older than 80 years could equally affect the
included in this survey had already experienced difficulties in interpretation of images [10].
accessing desmopressin and water during hospitalization, includ- Thus, with doubts regarding imaging, the diagnosis of DI and
ing an absence of intravenous compensation in patients who were elimination of differential diagnoses can be difficult. Though the
fasting being reported in 40% of cases [6]. Additionally, this survey diagnosis of nephrogenic DI has become more straightforward
appeared to confirm the necessity of a new nomenclature, since thanks to new diagnostic tools such as the copeptin assay (dis-
85% of patients were in favor of this change and preferred removal cussed below) [8], the distinction between primary polydipsia and
of the term ‘diabetes’ from the name. DI is not always clear [2].
Though interesting, this change in terminology is perhaps not In some cases, patients with DI can spontaneously display urine
sufficient to improve the management of this rare condition by hypo-osmolarity with increased basal sodium levels, higher than
physicians who may have little experience of the disease. 147 mmol/L, and plasma osmolality higher than 295 mOsm/kg. This
biochemical profile allows the diagnosis of primary polydipsia to
be excluded. In fact, primary polydipsia is more associated with low
3. Diagnostic tools
sodium levels, below 135 mmol/L and a plasma osmolality of less
than 280 mOsm/kg (Fig. 2) [11]. However, some patients fall into
A diagnosis of DI should be suspected where there is polydip-
none of these typical biochemical categories and thus justify the
sia associated with hypo-osmotic polyuria (osmolality below 300
use of stimulation tests.
mOsm/kg) [7]. Once identified, the etiology of the hypo-osmotic
The current ‘gold-standard’ is the response to indirect stimu-
polyuria should then be confirmed for an appropriate therapy to
lation of ADH by a water deprivation test. This test allows the
be proposed. Confirmation of a central origin is sometimes simple
measurement, indirectly, of ADH activity using its capacity to

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Fig. 2. Algorithm for etiologic diagnosis in the case of primary polydipsia. After confirmation of hypo-osmotic polyuria in the setting of a polyuric-polydipsic syndrome, the
use of plasma sodium and plasma osmolarity can direct the etiological diagnosis. If these values are normal, a stimulation test by water restriction followed by hypertonic
saline stimulation can be used to distinguish the different etiologies of DI. Figure adapted from [1,2], created with Biorender.com.

reduce renal excretion of free water and thus increase urine osmo- cases of complete central forms of DI. In this case, the diagnostic
larity in response to dehydration induced by restricted access to precision is close to 70%, with 86% sensitivity and 70% specificity
water over at least 8 hours, with plasma osmolality being mea- [7,8,13]. However, the diagnostic performance of the test appears
sured every 4 hours and urine osmolarity every 2 hours [12]. This lower for distinguishing partial forms of DI in primary polydipsia,
test must then be followed by administration of 2 ␮g desmopressin. dropping to 40%, with 54% sensitivity and 88% specificity [7,8,13].
A urine osmolarity of over 800 mOsm/kg during water depri- There are multiple causes for this poor diagnostic performance
vation is in favor of a diagnosis of primary polydipsia without including the test duration, and the need for medical supervision
abnormailty in the synthesis or action of ADH. Conversely, the per- during the test, aimed at combatting the extreme thirst that can
sistence of urine hypo-osmolarity, less than 300 mOsm/kg, shows distort the test results. Lastly, a lack of effect of desmopressin
a completely altered action of ADH. The profile of the response administration at the end of the test can be secondary to a down-
to administration of desmopressin allows the central form of DI regulation of renal ADH receptor (AVPR2) expression as a result of
(response of urine osmolarity greater than 50%) to be distinguished chronic polyuria [14]. A direct assay of vasopressin after stimula-
from the nephrogenic form of DI (response of urine osmolarity less tion by water deprivation could represent an interesting alternative
than 50%) (Fig. 2) [12]. [15], since vasopressin concentrations are, even before water
Though the first results on the use of this test were interesting restriction, very high in patients with nephrogenic DI (due to resis-
and the test is currently the ‘gold-standard’ for the diagnosis of tance to AVP), and are increased to a lesser degree by dehydration
DI [7,12], it is important to note that the test is more effective for in patients with primary polydipsia, while they are unchanged in

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patients with central DI [15–18]. However, the thresholds allowing of hyponatremia. In a survey on more than 1000 patients, 67%
these different etiologies to be distinguished require the sensitiv- of patients spontaneously omitted a dose of desmopressin and
ity of the vasopressin assay to be around 0.3 pmol/L, a sensitivity episodes of hyponatremia were reported in 17% of these patients,
which is only obtained with ‘artisanal’ radioimmunoassays that while in the 33% of patients who did not skip doses, 29% reported
are specifically prepared for this purpose, but not by the major- episodes of hyponatremia (OR = 0,44 [0,31,0,64]) [6].
ity of currently-available commercial immunoassays where the Despite appropriate replacement therapy, in a large survey, 64%
detection threshold is around 1 pmol/L. Lastly, the short half-life of of patients still reported an altered quality of life after the diag-
vasopressin and its pre-analytical instability make it difficult to use nosis of DI, and this was in spite of appropriate management and
in current practice. The diagnostic performance of this test (water independently of the presence of an anterior pituitary deficiency
deprivation with AVP assay) in current use is therefore limited, and [6]. Patients also reported increased anxiety, sleep disturbances
its diagnostic precision is not higher than 40% [13]. and mood problems. These problems represented conditions which
In view of the inherent limitations in these diagnostic tests, the were being monitored and treated in 11% of cases. Interestingly,
copeptin assay has been proposed as a new marker of vasopressin 52% of patients also reported problems with social interactions
secretion. Copeptin is a glycoprotein from the C-terminal part of and a reduced ability to experience joy/pleasure, which impacted
the AVP pro-hormone and is thus a stable reflection of endoge- on their physical and psychological well-being in around 40% of
nous vasopressin. A basal copeptin level of greater than 21.4 pmol/L cases. Apart from the effects on quality of life linked to having a
favors a diagnosis of nephrogenic DI [8]. The use of copeptin allows chronic disease, a somatic cause could be suggested since there
primary polydipsia to be distinguished from DI after hyperosmotic is a possible reduction in oxytocin secretion, oxytocin also being
stimulation. The copeptin assay provides better results after per- secreted from the posterior pituitary [23]. In addition to its effects
fusion with hypertonic solution than it does after fluid restriction on reproduction and metabolism [24,25], oxytocin is implicated in
[8]. Hyperosmotic stimulation is carried out by intravenous per- other processes, including some involving the central nervous sys-
fusion with a bolus of 250 ml of 3% hypertonic saline solution tem (CNS). The action of oxytocin in the CNS involves a number of
followed by continuous infusion at a rate of 0.15 ml/kg/min. A con- targets, notably the hippocampus and the amygdala (Fig. 3) [26].
centration of copeptin that stays below the threshold of 4.2 pmol/L, Oxytocin and oxytocin signaling are implicated in the regulation of
with a sodium level of greater than 150 mmol/L, gives a diagnostic social behaviors, such as attachment, social interactions, confidence
precision of 96.5% for diagnosing complete central DI (and 95.2% and anxiety, response to fear, and empathy [27,28].
for diagnosing partial central DI) (Fig. 2) [1,2,8]. However, use of The group of neurocognitive manifestations found in some
the copeptin assay, stimulated by intravenous hyperosmotic per- patients who have posterior pituitary dysfunction, could thus be
fusion, is complicated due to the necessity of reaching a sodium included with oxytocin deficiency associated with ADH deficiency,
level of greater than 150 mmol/L, putting the patient at risk of secondary to posterior pituitary dysfunction. Surgical treatment of
metabolic complications, and thus requiring close monitoring of craniopharyngioma is a good example. It can lead to metabolic and
plasma sodium levels, something that is difficult to do in current neurocognitive problems, which have led to oxytocin deficiency
practice. In view of these difficulties, other copeptin stimulation being suspected in this population. Assays of basal oxytocin lev-
tests have been proposed. Stimulation using arginine has been els have given contradictory results from one series of patients
proposed but with inferior results regarding diagnostic accuracy to another [29–32]. As for a number of hormone deficiencies,
compared to hypertonic infusion [19]. Finally, glucagon appear insufficiency can sometimes only be diagnosed after a stimula-
to be an interesting alternative, offering diagnostic efficacies of tion test, but studies examining the variation of oxytocin levels
greater than 90% but this method still need to be validated in after stimulation tests (physical exercise, macimorelin, arginine
prospective studies [20,21]. or hypertonic saline) have equally given disappointing results.
In conclusion, several tests can be proposed to exclude the diag- Even though some variations in oxytocin concentrations have been
nosis of primary polydipsia and retain the diagnosis of DI, which found to be statistically significant, overlap of the oxytocin lev-
will enable appropriate therapies to be proposed. However, the els between the various groups has limited the interpretation
combination of imaging of the hypothalamic-pituitary region and a and use of these tests in current practice [32–34]. It appears that
water deprivation test remains the first choice in current practice. patients with posterior pituitary dysfunction show altered recog-
The use of copeptin is a promising alternative for the most difficult nition of emotions compared with healthy controls and compared
cases. to patients with an isolated anterior pituitary deficiency [29]. The
administration of oxytocin, even though little-studied in this con-
text, can improve some performance on neurocognitive tests [35].
4. Management of central diabetes insipidus In order to confirm the involvement of oxytocin in these neu-
rocognitive manifestations and the existence of a real oxytocin
The management of central DI is based on replacement of ADH deficiency in these pathologies, a discriminating stimulation test is
with desmopressin. This analog has a longer half-life than endoge- needed.
nous vasopressin and acts directly on the renal AVPR2 receptor. A stimulation test using MDMA (2,4-MethyleneDioxy
It can be administered orally (sublingual), intranasally or subcu- MethAmphetamine), a psychoactive drug that is the principal
taneously, and results in restoration of free water reabsorption. ingredient in ‘ecstasy’, has been proposed. In fact, MDMA favors
The dose used varies between patients and should be adjusted to empathy, attachment, sociability and a sense of well-being. These
the symptoms. The most frequently-reported undesirable effect is neuropsychological manifestations are in some degree medi-
the appearance of hyponatremia due to over-dosage and excessive ated by oxytocin, and unlike other pyschoactive substances (e.g.
reabsorption of free water. In a retrospective analysis of biochem- amphetamines or LSD), administration of MDMA is accompanied
ical data in ambulatory patients over 10 years, carried out on 137 by a significant increase in plasma oxytocin concentrations [36,37].
patients with DI, severe hyponatremia was noted in 15% of patients, Thus, in a pilot study, stimulation by administration of 100 mg of
and less severe hyponatremia in 27% of patients [22]. The occur- MDMA led to an 82% increase in oxytocin concentrations in healthy
rence of hyponatremia can be avoided by voluntary omission of subjects, while showing no increase in subjects with neurohy-
desmopressin administration until polyuria occurs, allowing excess pophyseal dysfunction and central DI (n = 15 subjects/group) [38].
free water to be excreted. This strategy, which has not been prop- This absence of an increase in oxytocin was accompanied by an
erly evaluated by clinical studies, leads to a reduction in episodes attenuation of the positive effects classically observed in healthy

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Fig. 3. Different actions of oxytocin. Dendritic release of oxytocin has an effect in the central nervous system via local diffusion that can reach different regions in the brain.
In addition, parvocellular neurons project to various regions of the brain including the amygdala, hippocampus, striatum, suprachiasmatic nucleus, bed nucleus of the stria
terminalis and the cerebral trunk, where oxytocin can act as a neuromodulator or neurotransmitter. Figure adapted from [23,26], created with Biorender.com.

subjects after MDMA administration. These preliminary results The clinical management of central DI is straightforward thanks
appear to point to an oxytocin deficiency in patients with known to the use of desmopressin, but does require patient education to
neurohypophyseal dysfunction, and thus suggest an interest in use ensure their autonomy and also to avoid the appearance of compli-
of a replacement therapy. cations, particularly in the care setting. Lastly, the place of oxytocin
Treatment using oxytocin is generally via intravenous injection in this disease remains to be demonstrated but does offer interest-
in the setting of inducing labor in pregnancy and the treatment of ing future perspectives.
post-partum hemorrhage, while intranasal delivery has also been
used in other indications with satisfactory tolerance [23,39]. In Funding
patients operated for craniopharyngioma, administration of oxy-
tocin did not show strong effects, though studies were performed This article received institutional support from Ipsen Pharma,
on a small number of patients. However, administration of oxytocin the first author having participated in the MUST d’Endocrinologie
did result in an improvement in some sociocognitive characteristics meeting, 2023.
when it was used for other indications, such as Prader-Willi syn-
drome [35,39]. Currently, two studies are underway, in Switzerland
Author contributions
and the United States, which will examine the effects of oxytocin
substitution in patients presenting with vasopressin deficiency
All authors attest that they meet the current International Com-
(Clinical Trials NCT06036004 and NCT04789148).
mittee of Medical Journal Editors (ICMJE) criteria for Authorship.
Oxytocin deficiency in patients with DI is likely and thus certain
socio-cognitive consequences of the pathology could be integrated
Disclosure of interest
with this somatic component, though published data are thus far
insufficient to reach a firm conclusion. The prospect of a new
The authors declare that they have no competing interest.
oxytocin stimulation test is therefore interesting but needs to be
validated in a larger number of subjects and in further studies.
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