14 Posterior Pituitary Hormones

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Chapter 14 / Posterior Pituitary Hormones 211

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From: Endocrinology: Basic and Clinical Principles, Second Edition (S. Melmed and P. M. Conn, eds.) © Humana Press Inc., Totowa, NJ

14 Posterior Pituitary Hormones

Daniel G. Bichet, MD

C^ONTENTS

STRUCTURE OF NEUROHYPOPHYSIS: ANATOMY OF VASOPRESSIN-PRODUCING CELLS

ARGININE VASOPRESSIN

THE BRATTLEBORO RAT WITH AUTOSOMAL RECESSIVE NEUROGENIC DIABETES INSIPIDUS

QUANTITATING RENAL WATER EXCRETION

CLINICAL CHARACTERISTICS OF DIABETES INSIPIDUS DISORDERS

DIFFERENTIAL DIAGNOSIS OF P^OLYURIC S^TATES

MAGNETIC RESONANCE IMAGING IN PATIENTS WITH DIABETES INSIPIDUS

TREATMENT OF POLYURIC DISORDERS

SYNDROME OF INAPPROPRIATE SECRETION OF THE ANTIDIURETIC HORMONE

S^IGNS, S^YMPTOMS,^AND TREATMENT OF HYPONATREMIA

and paraventricular nuclei, which house the pericarya of the magnocellular neurons; (2) the axonal processes of the magnocellular neurons that form the supraoptical hypophyseal tract; and, (3) the neurosecretory material of these neurons, which is carried on to the posterior pituitary gland (Fig. 1).

2. ARGININE VASOPRESSIN 2.1. Synthesis

Nonapeptides of the vasopressin family are the key regulators of water homeostasis in amphibia, reptiles, birds, and mammals. Because these peptides reduce urinary output, they are also referred to as antidiuretic hormones. OT and AVP (Fig. 2) are synthesized in separate populations of magnocellular neurons (cell body diameter of 20–40 μm) of the supraoptic and paraventricular nuclei. OT and vasopressin magnocellular neurons are found intermingled in the magnocellular nuclei.

OT is most recognized for its key role in parturition and milk letdown in mammals. The axonal projections of AVP- and OT-producing neurons from supraoptic and

1. STRUCTURE OF NEUROHYPOPHYSIS:

ANATOMY OF VASOPRESSIN- PRODUCING CELLS

The hypothalamus (Fig. 1) embodies a group of nuclei that form the floor and ventrolateral walls of the trian- gular-shaped third ventricle. A thin membrane called the lamina terminalis forms the anterior wall of this compartment and contains osmoreceptor cells in a structure known as the organum vasculosum. The subfornical organ (SFO) also contains osmoreceptors. The organum vasculosum of the lamina terminalis (OVLT), the SFO, and the pituitary gland lack a blood-brain barrier. The supraoptic nucleus lies just dorsal to the optic chiasm and approx 2 mm from the third ventricle. The paraventricular nucleus lies closer to the thalamus in the suprachiasmatic portion of the hypothalamus, but it borders on the third ventricular space. These well- defined nuclei contain the majority of the large neuroen- docrine cell bodies, known as the magnocellular or neurosecretory cells, that manufacture arginine vasopressin (AVP) and oxytocin (OT). The neurohypophysis consists of (1) a set of hypothalamic nuclei, the supraoptic

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Fig. 1. Schematic representation of osmoregulatory pathway of hypothalamus (sagittal section of midline of ventral brain around third ventricle in mice). Neurons (lightly shaded circles) in the lamina terminalis—consisting of the OVLT, median preoptic nucleus (MnPO), and SFO—that are responsive to plasma hypertonicity send efferent axonal projections (gray lines) to magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei. The processes (black lines) of these magnocellular neurons form the hypothalamo-neurohypophysial pathway that courses in the median eminence to reach the posterior pituitary, where neurosecretion of vasopressin and OT occurs. (Modified with permission from Wilson et al., 2002.)

Fig. 2. Contrasting structures of AVP and OT. The peptides differ only by two amino acids (F3 I3 and R8 L8 in AVP and OT, respectively). The conformation of AVP was obtained from Mouillac et al. (1995), and the conformation of OT was obtained from the Protein Data Bank (PDB Id 1XY1).

paraventricular nuclei reflect the dual function of AVP and OT as hormones and as neuropeptides, in that they project their axons to several brain areas and to the neurohypophysis. Another pathway from parvocellular neurons (cell body diameter of 10–15 μm) to the hypophysial portal system transports high concentrations of AVP to the anterior pituitary gland. AVP produced by this pathway and the corticotropin-releasing hormone (CRH) are two major hypothalamic secretagogues regulating the secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary.

More than half of parvocellular neurons coexpress both CRH and prepro-AVP-NPII. In addition, while passing through the median eminence and the hypophysial stalk, magnocellular axons can also release AVP into the long portal system. Furthermore, a number of neuroanatomic studies have shown the existence of short portal vessels that allow communication between the posterior and anterior pituitary. Thus, in addition to parvocellular vasopressin, magnocellular vasopressin is able to influence ACTH secretion.

AVP and its corresponding carrier protein, neurophysin II, are synthesized as a composite precursor by the magnocellular and parvocellular neurons described previously. In contrast to conventional neurotransmit- ters (e.g., acetylcholine, excitatory and inhibitory amino acids, monoamines), which are synthesized in nerve terminals and can be packaged locally in recycled small vesicular membranes, the biosynthesis and secretion of neuropeptides such as OT and vasopressin in the hypothalamo-neurohypophysial system requires con- tinual de novo transcription and translation of peptide precursor proteins (Fig. 3). The precursor is packaged into neurosecretory granules and transported axonally in the stalk of the posterior pituitary. En route to the neurohypophysis, the precursor is processed into the active hormone. Prepro-vasopressin has 164 amino acids and is encoded by the 2.5-kb prepro-AVP-NPII gene located in chromosome region 20p13. The pre- pro-AVP-NPII gene and the prepro-OT-NPI gene are located within the same chromosomal locus, at a very short distance from each other (3–11 kb) in head-to- head orientation. Data from transgenic mouse studies indicate that the intergenic region between the OT and VP genes contains the critical enhancer sites for magnocellular neuron cell-specific expression. Exon 1 of the prepro-AVP-NPII gene encodes the signal peptide, AVP, and the NH₂-terminal region of NPII. Exon 2 encodes the central region of NPII, and exon 3 encodes the COOH-terminal region of NPII and the glycopeptide. Pro-vasopressin is generated by the removal of the signal peptide from prepro-vasopressin and the addition of a carbohydrate chain to the glycopeptide. Additional

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Fig. 3. Peptidergic neuron. Cellular and molecular properties of a peptidergic neuron (neurosecretory cell) are shown. The structure of the neurosecretory cell is depicted schematically with notations of the various cell biologic processes that occur in each topographic domain. Gene expression, protein biosynthesis, and packaging of the protein into large dense-core vesicles (LDCVs) occurs in the cell body, where the nucleus, rough ER (RER), and Golgi apparatus are located. Enzymatic processing of the precursor proteins into the biologically active peptides occurs primarily in the LDCVS (see inset), often during the process of anterograde axonal transport of the LDCVS to the nerve terminals on microtubule tracks in the axon. Upon reaching the nerve terminal, the LDCVS are usually stored in preparation for secretion. Conduction of a nerve impulse (action potential) down the axon and its arrival in the nerve terminal cause an influx of calcium ion through calcium channels. The increased calcium ion concentration causes a cascade of molecular events that leads to neurosecretion (exocytosis). Recovery of the excess LDCV membrane after exocytosis is performed by endocy- tosis, but this membrane is not recycled locally and, instead, is retrogradely transported to the cell body for reuse or degradation in lysosomes. ATP = adenosine triphosphate; ADP = adenosine 5´-diphosphate; GTP = guanosine 5´- triphosphate; TGN = trans-Golgi network; SSV = small secretory vesicles; PC1 or PC2 = prohormone convertase 1 or 2, respectively; CP-H = carboxypeptidase H;

PAM = peptiylglycine -amidating monooxygenase. (Reproduced with permission from Burbach et al. [2001].)

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posttranslation processing occurs within neurosecretory vesicles during transport of the precursor protein to axon terminals in the posterior pituitary, yielding AVP, NPII, and glycopeptide (Fig. 4). The AVP-NPII complex forms tetramers that can self-associate to form higher oligomers. Neurophysins should be seen as chaperone- like molecules serving intracellular transport in magnocellular cells.

In the posterior pituitary, AVP is stored in vesicles.

Exocytotic release is stimulated by minute increases in serum osmolality (hypernatremia, osmotic regulation) and by more pronounced decreases in extracellular fluid (hypovolemia, nonosmotic regulation). OT and neuro-

physin I are released from the posterior pituitary by the suckling response in lactating females.

2.2. Osmotic and Nonosmotic Stimulation

The regulation of antidiuretic hormone (ADH) release from the posterior pituitary is dependent primarily on two mechanisms involving the osmotic and nonosmotic pathways (Fig. 5). Vasopressin release can be regulated by changes in either osmolality or cerebrospinal fluid Na⁺ concentration.

Although magnocellular neurons are themselves osmosensitives, they require input from the lamina terminalis to respond fully to osmotic challenges. Neu- Fig. 4. Structure of the human vasopressin (AVP) gene and prohormone.

Fig. 5. Osmotic and nonosmotic stimulation of AVP. (A) The relationship between plasma AVP (P_AVP) and plasma sodium (P_Na) in 19 normal subjects is described by the area with vertical lines, which includes the 99% confidence limits of the regression line P_Na/ P_AVP. The osmotic threshold for AVP release is about 280–285 mmol/kg or 136 meq of sodium/L. AVP secretion should be abolished when plasma sodium is lower than 135 meq/L (Bichet et al., 1986). (B) Increase in plasma AVP during hypotension (vertical lines).

Note that a large diminution in blood pressure in healthy humans induces large increments in AVP. (Reproduced with permission from Vokes and Robertson, 1985.)

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rons in the lamina terminalis are also osmosensitive and because the SFO and the OVLT lie outside the blood- brain barrier, they can integrate this information with endocrine signals borne by circulating hormones, such as angiotensin II (Ang-II), relaxin, and atrial natriuretic peptide (ANP). While circulating Ang-II and relaxin excite both OT and vasopressin magnocellular neurons, ANP inhibits vasopressin neurons. In addition to an angiotensinergic path from the SFO, the OVLT and the median preoptic nucleus provide direct glutaminergic and GABAergic projections to the hypothalamo-neurohypophysial system. Nitric oxide may also modulate neurohormone release.

The cellular basis for osmoreceptor potentials has been characterized using patch-clamp recordings and morphometric analysis in magnocellular cells isolated from the supraoptic nucleus of the adult rat. In these cells, stretch-inactivating cationic channels transduce osmotically evoked changes in cell volume into functionally relevant changes in membrane potential. In addition, magnocellular neurons also operate as intrin- sic Na⁺detectors. The transient receptor potential channel (TRPV4) is an osmotically activated channel expressed in the circumventricular organs, the OVLT, and the SFO.

Vasopressin release can also be caused by the nonosmotic stimulation of AVP. Large decrements in blood volume or blood pressure (>10%) stimulate ADH release (Fig. 5). A fall in arterial blood pressure pro- duces a secretion of vasopressin owing to an inhibition of baroreceptors in the aortic arch and activation of chemoreceptors in the carotid body. Afferent from these receptors terminates in the dorsal medulla oblongata of the brain stem, including the nucleus of the tractus solitarus.

The osmotic stimulation of AVP release by dehydration, hypertonic saline infusion, or both is regularly used to determine the vasopressin secretory capacity of the posterior pituitary. This secretory capacity can be assessed directly by comparing the plasma AVP con- centrations measured sequentially during the dehydration procedure with the normal values and then correlating the plasma AVP values with the urine osmolality measurements obtained simultaneously (Fig. 6).

AVP release can also be assessed indirectly by mea- suring plasma and urine osmolalities at regular intervals during the dehydration test. The maximal urine osmolality obtained during dehydration is compared with the maximal urine osmolality obtained after the administration of vasopressin (Pitressin, 5 U subcuta- Fig. 6. (A) Relationship between plasma AVP and plasma osmolality during infusion of hypertonic saline solution. Patients with primary polydipsia and NDI have values within the normal range (open area) in contrast to patients with neurogenic diabetes insipidus, who show subnormal plasma ADH responses (stippled area). (B) Relationship between urine osmolality and plasma ADH during dehydration and water loading. Patients with neurogenic diabetes insipidus and primary polydipsia have values within the normal range (open area) in contrast to patients with NDI, who have hypotonic urine despite high plasma ADH (stippled area).

(Reproduced with permission from Zerbe and Robertson, 1984.)

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neously in adults, 1 U subcutaneously in children) or 1- desamino[8-D-arginine]vasopressin (desmopressin [dDAVP], 1–4 μg intravenously over 5–10 min).

The nonosmotic stimulation of AVP release can be used to assess the vasopressin secretory capacity of the posterior pituitary in a rare group of patients with the essential hypernatremia and hypodipsia syndrome.

Although some of these patients may have partial central diabetes insipidus, they respond normally to nonosmolar AVP release signals such as hypotension, emesis, and hypoglycemia. In all other cases of suspected central diabetes insipidus, these nonosmotic stimulation tests will not provide additional clinical information.

2.3. Clinically Important Hormonal Influences on Secretion of Vasopressin

Angiotensin is a well-known dipsogen and has been shown to cause drinking in all the species tested. Ang- II receptors have been described in the SFO and OVLT.

However, knockout models for angiotensinogen or for angiotensin-1A (AT1A) receptor did not alter thirst or water balance. Disruption of the AT2 receptor only induced mild abnormalities of thirst postdehydration.

Earlier reports suggested that the iv administration of atrial peptides inhibits the release of vasopressin, but this was not confirmed by later studies. Vasopressin secretion is under the influence of a glucocorticoid-negative feedback system, and the vasopressin responses to a variety of stimuli (hemorrhage, hypoxia, hypertonic saline) in healthy humans and animals appear to be attenuated or eliminated by pretreatment with gluco- corticoids. Finally, nausea and emesis are potent stimuli of AVP release in humans and seem to involve dopaminergic neurotransmission.

2.4. Cellular Actions of Vasopressin

The neurohypophyseal hormone AVP has multiple actions, including the inhibition of diuresis, contraction of smooth muscle, aggregation of platelets, stimulation of liver glycogenolysis, modulation of ACTH release from the pituitary, and central regulation of somatic functions (thermoregulation, blood pressure). These multiple actions of AVP could be explained by the interaction of AVP with at least three types of G protein–

coupled receptors (GPCRs); the V_1a(vascular hepatic) and V_1b(anterior pituitary) receptors act through phos- phatidylinositol hydrolysis to mobilize calcium, and the V₂ (kidney) receptor is coupled to adenylate cyclase.

The first step in the action of AVP on water excretion is its binding to AVP type 2 receptors (V₂receptors) on the basolateral membrane of the collecting duct cells (Fig. 7). The human V₂receptor gene, AVPR2, is located in chromosome region Xq28 and has three exons and two

small introns. The sequence of the cDNA predicts a polypeptide of 371 amino acids with a structure typical of guanine nucleotide (G) protein–coupled receptors with seven transmembrane, four extracellular, and four cyto-plasmic domains (Fig. 8). Activation of the V₂ receptor on renal collecting tubules stimulates adenylate cyclase via the stimulatory G protein (G_s) and promotes the cyclic adenosine monophosphate (cAMP)–mediated incorporation of water channels (aquaporins) into the luminal surface of these cells. This process is the molecular basis of the vasopressin-induced increase in the osmotic water permeability of the apical membrane of the collecting tubule. Aquaporin-1 (AQP1, also known as CHIP, a channel-forming integral membrane protein of 28 kDa) was the first protein shown to function as a molecular water channel and is constitutively expressed in mammalian red cells, renal proximal tubules, thin descending limbs, and other water-permeable epithelia.

At the subcellular level, AQP1 is localized in both apical and basolateral plasma membranes, which may represent entrance and exit routes for transepithelial water transport. The 2003 Nobel Prize in Chemistry was awarded to Peter Agre and Roderick MacKinnon, who solved two complementary problems presented by the cell membrane: (1) How does a cell let one type of ion through the lipid membrane to the exclusion of other ions? and (2) How does it permeate water without ions?

AQP2 is the vasopressin-regulated water channel in renal collecting ducts. It is exclusively present in principal cells of inner medullary collecting duct cells and is diffusely distributed in the cytoplasm in the euhydrated condition, whereas apical staining of AQP2 is intensified in the dehydrated condition or after administration of dDAVP, a synthetic structural analog of AVP. Short-term AQP2 regulation by AVP involves the movement of AQP2 from intracellular vesicles to the plasma membrane, a confirmation of the shuttle hypothesis of AVP action that was proposed two decades ago.

In the long-term regulation, which requires a sustained elevation of circulating AVP levels for 24 h or more, AVP increases the abundance of water channels. This is thought to be a consequence of increased transcription of the AQP2 gene. The activation of PKA leads to phos- phorylation of AQP2 on serine residue 256 in the cytoplasmic carboxyl terminus. This phosphorylation step is essential for the regulated movement of AQP2-con- taining vesicles to the plasma membrane on elevation of intracellular cAMP concentration.

The gene that codes for the water channel of the apical membrane of the kidney collecting tubule has been designated AQP2 and was cloned by homology to the rat aquaporin of collecting duct. The human AQP2 gene is located in chromosome region 12q13 and has four exons

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and three introns. It is predicted to code for a polypeptide of 271 amino acids that is organized into two repeats oriented at 180° to each other and has six membrane-spanning domains, both terminal ends located intracellularly, and conserved Asn-Pro-Ala boxes (Fig. 9). AQP2 is detectable in urine, and changes in urinary excretion of this protein can be used as an index of the action of vasopressin on the kidney.

AVP also increases the water reabsorptive capacity of the kidney by regulating the urea transporter UT1 that is present in the inner medullary collecting duct, pre- dominantly in its terminal part. AVP also increases the permeability of principal collecting duct cells to sodium.

In summary, in the absence of AVP stimulation, collecting duct epithelia exhibit very low permeabilities to sodium urea and water. These specialized permeability properties permit the excretion of large volumes of hypotonic urine formed during intervals of water diuresis.

By contrast, AVP stimulation of the principal cells of the collecting ducts leads to selective increases in the permeability of the apical membrane to water (P_f), urea (P_urea), and Na (P_Na).

These actions of vasopressin in the distal nephron are possibly modulated by prostaglandins E₂(PGE₂s) and by the luminal calcium concentration. High levels of E- prostanoid (EP₃) receptors are expressed in the kidney.

However, mice lacking EP₃receptors for PGE₂were found to have quasi-normal regulation of urine volume and osmolality in response to various physiologic stimuli. An apical calcium/polycation receptor protein expressed in the terminal portion of the inner medullary collecting duct of the rat has been shown to reduce AVP- elicited osmotic water permeability when luminal calcium concentration rises. This possible link between calcium and water metabolism may play a role in the pathogenesis of renal stone formation.

Fig. 7. Schematic representation of effect of AVP to increase water permeability in the principal cells of the collecting duct. AVP is bound to the V₂receptor (a GPCR) on the basolateral membrane. The basic process of GPCR signaling consists of three steps: a hepta-helical receptor detects a ligand (in this case, AVP) in the extracellular milieu, a G protein dissociates into a-subunits bound to guanosine 5´-triphosphate (GTP) and GL-subunits after interaction with the ligand-bound receptor, and an effector (in this case, adenylyl cyclase) interacts with dissociated G protein subunits to generate small-molecule second messengers. AVP activates adenylyl cyclase, increasing the intracellular concentration of cAMP. The topology of adenylyl cyclase is characterized by 2 tandem repeats of six hydrophobic transmembrane domains separated by a large cytoplasmic loop and terminates in a large intracellular tail.

Generation of cAMP follows receptor-linked activation of the heteromeric G protein (G_s) and interaction of the free G_as-chain with the adenylyl cyclase catalyst. Protein kinase (PKA) is the target of the generated cAMP. Cytoplasmic vesicles carrying the water channel proteins (represented as homotetrameric complexes) are fused to the luminal membrane in response to AVP, thereby increasing the water permeability of this membrane. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. The mechanisms underlying docking and fusion of AQP2-bearing vesicles are not known. The detection of the small GTP-binding protein Rab3a, synaptobrevin 2, and syntaxin 4 in principal cells suggests that these proteins are involved in AQP2 trafficking (Valenti et al., 1998). When AVP is not available, water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. AQP3 and AQP4 water channels are expressed on the basolateral membrane.

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Fig. 8. Schematic representation of V2receptor and identification of 183 putative disease-causing AVPR2mutations. Predicted amino acids are given as the one-letter code. A solid symbol indicates the location (or the closest codon) of a mutation; a number indicates more than one mutation in the same codon. The names of the mutations were assigned according to recommended nomenclature (Antonarakis S, and the Nomenclature Working Group, 1998). The extracellular, transmembrane, and cytoplasmic domains are defined according to Mouillac et al. (1995).

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Fig. 9. (A)Schematic representation of AQP2 protein and identification of 24 missense or nonsense putative disease-causing AQP2mutations. Seven frameshift and one splice- site mutations are not represented. A monomer is represented with six transmembrane helices. The location of the PKA phosphorylation site (Pa) is indicated. The extracellular (E), transmembrane (TM), and cytoplasmic (C) domains are defined according to Deen et al. (1994). As in Fig. 8, solid symbols indicate the location of the mutations.

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3. THE BRATTLEBORO RAT WITH AUTOSOMAL RECESSIVE NEUROGENIC DIABETES INSIPIDUS

The classic animal model for studying diabetes insipidus has been the Brattleboro rat with autosomal recessive neurogenic diabetes insipidus. di/di rats are homozy- gous for a 1-bp deletion (G) in the second exon that results in a frameshift mutation in the coding sequence of the carrier neurophysin II (NPII). Polyuric symptoms are also observed in heterozygous di/n rats. Homozy- gous Brattleboro rats may still demonstrate some V₂ antidiuretic effect since the administration of a selective nonpeptide V₂antagonist (SR121463A, 10 mg/kg intraperitoneally) induced a further increase in urine flow rate (200 to 354 ± 42 mL/24 h) and a decline in urinary osmolality (170 to 92 ± 8 mmol/kg). OT, which is present at enhanced plasma concentrations in Brattleboro rats, may be responsible for the antidiuretic activity observed. OT is not stimulated by increased plasma osmolality in humans. The Brattleboro rat model is therefore not strictly comparable with the rarely observed human cases of autosomal recessive neurogenic diabetes insipidus.

4. QUANTITATING RENAL WATER EXCRETION

Diabetes insipidus is characterized by the excretion of abnormally large volumes of hypoosmotic urine (<250 mmol/kg). This definition excludes osmotic diuresis, which occurs when excess solute is being excreted, as with glucose in the polyuria of diabetes mellitus. Other agents that produce osmotic diuresis are mannitol, urea, glycerol, contrast media, and loop diuretics. Osmotic diuresis should be considered when solute excretion exceeds 60 mmol/h.

5. CLINICAL CHARACTERISTICS OF DIABETES INSIPIDUS DISORDERS

5.1. Central Diabetes Insipidus

5.1.1. C^OMMON F^ORMS

Failure to synthesize or secrete vasopressin normally limits maximal urinary concentration and, depending on the severity of the disease, causes varying degrees of polyuria and polydipsia. Experimental destruction of the vasopressin-synthesizing areas of the hypothalamus (supraoptic and paraventricular nuclei) causes a permanent form of the disease. Similar results are obtained by sectioning the hypophyseal hypothalamic tract above the median eminence. Sections below the median eminence, however, produce only transient diabetes insipidus. Lesions to the hypothalamic-pituitary tract are

frequently associated with a three-stage response both in experimental animals and in humans:

1. An initial diuretic phase lasting from a few hours to 5 to 6 d.

2. A period of antidiuresis unresponsive to fluid administration. This antidiuresis is probably owing to vasopressin release from injured axons and may last from a few hours to several days. Since urinary dilution is impaired during this phase, continued administration of water can cause severe hyponatremia.

3. A final period of diabetes insipidus. The extent of the injury determines the completeness of the diabetes insipidus, and, as already discussed, the site of the lesion determines whether the disease will or will not be permanent.

Twenty-five percent of patients studied after transsphenoidal surgery developed spontaneous isolated hyponatremia, 20% developed diabetes insipidus, and 46% remained normonatremic. Normonatremia, hyponatremia, and diabetes insipidus were associated with increasing degrees of surgical manipulation of the posterior lobe and pituitary stalk during surgery.

Table 1 provides the etiologies of central diabetes insipidus in adults and in children are listed in. Rare causes of central diabetes insipidus include leukemia, thrombotic thrombocytopenic purpura, pituitary apo- plexy, sarcoidosis, Wegener granulomatosis, progressive spastic cerebellar ataxia and neurosarcoidosis.

Deficits in anterior pituitary hormones were docu- mented in 61% of patients a median of 0.6 yr (range: 01 to 18.0) after the onset of diabetes insipidus. The most frequent abnormality was growth hormone deficiency (59%), followed by hypothyroidism (28%), hypogo- nadism (24%) and adrenal insufficiency (22%). Sev- enty-five percent of the patients with Langerhans-cell histiocytosis had an anterior pituitary hormone deficiency that was first detected a median of 3.5 yr after the onset of diabetes insipidus. None of the patients with central diabetes insipidus secondary to prepro-AVP- NPII mutations developed anterior pituitary hormone deficiencies

5.1.2. RARE FORMS: AUTOSOMAL DOMINANT CENTRAL

DIABETES INSIPIDUS AND THE DIDMOAD SYNDROME

Neurogenic diabetes insipidus (OMIM 125700) is a now well-characterized entity, secondary to mutations in the prepro-AVP-NPII (OMIM 192340). This disorder is also referred to as central, cranial, pituitary, or neurohypophyseal diabetes insipidus. Patients with autosomal dominant neurogenic diabetes insipidus retain some lim- ited capacity to secrete AVP during severe dehydration, and the polyuropolydipsic symptoms usually appear after the first year of life, when an infant’s demand for water is more likely to be understood by adults. Thirty- four prepro-AVP-NPII mutations segregating with

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autosomal dominant or autosomal recessive neurogenic diabetes insipidus have been described. The mechanism(s) by which a mutant allele causes neurogenic diabetes insipidus could involve the induction of magnocellular cell death as a result of the accumulation of AVP precursors within the endoplasmic reticulum (ER). This hypothesis could account for the delayed onset and autosomal mode of inheritance of the disease. In addition to the cytotoxicity caused by mutant AVP precursors, the interaction between the wild-type and the mutant precursors suggests that a dominant-negative mechanism may also contribute to the pathogenesis of autosomal dominant diabetes insipidus. The absence of symptoms in infancy in autosomal dominant central diabetes insipidus is in sharp contrast with nephrogenic diabetes insipidus (NDI) secondary to mutations in AVPR2 or in AQP2 (vide infra) in which the polyuro- polydipsic symptoms are present during the first week of life. Of interest, errors in protein folding represent the underlying basis for a large number of inherited dis- eases and are also pathogenic mechanisms for AVPR2 and AQP2 mutants responsible for hereditary NDI (vide infra). Why are prepro-AVP-NPII misfolded mutants are cytotoxic to AVP-producing neurons is an unre- solved issue. The NDI AVPR2 missense mutations are likely to impair folding and to lead to the rapid degradation of the affected polypeptide and not to the accumulation of toxic aggregates since the other important functions of the principal cells of the collecting ducts (where AVPR2 is expressed) are entirely normal. Three families with autosomal recessive neurogenic diabetes insipidus have been identified in which the patients were homozygous or compound heterozygotes for

prepro-AVP-NPII mutations. As a consequence, early hereditary diabetes insipidus can be neurogenic or nephrogenic.

The acronym DIDMOAD describes the following clinical features of a syndrome: diabetes insipidus, dia- betes mellitus, optic atrophy, sensorineural deafness.

An unusual incidence of psychiatric symptoms has also been described in subjects with this syndrome. These included paranoid delusions, auditory or visual halluci- nations, psychotic behavior, violent behavior, organic brain syndrome typically in the late or preterminal stages of their illness, progressive dementia, and severe learn- ing disabilities or mental retardation or both. The syndrome is an autosomal recessive trait, the diabetes insipidus is usually partial and of gradual onset, and the polyuria can be wrongly attributed to poor glycemic control. Furthermore, a severe hyperosmolar state can occur if untreated diabetes mellitus is associated with an unrecognized pituitary deficiency. The dilatation of the urinary tract observed in the DIDMOAD syndrome may be secondary to chronic high urine flow rates and, per- haps, to some degenerative aspects of the innervation of the urinary tract. Wolfram syndrome (OMIM 222300) is secondary to mutations in the WFS1 gene (chromo- some region 4p16), which codes for a transmembrane protein expressed in various tissues including brain and pancreas.

5.1.3. THE SYNDROME

OF HYPERNATREMIA AND H^YPODIPSIA

Some patients with the hypernatremia and hypodipsia syndrome may have partial central diabetes insipidus.

These patients also have persistent hypernatremia, Table 1

Etiology of Hypothalamic Diabetes Insipidus in Children and Adults^d

Children and

Children (%) young adults (%) Adults (%)

Primary brain tumor^a 49.5 22 30

• Before surgery 33.5 — 13

• After surgery 16 — 17

Idiopathic (isolated or familial) 29 58 25

Histiocytosis 16 12 —

Metastatic cancer^b — — 8

Trauma^c 2.2 2.0 17

Postinfectious disease 2.2 6.0 —

aPrimary malignancy: craniopharyngioma, dysgerminoma, meningioma, adenoma, glioma, astrocytoma.

bSecondary: metastatic from lung or breast, lymphoma, leukemia, dysplastic pancytopenia.

cTrauma could be severe or mild.

dData from Czernichow et al. (1985), Greger et al. (1986), Moses et al. (1985), and Maghnie et al. (2000).

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which is not owing to any apparent extracellular volume loss; absence or attenuation of thirst; and a normal renal response to AVP. In almost all the patients studied to date, hypodipsia has been associated with cere- bral lesions in the vicinity of the hypothalamus. It has been proposed that in these patients there is a “resetting” of the osmoreceptor, because their urine tends to become concentrated or diluted at inappropriately high levels of plasma osmolality. However, by using the regression analysis of plasma AVP concentration vs plasma osmolality, it has been possible to show that in some of these patients the tendency to concentrate and dilute urine at inappropriately high levels of plasma osmolality is owing solely to a marked reduction in sensitivity or a gain in the osmoregulatory mechanism.

This finding is compatible with the diagnosis of partial central diabetes insipidus. In other patients, however, plasma AVP concentrations fluctuate randomly, bearing no apparent relationship to changes in plasma osmolality. Such patients frequently display large swings in serum sodium concentrations and frequently exhibit hypodipsia. It appears that most patients with essential hypernatremia fit one of these two patterns.

Both of these groups of patients consistently respond normally to nonosmolar AVP release signals, such as hypotension, emesis, or hypoglycemia or all three.

These observations suggest that the osmoreceptor may be anatomically as well as functionally separate from the nonosmotic efferent pathways and neurosecretory neurons for vasopressin.

5.2. Nephrogenic Diabetes Insipidus

5.2.1. X-LINKED NDI AND MUTATIONS IN AVPR2 GENE

X-linked NDI (OMIM 304800) is generally a rare disease in which the urine of affected male patients does not concentrate after the administration of AVP. Because it is a rare, recessive X-linked disease, females are unlikely to be affected, but heterozygous females exhibit variable degrees of polyuria and polydipsia because of skewed X chromosome inactivation. X-linked NDI is secondary to AVPR2 mutations that result in the loss of function or a dysregulation of the V₂ receptor.

5.2.1.1. Rareness and Diversity of AVPR2 Muta- tions . We estimated the incidence of X-linked NDI in the general population from patients born in the prov- ince of Quebec during the 10-yr period, from 1988–

1997, to be approx 8.8 per million (SD = 4.4 per million) male live births.

To date, 183 putative disease-causing AVPR2 mutations have been identified in 284 NDI families (Fig. 8) (additional information is available at the NDI Mutation Database at Website: http://www.medincine.mcgill.ca/

nephros/). Of these, we identified 82 different muta-

tions in 117 NDI families referred to our laboratory.

Half of the mutations are missense mutations. Frame- shift mutations owing to nucleotide deletions or insertions (25%), nonsense mutations (10%), large deletions (10%), in-frame deletions or insertions (4%), splice-site mutations, and one complex mutation account for the remainder of the mutations. Mutations have been identified in every domain, but on a per-nucleotide basis, about twice as many mutations occur in transmembrane domains compared with the extracellular or intracellular domains. We previously identified private mutations, recurrent mutations, and mechanisms of mutagenesis.

The 10 recurrent mutations (D85N, V88M, R113W, Y128S, R137H, S167L, R181C, R202C, A294P, and S315R) were found in 35 ancestrally independent families. The occurrence of the same mutation on different haplotypes was considered evidence for recurrent mutation. In addition, the most frequent mutations—D85N, V88M, R113W, R137H, S167L, R181C, and R202C—

occurred at potential mutational hot spots (a C-to-T or G-to-A nucleotide substitution occurred at a CpG di- nucleotide).

5.2.1.2. Benefits of Genetic Testing. The natural his- tory of untreated X-linked NDI includes hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy. Mental retardation, a consequence of repeated episodes of dehydration, was prevalent in the Crawford and Bode study, in which only 9 of 82 patients (11%) had normal intelligence; however, data from the Nijmegen group suggest that this complication was overestimated in their group of NDI patients. Early recognition and treatment of X-linked NDI with an abundant intake of water allows a normal life-span with normal physical and mental development.

Familial occurrence of males and mental retardation in untreated patients are two characteristics suggestive of X-linked NDI. Skewed X-inactivation is the most likely explanation for clinical symptoms of NDI in female carriers.

Identification of the molecular defect underlying X- linked NDI is of immediate clinical significance because early diagnosis and treatment of affected infants can avert the physical and mental retardation resulting from repeated episodes of dehydration. Affected males are immediately treated with abundant water intake, a low- sodium diet, and hydrochlorothiazide. They do not experience severe episodes of dehydration and their physical and mental development remains normal, however, their urinary output is only decreased by 30%

and a normal growth curve is still difficult to reach during the first 2 to 3 yr of their life despite the afore- mentioned treatments and intensive attention. Water should be offered every 2 h day and night, and tem- perature, appetite, and growth should be monitored.

(13)

Admission to hospital may be necessary for continuous gastric feeding. The voluminous amounts of water kept in patients’ stomachs will exacerbate physiologic gastrointestinal reflux as an infant and a toddler, and many affected boys frequently vomit and have a strong positive “Tuttle test” (esophageal pH testing). These young patients often improve with the absorption of an H-2 blocker and with metoclopramide (which could induce extrapyramidal symptoms) or with domperi- done, which seems to be better tolerated and effica- cious.

5.2.1.3. Most Mutant V2 Receptors Are Not Trans- ported to the Cell Membrane and Are Retained in the Intracellular Compartments. Classification of the defects of mutant V₂receptors is based on that of the low-density lipoprotein receptor, for which mutations have been grouped according to the function and subcellular localization of the mutant protein whose cDNA has been transiently transfected in a heterologous expression system. Following this classification, type 1 mutant receptors reach the cell surface but display impaired ligand binding and are, consequently, unable to induce normal cAMP production. Type 2 mutant receptors have defective intracellular transport. Type 3 mutant receptors are ineffectively transcribed. This subgroup seems to be rare because Northern blot analysis of transfected cells reveals that most V₂receptor mutations produce the same quantity and molecular size of receptor mRNA.

Of the 12 mutants that we tested, only three were detected on the cell surface. Similar results were obtained by other groups.

Other genetic disorders are also characterized by protein misfolding. AQP-2 mutations responsible for autosomal recessive NDI are also characterized by misrouting of the misfolded mutant proteins and trap- ping in the ER. The ΔF508 mutation in cystic fibrosis is also characterized by misfolding and retention in the ER of the mutated cystic fibrosis transmembrane con- ductance regulator that is associated with calnexin and Hsp70. The C282Y mutant HFE protein, which is responsible for 83% of hemochromatosis in the Cau- casian population, is retained in the ER and middle Golgi compartment, fails to undergo late Golgi processing, and is subject to accelerated degradation.

Mutants encoding other renal membrane proteins that are responsible for Gitelman syndrome and cystinuria are also retained in the ER.

5.2.1.4. Nonpeptide Vasopressin Antagonists Act as Pharmacological Chaperones to Functionally Rescue Misfolded Mutant V2 Receptors Responsible for X- Linked NDI . We recently proposed a model in which small nonpeptide V₂receptor antagonists permeate into

the cell and bind to incompletely folded mutant receptors. This would then stabilize a conformation of the receptor that allows its release from the ER quality control apparatus. The stabilized receptor would then be targeted to the cell surface, where on dissociation from the antagonist it could bind vasopressin and promote signal transduction. Given that these antagonists are specific to the V₂receptor and that they perform a chaperone-like function, we termed these compounds phar- macologic chaperones.

5.2.2. A^UTOSOMAL RECESSIVE AND D^OMINANT NDI OWING TO MUTATIONS INAQP2 GENE

To date, 26 putative disease-causing AQP2 mutations have been identified in 25 NDI families (Fig. 9). By type of mutation, there are 65% missense, 23% frameshift due to small nucleotide deletions or insertions, 8% nonsense, and 4% splice-site mutations (additional information is available at the NDI Mutation Database at Website: http://www.medicine.mcgill.ca/nephros/).

Reminiscent of expression studies done with AVPR2 proteins, misrouting of AQP2 mutant proteins has been shown to be the major cause underlying autosomal recessive NDI.

In contrast to the AQP2 mutations in autosomal reces- sive NDI, which are located throughout the gene, the dominant mutations are predicted to affect the carboxyl terminus of AQP2. The dominant action of AQP2 muta- tions can be explained by the formation of heterotetra- mers of mutant and wild-type AQP2 that are impaired in their routing after oligomerization.

5.2.3. A^CQUIRED N^EPHROGENIC D^IABETES I^NSIPIDUS The acquired form of NDI is much more common than the congenital form of the disease, but it is rarely severe. The ability to elaborate a hypertonic urine is usually preserved despite the impairment of the maximal concentrating ability of the nephrons. Polyuria and polydipsia are therefore moderate (3–4 L/d). Table 2 provides the more common causes of acquired NDI.

Administration of lithium has become the most common cause of NDI. Nineteen percent of these patients had polyuria, as defined by a 24-h urine output exceed- ing 3 L. Renal biopsy revealed a chronic tubulointer- stitial nephropathy in all patients with biopsy-proven lithium toxicity. The mechanism whereby lithium causes polyuria has been extensively studied. Lithium has been shown to inhibit adenylate cyclase in a number of cell types, including renal epithelia. Lithium also caused a marked downregulation of AQP2 and AQP3, only partially reversed by cessation of therapy, dehydration, or dDAVP treatment, consistent with clinical observations of slow recovery from lithium- induced urinary concentrating defects. Downregula-

(14)

tion of AQP2 has also been shown to be associated with the development of severe polyuria due to other causes of acquired NDI: hypokalemia, release of bilat- eral ureteral obstruction, and hypercalciuria. Thus, AQP2 expression is severely downregulated in both congenital and acquired NDI.

5.3. Primary Polydipsia

Primary polydipsia is a state of hypotonic polyuria secondary to excessive fluid intake. Primary polydipsia was extensively studied by Barlow and de Wardener in 1959; however, the understanding of the pathophysiol- ogy of this disease has made little progress over the past 30 yr. Barlow and de Wardener described seven women and two men who were compulsive water drinkers; their ages ranged from 48 to 59 yr except for one patient, 24.

Eight of these patients had histories of previous psycho- logic disorders, which ranged from delusions, depres- sion, and agitation to frank hysterical behavior. The other patient appeared psychologically normal. The consumption of water fluctuated irregularly from hour to hour or from day to day; in some patients, there were remissions and relapses lasting several months or longer.

In eight of the patients, the mean plasma osmolality was significantly lower than normal. Vasopressin tannate in oil made most of these patients feel ill; in one, it caused overhydration. In four patients, the fluid intake returned to normal after electroconvulsive therapy or a period of continuous narcosis; the improvement in three was tran-

sient, but in the fourth it lasted 2 yr. Polyuric female subjects might be heterozygous for de novo or previ- ously unrecognized AVPR2 mutations or autosomal dominant AQP2 mutations and may be classified as compulsive water drinkers. Therefore, the diagnosis of compulsive water drinking must be made with care and may represent ignorance of yet undescribed pathophysi- ologic mechanisms. Robertson has described, under the term dipsogenic diabetes insipidus, a selective defect in the osmoregulation of thirst. Three studied patients had under basal conditions of ad libitum water intake, thirst, polydipsia, polyuria, and high-normal plasma osmolality. They had a normal secretion of AVP, but osmotic threshold for thirst was abnormally low. These cases of dipsogenic diabetes insipidus might represent up to 10%

of all patients with diabetes insipidus.

5.4. Diabetes Insipidus and Pregnancy

5.4.1. PREGNANCY IN A PATIENT

KNOWN TO HAVE DIABETES INSIPIDUS

An isolated deficiency of vasopressin without a con- comitant loss of hormones in the anterior pituitary does not result in altered fertility, and with the exception of polyuria and polydipsia, gestation, delivery, and lacta- tion are uncomplicated. Treated patients may require increasing dosages of desmopressin. The increased thirst may be owing to a resetting of the thirst osmostat.

Increased polyuria also occurs during pregnancy in patients with partial NDI. These patients may be obliga- tory carriers of the NDI gene.

5.4.2. SYNDROMES OF DÎABETES I^NSIPIDUS T^HAT BÊGIN DÛRING GESTATION AND RÊMIT A^FTER DÊLIVERY

Barron et al. in 1984 described three pregnant women in whom transient diabetes insipidus developed late in gestation and subsequently remitted post- partum. In one of these patients, dilute urine was present in spite of high plasma concentrations of AVP.

Hyposthenuria in all three patients was resistant to administered aqueous vasopressin. Since excessive vasopressinase activity was not excluded as a cause of this disorder, Barron et al. labeled the disease-vasopressin diabetes insipidus resistant rather than NDI. It is suggested that pregnancy may be associated with several different forms of diabetes insipidus, including central, nephrogenic, and vasopressinase mediated.

6. DIFFERENTIAL DIAGNOSIS OF POLYURIC STATES

Plasma sodium and osmolality are maintained within normal limits (136–143 mmol/L for plasma sodium, 275–290 mmol/kg for plasma osmolality) by a thirst-ADH-renal axis. Thirst and ADH, both stimu- Table 2

Acquired Causes of NDI Chronic renal disease Drugs

• Polycystic disease • Alcohol

• Medullary cystic disease • Phenytoin

Pyelonephritis • Lithium

• Ureteral obstruction • Demeclocycline

• Far-advanced renal failure • Acetohexamide

failure • Tolazamide

Electrolyte disorders • Glyburide

• Hypokalemia • Propoxyphene

• Hypercalcemia • Amphotericin

Blood disease • Foscarnet

• Sickle cell disease • Methoxyflurane Dietary abnormalities • Norepinephrine

• Excessive water intake • Vinblastine

• Decreased sodium • Colchicine

chloride intake • Gentamicin

• Decreased protein intake • Methicillin

Miscellaneous • Isophosphamide

• Multiple myeloma • Angiographic dyes

• Amyloidosis • Osmotic diuretics

• Sjögren’s disease • Furosemide and

• Sarcoidosis ethacrynic acid