Endocrinology Basic and Clinical Principles - part 6 pps

Chapter 14 / Posterior Pituitary Hormones 213 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].) 214 Part IV / Hypothalamic–Pituitary 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 mag- nocellular 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 path- ways (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.) Chapter 14 / Posterior Pituitary Hormones 215 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-neuro- hypophysial 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 func- tionally relevant changes in membrane potential. In addition, magnocellular neurons also operate as intrin- sic Na + detectors. The transient receptor potential chan- nel (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 dehy- dration, 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 dehydra- tion procedure with the normal values and then correlating the plasma AVP values with the urine osmo- lality measurements obtained simultaneously (Fig. 6). AVP release can also be assessed indirectly by mea- suring plasma and urine osmolalities at regular inter- vals 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.) 216 Part IV / Hypothalamic–Pituitary 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 cen- tral diabetes insipidus, they respond normally to non- osmolar AVP release signals such as hypotension, eme- sis, 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 secre- tion 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 inter- action 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 V 2 (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 (V 2 receptors) on the basolateral membrane of the collecting duct cells (Fig. 7). The human V 2 receptor 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 V 2 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 molecu- lar 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 repre- sent 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 prin- cipal 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 admin- istration 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 hypoth- esis 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 cyto- plasmic 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 api- cal membrane of the kidney collecting tubule has been designated AQP2and 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 Chapter 14 / Posterior Pituitary Hormones 217 and three introns. It is predicted to code for a poly- peptide of 271 amino acids that is organized into two repeats oriented at 180° to each other and has six mem- brane-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, col- lecting duct epithelia exhibit very low permeabilities to sodium urea and water. These specialized permeability properties permit the excretion of large volumes of hy- potonic 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 E 2 (PGE 2 s) and by the luminal calcium concentration. High levels of E- prostanoid (EP 3 ) receptors are expressed in the kidney. However, mice lacking EP 3 receptors for PGE 2 were 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 cal- cium 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 V 2 receptor (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. 218 Part IV / Hypothalamic–Pituitary 218 Fig. 8. Schematic representation of V 2 receptor and identification of 183 putative disease-causing AVPR2 mutations. 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 cy toplasmic domains are defined according to Mouillac et al. (1995). Chapter 14 / Posterior Pituitary Hormones 219 219 Fig. 9. (A) Schematic representation of AQP2 protein and identification of 24 missense or nonsense putative disease-causing AQP2 mutations. Seven frameshift and one splice- site mutations are not represented. A monomer is represented with six transmembrane helices. The location of the PKA phosphoryl ation site (P a ) 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 i ndicate the location of the mutations. 220 Part IV / Hypothalamic–Pituitary 3. THE BRATTLEBORO RAT WITH AUTOSOMAL RECESSIVE NEUROGENIC DIABETES INSIPIDUS The classic animal model for studying diabetes insipi- dus 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 V 2 antidiuretic effect since the administration of a selec- tive nonpeptide V 2 antagonist (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 neuro- genic 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. COMMON FORMS 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 perma- nent form of the disease. Similar results are obtained by sectioning the hypophyseal hypothalamic tract above the median eminence. Sections below the median emi- nence, however, produce only transient diabetes insipi- dus. 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 administra- tion. 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 iso- lated 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, progres- sive 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 defi- ciency 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. R ARE 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 neurohy- pophyseal 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 Chapter 14 / Posterior Pituitary Hormones 221 autosomal dominant or autosomal recessive neurogenic diabetes insipidus have been described. The mechan- ism(s) by which a mutant allele causes neurogenic dia- betes insipidus could involve the induction of magno- cellular 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 addi- tion to the cytotoxicity caused by mutant AVP precur- sors, 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 degrada- tion of the affected polypeptide and not to the accumu- lation 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 neph- rogenic. 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 syn- drome 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. T HE SYNDROME OF HYPERNATREMIA AND HYPODIPSIA 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 — a Primary malignancy: craniopharyngioma, dysgerminoma, meningioma, adenoma, glioma, astrocytoma. b Secondary: metastatic from lung or breast, lymphoma, leukemia, dysplastic pancytopenia. c Trauma could be severe or mild. d Data from Czernichow et al. (1985), Greger et al. (1986), Moses et al. (1985), and Maghnie et al. (2000). 222 Part IV / Hypothalamic–Pituitary which is not owing to any apparent extracellular vol- ume loss; absence or attenuation of thirst; and a normal renal response to AVP. In almost all the patients stud- ied 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 “reset- ting” 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, bear- ing 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 dis- ease 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 V 2 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 muta- tions 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 inser- tions (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 iden- tified in every domain, but on a per-nucleotide basis, about twice as many mutations occur in transmembrane domains compared with the extracellular or intracellu- lar 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 fami- lies. The occurrence of the same mutation on different haplotypes was considered evidence for recurrent muta- tion. 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; how- ever, 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. [...]... —Peroxidase —Iodotyrosine deiodinase • Adrenal and testes —Cholesterol side-chain cleavage —3β-Hydroxysteroid dehydrogenase —17α-Hydroxylase • Adrenal —11β-Hydroxylase —21α-Hydroxylase • Testes —17,20-Desmolase —17-Ketosteroid reductase • Pancreas and Liver —Glucokinase gene • Multiple tissues —Aromatase —5α-Reductase —PC1, PC2 Other • KAL protein deficiency • AQP-2 water channel Disorder Growth retardation... hypothalamic-hyppogonadism have been described, and include the Prader-Willi syndrome, comprising early onset hyperphagia, pathologic obesity and glucose intolerance, infantile central hypotonia, and mild to moderate mental retardation, and the LaurenceMoon (L-M) and Bardet Biedl (B-B) syndromes, now regarded as distinct entities Both these autosomal recessive traits combine retinitis pigmentosa and hypogonadism... 2 5-( OH)vitamin D-1αa-hydroxylase enzyme that converts 25(OH)-vitamin D into 1,2 5-( OH)2-vitamin D, causing a hypervitaminosis D syndrome A similar mechanism of hypercalcemia is found in patients with granulomatous Table 15 Etiologies of Hypercalcemia Hyperparathyroidism Malignancy associated • PTH-related protein production • Cytokine production • Prostaglandin secretion • Dysregulation of 2 5-( OH)-Vitamin... (1981) 6. 4 Recommendations Table 5 provides recommendations for obtaining a differential diagnosis of diabetes insipidus 6. 5 Carrier Detection and Postnatal Diagnosis As developed earlier in this chapter, the identification, characterization, and mutational analysis of three different genes—prepro-AVP-NPII, AVPR2, and the vasopressin-sensitive water channel gene (AQP2)— provide the basis for the understanding... involving the testes, and it results in hyalinization and fibrosis of the gonad at the time of puberty, hypogonadism, eunuchoidal skeletal proportions, and gynecomastia The role of DAX-1 mutations in adrenal insufficiency was discussed earlier; because DAX-1 is also expressed in the testis (and weakly in the ovary), hypothalamus, and pituitary, hypogonadotropic hypogonadism can be part of the clinical picture... pancreatic carcinoid) • Macronodular adrenal hyperplasia (long-standing ACTH stimulation causing autonomous adrenal adenoma) • • • • Cortisol-secreting adrenal adenoma or carcinoma Primary pigmented nodular adrenal hyperplasia and Carney Complex McCune-Albright syndrome Macronodular adrenal and hyperplasia and aberrant receptor expression (ACTH-R, GIP-R) • Iatrogenic owing to exogenous glucocorticoids Table... Recognition of partial defects in antidiuretic hormone secretion Ann Intern Med 1970;73:721–729 Moses AM, Blumenthal SA, Streeten DHP Acid-base and electrolyte disorders associated with endocrine disease: pituitary and thyroid In: Arieff AI, de Fronzo RA, eds Fluid, Electrolyte and Acid-Base Disorders New York, NY: Churchill Livingstone, 1985;851–892 Mouillac B, Chini B, Balestre MN, Elands J, Trumpp-Kallmeyer... levels are elevated andstimulate adrenal androgen production 3.3 Gonadal Steroid Hormones 3.3.1 PRECOCIOUS PUBERTY Precocious puberty is the appearance of secondary sexual characteristics prior to age 9 in boys and 8 in girls Thus, development of axillary and pubic hair and rapid bone growth in both sexes, penile (and most often testicular) enlargement in males, and breast development and menarche in females... progressive loss of vasopressin-producing neurons J Clin Invest 2003;112: 169 7–17 06 Thibonnier M, Coles P, Thibonnier A, Shoham M The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists Annu Rev Pharmacol Toxicol 2001;41:175–202 Chapter 15 / Endocrine Disease 233 15 Endocrine Disease Value For Understanding Hormonal Actions Anthony P Heaney, MD, PhD and Glenn D Braunstein, MD... thirst-ADH-renal axis Thirst and ADH, both stimu- Chapter 14 / Posterior Pituitary Hormones lated by increased osmolality, have been termed a double-negative feedback system Thus, even when the ADH limb of this double-negative regulatory feedback system is lost, the thirst mechanism still preserves the plasma sodium and osmolality within the normal range but at the expense of pronounced polydipsia and . 180° to each other and has six mem- brane-spanning domains, both terminal ends located intracellularly, and conserved Asn-Pro-Ala boxes (Fig. 9). AQP2 is detectable in urine, and changes in urinary. for recurrent muta- tion. In addition, the most frequent mutations—D85N, V88M, R113W, R137H, S 167 L, R181C, and R202C— occurred at potential mutational hot spots (a C-to-T or G-to-A nucleotide substitution. identifica- tion, characterization, and mutational analysis of three different genes—prepro-AVP-NPII, AVPR2, and the vasopressin-sensitive water channel gene (AQP2)— provide the basis for the understanding