The neurohypophysis, or posterior pituitary, is formed by axons that originate in large cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. It produces two hormones: (1) arginine vasopressin (AVP), also known as antidiuretic hormone, and (2) oxytocin. AVP acts on the renal tubules to reduce water loss by concentrating the urine. Oxytocin stimulates postpartum milk letdown in response to suckling. A deficiency of AVP secretion or action causes diabetes insipidus (DI), a syndrome characterized by the production of large amounts of dilute urine. Excessive or inappropriate AVP production impairs urinary water excretion and predisposes to hyponatremia if water intake is not reduced in parallel with urine output.

SYNTHESIS AND SECRETION

AVP is a nonapeptide composed of a six-member disulfide ring and a tripeptide tail (Fig. 52-1). It is synthesized via a polypeptide precursor that includes AVP, neurophysin, and copeptin, all encoded by a single gene on chromosome 20. After preliminary processing and folding, the precursor is packaged in neurosecretory vesicles, where it is transported down the axon; further processed to AVP, neurophysin, and copeptin; and stored in neurosecretory vesicles until released by exocytosis into peripheral blood.

AVP secretion is regulated primarily by the “effective” osmotic pressure of body fluids. This control is mediated by specialized hypothalamic cells known as osmoreceptors, which are extremely sensitive to small changes in the plasma concentration of sodium and its anions but normally are insensitive to other solutes such as urea and glucose. The osmoreceptors appear to include inhibitory as well as stimulatory components that function in concert to form a threshold, or set point, control system. Below this threshold, plasma AVP is suppressed to levels that permit the development of a maximum water diuresis. Above it, plasma AVP rises steeply in direct proportion to plasma osmolarity, quickly reaching levels sufficient to effect a maximum antidiuresis. The absolute levels of plasma osmolarity/sodium at which minimally and maximally effective levels of plasma AVP occur, vary appreciably from person to person, apparently due to genetic influences on the set and sensitivity of the system. However, the average threshold, or set point, for AVP release corresponds to a plasma osmolarity or sodium of about 280 mosmol/L or 135 meq/L, respectively; levels only 2–4% higher normally result in maximum antidiuresis.

Although it is relatively stable in a healthy adult, the set point of the osmoregulatory system can be lowered by pregnancy, the menstrual cycle, estrogen, and relatively large, acute reductions in blood pressure or volume. Those reductions are mediated largely by neuronal afferents that originate in transmural pressure receptors of the heart and large arteries and project via the vagus and glossopharyngeal nerves to the brainstem, from which postsynaptic projections ascend to the hypothalamus. These pathways maintain a tonic inhibitory tone that decreases when blood volume or pressure falls by >10–20%. This baroregulatory system is probably of minor importance in the physiology of AVP secretion because the hemodynamic changes required to affect it usually do not occur during normal activities. However, the baroregulatory system undoubtedly plays an important role in AVP secretion in patients with disorders that produce large, acute disturbances of hemodynamic function. However, the baroregulatory system undoubtedly plays an important role in AVP secretion in patients with disorders that produce large, acute disturbances of hemodynamic function.

AVP secretion also can be stimulated by nausea, acute hypoglycemia, glucocorticoid deficiency, smoking, and, possibly, hyperangiotensinemia. The emetic stimuli are extremely potent since they typically elicit immediate, 50- to 100-fold increases in plasma AVP even when the nausea is transient and is not associated with vomiting or other symptoms. They appear to act via the emetic center in the medulla and can be blocked completely by treatment with antiemetics such as fluphenazine. There is no evidence that pain or other noxious stresses have any effect on AVP unless they elicit a vasovagal reaction with its associated nausea and hypotension.

ACTION

The most important, if not the only, physiologic action of AVP is to reduce water excretion by promoting concentration of urine. This antidiuretic effect is achieved by increasing the hydroosmotic permeability of cells that line the distal tubule and medullary collecting ducts of the kidney (Fig. 52-2). In the absence of AVP, these cells are impermeable to water and reabsorb little, if any, of the relatively large volume of dilute filtrate that enters from the proximal nephron. The lack of reabsorption results in the excretion of very large volumes (as much as 0.2 mL/kg per min) of maximally dilute urine (specific gravity and osmolarity ~1.000 and 50 mosmol/L, respectively), a condition known as water diuresis. In the presence of AVP, these cells become selectively permeable to water, allowing the water to diffuse back down the osmotic gradient created by the hypertonic renal medulla. As a result, the dilute fluid passing through the tubules is concentrated and the rate of urine flow decreases. The magnitude of this effect varies in direct proportion to the plasma AVP concentration and the rate of solute excretion. At maximum levels of AVP and normal rates of solute excretion, it approximates a urine flow rate as low as 0.35 mL/min and a urine osmolarity as high as 1200 mosmol/L. This effect is reduced by a solute diuresis such as glucosuria in diabetes mellitus. Antidiuresis is mediated via binding to G protein–coupled V₂ receptors on the serosal surface of the cell, activation of adenyl cyclase, and insertion into the luminal surface of water channels composed of a protein known as aquaporin 2 (AQP2). The V₂ receptors and aquaporin 2 are encoded by genes on chromosomes Xq28 and 12q13, respectively.

At high concentrations, AVP also causes contraction of smooth muscle in blood vessels in the skin and gastrointestinal tract, induces glycogenolysis in the liver, and potentiates adrenocorticotropic hormone (ACTH) release by corticotropin-releasing factor. These effects are mediated by V_1a or V_1b receptors that are coupled to phospholipase C. Their role, if any, in human physiology/pathophysiology is uncertain.

METABOLISM

AVP distributes rapidly into a space roughly equal to the extracellular fluid volume. It is cleared irreversibly with a half-life (t _1/2) of 10–30 min. Most AVP clearance is due to degradation in the liver and kidneys. During pregnancy, the metabolic clearance of AVP is increased three- to fourfold due to placental production of an N-terminal peptidase.

Because AVP cannot reduce water loss below a certain minimum level obligated by urinary solute load and evaporation from skin and lungs, a mechanism for ensuring adequate intake is essential for preventing dehydration. This vital function is performed by the thirst mechanism. Like AVP, thirst is regulated primarily by an osmostat that is situated in the anteromedial hypothalamus and is able to detect very small changes in the plasma concentration of sodium and its anions. The thirst osmostat appears to be “set” about 3% higher than the AVP osmostat. This arrangement ensures that thirst, polydipsia, and dilution of body fluids do not occur until plasma osmolarity/sodium starts to exceed the defensive capacity of the antidiuretic mechanism.

Oxytocin is also a nonapeptide that differs from AVP only at positions 3 and 8 (Fig. 52-1). However, it has relatively little antidiuretic effect and seems to act mainly on mammary ducts to facilitate milk letdown during nursing. It also may help initiate or facilitate labor by stimulating contraction of uterine smooth muscle, but it is not clear if this action is physiologic or necessary for normal delivery.

DIABETES INSIPIDUS

Clinical characteristics

A decrease of 75% or more in the secretion or action of AVP usually results in DI, a syndrome characterized by the production of abnormally large volumes of dilute urine. The 24-h urine volume exceeds 50 mL/kg body weight, and the osmolarity is less than 300 mosmol/L. The polyuria produces symptoms of urinary frequency, enuresis, and/or nocturia, which may disturb sleep and cause mild daytime fatigue or somnolence. It also results in a slight rise in plasma osmolarity that stimulates thirst and a commensurate increase in fluid intake (polydipsia). Overt clinical signs of dehydration are uncommon unless thirst and/or the compensatory increase of fluid intake are also impaired.

Etiology

A primary deficiency of AVP secretion usually results from agenesis or irreversible destruction of the neurohypophysis. It is referred to variously as neurohypophyseal DI, neurogenic DI, pituitary DI, cranial DI, or central DI. It can be caused by a variety of congenital, acquired, or genetic disorders, but in about one-half of all adult patients, it is idiopathic (Table 52-1). Pituitary DI caused by surgery in or around the neurohypophysis usually appears within 24 h. After a few days, it may transition to a 2- to 3-week period of inappropriate antidiuresis, after which the DI may or may not recur permanently. Five genetic forms of pituitary DI are now known. By far, the most common is transmitted in an autosomal dominant mode and is caused by diverse mutations in the coding region of one allele of the AVP–neurophysin II (or AVP-NPII) gene. All the mutations alter one or more amino acids known to be critical for correct processing and/or folding of the prohormone, thus interfering with its trafficking through the endoplasmic reticulum. The misfolded mutant precursor accumulates and interferes with production of AVP by the normal allele, eventually destroying the magnocellular neurons in which it is produced. The AVP deficiency and DI are usually not present at birth but develop gradually over a period of several months to years, progressing from partial to severe at different rates depending on the mutation. Once established, the deficiency of AVP is permanent, but for unknown reasons, the DI occasionally improves or remits spontaneously in late middle age. The parvocellular neurons that make AVP and the magnocellular neurons that make oxytocin appear to be unaffected. There are also rare autosomal recessive forms of pituitary DI. One is due to an inactivating mutation in the AVP portion of the gene; another is due to a large deletion involving the majority of the AVP gene and regulatory sequences in the intergenic region. A third form is caused by mutations of the WFS 1 gene responsible for Wolfram’s syndrome (DI, diabetes mellitus, optic atrophy, and neural deafness [DIDMOAD]). An X-linked recessive form linked to a region on Xq28 has also been described.

A primary deficiency of plasma AVP also can result from increased metabolism by an N-terminal aminopeptidase produced by the placenta. It is referred to as gestational DI because the signs and symptoms manifest during pregnancy and usually remit several weeks after delivery.

Secondary deficiencies of AVP secretion result from inhibition by excessive intake of fluids. They are referred to as primary polydipsia and can be divided into three subcategories. One of them, dipsogenic DI, is characterized by inappropriate thirst caused by a reduction in the set of the osmoregulatory mechanism. It sometimes occurs in association with multifocal diseases of the brain such as neurosarcoid, tuberculous meningitis, and multiple sclerosis but is often idiopathic. The second subtype, psychogenic polydipsia, is not associated with thirst, and the polydipsia seems to be a feature of psychosis or obsessive compulsive disorder. The third subtype, iatrogenic polydipsia, results from recommendations to increase fluid intake for its presumed health benefits.