The posterior lobe of the pituitary secretes antidiuretic hormone (ADH) and oxytocin. Both ADH and oxytocin are neuropeptides, synthesized in cell bodies of hypothalamic neurons and secreted from nerve terminals in the posterior pituitary.
Synthesis and Secretion of Antidiuretic Hormone and Oxytocin
Synthesis and Processing
ADH and oxytocin are homologous nonapeptides (containing nine amino acids) (Figs. 9-13 and 9-14) that are synthesized in the supraoptic and paraventricular nuclei of the hypothalamus. The ADH neurons have their cell bodies primarily in the supraoptic nuclei of the hypothalamus. The oxytocin neurons have their cell bodies primarily in paraventricular nuclei. While primarily dedicated to producing ADH or oxytocin, each nucleus also produces the “other” hormone. Similar genes located in close proximity on the chromosome direct synthesis of the preprohormones for ADH and oxytocin. The peptide precursor for ADH is prepropressophysin, which comprises a signal peptide, ADH, neurophysin II, and a glycoprotein. The precursor for oxytocin is prepro-oxyphysin, which comprises a signal peptide, oxytocin, and neurophysin I. In the Golgi apparatus, the signal peptides are removed from the preprohormones to form the prohormones, propressophysin and pro-oxyphysin, and the prohormones are packaged in secretory vesicles. The secretory vesicles, containing the prohormones, then travel down the axon of the neuron, through the hypothalamic-hypophysial tract, to the posterior pituitary. En route to the posterior pituitary, the neurophysins are cleaved from their respective prohormones within the secretory vesicles.
Figure 9–13 Synthesis, processing, and secretion of antidiuretic hormone (ADH) and oxytocin. NPI, Neurophysin I; NPII, neurophysin II.
Figure 9–14 Structures of antidiuretic hormone (ADH) and oxytocin. Homologous amino acid sequences are shown within the shaded boxes.
The secretory vesicles that arrive at the posterior pituitary contain either ADH, neurophysin II, and glycoprotein or oxytocin and neurophysin I. Secretion is initiated when an action potential is transmitted from the cell body in the hypothalamus, down the axon to the nerve terminal in the posterior pituitary. When the nerve terminal is depolarized by the action potential, Ca2+ enters the terminal, causing exocytosis of the secretory granules containing ADH or oxytocin and their neurophysins. The secreted hormones enter nearby fenestrated capillaries and are carried to the systemic circulation, which delivers the hormones to their target tissues.
ADH (or vasopressin) is the major hormone concerned with regulation of body fluid osmolarity. ADH is secreted by the posterior pituitary in response to an increase in serum osmolarity. ADH then acts on the principal cells of the late distal tubule and collecting duct to increase water reabsorption, thus decreasing body fluid osmolarity back toward normal. Osmoregulation and the actions of ADH on the kidney are discussed in Chapter 6.
Regulation of Antidiuretic Hormone Secretion
The factors that stimulate or inhibit the secretion of ADH by the posterior pituitary are summarized in Table 9-6.
Table 9–6 Factors Affecting Antidiuretic Hormone Secretion
Increased serum osmolarity
Decreased ECF volume
Decreased serum osmolarity
Atrial natriuretic peptide (ANP)
Increased plasma osmolarity is the most important physiologic stimulus for increasing ADH secretion (Fig. 9-15). For example, when a person is deprived of water, serum osmolarity increases. The increase is sensed by osmoreceptors in the anterior hypothalamus. Action potentials are initiated in cell bodies of the nearby ADH neurons and propagated down the axons, causing the secretion of ADH from nerve terminals in the posterior pituitary. Conversely, decreases in serum osmolarity signal the hypothalamic osmoreceptors to inhibit the secretion of ADH.
Figure 9–15 Control of antidiuretic hormone (ADH) secretion by osmolarity and extracellular fluid volume.
Hypovolemia, or volume contraction (e.g., due to hemorrhage), is also a potent stimulus for ADH secretion. Decreases in extracellular fluid (ECF) volume of 10% or more cause a decrease in arterial blood pressure that is sensed by baroreceptors in the left atrium, carotid artery, and aortic arch. This information about blood pressure is transmitted via the vagus nerve to the hypothalamus, which directs an increase in ADH secretion. ADH then stimulates water reabsorption in the collecting ducts, attempting to restore ECF volume. Importantly, hypovolemia stimulates ADH secretion, even when plasma osmolarity is lower than normal (see Fig. 9-15). Conversely, hypervolemia (volume expansion) inhibits ADH secretion, even when plasma osmolarity is higher than normal.
Pain, nausea, hypoglycemia, and various drugs (e.g., nicotine, opiates, antineoplastic agents) all stimulate the secretion of ADH. Ethanol, α-adrenergic agonists, and atrial natriuretic peptide inhibit secretion of ADH.
Actions of Antidiuretic Hormone
ADH (vasopressin) has two actions, one on the kidney and the other on vascular smooth muscle. These actions are mediated by different receptors, different intracellular mechanisms, and different second messengers.
Increase in water permeability. The major action of ADH is to increase the water permeability of principal cells in the late distal tubule and collecting duct. The receptor for ADH on the principal cells is aV2 receptor, which is coupled to adenylyl cyclase via a Gs protein. The second messenger is cAMP, which, via phosphorylation steps, directs the insertion of water channels, aquaporin 2 (AQP2), in the luminal membranes. The increased water permeability of the principal cells allows water to be reabsorbed by the collecting ducts and makes the urine concentrated, or hyperosmotic (see Chapter 6).
Contraction of vascular smooth muscle. The second action of ADH is to cause contraction of vascular smooth muscle (as implied by its other name, vasopressin). The receptor for ADH on vascular smooth muscle is a V1receptor, which is coupled to phospholipase C via a Gq protein. The second messenger for this action is IP3/Ca2+, which produces contraction of vascular smooth muscle, constriction of arterioles, and increased total peripheral resistance.
Pathophysiology of Antidiuretic Hormone
The pathophysiology of ADH is discussed in detail in Chapter 6 and is summarized here.
Central diabetes insipidus is caused by failure of the posterior pituitary to secrete ADH. In this disorder, circulating levels of ADH are low, the collecting ducts are impermeable to water, and the urine cannot be concentrated. Thus, persons with central diabetes insipidus produce large volumes of dilute urine, and their body fluids become concentrated (e.g., increased serum osmolarity, increased serum Na+concentration). Central diabetes insipidus is treated with an ADH analogue, dDAVP.
In nephrogenic diabetes insipidus, the posterior pituitary is normal but the principal cells of the collecting duct are unresponsive to ADH due to a defect in the V2 receptor, Gs protein, or adenylyl cyclase. As in central diabetes insipidus, water is not reabsorbed in the collecting ducts and the urine cannot be concentrated, resulting in excretion of large volumes of dilute urine. As a result, the body fluids become concentrated and the serum osmolarity increases. In contrast to central diabetes insipidus, however, ADH levels are elevated in nephrogenic diabetes insipidus due to stimulation of secretion by the increased serum osmolarity. Nephrogenic diabetes insipidus is treated with thiazide diuretics. The usefulness of thiazide diuretics in treating nephrogenic diabetes insipidus is explained as follows: (1) Thiazide diuretics inhibit Na+ reabsorption in the early distal tubule. By preventing dilution of the urine at that site, the final, excreted urine is less dilute (than it would be without treatment). (2) Thiazide diuretics decrease glomerular filtration rate; because less water is filtered, less water is excreted. (3) Thiazide diuretics, by increasing Na+ excretion, can cause a secondary ECF volume contraction. In response to volume contraction, proximal reabsorption of solutes and water is increased; because more water is reabsorbed, less water is excreted.
In syndrome of inappropriate ADH (SIADH), excess ADH is secreted from an autonomous site (e.g., oat cell carcinoma of the lung; Box 9-1). High levels of ADH cause excess water reabsorption by the collecting ducts, which dilutes the body fluids (e.g., decreases plasma osmolarity and Na+ concentration). The urine is inappropriately concentrated (i.e., too concentrated for the serum osmolarity). SIADH is treated with an ADH antagonist such as demeclocycline or water restriction.
BOX 9–1 Clinical Physiology: Syndrome of Inappropriate ADH
DESCRIPTION OF CASE. A 56-year-old man with oat cell carcinoma of the lung is admitted to the hospital after having a grand mal seizure. Laboratory studies yield the following information:
Osmolarity, 650 mOsm/L
Osmolarity, 225 mOsm/L
The man’s lung tumor is diagnosed as inoperable. He is treated with an IV infusion of hypertonic NaCl and is stabilized and discharged. He is given demeclocycline, an ADH-antagonist, and is ordered to severely limit his water intake.
EXPLANATION OF CASE. Upon his admission to the hospital, the man’s serum [Na+] and serum osmolarity are severely depressed (normal serum [Na+], 140 mEq/L; normal serum osmolarity, 290 mOsm/L). Simultaneously, his urine is hyperosmotic, with a measured osmolarity of 650 mOsm/L. In other words, his urine is inappropriately concentrated, given his very dilute serum osmolarity.
Independent of the posterior pituitary, the oat cell carcinoma synthesized and secreted ADH and caused the abnormal urine and serum values. Normally, ADH is secreted by the posterior lobe of the pituitary, which is under negative-feedback regulation by serum osmolarity. When the serum osmolarity decreases below normal, ADH secretion by the posterior pituitary is inhibited. However, ADH secretion by the tumor is not under such negative feedback regulation, and ADH secretion continues unabated (no matter how low the serum osmolarity) and causes SIADH.
The man’s serum and urine values are explained as follows: The tumor is secreting large amounts of ADH (inappropriately). This ADH circulates to the kidney and acts on the principal cells of the late distal tubule and collecting duct to increase water reabsorption. The reabsorbed water is added to the total body water, diluting the solutes. Thus, serum [Na+] and serum osmolarity are diluted by the excess water reabsorbed by the kidney. Although this dilution of serum osmolarity turns off ADH secretion by the posterior pituitary, it does not turn off ADH secretion by the tumor cells.
The man’s grand mal seizure was caused by swelling of brain cells. The excess water reabsorbed by the kidney was distributed throughout the total body water including ICF. As water flowed into the cells, their volume increased. For brain cells, this swelling was catastrophic because the brain is encased in a fixed cavity, the skull.
TREATMENT. The man is treated promptly with an infusion of hypertonic NaCl to raise the osmolarity of his ECF. As extracellular osmolarity becomes higher than intracellular osmolarity, water flows out of the cells, driven by the osmotic gradient, and decreases ICF volume. For brain cells, the reduction in cell volume decreases the probability of another seizure.
The man’s lung tumor is inoperable and will continue to secrete large quantities of ADH. His treatment includes water restriction and administration of demeclocycline, an ADH-antagonist that blocks the effect of ADH on water reabsorption in the principal cells.
Oxytocin produces milk “letdown” or milk ejection from the lactating breast by stimulating contraction of myoepithelial cells lining the milk ducts.
Regulation of Oxytocin Secretion
Several factors cause the secretion of oxytocin from the posterior pituitary including suckling; the sight, sound, or smell of the infant; and dilation of the cervix (Table 9-7).
Table 9–7 Factors Affecting Oxytocin Secretion
Sight, sound, or smell of the infant
Dilation of the cervix
The major stimulus for oxytocin secretion is suckling of the breast. Sensory receptors in the nipple transmit impulses to the spinal cord via afferent neurons. This information then ascends in the spinothalamic tract to the brain stem and, finally, to the paraventricular nuclei of the hypothalamus. Within seconds of suckling, oxytocin is secreted from nerve terminals in the posterior pituitary. If suckling continues, new oxytocin is synthesized in the hypothalamic cell bodies, travels down the axons, and replenishes the oxytocin that was secreted.
Suckling is not required for oxytocin secretion; conditioned responses to the sight, sound, or smell of the infant also cause milk letdown. Oxytocin also is secreted in response to dilation of the cervix during labor and orgasm.
Actions of Oxytocin
Milk ejection. Prolactin stimulates lactogenesis. The milk is stored in mammary alveoli and small milk ducts. The major action of oxytocin is to cause milk letdown. When oxytocin is secreted in response to suckling or to conditioned responses, it causes contraction of myoepithelial cells lining these small ducts, forcing the milk into large ducts. The milk collects in cisterns and then flows out through the nipple.
Uterine contraction. At a very low concentration, oxytocin also causes powerful rhythmic contractions of uterine smooth muscle. Although it is tempting to speculate that oxytocin is the critical hormone involved in parturition, it is unclear whether oxytocin plays a physiologic role in either the initiation of or the normal course of labor. However, this action of oxytocin is the basis for its use in inducing laborand in reducing postpartum bleeding.