Chapter 2. The Hypothalamus and Posterior Pituitary Gland

• Describe the physiologic and anatomic relationships between the hypothalamus and the anterior and the posterior pituitary.
• Understand the integration of hypothalamic and pituitary function and identify the 2 different pathways used for hypothalamic-pituitary interactions.
• Identify the appropriate hypothalamic releasing and inhibitory factors controlling the secretion of each of the anterior pituitary hormones.
• Differentiate between the routes of transport of hypothalamic neuropeptides to the posterior and anterior pituitary.
• Identify the mechanisms that control the release of oxytocin and arginine vasopressin (AVP).
• Understand the physiologic target organ responses and the cellular mechanisms of oxytocin and AVP action.

The hypothalamus is the region of the brain involved in coordinating the physiologic responses of different organs that together maintain homeostasis. It does this by integrating signals from the environment, from other brain regions, and from visceral afferents and then stimulating the appropriate neuroendocrine responses. In doing so, the hypothalamus influences many aspects of daily function, including food intake, energy expenditure, body weight, fluid intake and balance, blood pressure, thirst, body temperature, and the sleep cycle. Most of these hypothalamic responses are mediated through hypothalamic control of pituitary function (Figure 2–1). This control is achieved by 2 mechanisms: (1) release of hypothalamic neuropeptides synthesized in hypothalamic neurons and transported through the hypothalamo-hypophysial tract to the posterior pituitary, and (2) neuroendocrine control of the anterior pituitary through the release of peptides that mediate anterior pituitary hormone release (hypophysiotropic hormones) (Figure 2–2). Because of this close interaction between the hypothalamus and the pituitary in the control of basic endocrine physiologic function, they are presented as an integrated topic.

The hypothalamus is the part of the diencephalon located below the thalamus and between the lamina terminalis and the mamillary bodies forming the walls and the floor of the third ventricle. At the floor of the third ventricle, the 2 halves of the hypothalamus are rejoined to form a bridge-like region known as the median eminence (see Figure 2–2). The median eminence is important because this is where axon terminals of hypothalamic neurons release neuropeptides involved in the control of anterior pituitary function. In addition, the median eminence is traversed by the axons of hypothalamic neurons ending in the posterior pituitary. The median eminence funnels down to form the infundibular portion of the neurohypophysis (also called the pituitary or infundibular stalk). In practical terms, the neurohypophysis or posterior pituitary can be considered an extension of the hypothalamus.

Hypothalamic Nuclei

In the hypothalamus, the neuronal bodies are organized in nuclei. These are clusters or groups of neurons that have projections reaching other brain regions as well as ending in other hypothalamic nuclei. This intricate system of neuronal connections allows continuous communication between the hypothalamic neurons and other brain regions. The hypothalamic nuclei can be classified on the basis of their anatomic location or the principal neuropeptide that their cells produce. However, these are not discrete definitions of cell groups; some hypothalamic nuclei may contain more than 1 neuronal cell type. It is best to consider the groups of neurons as clusters of neurons and not as well-defined and delineated nuclei made of a single neuronal type.

Some of the neurons that make up the hypothalamic nuclei are neurohormonal in nature. Neurohormonal refers to the ability of these neurons to synthesize neuropeptides that function as hormones and to release these neuropeptides from axon terminals in response to neuronal depolarization. Two types of neurons are important in mediating the endocrine functions of the hypothalamus: the magnocellular and the parvicellular neurons (Figure 2–3). The magnocellular neurons are predominantly located in the paraventricular and supraoptic nuclei of the hypothalamus and produce large quantities of the neurohormones oxytocin and arginine vasopressin (AVP). The unmyelinated axons of these neurons form the hypothalamo-hypophysial tract, the bridge-like structure that traverses the median eminence and ends in the posterior pituitary. Oxytocin and AVP are released from the posterior pituitary in response to an action potential. Parvicellular neurons have projections that terminate in the median eminence, brainstem, and spinal cord. These neurons release small amounts of releasing or inhibiting neurohormones (hypophysiotropic hormones) that control anterior pituitary function.

Blood Supply

The specialized capillary network that supplies blood to the median eminence, infundibular stalk, and pituitary plays an important role in the transport of hypophysiotropic neuropeptides to the anterior pituitary. Hypophysiotropic peptides released near the median eminence are transported down the infundibular stalk to the anterior pituitary, where they exert their physiologic effects. Branches from the internal carotid artery provide the blood supply to the pituitary. The superior hypophysial arteries form the primary capillary plexus that supplies blood to the median eminence. From this capillary network, the blood is drained in parallel veins called long hypophysial portal veins down the infundibular stalk into the secondary plexus (see Figure 2–2). The hypophysiotropic peptides released at the median eminence enter the primary plexus capillaries. From there, they are transported to the anterior pituitary via the long hypophysial portal veins to the secondary plexus. The secondary plexus is a network of fenestrated sinusoid capillaries that provides the blood supply to the anterior pituitary or adenohypophysis. Because of the fenestrated architecture of these capillary vessels, the neuropeptides easily diffuse out of the circulation to reach the cells of the anterior pituitary. The cells of the anterior pituitary express specific cell surface G protein–coupled receptors (see Chapter 1, Figure 1–5) that bind the neuropeptides, activating intracellular second-messenger cascades that produce the release of anterior pituitary hormones.

The blood supply to the posterior pituitary and to the pituitary stalk is provided mostly by the middle and inferior hypophysial arteries and, to a lesser extent, by the superior hypophysial arteries. Short portal vessels provide venous connections that originate in the neural lobe and pass across the intermediate lobe of the pituitary to the anterior lobe. This structure allows neuropeptides released from the posterior pituitary to have access to cells in the anterior pituitary, so that the functions of the 2 main regions of the pituitary cannot be dissociated from each other. Blood from the anterior and posterior pituitary drains into the intercavernous sinus and then into the internal jugular vein, entering the systemic venous circulation.

Hypothalamic Neuropeptides

Regulation of Hormone Release

Hormones can signal the hypothalamus to either inhibit or stimulate hypophysiotropic hormone release. This control mechanism of negative (or positive) feedback regulation, discussed in detail in Chapter 1, consists of the ability of a hormone to regulate its own cascade of release (see Figure 1–11). For example, as discussed in greater detail in Chapter 6, cortisol produced from the adrenal gland can inhibit the release of CRH, thus inhibiting the production of proopiomelanocortin and ACTH and consequently decreasing adrenal gland synthesis of cortisol. This loop of hormonal control and regulation of its own synthesis is critical in maintaining homeostasis and preventing disease. A shorter loop of negative feedback inhibition also exists, which depends on the inhibition of hypophysiotropic neuropeptide release by the pituitary hormone that it stimulates. In this case, an example would be the ability of ACTH to inhibit CRH release by the hypothalamus. Some neuropeptides also possess an ultrashort feedback loop, in which the hypophysiotropic neuropeptide itself is able to modulate its own release. As an example, oxytocin stimulates its own release, creating a positive feedback regulation of neuropeptide release. These feedback loops are illustrated in Figure 1–12, Chapter 1.

This continuous regulation of hormonal release is dynamic; it is continuously adapting to changes in the environment and in the internal milieu of the individual. Throughout a given day, the hypothalamus integrates a multitude of signals to ensure that the rhythms of hormone release are kept in pace with the needs of the organism. Disruption of these factors can alter the patterns of hormone release. For example, a patient in the intensive care unit, where the lights are on throughout the 24 hours of the day, will have a disrupted cycle of hormone release. Other situations that disrupt the normal cycles of hormone release are travel across time zones, night-shift employment, and aging.

Oxytocin and AVP are closely related peptides consisting of 9 amino acids (nonapeptides) with ring structures (Figure 2–4). They are synthesized as part of a larger precursor protein, consisting of a signal peptide, the hormone, a peptide called neurophysin 2, and a glycopeptide called copeptin. Following cleavage of the signal peptide in the endoplasmic reticulum, the remaining precursor folds, dimerizes, exits from the Golgi apparatus, and moves down the neurohypophyseal axons packaged within neurosecretory vesicles (see Figure 2–4).

Neurophysins

Neurophysins are by-products of post-translational prohormone processing in the secretory vesicles. The release of AVP and oxytocin is accompanied by the release of neurophysins from the secretory granules. Although the exact function of these by-products is not clear, it appears that neurophysins play an important role in AVP release. This role has become more evident since the identification of the inherited disease of familial neurogenic diabetes insipidus (DI). This disease is characterized by AVP deficiency caused by mutations in neurophysins and improper targeting of the hormone to neurosecretory granules. Neurophysins thus have an important role in the transport of AVP from the cell bodies of magnocellular neurons to their final release from the posterior pituitary. Impairment in hormone targeting leads to retention of the mutated neuropeptide precursor in the endoplasmic reticulum of the magnocellular neurons, and these cells progress to programmed cell death (apoptosis).

Oxytocin

The neuropeptide oxytocin is synthesized by magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus and is released from the posterior pituitary into the peripheral circulation. The release of oxytocin is stimulated by sucking during breast-feeding (lactation) and stretch of the cervix during childbirth (parturition) (Figure 2–5).

Physiologic Effects of Oxytocin

The 2 main target organs for oxytocin’s physiologic effects are the lactating breast and the uterus during pregnancy (see Figure 2–5). In the lactating breast, oxytocin stimulates milk ejection by producing contraction of the myoepithelial cells that line the alveoli and ducts in the mammary gland. In the pregnant uterus, oxytocin produces rhythmic smooth muscle contractions to help induce labor and to promote regression of the uterus following delivery (see Chapter 9). Oxytocin analogs may be used clinically during labor and delivery to promote uterine contractions and during the postpartum period to help decrease bleeding and return the uterus to its normal size (uterine involution) (Table 2–2).

The physiologic effects of oxytocin in the pregnant uterus are augmented by a dramatic increase in sensitivity to the hormone during the onset of labor. This increased sensitivity to oxytocin is caused by an increased density (upregulation) of oxytocin receptors in the uterine muscle. Receptor levels can be 200 times greater at the onset of labor than in the nonpregnant uterus. Because of this increase, levels of oxytocin that would normally not be effective can produce forceful uterine contractions toward the end of pregnancy. The increased density of oxytocin receptors is mediated by steroid hormone regulation of oxytocin-receptor synthesis. Responsiveness of the uterus is also enhanced by increased gap-junction formation between smooth muscle cells, facilitating conduction of action potentials between one cell and the next; and by increased synthesis of prostaglandin, a known stimulator of uterine contraction toward the end of gestation. All of these factors enhance myometrial contractile activity in response to oxytocin at term (see Chapter 9). Additional secondary effects that have been attributed to oxytocin are potentiation of the release of ACTH by CRH, interaction with the AVP receptor to produce vasoconstriction, stimulation of prolactin release, and an influence on maternal behavior and amnesia.

Control of Oxytocin Release

The principal stimulus for oxytocin release is mechanical stimulation of the uterine cervix by the fetus near the end of gestation. Oxytocin release is also stimulated by the forceful contractions of the uterus during the fetal expulsion reflex. Hence, the contractile activity of the uterus acts through positive feedback mechanisms during parturition to stimulate oxytocin neurons, and this further increases the secretion of oxytocin. Before the oxytocin neurons can secrete oxytocin, they must be released from inhibition by other neurons containing endogenous opioids, nitric oxide, and γ-aminobutyric acid. This modulation of oxytocin release is partly caused by the declining blood levels of progesterone and increasing levels of estrogen during late pregnancy. The neurotransmitters involved in stimulating oxytocin release are thought to be acetylcholine and dopamine.

Oxytocin release is also triggered by stimulation of tactile receptors in the nipples of the lactating breast by suckling (see Figure 2–5). Breast-feeding generates sensory impulses that are transmitted to the spinal cord and then to the oxytocin-producing neurons in the hypothalamus. The information transmitted by these sensory afferents produces intermittent synchronized burst-firing of oxytocin neurons, resulting in pulsatile release of oxytocin and increases in blood oxytocin concentrations.

In addition to its secretion from neurohypophysial terminals in the posterior pituitary, oxytocin is released within the hypothalamic supraoptic and paraventricular nuclei. The function of this intrahypothalamic release of oxytocin is to control the activity of oxytocin neurons in an autocrine fashion by a positive feedback mechanism, increasing the neurohypophysial release of oxytocin. The release of oxytocin is inhibited by severe pain, increased body temperature, and loud noise. Note how the environmental, hormonal, and neural mechanisms of hypothalamic hormone regulation are in play to regulate oxytocin release at the appropriate time of gestation and in response to the relevant stimuli. The role of oxytocin in males is not clear, although recent studies have suggested that it may participate in ejaculation.

Oxytocin Receptors

The physiologic effects of oxytocin are achieved by binding to cell membrane Gq/11 protein–coupled oxytocin receptors expressed in the uterus, mammary glands, and brain (Figure 2–6). Binding of oxytocin to the receptor activates phospholipase C, producing an increase in inositol trisphosphate and 1,2-diacylglycerol, which in turn results in an increase in cytosolic calcium concentrations leading to smooth muscle contraction.

Disorders of Oxytocin Production

Diseases resulting from oxytocin excess have not been described. Although oxytocin deficiency causes difficulty with nursing because of impaired milk ejection, it is not associated with altered fertility or delivery. Normal oxytocin levels have been detected in women with DI (AVP deficiency).

Arginine Vasopressin

AVP, also known as antidiuretic hormone (ADH), is the other neuropeptide produced by magnocellular neurons of the hypothalamus and released from the posterior pituitary. The principal effect of AVP is to increase water reabsorption by enhancing permeability to water in the distal convoluted tubules and the medullary collecting ducts in the kidney. In addition, AVP increases vascular resistance. This function of AVP may be important during periods of severe lack of responsiveness to other vasoconstrictors, as may occur during severe blood loss (hemorrhagic shock) or systemic infection (sepsis). The circulating concentrations of AVP range from 1.5 to 6 ng/L.

Arginine Vasopressin Receptors

The cellular effects of AVP are mediated by binding to G protein–coupled membrane receptors. Three AVP receptors have been characterized thus far, which differ in terms of where they are expressed as well as in the specific G proteins to which they are coupled and, thus, in the second-messenger systems that they activate.

V1R (also known as V1a) is coupled to Gq/11 and is specific for AVP. It is found in the liver, smooth muscle, brain, and adrenal glands. It activates phospholipases C, D, and A2 and stimulates the hydrolysis of phosphatidylinositol, resulting in an increase in intracellular calcium concentrations. The vasopressor effects of AVP are mediated through the V1R.

V2R is coupled to Gs and is expressed in the kidney. Binding of AVP to the V2R receptor activates adenylate cyclase and increases cyclic 3′,5′-adenosine monophosphate (cAMP) formation and aquaporin 2 (AQP2) phosphorylation and insertion into the luminal membrane. The water reabsorptive effects of AVP are mediated through the V2R.

V3R (also known as V1b) is coupled to Gq/11 and is expressed in the majority of anterior pituitary corticotroph cells and in several tissues, including the kidney, thymus, heart, lung, spleen, uterus, and breast. Binding of AVP to the V3R receptor stimulates the activity of phospholipase C, resulting in an increase in intracellular calcium.

Physiologic Effects of Arginine Vasopressin

The importance of AVP is better understood in terms of the total amount of urine that would be excreted in its absence. For example, in a healthy individual an average of 180 L of glomerular filtrate is formed per day. Thus, without AVP-mediated reabsorption of 10% of filtered water in the distal collecting ducts, urine output would be close to 18 L/d. This is 10-fold higher than the volume of urine output (1.5–2 L/d) under normal conditions.

The increase in cAMP that is stimulated by AVP binding to the receptor located in the basolateral membrane activates protein kinase A and subsequently the phosphorylation of AQP2, another protein. Phosphorylation of AQP2 is essential for its movement from cytoplasmic pools and its insertion in the luminal (apical) epithelial cell membrane of the collecting duct cells. The result is an increase in the number of functional water channels in the luminal membrane, making it more permeable to water. Thus, AVP-mediated insertion of AQP2 into the luminal membrane results in water conservation and urine concentration. This event is a short-term regulation of water permeability in response to an increase in circulating levels of AVP. In addition, AVP is thought to regulate water permeability over hours to days as a result of an increase in the total cellular amount of AQP2 caused by increased protein synthesis.

AQP2, one of several members of the aquaporin family, is exclusively expressed in the collecting ducts of the kidney. It is the only aquaporin that is directly regulated by ADH via the V2 AVP receptor. Water that diffuses into the cells through AQP2 exits through the basolateral side through aquaporin 3 (AQP3) and 4 (AQP4) eventually entering the vasculature. AQP3 and AQP4 are constitutively expressed in the basolateral membranes of the collecting ducts.

Water reabsorption through this mechanism is driven by the hydroosmotic gradient generated by a countercurrent mechanism in the renal medulla. The result is an increase in the concentration and reduction of urine volume, which minimizes urinary water loss. This antidiuretic mechanism may increase urine osmolarity to approximately 1200 mmol/L and reduce urine flow to approximately 0.5 mL/min. Without AVP-mediated effects, the principal cells of the collecting duct are impermeable to water, resulting in large volumes of diluted urine entering the collecting tubules from the ascending limb of the loop of Henle. As mentioned above, this could translate into excessive urine output and reduced urine osmolarity.

AVP also binds the V1 receptor, expressed in vascular smooth muscle, producing contraction and increasing peripheral vascular resistance (Figure 2–8). The hormone is known as vasopressin because of these vasoconstrictor effects. In particular, renal medullary blood flow has been demonstrated to be under AVP regulation. AVP circulates unbound and is distributed in a volume approximately equal to that of the extracellular space. Because of its relatively low molecular weight, AVP permeates peripheral and glomerular capillaries readily, so the urinary excretion rate of AVP is extraordinarily high.

Control of Arginine Vasopressin Release

AVP secretion is also stimulated by a decrease in blood pressure of greater than 10% (see Figure 2–9). Decreases in blood volume or blood pressure are detected by pressure-sensitive receptors in the cardiac atria, aorta, and carotid sinus. Factors that reduce cardiac output, such as a decrease in blood volume, orthostatic hypotension, and positive-pressure breathing, are all potent stimuli for AVP release. A decrease in blood pressure decreases the stretch of the baroreceptors and decreases their firing rate. These signals are transmitted to the central nervous system by neurons of the vagus and glossopharyngeal nerves. The reduced stimulation produces a decrease in tonic inhibition of AVP release, leading to an increase in AVP release from the magnocellular neurosecretory neurons. In addition to signaling the brain to stimulate the release of AVP, the decrease in blood pressure is also perceived by the macula densa in the kidney. This results in stimulation of renin release from the juxtaglomerular apparatus in the kidney. Renin catalyzes the conversion of angiotensinogen produced in the liver to angiotensin I, which is then converted to angiotensin II, by angiotensin-converting enzyme. The resulting rise in circulating levels of angiotensin II sensitizes the osmoreceptors, leading to enhanced AVP release. This is another example of hormonal regulation of hypothalamic neuropeptide release.

The volume-induced sensitization of AVP release results in a more accentuated AVP response to changes in plasma osmolarity. However, AVP secretion is far more sensitive to small changes in plasma osmolarity than to changes in blood volume. AVP is barely detectable below a certain plasma osmolarity (287 mOsm/L) threshold. Above this threshold, the plasma AVP concentration increases steeply in direct proportion to plasma osmolarity. An increase in osmolarity of only 1% will change AVP by an average of 1 pg/mL, an amount sufficient to significantly alter urine concentration and output. Circulating levels of AVP may reach 15–20 pg/mL under a strong osmotic stress. Because of this extraordinary sensitivity, the osmoreceptor plays the primary role in mediating the antidiuretic response to changes in water balance. In contrast, the response to pressure-volume changes is exponential. Reductions in plasma volume by 5%–10% usually have little effect on AVP levels, whereas decreases of 20%–30% result in intense hormone secretion, bringing AVP concentrations to a level many times higher than that required to produce maximum antidiuresis (up to 50–100 pg/mL). In other words, small changes in plasma osmolarity are more effective than small changes in blood pressure and volume in stimulating AVP release. Release of AVP can be modulated by estrogen and progesterone, opiates, nicotine, alcoholic beverages, and atrial natriuretic factor.

Disorders of Arginine Vasopressin Production

Diabetes Insipidus

DI is characterized by the excretion of abnormally large volumes (30 mL/kg of body weight per day for adult subjects) of dilute (<250 mmol/kg) urine and excessive thirst. Three basic defects have been identified in the etiology. Only the first 2 pertain to alterations related to components of the AVP system itself. The third, excess water intake does not involve alterations in ADH release.

Decreased Arginine Vasopressin Release

Neurogenic (central or hypothalamic) DI is the most common defect and is caused by a decrease in AVP release resulting from diseases affecting the hypothalamic-neurohypophysial axis. Three causes can be identified: traumatic, inflammatory or infectious, and cancer related.

Decreased Renal Responsiveness to Arginine Vasopressin

Renal (nephrogenic) DI results from renal insensitivity to the antidiuretic effect of AVP. AVP production and release are not affected, but responsiveness at the distal tubule is impaired. Nephrogenic DI can be inherited or acquired and is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of AVP. Approximately 90% of cases are males with the X-linked recessive form of the disease who have mutations in the AVP type-2 receptor gene. A small number of cases of inherited nephrogenic DI are caused by mutations in the AQP2 water channel gene. Acquired nephrogenic DI can result from lithium treatment, hypokalemia, and postobstructive polyuria.

Differential Diagnosis

The differential diagnosis of DI relies on an understanding of the physiologic regulation of AVP release and its effects on the kidney. Plasma levels of AVP are interpreted together with the indirect assessment of antidiuretic activity triggered by a dehydration test. This test determines the ability of the body to increase the production and release of AVP during water deprivation. Fluids are withheld from the individual, and the rise in urine osmolarity, which indicates the response of the body to conserve fluid, is measured. Normal function consists of an increase in urine osmolarity and a decrease in urine output during water deprivation alone.

Another way of testing the system is by a challenge test with synthetic AVP. Individuals with normal pituitary function do not exhibit a further increase in urine osmolarity following the administration of a synthetic AVP analog (desmopressin). Individuals with central DI have a greater than 9% increase in urine osmolarity following desmopressin administration, indicating that the body is not capable of producing maximal release of AVP and consequently does a better job when a synthetic analog of AVP is administered. Another approach to diagnosing central DI is also based on the physiologic regulation of AVP release and uses the response to osmotic stimulation produced by the intravenous infusion of hypertonic (5%) saline solution. These examples illustrate that understanding the etiology of the disease requires an understanding of the normal physiologic regulation of the endocrine system in question.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

An increase or excess in the release of ADH, in the absence of a physiologic stimuli for its release (thus the name inappropriate) is known as SIADH. This may be the result of brain injury or tumor production of AVP. The tumor can be located in the brain, but malignancies of other organs, such as the lung, have also been shown to produce high levels of AVP. The excess production of AVP results in the production of very small volumes of concentrated urine and dilutional hyponatremia. Management of this condition entails fluid restriction and, in some cases, the use of saline solutions to restore adequate plasma sodium levels.

• Hypothalamic peptides released at the median eminence are transported to the anterior pituitary, where they regulate the release of anterior pituitary hormones.
• The hypothalamus integrates information from various brain regions, the environment, and peripheral organs and mediates systemic responses that help maintain homeostasis.
• Oxytocin and AVP are neuropeptides made in hypothalamic neurons and released from the posterior pituitary into the systemic circulation.
• Prohormone posttranslational modification and processing of oxytocin and AVP occur inside the secretory granules during axonal transport and generate neurophysins.
• AVP binds to the V2 receptor in tubular collecting-duct epithelial cells, stimulating the insertion of AQP2 into the apical (luminal) membrane leading to increased water reabsorption.
• The release of AVP is more sensitive to small changes in plasma osmolarity than to small changes in blood volume.
• Deficiency of AVP results in the production of large volumes of dilute urine.
• Excess AVP release results in small volumes of concentrated urine and hemodilution leading to hyponatremia.