Principles and Practice of Endocrinology and Metabolism



Hypothalamic-Pituitary Unit


Functional Neuroanatomy

Hypophysiotropic Hormones
Functions of the Nonendocrine Hypothalamus

Temperature Regulation

Appetite Regulation

Emotion and Libido

Autonomic Functions

Biologic Rhythms


Hypothalamic Syndromes
Chapter References

The brain and endocrine system have been linked since the 1940s, when the hypothalamus was first assigned a central role in the control of anterior pituitary secretion.1,2
This chapter discusses the functional neuroanatomy of the hypothalamic-pituitary unit, as well as the important nonendocrine functions of the hypothalamus.
Between the third and fourth weeks of embryonic development, a longitudinal groove, the sulcus limitans, appears in the lumen of the neural tube. This sulcus divides the alar (dorsal) plate from the basal (ventral) plate. The basal plate plays no part in the development of the hypothalamus or pituitary, participating only in the formation of nervous tissue caudal to the diencephalon. At ~5.5 weeks, the alar plate, in the region that gives rise to the diencephalon, develops a longitudinal groove contiguous with the sulcus limitans. This groove, the hypothalamic sulcus, divides the alar plate into a dorsal portion, which gives rise to the thalamus, and a ventral portion, which gives rise to the hypothalamus3 (Fig. 9-1A and Fig. 9-1B).

FIGURE 9-1. A, Cross section of a human embryo (3.5 weeks) through the first cervical somite. B, Cross section of a human embryo (5.5 weeks) in the region of the diencephalon. C, Midsagittal section of the hypothalamus of a human embryo (11 weeks).

During the fifth week of embryonic life, the anterior pituitary begins to form as a diverticulum (Rathke pouch) of the buccal cavity. It expands dorsally to join the basal portion of the forebrain (see Fig. 9-1C) so that by the eighth week, the posterior pituitary, which begins as a diverticulum of the floor of the third ventricle, has contacted the Rathke pouch and been invested by it. By the 11th week, the cavity of the Rathke pouch becomes flattened and loses its connection with the buccal cavity.3 Remnants of its attachment to the buccal cavity form the craniopharyngeal duct, residual cells of which persist in the posterior lobe of the pituitary, the hypophysial stalk, and the basisphenoid. Traditionally, these residual cells are thought to be the origin of craniopharyngioma; however, because craniopharyngiomas occasionally develop in the sella or along the craniopharyngeal duct itself, this idea on the origin of these tumors has been questioned. Careful examination of the superior pharynx in infants and adults almost always reveals a pharyngeal hypophysis at the buccal end of the craniopharyngeal duct. It is composed mainly of undifferentiated epithelial cells with a few chromophobes and chromophils, although rarely this residual pharyngeal hypophysial tissue has been reported to produce excessive pituitary hormone secretion.
Neuroanatomically, the traditional borders of the hypothalamus are the lamina terminalis (rostrally); the posterior edge of the mammillary body (caudally); the hypothalamic sulcus (dorsally); the floor of the third ventricle (ventrally); and the internal capsule, basis pedunculi, and subthalamus (laterally). The hypothalamus usually is divided into three regions: the chiasmatic (preoptic region), the tuberal region, and the mammillary complex. Of these three, the first two contain the neuronal groups and tracts that are of most significance in neuroendocrine regulation (Table 9-1).

TABLE 9-1. Hypothalamic Regions and Nuclei of Neuroendocrine Interest

Histologically, the hypothalamus contains two types of neurons: large (magnocellular) and small (parvicellular). Magno-cellular neurons are of two classes: those that secrete arginine vasopressin (AVP) and neurophysin II, and those that secrete oxytocin and neurophysin I. AVP often is colocalized with dynorphin or angiotensin II, whereas oxytocin frequently is colocalized with cholecystokinin (CCK), corticotropin-releasing hormone (CRH), metenkephalin, or proenkephalin. Parvicellular neurons contain a variety of neuropeptides or biogenic amines, many of which are colocalized.
The parvicellular neurons of the hypothalamus that are found in the immediate periventricular region of the third ventricle, from the preoptic area to the mammillary bodies, project to the median eminence, where their neurosecretory products are released to influence anterior pituitary function. Functionally discrete groups of parvicellular neurons have been located in the anterior preoptic region, the paraventricular nucleus, and the arcuate nucleus.
The more medial area of the hypothalamus has collections of neurons that receive inputs from the brainstem and the limbic system. They, in turn, project to the periventricular zone, the limbic system, the brainstem, and the spinal cord in a circuit that is suited to the coordination of endocrine, autonomic nervous, and more complex behavioral responses to ensure homeostasis.
In the lateral hypothalamic area is found the medial fore-brain bundle, a neural pathway that connects the brainstem reticular formation with the septum and the limbic system and also has input into the periventricular secretory neurons.
The anterior pituitary is known to produce six peptide hormones (Table 9-2). The secretion of each of these is under the control of one or more hypothalamic neuropeptides and several other classic neurotransmitters. A comprehensive review of these intricate interactions has been published elsewhere.4

TABLE 9-2. Anterior Pituitary and Hypophysiotropic Hormones

In primates, a few neurons containing gonadotropin-releasing hormone (GnRH) are found in clusters above the optic chiasm, medial to the supraoptic nuclei, but most are found in the medial basal hypothalamus.5 Their axons project to the median eminence, where GnRH is released in a pulsatile fashion. In humans, GnRH-positive neurons are found in the arcuate nucleus.4 The GnRH-containing neurons of the medial basal hypothalamus have an intrinsic firing pattern that results in the pulsatile release of GnRH. Norepinephrine, epinephrine, serotonin, acetylcholine, and N-methyl D-aspartic acid all stimulate GnRH release, as do angiotensin II (probably through its action on norepinephrine) and neuropeptide Y.4 Opioid peptides and g-aminobutyric acid (GABA) inhibit GnRH release.4
CRH-containing neurons are found in the medial portion of the paraventricular nucleus. From there, they project to the median eminence, where they release CRH in a pulsatile fashion (see Chap. 8). CRH release is stimulated by norepinephrine, epinephrine, serotonin, glutamine, aspartamine, acetylcholine, angiotensin II, and neuropeptide Y, and is inhibited by GABA, AVP, opioid peptides, and substance P.4
Neurons containing thyrotropin-releasing hormone (TRH) are found in the periventricular portion of the paraventricular nucleus and in a similar location in the anterior hypothalamus. They project to the median eminence through the lateral retrochiasmatic area.5 TRH release is responsive to triiodothyronine (T3) and thyroxine (T4) levels. It also is stimulated by norepi-nephrine, dopamine, and serotonin, and is inhibited by GABA and opioid peptides.4
Prolactin release is inhibited by dopamine and stimulated by TRH and vasoactive intestinal peptide (VIP). Dopamine-containing neurons are found in the arcuate nucleus and the preoptic ventricular nucleus.6 They project into hypothalamic regions rich in TRH and somatostatin. VIP-containing neurons are found in the paraventricular nucleus and project to the median eminence. They also are found in the suprachiasmatic nucleus.
Neurons containing growth hormone–releasing hormone are found in the arcuate nucleus, just lateral to the median eminence. Their nerve terminals project to the median eminence and pituitary stalk.7,8 The release of growth hormone–releasing hormone is stimulated by norepinephrine and serotonin.4
Neurons containing somatostatin (growth hormone release– inhibiting hormone) are distributed widely in the central nervous system (see Chap. 169). In the hypothalamus, they are localized to neurons in the paraventricular nucleus. Their axons travel laterally and ventrally toward the optic chiasm and then caudally to the median eminence. The arcuate and ventromedial nuclei receive somatostatinergic innervation from other sources. Many somatostatin-containing nerve terminals are found in the ventromedial arcuate complex, the suprachiasmatic nucleus, the ventral premammillary nuclei, and the organum vasculosum of the lamina terminalis.5,9
Hypothalamic afferent pathways carry important information on emotion and visceral function. Ascending visceral afferents convey data to the hypothalamus from baroreceptors, volume receptors, and taste receptors. These inputs reach the hypothalamus over poorly defined pathways that relay in the reticular formation and midline thalamic nuclei. Somatosensory information also reaches the hypothalamus. The limbic system has rich afferent connections to the hypothalamus. The medial fore-brain bundle serves as an important integrative pathway between the brainstem and the limbic system. The amygdala sends fibers to the hypothalamus through the stria terminalis, and the fornices relay information from the hippocampal formation to the mammillary bodies of the hypothalamus. The mammillary bodies also receive input from and provide input to the anterior thalamic nuclei through the mammillothalamic tract and, therefore, are indirectly connected to the cingulate cortex. Finally, afferent hypothalamic connections from the dorsomedial thalamic nucleus and direct corticohypothalamic connections from the orbital surface of the frontal lobe are found.10
Two major hypothalamic efferent pathways are the dorsal longitudinal fasciculus and the mammillotegmental fasciculus. The fibers of the dorsal longitudinal fasciculus terminate in the dorsal motor nucleus of the vagus, the salivatory and lacrimal nuclei, the intermediolateral cell column of the thoracolumbar cord, and the sacral autonomic area. In addition, efferents from this tract go to various brainstem motor nuclei connected with eating and drinking, and to spinal cord motor neurons that participate in the shivering that raises body temperature. The fibers of the mammillotegmental fasciculus end in the raphe nuclei of the midbrain and pons. Finally, the mammillothalamic fasciculus contains two-way connections with the anterior nuclei of the thalamus.10
Through these rich connections, the hypothalamus monitors and influences body functions, preserving the constancy of the internal milieu.
The suprachiasmatic nucleus is responsible for generating circadian rhythms in all mammals, including humans. It is composed of neurons that contain AVP, VIP, neuropeptide Y, and neurotensin. A marked seasonal variation exists in suprachiasmatic nucleus cell numbers and volumes in humans, with summer values being approximately half those found in the fall. Hypothalamic tumors that involve the anterior hypothalamus disturb circadian rhythms in humans.11,12
The volume of the suprachiasmatic nucleus and the number of cells is similar in men and women, although the shape of the nucleus is different.13 Homosexual males have been reported to have a suprachiasmatic nucleus that is 1.7 times larger than that in heterosexual males and contains 2.1 times as many cells.14 The functional implication of this finding, if confirmed, remains to be determined.
The sexually dimorphic nucleus, or intermediate nucleus, is found in the preoptic area. It contains twice as many cells in young adult males as in comparable adult females.15 Cell numbers in the nucleus are similar in males and females at birth and not until ~4 years of age can any difference be detected. No difference in cell number in this nucleus is observed when the brains of homosexual and heterosexual males are compared.14,16
The third nucleus of the interstitial nuclei of the anterior hypothalamus has been found to be larger in males than in females, and is approximately half as large in homosexual males as in heterosexual males.17 This finding, which has not been confirmed, suggests yet another hypothalamic area that is dimorphic with respect to gender as well as sexual orientation.
The hypothalamus receives its arterial blood supply from the circle of Willis, the internal carotid and posterior cerebral arteries. Apart from blood that drains into the pituitary gland, most blood from the hypothalamus enters the basal vein of Rosenthal through numerous small venous plexuses in and around the hypothalamus.
The blood supply of the pituitary gland is more complex (see Chap. 11). The posterior pituitary (neurohypophysis) is supplied by blood directly from the inferior hypophysial artery and drains into the inferior hypophysial veins. At its most rostral portion, in the median eminence, the neurohypophysis is supplied by the superior hypophysial arteries; free communication exists between the blood supply of the median eminence and that of the posterior pituitary. Apart from the most superficial layers of the gland, which are supplied by small capsular arteries, the anterior pituitary gland lacks a direct arterial blood supply. Blood is supplied to the median eminence by the superior hypophysial arteries, and the major venous drainage of the median eminence is through the portal veins to the anterior pituitary. Blood then drains from the anterior pituitary into the posterior pituitary, from which it enters the cavernous sinus or returns to the median eminence. This anatomic configuration means that blood from the median eminence, rich in hypothalamic factors and neurotransmitters, is directed toward the anterior pituitary, where it influences the secretion of pituitary hormones. Whether blood from the anterior pituitary, rich in pituitary hormones, returns to the median eminence to participate in feedback control and other possible effects on the brain is debated.18,19
Disorders of the hypothalamic-pituitary unit may be seen clinically because of neuroendocrine dysfunction or because of symptoms caused by compression of local structures. To fully understand the symptoms produced by compression, one must understand the anatomy of the parapituitary area (Fig. 9-2).

FIGURE 9-2. Anatomic relationships of the pituitary fossa and cavernous sinus. The lateral wall of the sella turcica is formed by the cavernous sinus. The sinus contains the carotid artery, two branches of the fifth cranial nerve (ophthalmic [Ophth.] and maxillary [Max.]), the third nerve (oculomotor), the fourth nerve (trochlear), and the sixth nerve (abducens). The optic chiasm and optic tract are located superior and lateral, respectively, to the pituitary. (A, artery; N, nerve.) (From Martin JB, Reichlin S, Brown GM, eds. Clinical neuroendocrinology. Philadelphia: FA Davis, 1987:447.)

The pituitary gland rests in the sella turcica. Inferiorly, it is bounded by the sphenoid sinus. Superiorly, it is separated from the cranial cavity by a double layer of dura mater, the diaphragma sellae; through this passes the pituitary stalk. Normally, the dura tightly surrounds the stalk. If the opening is larger or if the intracranial pressure is increased, however, the arachnoid membrane may herniate into the sella, displacing the pituitary gland peripherally and enlarging the sella—the empty sella syndrome (see Chap. 11 and Chap. 17). The diaphragma sellae is pain sensitive; stretching of this tissue by pituitary enlargement may give rise to frontotemporal headaches.
The optic chiasm lies 3 to 10 mm above the pituitary fossa. In 90% of persons, the chiasm is partly or completely above the diaphragma. Of the remaining 10% of persons, approximately half have an anteriorly placed chiasm (“prefixed”) and half have a posteriorly placed chiasm (“postfixed”).20 This anatomic variability accounts for the lack of visual field abnormalities in some patients with a large suprasellar extension of a pituitary tumor. Compression of the optic chiasm by a pituitary tumor usually affects the crossing fibers in the chiasm. These come from the nasal portions of the retina, which serve the temporal fields. Thus, the typical visual field abnormality that occurs in chiasmatic compression is a bitemporal hemianopsia. Because the most inferiorly placed fibers in the optic chiasm carry information from the superior visual fields, tumors pushing on the chiasm from below tend to cause superior quadrantanopsias of the bitemporal variety, whereas lesions pushing on the chiasm from above cause inferior bitemporal quadrantanopsias. Unfortunately, several exceptions to these rules do occur. Lesions in and around the optic chiasm tend to produce incongruous visual field defects (i.e., of a different configuration in each eye; see Chap. 19).
Immediately lateral to the pituitary gland are the cavernous sinuses. Within each is found the carotid artery and its sympathetic plexus; cranial nerves III, IV, and VI; and the ophthalmic and maxillary divisions of the trigeminal nerve. Sudden expansion of a pituitary tumor into the cavernous sinus may produce cranial nerve palsy. Conversely, an aneurysm of the cavernous portion of the carotid artery can erode laterally and mimic the plain skull radiographic appearance of a pituitary tumor and even lead to mild hypopituitarism.
For the body to function efficiently, its temperature must be maintained within narrow limits. Wide variations beyond this range can result in serious metabolic derangement and death. The hypothalamus ensures that the heat gained by the body from metabolic activity, and in some circumstances from the environment, is balanced by the heat lost.21,22
The preoptic anterior hypothalamus contains thermosensitive neurons that monitor the temperature of blood (Fig. 9-3). Experiments have shown that serotonin (5-hydroxytryptamine) released in this area stimulates hypothalamic heat production centers. This effect is blocked by norepinephrine or epinephrine.

FIGURE 9-3. Hypothalamic temperature regulation mechanisms. The preoptic anterior hypothalamic area functions as a thermostat and contains mechanisms for regulation of heat loss. The posterior hypothalamus integrates heat production mechanisms. Lesions of the preoptic anterior hypothalamic area cause hyperthermia; lesions of the posterior hypothalamus cause hypothermia or poikilothermia. (Modified from Myers RD. Ionic concepts of the set-point for body temperature. In: Lederis K, Cooper KE, eds. International symposium on recent studies of hypothalamic function, Calgary, 1973. Basel: S Karger, 1974:371; and from Cooper PE, Martin JB. Neuroendocrinologic diseases. In: Rosenberg R, ed. Comprehensive neurology. New York: Raven Press, 1991:608.)

The caudolateral portion of the hypothalamus is insensitive to changes in body temperature, but the regulatory center that determines the normal setpoint of 37°C is located here. The injection of acetylcholine-like substances into this region causes profound and long-lasting hypothermia. It also is through this area that the main pathways controlling heat loss and heat conservation travel to the midbrain, pons, medulla, and spinal cord.
Intraventricular injection of the neuropeptides mammalian bombesin, neurotensin, TRH, somatostatin, and b-endorphin decreases body temperature and thus implicates these substances in thermoregulation. CRH appears to be an important mediator of thermogenesis in response to serotonin and its agonists and to cytokines. No peptide or group of peptides, however, has been singled out as the physiologic regulator of body temperature.20 In some experiments, prostaglandin E2 has increased body temperature.
Hypothalamic injury after head trauma or cerebral infarction can produce prolonged hypothermia resulting either from a change in the setpoint or from an impairment of heat production mechanisms. Paroxysmal hypothermia has been described in a few patients. These persons appear to have a temporary alteration in setpoint, with the body temperature falling to 32°C or lower. The hypothermia may last for minutes to days and is associated with fatigue, decreased alertness, hypoventilation, and even cardiac arrhythmia. The loss of body heat is caused by increased sweating and vasodilation. Although the paroxysmal nature of these episodes has suggested an epileptic etiology, the attacks are not prevented by use of anticonvulsants.21
Paroxysmal hyperthermia can occur in some conditions. Acute damage to the preoptic anterior hypothalamus from surgery, subarachnoid hemorrhage, or cerebral infarction can lead to profound impairment of heat loss mechanisms, and the resulting hyperthermia can be lethal. Cyclic hyperthermia has been seen in some patients, but the neuropathologic substrate for this condition is unknown. Some have responded to therapy with phenytoin. Sustained hyperthermia probably is not seen in hypothalamic dysfunction. Reported case studies of prolonged hyperthermia attributed to hypothalamic dysfunction have not excluded an underlying malignancy or unrecognized infection. Cyclic hypothermia, responsive to treatment with anticonvulsant agents, such as clonidine or cyproheptadine, has been described.23
Large lesions in the posterior hypothalamus or lesions in the brainstem that damage the hypothalamic outflow tracts may result in poikilothermia, a condition in which the body temperature varies with environmental temperature. Most affected patients have hypothermia, although in hot, humid conditions, hyperthermia may be a problem.21
During fever, the body’s temperature setpoint is elevated, although the ability to regulate temperature around the new setpoint is normal.24 In response to an infection or other cause of inflammation, the body’s inflammatory cells—primarily monocytes—release cytokines,25 which act at the hypothalamus to cause fever.24 Interleukin-1 (IL-1) releases phospholipases in the hypothalamus that, in turn, release arachidonic acid from plasma membranes. Arachidonic acid causes a rise in prostaglandin E, which raises the body temperature setpoint. Treatment with acetylsalicylic acid or acetaminophen to reduce fever probably affects this process. Animal studies suggest that the action of IL-1 occurs in the preoptic anterior hypothalamus through the reduction of the sensitivity of “warm-sensitive” neurons, allowing the body to tolerate a higher temperature. Once this new setpoint has been established, the hypothalamus uses normal physiologic mechanisms to maintain body temperature by peripheral vasoconstriction, reduced sweating, and, if necessary, increases in heat production through shivering.
Tumor necrosis factor (TNF) is another cytokine that alters the setpoint in the hypothalamus and increases the production of IL-1 locally, in the hypothalamus. Most TNF seems to be produced in macrophages stimulated by bacterial endotoxin. Inter-leukin-6 (IL-6) and interferon-g also act directly at the hypothalamus to raise the setpoint.
The exact role of the cytokines in regulating body temperature and in causing fever is unclear because complex interactions exist among these compounds. IL-1, for example, stimulates its own production and interferon-g stimulates IL-1 production, whereas interleukin-4 suppresses the production of IL-1, TNF, and IL-6. IL-1 production also is inhibited by glucocorticoids and prostaglandin E.
The fulminant hyperthermia (malignant hyperthermia) that can occur during anesthesia is not hypothalamic in origin. Rather it results from excessive muscle contraction caused by an abnormality of the muscle membrane. Another syndrome of hyperthermia is the neuroleptic malignant syndrome. This condition, characterized clinically by hyperthermia, rigidity of skeletal muscles, autonomic instability, and fluctuating levels of consciousness, has been associated with the use of major tranquilizers, rapid withdrawal from treatment with dopaminergic agents (e.g., L-dopa or bromocriptine), and, less commonly, the use of tricyclic antidepressants. The common denominator in the syndrome seems to be an alteration in dopamine function in the hypothalamus. Treatment consists of discontinuing the use of neuroleptics, providing general support, and administering anticholinergics for mild cases, bromocriptine (5 mg orally or nasogastrically four times daily) for more severe cases, and benzodiazepines or dantrolene (2–3 mg/kg per day intravenously to a maximum of 10 mg/kg per day) for resistant cases.26,27
In most animals, the body is able to balance its intake of food and output of energy to maintain body weight. It is the hypothalamus that receives inputs from the periphery that either stimulate or inhibit the intake of food, and it is the hypothalamus that, likewise, sends signals to other parts of the brain to influence endocrine, autonomic, and motor nervous system function.28 The interaction between the limbic system and the hypothalamus is critical in translating the need for food into behaviors such as hunting and stalking.
The destruction of both ventromedial nuclei in the rat or the cat markedly increases food intake for a few days. As the animal becomes obese, the overeating decreases; if it is then fasted back to ideal weight and given free access to food, the animal again increases its food intake until it becomes obese. Lesions of the ventromedial nuclei, however, do not produce a pure syndrome of obesity. During the phase of overeating, the animals often are irritable and aggressive, becoming lethargic and passive when the increased weight is achieved. The pituitary gland is not necessary for the weight gain because hypophysectomized animals also become obese. If hyperphagia is prevented by tube feeding, the animals still become obese. Hyperinsulinemia has been observed in lesioned animals within minutes of surgery; if this is prevented by lesioning the pancreatic B cells with streptozocin, the obesity and hyperphagia are prevented.
Classic neurophysiology explained the hyperphagia in animals with a lesion of the ventromedial nuclei on the basis of unopposed activity of a hypothalamic “feeding center” in the lateral hypothalamus. Implantation of electrodes in this lateral area causes, after stimulation, marked increases in food intake, whereas destruction of this area causes aphagia, even in animals with concomitant ventromedial nuclei lesions.
The limbic system plays an important role in appetite. One suggested interaction is that the urge to eat arises in the hypothalamus and the limbic structures modify food intake through a discriminative function. Bilateral lesions in the amygdala cause prolonged aphagia and adipsia. Stimulation of this same area in the fed animal does not cause increased eating, but intake increases if the stimulation is performed while the animal is eating.
Cells in the ventromedial hypothalamus also monitor blood glucose levels and coordinate the hypothalamic response to hypoglycemia. Although hypothalamic lesion studies have shown that blood glucose is decreased on stimulation of the anterior and tuberal regions medially, acute hypothalamic damage tends to produce hyperglycemia by activation of the sympathetic nervous system and a resulting glycogenolysis in the liver. Another important effect is the elevation of growth hormone, a contrainsulin hormone, which causes glucose levels to rise. In patients deficient in growth hormone, on either a hypothalamic or a pituitary basis, profound hypoglycemia can occur and may even be a presenting symptom, especially in children.
Many of the features of lateral hypothalamic lesions in animals have been thought to result from damage to the nigrostriatal bundle, a dopamine-containing tract connecting the substantia nigra to the basal ganglia. Lesions in this tract cause anorexia and weight loss, whereas lesions in the ventral adrenergic bundle, a norepinephrine-containing tract originating in the locus coeruleus, cause hyperphagia and obesity. Serotonin is thought to inhibit eating, whereas GABA agonists have the opposite effect.
Of interest has been the putative role of neuropeptides in the regulation of appetite. The gastrointestinal peptides CCK, bombesin, and glucagon can inhibit feeding behavior through an action on the vagal nucleus. Neuropeptide Y can cause hypothalamic obesity by inhibiting sympathetic drive and stimulating insulin release.29
An important putative stimulator of appetite is b-endorphin. One potential mechanism for this action is its ability to stimulate the release of insulin. Other neurotransmitters have been assumed to play a role in the control of appetite. Experimentally, the following substances decrease appetite: norepinephrine, serotonin, CCK, neurotensin, bombesin, TRH, naloxone, somatostatin, and VIP. The following substances increase appetite: dopamine, GABA, b-endorphin, enkephalin, and neuropeptide Y.30 (Also see Chap. 125.)
Increased oxidation of fatty acids raises levels of 3-hydroxy-butyrate, which can reduce food intake through an action at the level of the hypothalamus. The ob, db, and fa genes have all been implicated in the regulation of feeding in animals through production of a circulating factor. In the case of the ob gene, this circulating factor is leptin. Genetically obese mice have a leptin deficiency that, when corrected, leads to a reduction in food intake with a resulting fall in body weight. Leptin levels have been found to be high in obese humans. This suggests an insensitivity to endogenous leptin in these individuals.31 A discussion of the role of other peptides such as uncoupling proteins, agouti protein, melanocortin receptor isoforms, melanin-concentrating hormone, and the proteins responsible for the tub and fat monogenic mouse models of obesity is beyond the scope of this chapter but has been reviewed.32
Hypothalamic tumors that cause hyperphagia, aggressive behavior, and the development of marked obesity have been described. Similar clinical syndromes can be seen in patients with hypothalamic damage caused by radiation therapy or encephalitis. For many years, the syndromes of anorexia nervosa and bulimia nervosa have been considered by many to be purely psychiatric; however, the finding of reduced serotonin levels in the cerebrospinal fluid of patients with bulimia nervosa, the low cerebrospinal fluid levels of norepinephrine in patients with anorexia nervosa, and the enhanced secretion of CCK-8-S in patients with anorexia nervosa suggest that neurotransmitter or neuropeptide abnormalities could be responsible for at least some of the clinical features of these syndromes.33 The question remains whether these changes are a result of the condition or its cause (see Chap. 128).
The anatomic substrate for emotion is widespread and not confined to any single area of the brain; the frontal and temporal lobes, the limbic system, and the hypothalamus all participate in emotion. The hypothalamus is thought to play an important role in the integration and expression of emotion, especially sexual and aggressive behaviors.34
The hypothalamus is necessary for angry behavior in cats. If all cerebral tissue rostral to the tuberal region is removed, angry behavior still can be induced by minor stimuli, but if the remaining hypothalamus then is removed, this activity no longer can be provoked. Electrical stimulation of the caudal hypothalamus in the cat can elicit rage reactions.
Bilateral anteromedial hypothalamic lesions cause normally friendly cats to become aggressive, as do bilateral lesions in the ventromedial nuclei, or electrical stimulation in the perifornical region or the periaqueductal gray area between the third and fourth ventricles.
The limbic system appears to exert a tonic inhibition on the perifornical region of the hypothalamus. Damage to these inhibitory pathways or stimulation in this area results in angry behavior.
Ablation of certain areas in the hypothalamus produces fearful behavior, and stimulation of certain hypothalamic areas in the dorsal hippocampal formation and the septal region produces pleasure reactions. For such reactions to occur, the basal telencephalon and thalamus must be intact.
Some humans report a pleasurable or glowing feeling with electrical stimulation in the septal area; others report a feeling of sexual gratification.
Primates from which the amygdala, piriform cortex, and part of the hippocampal formation have been removed bilaterally exhibit several behavioral disturbances, including hyper-sexuality, loss of discrimination of taste for thirst-quenching liquids, hyperoral behavior, and loss of awareness of harmful or painful objects (Klüver-Bucy syndrome).
Rage attacks have occurred in patients with lesions in the caudal hypothalamus, the subthalamus, and even the midbrain. They also have been induced by manipulation of the hypothalamus during surgery. Fear and rage in patients with hypothalamic disorders usually occur in situations that normally would be associated with these same emotions, but in lesser degrees. In those cases examined pathologically, lesions of the basal portion of the brain, especially the descending pathways to the hypothalamus from the cerebral cortex, or the ventromedial nuclei, usually are found.
Stimulation of the posterior portion of the hypothalamus in humans can arouse feelings of fear and horror. Lesions of the mammillary bodies and vicinity are associated with drowsiness, somnolence, apathy, and indifference. Psychosurgery directed at the medial posterior hypothalamus or the caudolateral region has caused apathy in previously aggressive persons. Euphoria rarely is seen in adults with hypothalamic disease but is seen in children as part of the diencephalic syndrome. This syndrome most commonly manifests in infancy as failure to thrive; a glioma of the anterior hypothalamus usually is found. Children with this condition are emaciated despite normal or excessive food intake, and are described as jovial and as having excessive energy. Approximately 50% of affected children have nystagmus. A tendency to hypoglycemia also may bring these children to medical attention. Despite growth failure, growth hormone levels usually are elevated. Computed tomography demonstrates abnormalities in most cases (see Chap. 18).
Normal libido is the product of an interaction between hypothalamic and extrahypothalamic sites. Usually, hypothalamic damage leads to decreased GnRH levels and reduced libido. Hypersexuality is a rare accompaniment of hypothalamic disease and may be seen with or without increased libido.35 Paroxysmal hypersexuality consisting of sexual urges, genital sensations, and orgasm has been observed in association with temporal lobe tumors or epilepsy but not with primary hypothalamic disease. Altered sexual preference has been described in association with hypothalamic lesions.36
Epileptiform activity in the temporal lobe has been linked to violent behavior. This is extremely rare, however. In a review of 5400 patients with epilepsy, violent behavior during a seizure was found in only 19 cases.37
Evidence is accumulating to suggest that the hypothalamus plays a role in the symptoms of fibromyalgia and chronic fatigue syndrome.38
The hypothalamus plays an important role in the integration of the functions of the autonomic nervous system.39
Signals of cardiovascular status are sent to the brain from baroreceptors and chemoreceptors at the carotid sinus and aortic arch, and from pressure/volume receptors in the atrium. This information is fed into the nucleus of the tractus solitarius, as well as into cells of the paramedian reticular nuclei in the medulla. In the medulla, these afferent signals are modulated by inputs from higher centers, particularly the hypothalamus.
The main sympathetic outflow to the heart begins in the paraventricular nucleus of the hypothalamus. Some of the paraventricular neurons project to the intermediolateral cell column of the spinal cord (the site of origin of preganglionic sympathetic neurons), whereas others project to the dorsal motor nucleus of the vagus where they can influence parasympathetic output to the heart.40
Stimulation of the anterior hypothalamus, particularly the preoptic area, causes bradycardia, hypotension, and decreased baroreflex activity. Such stimulation also can lower the threshold for ventricular fibrillation and cause a variety of electrocardiographic changes. Such changes are common in patients with subarachnoid hemorrhage.
Hypothalamic disease also may cause hypertension, and the disrupted autonomic function that occurs in subarachnoid hemorrhage can cause myocardial necrosis, an effect blocked by sympathetic blockade.
The hypothalamus receives input from the nucleus of the tractus solitarius and relays information from higher cortical centers to brainstem vasomotor centers. The many and varied cardiovascular phenomena that occur in response to emotion, especially hypertension and cardiac arrhythmias, probably are mediated by the hypothalamus.40
The anterior portion of the ventral third ventricle has been shown, by lesion studies, to be a site at which body fluid homeostasis and arterial blood pressure are regulated. Angiotensin II levels reflect changes in serum osmolality or sodium concentration. In addition, the area receives sensory neural input from the kidney, carotid sinus, and other baroreceptors. Output from this area can induce vasoconstriction (through the sympathetic nervous system), and abnormal function of this region has been implicated in the pathogenesis of hypertension.41
Acute pulmonary edema has been described in association with numerous injuries to the central nervous system, such as increased intracranial pressure, epilepsy, and hypothalamic injury.41a Classically, neurogenic pulmonary edema was defined as normal pulmonary capillary wedge pressures with increased protein content of edema fluid in the lung. One hypothesis has been that noncardiac pulmonary edema can be caused by excessive sympathetic outflow from the hypothalamus. Virtually all cases of this type of pulmonary edema, however, are accompanied by system hypertension; therefore, when the experimental physiologic data are reviewed, separation of cardiac from noncardiac causes of edema is impossible. Most of the data support centrally induced systemic hypertension as the cause of the syndrome.42
Under normal resting conditions, gastric motility is relatively autonomous. Higher cortical centers, including the neocortex and limbic lobe, may influence gastric activity through their connections with the hypothalamus. Afferent signals go to the gut through the vagus nerves.
Electrical stimulation of areas of the rostral hypothalamus causes a prompt fall in gastric pH, an effect that is prevented by vagotomy. Stimulation of the tuberal and caudolateral areas of the hypothalamus causes reduced secretion of gastric acid that is of slower onset. This is unaffected by vagotomy but is prevented by bilateral adrenalectomy.
Stimulation and ablation studies in the monkey have shown that cortical areas affect peristalsis, the volume of gastric secretion, and its enzyme and acid content. Similar effects can be seen with stimulation or lesioning of the amygdala.
Bilateral lesions in the anterolateral hypothalamus increase basal gastric acid secretion, an effect that is abolished by interruption of the fibers of the fornix and medial forebrain bundle. This observation suggests that the limbic lobe and frontal neocortex normally exert a tonic, inhibitory effect on basal gastric secretion.
Prolonged hypothalamic stimulation often results in hemorrhage and ulceration in the gastric mucosa of monkeys and dogs, whereas sympathectomy prevents the hemorrhage but not the ulceration.
Lesions anywhere from the rostral hypothalamus to the region of the vagal nuclei in the medulla oblongata may cause acute hemorrhagic erosions of the gastric mucosa; extensive ulceration of the lower esophagus and stomach; and acute perforation of the esophagus, stomach, and duodenum. Such lesions are most likely to occur after damage to or pressure on the hypothalamus, particularly its tuberal region.
Biologic rhythms are ubiquitous in the animal and plant kingdoms, occurring in single cells, tissues, organs, individual animals, and populations (see Chap. 6). Their periods range from milliseconds to years. Many endocrine rhythms are circadian, having a period ~24 hours long.43 Ultradian rhythms, with periods shorter than 24 hours, and infradian rhythms, with periods longer than 24 hours, certainly exist, but the neural mechanisms responsible for these rhythms are debated. Circadian rhythms have been studied extensively. Integrity of the retinohypothalamic projection, which terminates in the suprachiasmatic nucleus, appears to be essential for the light entrainment of circadian rhythms, and the suprachiasmatic nucleus appears essential for circadian rhythmicity. Ablation of the suprachiasmatic nucleus is associated with the loss of all circadian rhythms. The exact functioning of the suprachiasmatic nucleus in the generation of circadian rhythms is unknown, but at least two coupled oscillators appear to exist. These oscillators cause the circadian variations seen in brain monoamines, plasma amino acids, corticotropin and cortisol, growth hormone, prolactin, vasopressin, aldosterone, insulin, glucose, and sex steroids, as well as pineal activity, body temperature, and autonomic function.44
The hypothalamus is closely linked to nervous structures associated with memory function: the reticular formation, hippocampal formation, and other limbic structures.45,46 Although lesions in the mammillary bodies are found in virtually all cases of Wernicke-Korsakoff syndrome (retrograde amnesia, confabulation, apathy),47 the memory deficit in this condition has been thought to correlate best with lesions in the dorsomedial nucleus of the thalamus. Nonetheless, a case report of a brain-injured patient who was studied using magnetic resonance imaging suggests that, at least in trauma, hypothalamic injury alone, without accompanying thalamic injury, can cause marked, relatively focal, memory deficits.48 Many patients with hypothalamic lesions exhibit disturbances of short-term memory, with sparing of immediate recall and long-term memory. Bilateral hippocampal lesions are associated with severe memory disturbance, although some controversy exists about whether involvement of the fornices, the major outflow tract of the hippocampal formation, produces permanent memory loss. Evidence suggests that fornix transection can cause wide-ranging memory disturbance in humans (see Chap. 176).49
The region of the hypothalamic-midbrain junction appears to play an important role in sleep and wakefulness. Two types of patients were seen in the encephalitis pandemics50 of 1917 and 1920: those with prolonged somnolence and ophthalmoplegia, and those with agitation and hyperkinesia. Pathologically, somnolence correlated with damage to the tegmentum of the midbrain, and agitation was seen in patients with anterior hypothalamic lesions. Damage to the hypothalamic-midbrain junction by multiple sclerosis, abscess, or infarction has been described as causing hypersomnia or inversion of the sleep-waking cycles. Some studies support the concept of a “sleep center” in the anterior hypothalamus that, if damaged, causes hyperactivity and sleeplessness, whereas the posterior hypothalamus appears to be involved in the production of rapid eye movement sleep.
The ascending reticular formation participates in normal wakefulness. Damage to it results in coma (complete unresponsiveness). Alternatively, the hypothalamus seems to be the generator of normal sleep-wake cycles. Damage to the hypothalamus causes either excessive wakefulness or somnolence (i.e., an unresponsive state from which the patient can be aroused, at least temporarily).
Several clinical syndromes have been attributed to hypothalamic dysfunction.51 Previously, patients have been described who had autonomic overactivity associated with tumors in the region of the hypothalamus and third ventricle. This was termed diencephalic epilepsy, although its epileptic nature is in doubt because electroencephalograms do not show seizure activity during spells and the condition does not respond to administration of anticonvulsants.
Glioma of the anterior hypothalamus in early childhood produces a clinical syndrome characterized by profound emaciation despite normal or excessive food intake, excess energy, and euphoria—the diencephalic syndrome of infancy (see Chap. 18).
Kleine-Levin syndrome is characterized by episodes of somnolence followed by hyperactivity, irritability, and increased appetite. Adolescent boys are most commonly affected. The attacks occur every 3 to 6 months and last days to weeks. The cause is unknown, and the specific hypothalamic pathology has not been determined.52

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